METALLOPROTEINASES AND METALLOPROTEINASES TISSUE INHIBITOR IN THE SKIN WOUND SURFACE OF FEMALE RATS WITH METABOLIC SYNDROME UNDER THE MELANIN ACTION
DOI:
https://doi.org/10.11603/mcch.2410-681X.2026.i1.15804Keywords:
glutamate-induced obesity; full-thickness planar wounds; metalloproteinases; metalloproteinases tissue inhibitor; carbopol gel with melanin.Abstract
Introduction. Matrix metalloproteinases are involved in the pathophysiological complications of metabolic syndrome. Among the compounds capable of accelerating wound healing, melanin occupies a special place. The aim of the study – to determine the participation of metalloproteinases and tissue inhibitor of metallo- proteinases in the skin of obese female rats in wound healing under the condition of their treatment with melanin. Research Methods. The studies were conducted on 40 female white nonlinear rats. The animals were divided into 6 groups. Three groups – without obesity and three groups with glutamate-induced obesity (GIO). Simulation of wounds on the dorsal surface was carried out under general anesthesia using sodium thiopental at a dose of 60 mg/kg of animal weight. In the 4th group of animals without GIO and the 6th group of animals with GIO, the wounds were treated daily with carbopol gel (0.5 %) with melanin (0.1 %). The concentrations of metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) were determined using the appropriate reagent sets by the indirect enzyme-linked immunosorbent assay (ELISA). Results and Discussion. No statistically significant changes in the content of MMP-1 were found in the control groups of animals -1, -2 and -3, as well as in the groups with GIO -4, -5 and -6. In GIO, where wound healing took place in the presence of melanin (group 6), the concentration of MMP-2 increased by 1.3 times compared to the control (group 4). In GIO (group 4), the concentration of MMP-3 decreased by 1.8 times compared to the control (group 1). In GIO, GIO and flat wound, as well as GIO and flat wound treated with melanin, the concentration of MMP-3 practically does not change compared to the corresponding controls without GIO. In GIO and flat wound, the concentration of MMP-9 decreases by 1.6 times compared to the corresponding control value without GIO. In rats of the control group with GIO, the concentration of MMP-12 decreases by 1.8 times compared to the control without GIO. The concentration of TIMP in GIO (group 4) decreases by 1.5 times compared to the control without GIO (group 1). Conclusions. 1. Melanin practically does not affect the activity of metalloproteinases – MMP-1, MMP-2, MMP-3, MMP-8 and MMP-12 of the skin of the wound surface in obese female rats. However, when treating flat wounds of obese female rats with melanin gel, MMP-9 activity increases, which indicates its participation in regenerative processes. 2. In obesity, the concentration of tissue inhibitor of skin metalloproteinases increases relative to control values without obesity, however, melanin does not affect the concentration of this inhibitor.
References
Matsuzawa, Y., Funahashi, T., Nakamura T. (2011). The concept of metabolic syndrome: Contribution of visceral fat accumulation and its molecular mechanism. J. Atheroscler. thromb., 18, 629–639. DOI: 10.5551/jat.7922.
Ortega, F. B., Lavie, C. J., Blairm, S. N. (2016). Obesity and cardiovascular disease. Circ. res.,118, 1752–1770. DOI: 10.1161/CIRCRESAHA.115.306883.
Laronha, H., Caldeira, J. (2020). Structure and Function of Human Matrix Metalloproteinases. CELLS. 26, 9 (5), 1076. DOI: 10.3390/cells9051076.
Chun, T. H., et al. (2010). Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes. 59, 2484–2494. DOI: 10.2337/ db10-0073.
Tinahones, F. J., et al. (2012). Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels. Bmc physiol.,12, 4. DOI: 10.1186/1472-6793-12-4.
Hopps, E., Caimi, G. (2012). Matrix metalloproteinases in metabolic syndrome. Eur. j. intern. med., 23, 99–104. DOI: 10.1016/j.ejim.2011.09.012.
Boumiza, S., Chahed, K., Tabka, Z., Jacob, M. P., Norel, X., Ozen, G. (2021). MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity. Sci rep., 11 (1), 20052. DOI: 10.1038/s41598-021-99577-2.
Caimi, G., et al. (2019). Lipid peroxidation, protein oxidation, gelatinases, and their inhibitors in a group of adults with obesity. Horm. metab. res., 51, 389–395. DOI: 10.1055/a-0887-2770.
Molière, S., Jaulin, A., Tomasetto, C.L., Dali- Youcef, N. (2023). Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease. Int j mol sci., 24 (13), 10649. DOI: 10.3390/ijms241310649.
Berg, G., Schreier, L., Miksztowicz, V. (2014). Circulating and adipose tissue matrix metalloproteinases in cardiometabolic risk environments: pathophysiological aspects. Horm mol biol clin investig. 17 (2), 79–87. DOI: 10.1515/hmbci-2013-0069.
Malyk, C .B., Osipov, O. C. (2018). Postoperative wound complications in obese patients: risk factors, pre- vention, early diagnosis. Kharkiv: Publisher O.A. Miroshnychenko, 104 p. [in Ukrainian].
Alma, A., Marconi, G. D., Rossi, E., Magnoni, C., Paganelli, A. (2023). Obesity and Wound Healing: Focus on Mesenchymal Stem Cells. Life,13 (3), 717. DOI: https://doi.org/10.3390/life13030717
Aragona, M., Dekoninck, S., Rulands, S., Lenglez, S., Mascré, G., Simons, B.,D., et al. (2017). Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat commun, 2017, 8, 14684. DOI: 10.1038/ncomms14684
Díaz-García, D., Filipová, A., Garza-Veloz, I., Martinez-Fierro, M. L. (2021). A beginner’s introduction to skin stem cells and wound healing. Int j mol sci., 22, 11030. DOI: 10.3390/ijms222011030
Mamun, A. A, Shao, C., Geng, P., Wang, S., Xiao, J. (2024). Recent advances in molecular mechanisms of skin wound healing and its treatments. Front. immunol., 15, 1395479. DOI: org/10.3389/fimmu.2024.1395479
Chou, W. C., Takeo, M., Rabbani, P., Hu, H., Lee, W., Chung, Y.R., et al. (2013). Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. Nat med., 19, 924–929. DOI: 10.1038/nm.3194
Leclère, F. M. (2017). The use of integra® Dermal regeneration template versus flaps for reconstruction of full-thickness scalp defects involving the calvaria: A cost– benefit analysis. Aesthetic plast surg., 41, 472–473. DOI: 10.1007/s00266-016-0765-z
Boyce, S.T., Lalley, A.L. (2018). Tissue engineering of skin and regenerative medicine for wound care. Burn trauma, 6, 4. DOI: 10.1186/s41038-017-0103-y
Rodrigues, M., Kosaric, N., Bonham, C. A., Gurtner, G. C. (2019). Wound healing: A cellular perspective. Physiol rev., 99, 665–706. DOI: 10.1152/physrev.00067.2017
Tottoli, E. M., Dorati, R., Genta, I., Chiesa, E., Pisani, S., Conti, B. (2020). Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics, 12, 1–30. DOI: 10.3390/ pharmaceutics12080735
Agrawal, M. (2015). Natural polyphenols based new therapeutic avenues for advanced biomedical applications. Drug metabolism reviews, 47 (4), 1–11.
Diaz, D. F. Z., Busch, L., Kroger, M., Klein, A. L., Lohan, S. B. et al. (2024). Significance of melanin distribution in the epidermis for the protective effect against UV light. Scientific reports, 14, 3488. doi: 10.1038/ s41598-024-53941-0.
Solano, F. (2020). Photoprotection and Skin Pigmenation: Melanin-Related Molecules and Some Other New Agents Obtained from Natural Sources. Molecules, 2020, 25 (7), 1537. DOI: 10.3390/molecules25071537.
Taburets, O. V., Morgaienko, O. O., Kondratyuk, T. O., Beregova, T. V., Ostapchenko, L. I. (2016). The Effect of “Melanin-Gel” on the Wound Healing. Research journal of pharmaceutical, biological and chemical sciences, 7 (3), 2031–2038.
Taburets, O. V., Grinchenko, O. O., Dvorshchenko, K. O., Vereshchaka, V. V., Ostapchenko, L. I. (2017). The effect of melanin on prooxidant-oxidant homeostasis in blood serum under conditions of cut wounds of the skin of shurikens. Bulletin of problems of biology and medicine, 1, 191–196. Retrieved from: http://nbuv.gov.ua/UJRN/Vpbm_2017_1_41. [in Ukrainian].
Papier, K., Knuppel, A., Perez-Cornago, A., Watts, E. L., Tong, T. Y. N., Schmidt J. A., Allen, N., Key, T. J., Travis, R.C. (2022). Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank study. Eur j epidemiol., 37 (1), 25–34. DOI: 10.1007/s10654-021-00811-y.
Azevedo, P. S., Gumieiro, D. N., Polegato, B. F., Pereira, G. J., Silva, I. A., Pio, S. M., Junior, C. P., Junior, E. L., de Paiva, S. A., Minicucci, M. F., Zornoff, L. A. (2017). Goldman score, but not Detsky or Lee indices, predicts mortality 6 months after hip fracture. Bmc musculoskelet disord., 18 (1):134. DOI: 10.1186/s12891-017-1480-x.
Crowther, J. R. (2001). The ELISA Guidebook. Totowa, New Jersey: Humana Press. 436 p.
Laronha, H., Caldeira, J. (2020). Structure and Function of Human Matrix Metalloproteinases. Cells, 9 (5), 1076. DOI: 10.3390/cells9051076.
Sekhon, B. S. (2010). Matrix metalloproteinases – An overview. Research and reports in biology, 1–20. DOI: 10.2147/RRB.S120434.
de Almeida, L. G. N., Thode, H., Eslambolchi, Y., Chopra, S., Young, D. et al. (2022). Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacological reviews, 74 (3), 714–770. ff10.1124/pharmrev.121.000349ff. ffhal-03966470f
Hey, S., Linder, S. (2024). Matrix metalloproteinases at a glance. J cell sci., 137, jcs261898. DOI: 10.1242/jcs.261898.
Li, K., Tay, F. R., Yiu, C. K. Y. (2020). The past, present and future perspectives of matrix metalloproteinase inhibitors. Pharmacol. ther., 207, 107465. DOI: 10.1016/j.pharmthera.2019.107465
Raeeszadeh-Sarmazdeh, M., Do, L. D., Hritz, B. G. (2020). Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics. Cells, 9, 1313. DOI: 10.3390/cells9051313
Krebber, M. M., van Dijk, C. G. M., Vernooij, R. W. M., Brandt, M. M., Emter, C. A., Rau, C. D., Fledderus, J. O., Duncker, D. J., Verhaar, M. C., Cheng, C., Joles, J. A. (2020). Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis. International journal of molec- ular sciences, 21 (18), 6742. DOI: https://doi.org/10.3390/ ijms21186742
Bhartiya, P., Masur, K., Shome, D., Kaushik, N., Nguyen, L. N., Kaushik, N. K., & Choi, E. H. (2021). Influence of Redox Stress on Crosstalk between Fibroblasts and Keratinocytes. Biology, 10 (12), 1338. DOI: https://doi.org/10.3390/biology10121338
Stetler-Stevenson, W.G. (2023). The Continuing Saga of Tissue Inhibitor of Metalloproteinase 2: Emerging Roles in Tissue Homeostasis and Cancer Progression, The american journal of pathology, 193 (10), 1336–1352. DOI: https://doi.org/10.1016/j.ajpath.2023.08.001.
Toriseva, M., Kahari, V.M. (2009). Proteinases in cutaneous wound healing. Cell mol life sci., 66, 203–224. DOI: 10.1007/s00018-008-8388-4.
Widgerow, A. D. (2011). Chronic wound fluid-thinking outside the box. Wound repair regen., 19, 287–291 DOI: 10.1111/j.1524-475X.2011.00683.x
Kandhwal, M., Behl, T., Singh, S., Sharma, N., Arora, S., Bhatia, S., Al-Harrasi, A., Sachdeva, M., Bungau, S. (2022). Role of matrix metalloproteinase in wound healing. Am j transl res. 14 (7), 4391–4405.
Fang, W.-C., Lan, C.-C. E. (2023). The Epidermal Keratinocyte as a Therapeutic Target for Management of Diabetic Wounds. International journal of molecular sciences, 24 (5), 4290. DOI: https://doi.org/10.3390/ ijms24054290
Raeeszadeh-Sarmazdeh, M., Do, L. D., Hritz, B. G. (2020). Metalloproteinases and their inhibitors: potential for the development of new therapeutics. Cells, 9 (5), 1313. DOI: 10.3390/cells9051313.
Wiśniewski, K., Choromańska, B., Maciejczyk, M., Dadan, J., Myśliwiec, P. (2025). Modulating Matrix Metalloproteinase Activity in Obesity: Comparative Effects of Bariatric Surgery and GLP-1/GIP- Based Pharmacotherapy. Journal of clinical medicine, 14 (21), 7648. DOI: https://doi.org/10.3390/jcm14217 648
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Accepted 2026-03-06
Published 2026-04-28
