Zinc-dependent mechanisms of reparative regeneration: theoretical aspects and translational perspectives

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Zinc is an essential component of more than 10% of the human proteome and serves as a cofactor for nearly 300 metalloenzymes. Interaction with zinc regulates protein activity and influences numerous intracellular processes, whereas removal of zinc from an enzyme results in complete loss of its enzymatic activity. Thus, zinc functions as an intracellular signaling molecule at all levels of signal transduction, affecting multiple metabolic pathways. Reparative regeneration is a cascade mechanism for restoring cells and tissues lost due to pathological processes. Understanding the molecular mechanisms of reparative regeneration is crucial for developing clinical strategies to enhance tissue repair capacity. Zinc plays a key role in reparative regeneration. Modulation of zinc-dependent signaling pathways represents a promising approach in experimental pharmacology. Novel Russian zinc complexes with N-alkenylimidazoles have demonstrated efficacy as pharmacologic agents in correcting a wide range of pathological conditions associated with reparative regeneration. These compounds have shown antihypoxic, antioxidant, wound-healing, anti-inflammatory, antiulcer, and analgesic effects. Their safety and high bioavailability offer broad translational potential. Wound healing is a complex and evolving process involving multiple cell types, including immune cells. These cells secrete cytokines and growth factors that contribute to the amplification of inflammation. This review provides a contemporary overview of zinc-dependent intracellular and systemic processes and highlights possible mechanisms of action of zinc complexes within the molecular and cellular pathways of reparative regeneration.

Full Text

Restricted Access

About the authors

Svetlana A. Lebedeva

Peoples’ Friendship University of Russia

Email: Lebedeva502@yandex.ru
ORCID iD: 0000-0003-0325-6397
SPIN-code: 4031-4932

Dr. Sci. (Biology)

Russian Federation, Moscow

Pavel A. Galenko-Yaroshevsky

Ekaterininskaya Clinic

Email: Pavelgalenko@bk.ru
ORCID iD: 0000-0002-6279-0242
Russian Federation, Krasnodar

Boris A. Trofimov

Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: boris_trofimov@irioch.irk.ru
ORCID iD: 0000-0002-0430-3215
SPIN-code: 5179-9902

Dr. Sci. (Chemistry)

Russian Federation, Irkutsk

Lidiya N. Parshina

Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: parshina@irioch.irk.ru
ORCID iD: 0000-0002-5516-6214
SPIN-code: 8333-2047

Dr. Sci. (Chemistry)

Russian Federation, Irkutsk

Olga V. Shelemekh

Rostov State Medical University

Email: lioli777@yandex.ru
ORCID iD: 0000-0003-3488-9971
Russian Federation, Rostov-on-Don

Alina V. Sergeeva

Kuban State Medical University

Author for correspondence.
Email: alina_sergeeva_v@mail.ru
ORCID iD: 0000-0003-4335-2156
SPIN-code: 1917-7035
Russian Federation, Krasnodar

Grigori R. Murashko

Kuban State Medical University

Email: grihsanfeed@gmail.com
ORCID iD: 0009-0008-7023-6357
Russian Federation, Krasnodar

Natalya D. Bunyatyan

Scientific Centre for Expert Evaluation of Medicinal Products

Email: ndbun@mail.ru
ORCID iD: 0000-0001-9466-1261
SPIN-code: 9853-1232

Dr. Sci. (Pharmacy)

Russian Federation, Moscow

Maria Yu. Materenchuk

The First Sechenov Moscow State Medical University

Email: mariamatter231@gmail.com
ORCID iD: 0000-0002-0711-4153
SPIN-code: 4360-1756
Russian Federation, Moscow

Anait V. Zelenskaya

Kuban State Medical University

Email: anait_06@mail.ru
ORCID iD: 0000-0001-9512-2526
SPIN-code: 7646-3620

MD, Cand. Sci. (Medicine)

Russian Federation, Krasnodar

Pavel A. Galenko-Yaroshevsky

Kuban State Medical University

Email: Galenko.Yaroсhevsky@gmail.com
ORCID iD: 0000-0003-3190-1437
SPIN-code: 1575-6129

MD, Dr. Sci. (Medicine), Corresponding Member of the Russian Academy of Sciences

Russian Federation, Krasnodar

References

  1. Freeland-Graves JH, Sanjeevi N, Lee JJ. Global perspectives on trace element requirements. J Trace Elem Med Biol. 2015;31: 135–141. doi: 10.1016/j.jtemb.2014.04.006
  2. Livingstone C. Zinc: physiology, deficiency, and parenteral nutrition. Nutr Clin Pract. 2015;30(3):371–382. doi: 10.1177/0884533615570376
  3. Maret W. Zinc in cellular regulation: The nature and significance of “zinc signals.” Int J Mol Sci. 2017;18(11):2285. doi: 10.3390/ijms18112285
  4. Krężel A, Maret W. The functions of metamorphic metallothioneins in zinc and copper metabolism. Int J Mol Sci. 2017;18(6):1237. doi: 10.3390/ijms18061237
  5. Lin P-H, Sermersheim M, Li H, et al. Zinc in wound healing modulation. Nutrients. 2017;10(1):16. doi: 10.3390/nu10010016
  6. Kimura T, Kambe T. The functions of metallothionein and ZIP and ZnT transporters: An overview and perspective. Int J Mol Sci. 2016;17(3):336. doi: 10.3390/ijms17030336
  7. Duerr GD, Dewald D, Schmitz EJ, et al. Metallothioneins 1 and 2 modulate inflammation and support remodeling in ischemic cardiomyopathy in mice. Mediators Inflamm. 2016;2016:7174127. doi: 10.1155/2016/7174127
  8. Baltaci AK, Yuce K, Mogulkoc R. Zinc metabolism and metallothioneins. Biol Trace Elem Res. 2018;183(1):22–31. doi: 10.1007/s12011-017-1119-7
  9. Maret W. Zinc in the biosciences. Metallomics. 2014;6(7):1174. doi: 10.1039/c4mt90021a
  10. Kocyła A, Adamczyk J, Krężel A. Interdependence of free zinc changes and protein complex assembly — insights into zinc signal regulation. Metallomics. 2018;10(1):120–131. doi: 10.1039/c7mt00301c
  11. Krężel A, Maret W. The biological inorganic chemistry of zinc ions. Arch Biochem Biophys. 2016;611:3–19. doi: 10.1016/j.abb.2016.04.010
  12. Kambe T, Tsuji T, Hashimoto A, Itsumura N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol Rev. 2015;95(3):749–784. doi: 10.1152/physrev.00035.2014
  13. Kambe T, Matsunaga M, Takeda T-a. Understanding the contribution of zinc transporters in the function of the early secretory pathway. Int J Mol Sci. 2017;18(10):2179. doi: 10.3390/ijms18102179
  14. Thingholm TE, Rönnstrand L, Rosenberg PA. Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation. Cell Mol Life Sci. 2020;77(16): 3085–3102. doi: 10.1007/s00018-020-03473-3
  15. Hara T, Yoshigai E, Ohashi T, Fukada T. Zinc transporters as potential therapeutic targets: An updated review. J Pharmacol Sci. 2022;148(2):221–228. doi: 10.1016/j.jphs.2021.11.007
  16. Hojyo S, Fukada T. Zinc transporters and signaling in physiology and pathogenesis. Arch Biochem Biophys. 2016;611:43–50. doi: 10.1016/j.abb.2016.06.020
  17. Cheng Y, Zhao C, Bin Y, et al. The pathophysiological functions and therapeutic potential of GPR39: Focus on agonists and antagonists. Int Immunopharmacol. 2024;143–3:113491. doi: 10.1016/j.intimp.2024.113491
  18. Mlyniec K. Interaction between zinc, GPR39, BDNF and neuropeptides in depression. Curr Neuropharmacol. 2021;19(11): 2012–2019. doi: 10.2174/1570159X19666210225153404
  19. Siodłak D, Nowak G, Mlyniec K. Interaction between zinc, the GPR39 zinc receptor and the serotonergic system in depression. Brain Res Bull. 2021;170:146–154. doi: 10.1016/j.brainresbull.2021.02.003
  20. Starowicz G, Siodłak D, Nowak G, Mlyniec K. The role of GPR39 zinc receptor in the modulation of glutamatergic and GABAergic transmission. Pharmacol Rep. 2023;75(3):609–622. doi: 10.1007/s43440-023-00478-0
  21. Rychlik M, Mlyniec K. Zinc-mediated neurotransmission in Alzheimer’s disease: A potential role of the GPR39 in dementia. Curr Neuropharmacol. 2020;18(1):2–13. doi: 10.2174/1570159X17666190704153807
  22. Rychlik M, Starowicz G, Starnowska-Sokol J, Mlyniec K. The zinc-sensing receptor (GPR39) modulates declarative memory and age-related hippocampal gene expression in male mice. Neuroscience. 2022;503:1–16. doi: 10.1016/j.neuroscience.2022.09.002
  23. Rychlik M, Starnowska-Sokol J, Mlyniec K. Chronic memantine disrupts spatial memory and up-regulates Htr1a gene expression in the hippocampus of GPR39 (zinc-sensing receptor) KO male mice. Brain Res. 2023;1821:148577. doi: 10.1016/j.brainres.2023.148577
  24. Chen Z, Gordillo-Martinez F, Jiang L, et al. Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway. Cardiovasc Res. 2021;117(3):820–835. doi: 10.1093/cvr/cvaa090
  25. Iovino L, Cooper K, deRoos P, et al. Activation of the zinc-sensing receptor GPR39 promotes T-cell reconstitution after hematopoietic cell transplant in mice. Blood. 2022;139(25):3655–3666. doi: 10.1182/blood.2021013950
  26. Xia P, Yan L, Ji X, et al. Functions of the zinc-sensing receptor GPR39 in regulating intestinal health in animals. Int J Mol Sci. 2022;23(20):12133. doi: 10.3390/ijms232012133
  27. Allouche-Fitoussi D, Breitbart H. The role of zinc in male fertility. Int J Mol Sci. 2020;21(20):7796. doi: 10.3390/ijms21207796
  28. He C, Dai F-F, Liu J-S, et al. Expressions of zinc homeostasis proteins, GPR39 and ANO1 mRNA in the sperm of asthenozoospermia patients and their clinical significance. Zhonghua Nan Ke Xue. 2024;30(1):18–25. (In Chinese)
  29. Laitakari A, Liu L, Frimurer TM, Holst B. The zinc-sensing receptor GPR39 in physiology and as a pharmacological target. Int J Mol Sci. 2021;22(8):3872. doi: 10.3390/ijms22083872
  30. Hershfinkel M, Moran A, Grossman N, Sekler I. A zinc-sensing receptor triggers the release of intracellular Ca2+ and regulates ion transport. PNAS USA. 2001;98(20):11749–11754. doi: 10.1073/pnas.201193398
  31. Hershfinkel M. Cross-talk between zinc and calcium regulates ion transport: A role for the zinc receptor, ZnR/GPR39. J Physiol. 2024;602(8):1579–1594. doi: 10.1113/JP283834
  32. Doboszewska U, Maret W, Wlaź P. GPR39: An orphan receptor begging for ligands. Drug Discov Today. 2024;29(2):103861. doi: 10.1016/j.drudis.2023.103861
  33. Hershfinkel M. The zinc sensing receptor, ZnR/GPR39, in health and disease. Int J Mol Sci. 2018;19(2):439. doi: 10.3390/ijms19020439
  34. Prasad AS. Impact of the discovery of human zinc deficiency on health. J Trace Elem Med Biol. 2014;28(4):357–363. doi: 10.1016/j.jtemb.2014.09.002
  35. Searle T, Ali FR, Al-Niaimi F. Zinc in dermatology. J Dermatolog Treat. 2022;33(5):2455–2458. doi: 10.1080/09546634.2022.2062282
  36. Yee BE, Richards P, Sui JY, Marsch AF. Serum zinc levels and efficacy of zinc treatment in acne vulgaris: A systematic review and meta-analysis. Dermatol Ther. 2020;33(6):e14252. doi: 10.1111/dth.14252
  37. Kogan S, Sood A, Garnick MS. Zinc and wound healing: A review of zinc physiology and clinical applications. Wounds. 2017;29(4):102–106.
  38. Maxfield L, Shukla S, Crane JS. Zinc deficiency. In: StatPearls. StatPearls Publ.; 2024.
  39. Hajj J, Sizemore B, Singh K. Impact of epigenetics, diet, and nutrition-related pathologies on wound healing. Int J Mol Sci. 2024;25(19):10474. doi: 10.3390/ijms251910474
  40. Tang Y, Yang Q, Lu J, et al. Zinc supplementation partially prevents renal pathological changes in diabetic rats. J Nutr Biochem. 2010;21(3):237–246. doi: 10.1016/j.jnutbio.2008.12.010
  41. Li MS, Adesina SE, Ellis CL, et al. NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage. Am J Physiol – Cell Physiol. 2016;312(1):C47–C55. doi: 10.1152/ajpcell.00208.2016
  42. Stiles LI, Ferrao K, Mehta KJ. Role of zinc in health and disease. Clin Exp Med. 2024;24(1):38. doi: 10.1007/s10238-024-01302-6
  43. Aliev G, Li Y, Chubarev VN, et al. Application of Acyzol in the context of zinc deficiency and perspectives. Int J Mol Sci. 2019;20(9):2104. doi: 10.3390/ijms20092104
  44. Skalny AV, Skalnaya MG, Grabeklis AR, et al. Zinc deficiency as a mediator of toxic effects of alcohol abuse. Eur J Nutr. 2018;57(7):2313–2322. doi: 10.1007/s00394-017-1584-y
  45. Siva S, Rubin DT, Gulotta G, et al. Zinc deficiency is associated with poor clinical outcomes in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(1):152. doi: 10.1097/MIB.0000000000000989
  46. Ehrlich S, Mark AG, Rinawi F, et al. Micronutrient deficiencies in children with inflammatory bowel diseases. Nutr Clin Pract. 2020;35(2):315–322. doi: 10.1002/ncp.10373
  47. MacMaster MJ, Damianopoulou S, Thomson C, et al. A prospective analysis of micronutrient status in quiescent inflammatory bowel disease. Clin Nutr. 2021;40(1):327–331. doi: 10.1016/j.clnu.2020.05.010
  48. Bai Y, Liu CP, Song X, et al. Photo- and pH- Dual-Responsive β-Cyclodextrin-based supramolecular prodrug complex self-assemblies for programmed drug delivery. Chem Asian J. 2018;13(24): 3903–3911. doi: 10.1002/asia.201801366
  49. Zhao H, Song A, Wang L, et al. Research on the damage and wound repair of cornea by GO and ZnO. Cutan Ocul Toxicol. 2024;43(4):237–252. doi: 10.1080/15569527.2024.2387592
  50. Kavanagh O, Elmes R, O’Sullivan F, et al. Investigating structural property relationships to enable repurposing of pharmaceuticals as zinc ionophores. Pharmaceutics. 2021;13(12):2032. doi: 10.3390/pharmaceutics13122032
  51. Marukhlenko AV, Morozova MA, Mbarga AMJ, et al. Chelation of zinc with biogenic amino acids: Description of properties using balaban index, assessment of biological activity on spirostomum ambiguum cellular biosensor, influence on biofilms and direct antibacterial action. Pharmaceuticals. 2022;15(8):979. doi: 10.3390/ph15080979
  52. Shakhmardanova SA, Galenko-Yaroshevskii PA. N-alkenylimidazole metal complex derivatives as effective agents for the hypoxic conditions. Research Results in Pharmacology. 2017;3(1):49–72. doi: 10.18413/2500-235X-2017-3-1-49-72
  53. Shakhmardanova SA, Galenko-Yaroshevsky PA. Zinc complex compound with N-alkenylimidazoles: biological activity and application in medicine (review). Sechenov medical journal. 2022;(3):84–90.
  54. Shakhmardanova SA, Galenko-Yaroshevsky PA. Metal complex derivatives of 1-alkenylimidazole. Antihypoxic properties, mechanisms of action, prospects for clinical use. Krasnodar: Prosveshchenie-Yug; 2015. 267 p. EDN: UWNLBR (In Russ.)
  55. Lebedeva SA, Galenko-Yaroshevsky PA, Fateeva TV, et al. Effective wound healing agents based on N-alkenylimidazole zinc complexes derivatives: future prospects and opportunities. Research Results in Pharmacology. 2023;9(3):27–39. doi: 10.18413/rrpharmacology.9.10047 EDN: GUANYX
  56. Galenko-Yaroshevsky PA, Slavinskiy AА, Todorov SS, et al. The effect of zinc complex of N-isopropenylimidazole on the morphological characteristics of gum tissues in experimental endodontic-periodontal lesions in rats. Research Results in Pharmacology. 2023;9(4):1–12. doi: 10.18413/rrpharmacology.9.10040 EDN: XSJCRL
  57. Galenko-Yaroshevsky PA, Shelemekh OV, Popkov VL, et al. Study of the anti-inflammatory, analgesic, ulcerogenic and anti-ulcerogenic activity of N-isopropenylimidazole zinc complex derivative. Research Results in Pharmacology. 2024;10(1):23–43. doi: 10.18413/rrpharmacology.10.443 EDN: SYEQCA
  58. Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6. doi: 10.1126/scitranslmed.3009337
  59. Morris CJ. Carrageenan-induced paw edema in the rat and mouse. In: Winyard PG, Willoughby DA, editors. Inflammation protocols. Methods in molecular biology. Vol. 225. Humana Press; 2003. P. 115–121. doi: 10.1385/1-59259-374-7:115
  60. Galenko-Yaroshevsky PA, Pavlyuchenko II, Shelemekh OV, et al. Study of anti-inflammatory, antioxidant, antimicrobial and mineralizing effects of an N-isopropenylimidazole zinc metal complex derivative in experimental endodontic-periodontal lesions in rats. Research Results in Pharmacology. 2024;10(4):1–13. doi: 10.18413/rrpharmacology.10.515 EDN: OITWOK
  61. Belyanina EV, Bolotnikova MV, Lykov MV. Application of laser Doppler flowmetry to improve the objectivity of measuring carrageenan-induced edema in rats. Russian Journal of Biotherapy. 2016;15(1):11–12. EDN: WGIFGR (In Russ.)
  62. Lebedeva SA, Galenko-Yaroshevsky PA, Samsonov MY, et al. Molecular mechanisms of wound healing: the role of zinc as an essential microelement. Research Results in Pharmacology. 2023;9(1):25–39. doi: 10.18413/rrpharmacology.9.10003 EDN: DBMFVD
  63. Guschin YaA, Kovaleva MA. Comparative morphology of human and laboratory animals. Laboratory Animals for Science. 2019;(2):6. doi: 10.29296/2618723X-2019-02-06 EDN: GNZOWC
  64. Nunan R, Harding KG, Martin P. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity. Dis Model Mech. 2014;7(11):1205. doi: 10.1242/dmm.016782
  65. Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35–43. doi: 10.1159/000339613
  66. Kuravi SJ, Ahmed NS, Taylor KA, et al. Delineating zinc influx mechanisms during platelet activation. Int J Mol Sci. 2023;24(14):11689. doi: 10.3390/ijms241411689
  67. Sobczak AIS, Ajjan RA, Stewart AJ. Zn2+ differentially influences the neutralisation of heparins by HRG, fibrinogen, and fibronectin. Int J Mol Sci. 2023;24(23):16667. doi: 10.3390/ijms242316667
  68. Martins-Green M, Petreaca M, Wang L. Chemokines and their receptors are key players in the orchestra that regulates wound healing. Adv Wound Care. 2013;2(7):327. doi: 10.1089/wound.2012.0380
  69. Tang D, Kang R, Coyne CB, et al. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012;249(1): 158–175. doi: 10.1111/j.1600-065X.2012.01146.x
  70. Saidov MZ. Cellular and molecular mechanisms of pathogenesis of immune-inflammatory rheumatic diseases. Makhachkala: Lotus; 2023. 280 p. (In Russ.)
  71. Kaisho T, Akira S. Toll-like receptor function and signaling. J Allergy Clin Immunol. 2006;117(5):979–987. doi: 10.1016/j.jaci.2006.02.023
  72. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–820. doi: 10.1016/j.cell.2010.01.022
  73. Piipponen M, Li D, Landén NX. The immune functions of keratinocytes in skin wound healing. Int J Mol Sci. 2020;21(22):8790. doi: 10.3390/ijms21228790
  74. Larouche J, Sheoran S, Maruyama K, Martino MM. Immune regulation of skin wound healing: Mechanisms and novel therapeutic targets. Adv Wound Care. 2018;7(7):209. doi: 10.1089/wound.2017.0761
  75. Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in Wound Healing: A Comprehensive Review. Adv Wound Care. 2014;3(7):445. doi: 10.1089/wound.2013.0473
  76. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: A cellular perspective. Physiol Rev. 2018;99(1):665–706. doi: 10.1152/physrev.00067.2017
  77. Coger V, Million N, Rehbock C, et al. Tissue concentrations of zinc, iron, copper, and magnesium during the phases of full thickness wound healing in a rodent model. Biol Trace Elem Res. 2018;191(1):167–176. doi: 10.1007/s12011-018-1600-y
  78. Sharir H, Zinger A, Nevo A, et al. Zinc released from injured cells is acting via the Zn2+-sensing receptor, ZnR, to trigger signaling leading to epithelial repair. J Biol Chem. 2010;285(34):26097–26106. doi: 10.1074/jbc.M110.107490
  79. Lebedeva SA, Galenko-Yaroshevsky PA, Rychka VO, et al. Molecular aspects of the wound healing effect of zinc as an essential trace element. Trace elements in medicine. 2022;23(1):14–23. doi: 10.19112/2413-6174-2022-23-1-14-23 EDN: UQLYOZ
  80. Takagishi T, Hara T, Fukada T. Recent advances in the role of SLC39A/ZIP zinc transporters in vivo. Int J Mol Sci. 2017;18(12):2708. doi: 10.3390/ijms18122708
  81. Lansdown ABG, Mirastschijski U, Stubbs N, et al. Zinc in wound healing: theoretical, experimental, and clinical aspects. Wound Repair Regen. 2007;15(1):2–16. doi: 10.1111/j.1524-475X.2006.00179.x
  82. Al-Khafaji Z, Brito S, Bin B-H. Zinc and zinc transporters in dermatology. Int J Mol Sci. 2022;23(24):16165. doi: 10.3390/ijms232416165
  83. Satianrapapong W, Pongkorpsakol P, Muanprasat C. A G-protein coupled receptor 39 agonist stimulates proliferation of keratinocytes via an ERK-dependent pathway. Biomed Pharmacother. 2020;127:110160. doi: 10.1016/j.biopha.2020.110160
  84. Nishida K, Hasegawa A, Yamasaki S, et al. Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis. Sci Rep. 2019;9:10842. doi: 10.1038/s41598-019-47132-5
  85. Sunuwar L, Medini M, Cohen L, et al. The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis. Philos Trans Royal Soc B: Biol Sci. 2016;371(1700):20150420. doi: 10.1098/rstb.2015.0420
  86. Opoka W, Adamek D, Plonka M, et al. Importance of luminal and mucosal zinc in the mechanism of experimental gastric ulcer healing. J Physiol Pharmacol. 2010;61(5):581–591.
  87. Bai H-H, Wang K-L, Zeng X-R, et al. GPR39 regulated spinal glycinergic inhibition and mechanical inflammatory pain. Sci Adv. 2024;10(5):eadj3808. doi: 10.1126/sciadv.adj3808
  88. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu Rev Immunol. 2010;28:321–342. doi: 10.1146/annurev-immunol-030409-101311
  89. Summersgill H, England H, Lopez-Castejon G, et al. Zinc depletion regulates the processing and secretion of IL-1β. Cell Death Dis. 2014;5(1):e1040. doi: 10.1038/cddis.2013.547
  90. Brough D, Pelegrin P, Rothwell NJ. Pannexin-1-dependent caspase-1 activation and secretion of IL-1β is regulated by zinc. Eur J Immunol. 2009;39(2):352–358. doi: 10.1002/eji.200838843
  91. Brennan MA, Cookson BT. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol. 2000;38(1):31–40. doi: 10.1046/j.1365-2958.2000.02103.x
  92. Alsina L, Israelsson E, Altman MC, et al. A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4. Nat Immunol. 2014;15(12):1134. doi: 10.1038/ni.3028
  93. Prasad AS. Zinc: An antioxidant and anti-inflammatory agent: Role of zinc in degenerative disorders of aging. J Trace Elem Med Biol. 2014;28(4):364–371. doi: 10.1016/j.jtemb.2014.07.019
  94. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med. 2013;5(167):167sr1. doi: 10.1126/scitranslmed.3004700
  95. Wen X, Aoi J, Mijee T, et al. SLC39A7 upregulation links to skin fibrosis in systemic sclerosis via TGF-β/SMAD pathway. J Dermatol. 2024;51(6):863–868. doi: 10.1111/1346-8138.17103
  96. Kim SH, Oh JM, Roh H, et al. Zinc-Alpha-2-glycoprotein peptide downregulates type I and III collagen expression via suppression of TGF-β and p-Smad 2/3 pathway in keloid fibroblasts and rat incisional model. Tissue Eng Regen Med. 2024;21(7):1079–1092. doi: 10.1007/s13770-024-00664-y
  97. Jiang Y, Tsoi LC, Billi AC, et al. Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin. JCI Insight. 2020;5(20):e142067. doi: 10.1172/jci.insight.142067
  98. Feldmeyer L, Keller M, Niklaus G, et al. The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by keratinocytes. Curr Biol. 2007;17(13):1140–1145. doi: 10.1016/j.cub.2007.05.074
  99. Koike S, Yamasaki K. Melanogenesis connection with innate immunity and toll-like receptors. Int J Mol Sci. 2020;21(24):9769. doi: 10.3390/ijms21249769
  100. Cioce A, Cavani A, Cattani C, Scopelliti F. Role of the skin immune system in wound healing. Cells. 2024;13(7):624. doi: 10.3390/cells13070624
  101. Dierichs L, Kloubert V, Rink L. Cellular zinc homeostasis modulates polarization of THP-1-derived macrophages. Eur J Nutr. 2018;57(6):2161–2169. doi: 10.1007/s00394-017-1491-2
  102. Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci. 2016;73(20):3861–3885. doi: 10.1007/s00018-016-2268-0
  103. Mosser DM. The many faces of macrophage activation. J Leukoc Biol. 2003;73(2):209–212. doi: 10.1189/jlb.0602325
  104. Brancato SK, Albina JE. Wound macrophages as key regulators of repair: Origin, phenotype, and function. Am J Pathol. 2011;178(1):19–25. doi: 10.1016/j.ajpath.2010.08.003
  105. Vogel DYS, Glim JE, Stavenuiter AWD, et al. Human macrophage polarization in vitro: maturation and activation methods compared. Immunobiology. 2014;219(9):695–703. doi: 10.1016/j.imbio.2014.05.002
  106. Sindrilaru A, Peters T, Wieschalka S, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest. 2011;121(3):985–997. doi: 10.1172/JCI44490
  107. Barrientos S, Stojadinovic O, Golinko MS, et al. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601. doi: 10.1111/j.1524-475X.2008.00410.x
  108. Kim B, Lee W-W. Regulatory role of zinc in immune cell signaling. Mol Cell. 2021;44(5):335–341. doi: 10.14348/molcells.2021.0061
  109. Colomar-Carando N, Meseguer A, Company-Garrido I, et al. Zip6 transporter is an essential component of the lymphocyte activation machinery. J Immunol. 2019;202(2):441–450. doi: 10.4049/jimmunol.1800689

Copyright (c) 2025 Eco-Vector

License URL: https://eco-vector.com/for_authors.php#07
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 65565 от 04.05.2016 г.