MOLECULAR MECHANISMS OF WOUND HEALING: THE ROLE OF ZINC AS AN ESSENTIAL MICROELEMENT Текст научной статьи по специальности «Фундаментальная медицина»

m

Research Results in Pharmacology

Research Results in Pharmacology 9(1): 25-39 UDC: 616-001.4 DOI 10.18413/rrpharmacology.9.10003

Molecular mechanisms of wound healing: the role of zinc as an essential microelement

Svetlana A. Lebedeva1, Pavel A. Galenko-Yaroshevsky (Jr.)1'2, Mikhail Yu. Samsonov1, Arkadiy B. Erlich1, Arus G. Margaryan1, Maria Yu. Materenchuk1, Iaroslav R. Arshinov1, Yuriy V. Zharov1, Anait V. Zelenskaya3, Olga V. Shelemekh3, Izabella G. Lomsadze3, Tatiana A. Demura1

1 IM. Sechenov First Moscow State Medical University (Sechenov University) 8-2Trubetskaya St., Moscow 119991 Russia

2 State Budgetary Health Care Institution "Leningrad Central District Hospital " of the Ministry ofHealth of the Krasnodar Territory, 24 302 Divisii St., Leningradskaya Stanitsa, Leningradsky District, Krasnodar Territory 353740 Russia

3 Kuban State Medical University, 4 Mitrofan Sedin St., Krasnodar 350063 Russia

4 Rostov State Medical University, 29 Nahichevansky Ave., Rostov-on-Don 344022 Russia

Corresponding author: Svetlana A. Lebedeva (lebedeva502@yandex.ru)

Academic editor: Mikhail V. Korokin ♦ Received 11 December 2022 ♦ Accepted 07 February 2023 ♦ Published 31 March 2023

Citation: Lebedeva SA, Galenko-Yaroshevsky PA (Jr.), Samsonov MYu, Erlich AB, Margaryan AG, Materenchuk MYu, Arshinov IaR, Zharov YuV, Zelenskaya AV, Shelemekh OV, Lomsadze IG, Demura TA (2023) Molecular mechanisms of wound healing: the role of zinc as an essential microelement. Research Results in Pharmacology 9(1): 25-39. https://doi.org/10.18413/rrpharmacology.9.10003

Introduction: In the course of evolution, humans developed a number of complex multi-step wound healing mechanisms which limit the infectious agents access to the bloodstream, protect the organism from blood loss, and restore skin integrity. The process of skin wound healing includes the following stages: haemostasis, inflammation, proliferation, and remodeling. These processes are possible because of modulators, growth factors, cytokines, matrix metalloproteinases and cellular receptors, as well as some trace elements like zinc.

Materials and Methods: The presented data was analyzed and compiled using all relevant articles describing the role of zinc in blood coagulation, proliferation, damaged tissues regeneration and angiogenesis.

Results and Discussion: There are some on-going studies about zinc effects on blood coagulation, proliferation, damaged tissues regeneration and angiogenesis. However, molecular mechanisms of these processes are not yet fully understood and require further study. The analysis of scientific efforts to investigate the role of zinc in wound healing molecular mechanisms is especially relevant to the understanding of treatment of skin wound injuries.

Conclusion: Wound healing is a complex multi-phase process consisting of several phases. Each stage involves metal ions, primarily zinc, which stimulates re-epithelialization, decreases inflammation and bacterial growth. The use of known zinc-based drugs is accompanied by side effects and low efficacy due to low skin absorption. These factors significantly limit use of such drugs and highlight the urgency of finding new, more effective and safe treatment. The emerging field of nanobiotechnology may provide an alternative platform to develop new therapeutic agents for the wound healing process.

Copyright Lebedeva SA et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Graphical Abstract

1. Hemostasis

Stages of wound healing

2. Inflammatory 3. Proliferative

Increase in platelet activity and aggregation Fibrin clot formation

Affects cytokine production Increase in expression of A20 proteins and PPARs T-cells activation Mast cells activation

f

In"

4. Remodeling

Zn!*

Zn*

Increase in proliferation and migration of keratinocytes Re-epithelial ization Inducing deposition of collagen and ECM

Inducing granulation tissue forms up Increase in MTs levels

Zn1* MMP activation

Keywords

haemostasis, inflammation, keratinocyte, metalloproteinases, platelets, proliferation, remodeling, skin, wound healing, zinc.

Introduction

The integrity of skin plays an important key role in maintaining physiological homeostasis, viability and internal organs functioning. Deep understanding of the physiology of wound healing is a theoretical base for developing new therapeutic approaches in treatment of wounds. Zinc plays an important role in wound healing processes.

Zinc is an essential micronutrient in human body. It is involved in growth and development processes, bone tissue metabolism, and functioning of nervous and immune systems (Roohani et al. 2013). Approximately 3000 zinc-dependent proteins play an indispensable role in transcription, apoptosis, deoxyribonucleic acid (DNA) repair, extracellular matrix (ECM) regulation, and antioxidant defence (Pawlak et al. 2012; Zheng et al. 2015; Cho et al. 2016; Kimura and Kambe 2016). Intracellular Zn homeostasis in mammals is regulated by two types of zinc transporters: ZnTs and ZIPs (Bin et al. 2018; Hoch et al. 2020). ZIP family members provide an inflow of Zn2+ from the extracellular space into cells or from the intracellular zinc ions stock into cytoplasm, increase intracellular Zn [Zn2+]i (Zhang et al. 2019). ZnT isoforms regulate Zn2+ outflow from cytosol to the extracellular space or to intracellular organelles, decreasing their cytoplasmic concentration (Fukada and Kambe 2011; Kambe 2012).

Human skin contains about 20 % of total zinc content in the body, being second only to muscle fibers and bone tissue. Zinc plays an extremely important role in the physiology of skin and its appendages. Currently, it has been demonstrated that wound healing process goes more slowly in zinc-deficient conditions (Lin et al. 2017).

Within the first twenty-four hours from injury, zinc content in the wound increases by 15-20 %, reaching its maximum of 30 % during the period of intensive granulation tissue formation and epidermis proliferation (from 8 hours to 3 days after surgery). This increase in Zn2+ may be attributable to recruitment of cells with high Zn2+ content (including erythrocytes, neutrophils, lymphocytes, and platelets), and may represent a mechanism by which Zn2+ is delivered to sites of vascular damage (Ahmed et al. 2021). In the late stages of healing, zinc content decreases; it points out to mitotic activity decrease and scar tissue maturation (Lin et al. 2017).

Up to date, the role of zinc in burn injury (Adjepong et al. 2016; Kurmis et al. 2016), subcutaneous abscess, surgical interventions (Mirastschijski et al. 2013), and bed sores (Posthauer 2014) has been also demonstrated. Zinc deficiency and its metabolism disorders are the pathogenetic link in a number of skin diseases (Gupta et al. 2014; Maxfield et al. 2022) and delay wound healing (Kogan et al. 2017). However, the mechanisms by which zinc exerts its activity have not been fully studied yet.

Wound healing stages

A wound is a disruption of anatomical continuity of skin or mucous membranes caused by an external mechanical action, with possible damage to deeper lying tissues. Wound healing process includes regeneration of the epithelial wound and formation of a scar consisting of connective tissue cells. Wounding is followed by activation of coagulation processes, and a blood clot consisting of erythrocytes, fibrin, fibronectin

and complement system proteins gets formed on the wound surface. The blood clot acts as a barrier which stops bleeding and cell migration caused by growth factors, cytokines and chemokines release at the site of skin injury.

At the first stage of wound healing, vascular endothelial growth factor (VEGF) is released; it causes swelling of the surrounding tissues. After the blood clot on the outer surface gets dried, a crust forms. Then, during the first twenty-four hours, neutrophils accumulate at the wound edges and migrate to the formed fibrin clot. They secrete proteolytic enzymes, which help to initiate the wound cleansing from cellular detritus. In the period from 24 to 48 hours after the wounding, epithelial cells from its edges start migration and proliferate along the dermis surface, thus forming basement membrane components again. Then, they move to the midline of the evolving crust, and form a thin but continuous layer that closes the wound.

Three days after the wounding, macrophages replace neutrophils, granulation tissue begins to penetrate into the wound area, and well-identifiable collagen fibers appear on the wound edges. Macrophages are the main cellular components that promote angiogenesis and ECM formation, carry out tissue repair processes, cleansing from extracellular detritus, fibrin, and other foreign components. At the meantime, epithelization goes on actively, which leads to the restoration of the normal epidermis thickness.

Five days after the wounding, neovascularization process reaches its peak as the wound space gets filled with granulation tissue. Newly formed vessels become permeable to blood plasma proteins and fluids, which easily pass into the extravascular space, causing tissue swelling. Fibroblasts migration into the wound space and their subsequent proliferation occur under the influence of tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), transforming growth factor p (TGF-P), and fibroblast growth factor (FGF), interleukin-1 (IL-1). Fibroblasts begin to produce proteins that constitute ECM, as well as collagen fibers in large quantities. After the surface cell differentiation, the epidermis mature architecture begins to form with keratinization of its surface.

During the second week, collagen accumulation and fibroblast proliferation process goes on. At this time, leukocyte infiltration of the wound area decreases, edema goes down, and vascularization decreases. As a result of collagen fiber accumulation inside the forming scar, as well as decreased number of vessels, the wound becomes whiter in appearance.

By the end of the first month, the scar consists of connective tissue free of inflammatory cells. Despite the fact that the scar is covered with normal epidermis, the skin appendages destroyed during the wounding process do not get restored. Over time, one may notice an increase in the formed scar mechanical tensile strength.

Thus, wound healing is a complex and dynamic process that can be divided into a number of phases:

1) haemostasis with coagulating fibrin clot formation (from several seconds to 1 hour); 2) inflammatory response (from several minutes to several days); 3) proliferation (begins 18-24 hours after wounding and lasts from several days to weeks); 4) matrix remodeling and scar formation (over several months) (Diegelmann and Evans 2004).

Each wound healing phase duration depends on various factors: type and size of the wound, age, physical condition, comorbidities, wound location, and treatment (Mirastschijski et al. 2013).

These phases involve a wide range of biologically active substances: reactive oxygen species (ROS), cytokines, growth factors, ECM proteins, as well as platelets, leukocytes, keratinocytes, fibroblasts, immune, epithelial, and stem cells.

The role of zinc in wound healing

At each of the wound healing stages described above, zinc plays an important biological role, which is primarily due to its effect on cell behavior and enzymatic activity regulation.

Haemostasis

Haemostasis system is based on maintaining balance between coagulation and anticoagulation systems. When a vessel is damaged, blood components pass into the wound area, and vasoactive factors get released, which leads to blood coagulation and haemostasis cascade activation.

Platelet haemostasis

Platelets are an important element of coagulation system; they release vasoactive substances, growth factors, and pro-inflammatory cytokines. Initially, little attention was paid to the role of zinc in platelet activation. The studies were mostly focused on the role of calcium ions. However, it has been known for decades that zinc also promotes platelet activity and aggregation and serves as an important haemostatic co-factor, acting as both a platelet agonist and a secondary messenger. Indeed, as far back as in the twentieth century, experiments on zinc-deficient rodents showed increased bleeding tendency, prolonged tail bleeding time and more difficult parturition (Apgar 1968; O'Dell et al. 1977; Emery et al. 1990).

It illustrates a potential role of Zn2+ during thrombosis and haemostasis and highlights its recognition as an intracellular and extracellular platelet regulator (Ahmed et al. 2021).

Currently, the possibility of synergistic relationship between calcium and zinc ions is assumed, but no evidence to this theory has been provided yet (Watson et al. 2016). An interesting fact is that Zn2+ often interacts with proteins with a higher affinity than Ca2+ (Dudev and Lim 2003).

Zinc ions are involved in platelet biogenesis from megakaryocytes, but these processes have not been studied yet (Mammadova-Bach and Braun 2019). Hematopoietic Zn2+-finger gene (Hzf) is expressed in megakaryocyte lineage, and Hzf domain modification with zinc fingers leads to abnormal synthesis of a-granules, packing of substances into them, and platelet biogenesis (Kimura and Kambe 2016). To maintain the required level of zinc, megakaryocyte membrane contains various ZIP/ZnT transporters (Hojyo and Fukada 2016; Kimura and Kambe 2016; Hara et al. 2017; Kambe et al. 2017; Bin et al. 2018); however, to understand the molecular mechanisms of capture, storage, and release of zinc ions by platelets, further studies of zinc transporters subcellular localization and ZIP/ZnT isoforms contribution to zinc homeostasis are required (Mammadova-Bach and Braun 2019).

Due to their active transport mechanisms, platelets are able to absorb Zn2+ from blood plasma and accumulate them in a-granules (Taylor and Pugh 2016; Kiran Gotru et al. 2019). Apart from a-granules that contain a significant part of zinc (Mammadova-Bach and Braun 2019), zinc is present in platelet cytosol, either bound to metallothionein (MT) or in a free state.

Mechanisms of platelet function regulation with the participation of zinc have not yet been studied. K.A. Taylor and N. Pugh (2016) presented a model that describes the mechanisms of platelet activation, which are influenced by zinc ions. According to this model, amounts of [Zn2+]i significantly increase after vascular damage and primary activation of platelets by collagen. It is assumed that this is caused by membrane ion channels and transporters. Also, a part of ions is released from internal storages (Taylor and Pugh 2016). Labile zinc acts as a platelet agonist: at low concentrations, it potentiates platelet response to other agonists, and at high concentrations it stimulates aggregation (Watson et al. 2016).

Zinc ions increase GpVI receptor affinity for collagen, thus inducing primary activation of platelets, release of thromboxane A2 (TxA2) and a-granules (Watson et al. 2016). Zinc ions also interact with protein kinase C (PKC), activating tyrosine phosphorylation for signaling proteins and a subsequent change in GpIIbIIIa glycoprotein conformation, which promotes their binding to fibrin, and clot formation (Ahmed et al. 2019).

Zinc is also a regulator of platelet granule biogenesis and release. A-granules contain fibrinogen, prothrombin, coagulation factors V, XI, XIII, von Willebrand factor (VWF), fibronectin, P-selectin, PDGF, epidermal growth factors (EGF), P-thromboglobulin, albumin, kallikrein, a-2-antiplasmin (Taylor and Pugh 2016). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP), guanosine diphosphate (GDP), serotonin, calcium, and inorganic phosphates. The content of granules enhances aggregation of platelets, maintains integrity and stimulates restoration of vascular wall and connective tissue.

Platelet activation depends on rapid phosphorylation and dephosphorylation of key signaling proteins, especially tyrosine residues. According to the study, even a slight increase in [Zn2+]i is able to inhibit activity of many tyrosine phosphatases and maintain phosphorylation of platelet proteins (Taylor and Pugh 2016). Tyrosine kinases that regulate protein tyrosine phosphorylation after activation of platelets, also get activated.

An important factor of platelet activation regulation are changes in intracellular level of cyclic nucleotides: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). According to the studies, zinc prevents further cAMP synthesis by changing adenylate cyclase conformation (Klein et al. 2004). By inhibiting cyclic nucleotide phosphodiesterase (PDE), zinc ions increase cGMP levels (Watjen et al. 2001). A decrease in cAMP and and increase in cGMP lead to a lower influence of negative regulation in platelet activation process, and promote their aggregation.

The role of Zn2+-dependent signaling mechanisms on ROS formation during platelet activation has been shown (Ruttkay-Nedecky et al. 2013; Lopes-Pires et al. 2021). Since ROS regulate the storage of MTs containing zinc ions (Ruttkay-Nedecky et al. 2013), platelet incubation with MT or administration of MT to mice suppresses the aggregation response to collagen by reducing calcium ions mobilization and TxA2 synthesis (Ruttkay-Nedecky et al. 2013) (Fig. 1).

After platelet activation, degranulation sets in; it promotes coagulation, wound healing, and inflammation.

Vascular haemostasis

Zinc released from a-granules participates in fibrin clot formation process along with calcium ions. The basic reaction is soluble fibrinogen conversion into insoluble fibrin fibers via fibrinopeptide A removal by thrombin. Fibrin fibers polymerize into protofibrils, and their cohesion, in turn, forms a fibrin fiber. Accumulation of fibrin fibers forms a network within the blood clot, which then becomes a thrombus basis.

Many factors influence the formation process, structure and properties of fibrin, and, consequently, fibrin network: ionic strength, medium pH, various exogenous substances, and medium ionic composition (calcium and zinc ion concentration). An increased thrombin activity leads to formation of a network consisting of thinner fibrin fibers, which, in turn, form an extensive network with a smaller pore diameter. Such network will be more rigid, and it will significantly increase the chances of a thrombus separation and subsequent development of thromboembolism. A decreased thrombin activity leads to formation of thicker fibers and a less extensive network with a large pore diameter. In this case, a more flexible thrombus is formed, and it can change its shape under external mechanical factors and retain its function (Weisel and Litvinov 2017).

The main modulator of mechanical rigidity is factor XIII, which contributes to fibrin fiber compaction and

to formation of an elastic network together with Zn2+ from activated platelets (Weisel and Litvinov 2017).

Figure 1. Adhesion. (1) Platelets respond to vessel injury by interacting with basal membrane collagen via collagen-sensitive platelet receptor glycoprotein 1a (Gp1a), and glycoprotein of endothelial and subendothelial tissue cells, von Willebrand factor (VWF), which binds to a specific receptor, glycoprotein 1b (Gp1b) via the A1 domain and to collagen via the A3 domain. Activation. (2) Increased activity of cyclooxygenase type 1 (COX 1) enhances TxA2 synthesis, which results in Zn2+ release from intracellular stores (3). Increased ROS generation results in the reduction of thiols on MT binding Zn2+, and leads to Zn2+ release (4). Affected by TxA2, Gq proteins get activated (5), which leads to an increase in inositol-3-phosphate formation, an increase in Ca2+ content in the platelet, and a change in Gp2b/3a conformation (6). An increased content of [Zn2+]i activates the PKC and leads to a-granule release (7). [Zn2+]i inhibits adenylate cyclase, reducing cAMP and promoting platelet aggregation (8).

Much earlier studies showed that, at elevated Zn2+ concentrations, thrombin binding to fibrin and fibrinopeptide A cleavage decreased (Marx and Hopmeier 1986; Hopmeier et al. 1990). Accordingly, at lower ions concentrations, thrombin adsorption increased. Thus, one can conclude that Zn2+ participation in fibrin clot formation is focused not on fibrin formation stimulation, but on its subsequent transformations and fibrin network formation.

Zinc ions regulate several stages of coagulation. For example, they bind to factor XII, inducing conformational changes, thereby improving its susceptibility to enzymatic activation (Wang et al. 2019). Zn2+ binds to such neutralizing proteins as fibrinogen, high-molecular-weight kininogen

(HMWK) and histidine-rich-glycoprotein (HRG), increasing their affinity for anticoagulants and is thus an important regulator of glycosaminoglycans (GAGs) neutralization and haemostasis (Sobczak et al. 2018). It has been proved that zinc deficiency disrupts coagulation cascade and fibrin formation, which leads to a bleeding time increase (Taylor and Pugh 2016).

Conformational changes in factor XII under influence of zinc ions induce the kallikrein-kinin system (Chaudhry et al. 2020). As a result, bradykinin releases and accumulates on endothelial cells surface, and it promotes adhesion of inflammatory immune cells.

Thus, zinc can promote haemostasis by virtue of several platelets aggregation modulating mechanisms,

coagulation, and fibrin network formation (Mammadova-Bach and Braun 2019). Zinc acts as a haemostatic regulator after degranulation, as a platelet agonist, and also as an intracellular regulator of platelet responses (Ahmed et al. 2021). Nevertheless, this model still remains incomplete. There is a need of further studies aimed to elucidate the paths by which ions enter platelet cytosol, and zinc-induced signaling pathways.

Coagulation-induced haemostasis provides the basis for wound healing inflammatory phase and tissue formation. Haemostatic plug creates a matrix into which effector cells and ECM components migrate.

Inflammation

The inflammation stage is a complex process involving coordination between a variety of cells. The inflammatory response to wounding promotes rapid migration of keratinocytes from the wound edges and from hair follicles and sweat glands into the wound bed where matrix molecules begin to appear. Fibroblasts begin to produce new cells; ECM, EGF and transforming growth factor (TGF) initiate epithelialization. Epithelialization is a sequence of migration, proliferation and differentiation of keratinocytes and is stimulated by altered ECM proteins and cytokines (Rousselle et al. 2019). The main cytokine producers are macrophages and other immune cells.

Numerous studies have shown that zinc affects cytokine production by reducing nuclear factor-kappa B (NF-kB) activation (Voelkl et al. 2018). Rel/NF-KB transcription factor family regulates expression of many genes responsible for immune system functioning, inflammatory response formation, and for other biological processes. Besides, NF-KB plays a critical part in regulating survival, activation, and differentiation of innate immune cells and inflammatory T-cells (Liu et al. 2017).

Various external and internal factors can cause activation of NF-kB, for example, bacterial and viral infections, inflammatory cytokines, UV- and y-radiation, physiological conditions (ischemia, hyperosmotic shock), and oxidative stress (ROS). NF-kB transcription factor family consists of five proteins: p65 (RelA), RelB, c-Rel, p105/p50 (NF-kB1), and p100/52 (NF-kB2). By binding to each other, they form about 15 different transcriptionally active homo-and heterodimeric complexes. In cells, NF-kB dimers stay in a complex with inhibitor of kappa B (IkB), which allows them to remain normally inactive. However, upon signaling pathway activation, these complexes are phosphorylated by IkB kinase (IKK), and it leads to NF-kB dimer activation, its nuclear translocation, and induces transcription of target genes. Activation of NF-kB signaling pathway induces the formation of molecules and mediators that regulate

immunoregulatory proteins synthesis (serum amyloid, a component of C3 complement system, VCAM, ICAM, TCR a, P, MNC-1), cytokines (TNFa, IL-1, IL-6, IL-12), IkB kinases (IkBa, c-Rel, p105), granulocyte-macrophage colony-stimulating factor, and apoptosis regulators (Bcl-XL, IAPs) (Oeckinghaus and Ghosh 2009).

It is known that zinc is involved in NF-KB pathway regulation; however, its impact is rather controversial. For example, some studies report that zinc is necessary for NF-kB binding to DNA in purified or recombinant NF-kB p50 lines or T-helper cells (Zabel et al. 1991; Prasad et al. 2001).

On the other hand, it has been shown that zinc is able to inhibit activity and expression of cyclic nucleotide PDE, which results in elevation of cGMP cellular content. Zinc-mediated cGMP elevation led to cross activation of protein kinase G. By this mechanism, zinc suppresses activation of IKK and NF-kB and subsequent TNF-a production (von Bulow et al. 2007; Haase et al. 2008). Besides, it has been shown that ZIP8-mediated zinc upregulation inhibits IKK upon binding to a specific site within the kinase domain. Thus, ZIP8 negatively regulates the NF-kB pathway, indicating that the zinc-ZIP8-NF-KB axis plays crucial roles during host defense (Bin et al. 2018).

The main mechanism for suppressing zinc-induced inflammation is an increase in expression of zinc-containing A20 proteins and peroxisome proliferator-activated receptors (PPARs). Zinc finger protein A20 (also known as Tumor Necrosis Factor Alpha-Induced Protein 3 or TNFAIP3) is a central negative regulator of NF-kB. The ability of zinc to regulate A20 is determined by the presence of seven "zinc fingers" in its C-terminal domain. Little is known about the molecular mechanisms that regulate the ubiquitin-editing and NF-KB inhibitory function of A20. It is likely that A20 acts at several stages of NF-KB signaling pathway, inhibiting TNF- and TLR4-induced NF-KB activation, which ultimately leads to termination of signaling and decreases production of downstream mediators (Vereecke et al. 2009; Shembade et al. 2010).

PPAR is a family of nuclear receptors with two "zinc fingers" in the structure of DNA-binding domain (Shi et al. 2020). The PPARs consist of three main subtypes: a, p/5, and y. It has been found out that PPAR functions are quite extensive. Not only do they activate proliferation of peroxisomes, but also control metabolism of carbohydrates, fats and proteins in the cell, the processes of cell differentiation and apoptosis. PPARs participate in the transcriptional regulation of metabolism, inflammation, angiogenesis, and fibrotic reaction (Nakano et al. 2020.; Tobita et al. 2020). It is known that all PPAR subtypes get activated to suppress inflammation through inhibition of NF-KB (Korbecki et al. 2019; Tobita et al. 2021). (Fig. 2).

Figure 2. The role of zinc in NF-kB signaling pathway.

Besides, PPAR-a and ß/5 play an important part in wound healing (Gupta et al. 2015). A model of rat alkaline corneal burn was used to demonstrate accelerated healing after topical application of ophthalmic solution of PPAR agonists; accelerated healing was achieved due to enhancement of proliferative capacity and inhibition of inflammation (Tobita et al. 2021).

An important role in wound healing belongs to the immune system, which is especially sensitive to changes in zinc levels. It is known that zinc transporters (ZIP6, ZIP8, ZIP10) are involved in many immune responses (Bin et al. 2018; Thingholm et al. 2020). For example, it has been shown that T-cell activation directs zinc influx from extracellular and subcellular sources through the ZIP6 and ZIP8 zinc transporters, respectively (Yu et al. 2011; Bin et al. 2018). ZIP6 is an important molecule in CD4 T cells (Bin et al. 2018). T-cell receptor (TCR) activation on the surface of CD4 T cells promotes their differentiation into various T-cells, including Th1, Th2, Th17, and Treg cells. TRC activation induces ZIP8 expression in human T-cells. An increased ZIP8-mediated zinc level blocks calcineurin activity, and,

thereby, the phosphorylation of CREB for INF-gamma transcription. By the present time, it has been shown that ZIP8 is important for various immune cells associated with innate immunity (Bin et al. 2018).

Zinc deficiency reduces monocyte adhesion to endothelium (Lee et al. 2012), cytokine production by granulocytes, phagocytosis of macrophages, activity of cytokines secreted by T-cells and macrophages, activity of NK-cells, differentiation of T-cells, and release of certain interleukins and antibodies, and granulation of neutrophils (Kuzmicka et al. 2020).

Zinc ions are an important component of thymulin, thymopoietic hormone necessary for proliferation and differentiation of Th-cells (Prasad 2020). Besides, zinc deficiency negatively affects the expression of IL-2 and IFN-y from Th1-cells. In turn, IL-2 deficiency reduces lytic activity of NK-cells and cytotoxic T-cells, while IFN-y deficiency inhibits macrophage functions (Prasad 2020). Zinc deficiency also increases production of pro-inflammatory cytokines IL-10, IL-6, and TNF-a (Wessels et al. 2013).

It has been shown that B-lymphocytes contribute to cleaning of wounds and also produce antibodies that detect damaged tissue. Zinc deficiency caused by ZnT7

protein-disrupted transportation of ions inhibits CD145-stimulated p38 MAPK phosphorylation, which ultimately leads to inhibition of T-cell-mediated activation of B-lymphocytes.

Zinc-containing enzyme alkaline phosphatase is a marker of angiogenesis early stages, typical for post-traumatic inflammation and connective tissue proliferation. Alkaline phosphatase dephosphorylates adenosine monophosphate (AMP) with formation of adenosine, which has a pronounced anti-inflammatory effect and is important for interrupting wound process inflammation phase.

Currently, the role of mast cells (MCs) is being studied at various stages of wound healing, including inflammation, proliferation, and remodeling. Upon skin injury, they release pro-inflammatory and immunomodulatory mediators, predominantly histamine, VEGF, IL-6, IL-8, which increase endothelium permeability and vasodilation, and promote migration of monocytes and neutrophils to the injury site. MCs stimulate fibroblast proliferation phase via IL-4, VEGF, basic fibroblast growth factor (bFGF) to produce a new ECM. Mediators released from MCs (FGF-2, VEGF, PDGF, TGF-P, nerve growth factor (NGF), IL-4, IL-8) promote neoangiogenesis, fibrinogenesis, and re-epithelization (Komi et al. 2020). Currently, there is no doubt that zinc is involved in activation of mast cells and is required both for their degranulation and for production of cytokines (Nishida and Uchida 2017, 2018).

It was found that Zn and MCs induce IL-6 production from skin fibroblasts through signaling pathways mediated by the Zn G-protein-coupled receptor 39 GPR39 (Nishida et al. 2019). GPR39 is an orphan receptor bound with G protein. It is expressed in peripheral tissues including skin, intestine, and brain. To date, data have been accumulated showing that GPR39 mediates Zn-dependent signaling in keratinocytes, colonocytes, and neurons (Hershfinkel 2018).

Therefore, inflammation phase is aimed at repairing damaged tissues by activating cells and releasing inflammatory mediators, interaction between which causes local and systemic acute inflammatory response development. About 3-5 days after wounding, the signs of inflammation decrease and proliferation stage develops.

Proliferation

Proliferation phase consists of three main processes: re-epithelialization, including keratinocyte proliferation and migration over the wound bed, granulation tissue formation, including proliferation, migration, and synthesis of ECM components by fibroblasts, and neovascularization.

At a time of wound healing, it is important to suppress the inflammatory process as early as possible and prevent it from becoming chronic. It is necessary to eliminate inflammation and promote re-

epithelialization and shrinkage of wound Treg (Nosbaum et al. 2016). A number of studies have shown that zinc supplements regulate Treg signaling pathways and contribute to their induction and stability (Rosenkranz et al. 2016, 2017; Maywald and Rink 2017). Under impact of collagenases, plasminogen activators and zinc-dependent matrix metalloproteinase (MMP), fibrin clot degrades and provides space for cell growth, migration, and angiogenesis.

Re-epithelialization, i.e. reproduction of epithelial cells and subsequent settlement and closure of the wound by them, is induced. Inability to re-epithelialize is a clear indicator of chronic non-healing wounds, which fail to proceed through the normal phases of wound healing in an orderly and timely manner (Rousselle et al. 2019).

The known zinc-finger X-linked protein (ZFX) additionally promotes proliferation and migration of keratinocyte cells (Feng et al. 2021). Zinc is a necessary co-factor for normal functioning of SMAD proteins, which are the main converters of signaling molecules to TGF-P receptors. Thus, deposition of collagen and ECM is induced, and then granulation tissue forms up (Maywald et al. 2017).

By the present time it has been shown that ZIP4 is expressed in human keratinocytes, and its expression is dramatically reduced on epidermal differentiation (Bin et al. 2017), and an increase in zinc concentration from 8 h to 3 days after wounding can cause keratinocytes proliferation (Coger et al. 2019). Besides, by using immortalized human keratinocytes (HaCaT) it was found that zinc-sensitive GPR39, which is highly expressed in keratinocytes, promotes skin wound healing (Satianrapapong et al. 2020).

Keratinocytes proliferation is followed by increased levels of MTs - redox-sensitive antioxidant proteins. Regulation of oxidation-reduction reactions is essential in wound healing. About 20 % of intracellular zinc is associated with MT, and it has been shown that zinc enhances MT expression (Lin et al. 2017).

MTs are cysteine-rich 6-7 kDa proteins that regulate intracellular Zn movement based on physiological needs (Kimura and Kambe 2016). In skin, the most common are MT-1 and MT-2. Results obtained using models of normal human epidermal keratinocytes (NHEK) and in injured murine skin have shown that MTs and Zn levels increase with proliferation of keratinocytes (Bin et al. 2017).

Angiogenesis

Simultaneously with re-epithelialization, endothelial cells migrate and proliferate at the wound site to form up new blood vessels. In this way, new cells are provided with the oxygen and nutrients necessary for their life and growth. The exact role of zinc in angiogenesis regulation has not been studied yet. It is known that expression of zinc-dependent protein ZEB2 is increased in damaged cardiomyocytes. On administering a therapeutic dose of ZEB2 into

cardiomyocytes, angiogenesis is induced, and the density of newly formed vascular network increases, which leads to a decreased scarring and preservation of cardiac function (Gladka et al. 2021). On the other hand, zinc deficiency stimulates migration of endothelial cells of human microvessels (Maywald and Rink 2017). The study of zinc transporter Slc39a5 role in venous angiogenesis in Danio rerio embryo model shows that its destruction leads to systemic accumulation of zinc and delayed growth and development of veins.

Remodeling

The remodeling phase comes after the complete restoration of epidermis and is aimed at replacing granulation tissue with healthier skin via re-epithelialization (Coger et al. 2019). Remodeling is a delicate balance between tissue formation and tissue degradation, controlled by proteolytic enzymes activity.

Degradation of various proteins in the ECM is an important process in tissue remodeling and repair. Degradation is carried out by various types of proteases, but the main ones are MMPs.

MMPs are a family of zinc-dependent endopeptidases, identified in various tissues (Agren and Auf dem Keller 2020) and secreted by various cell types: inflammatory cells, keratinocytes, endothelial cells, fibroblasts, vascular smooth muscle (VSM), etc. All members of the MMP family contain common domains, of which zinc is required in catalytic domain for proteolytic activation of protein (Wang and Khalil 2018).

In skin, MMPs are involved in many cellular, molecular, and biochemical processes (Sabino and Keller 2015) and modulate release of cytokines, growth factors, and other active agents that are sequestered in ECM (Krishnaswamy et al. 2017; Wang and Khalil 2018).

Human acute injury wound-healing models were used to have demonstrated that neoepithelium formation gets impaired due to MMP activity blocking (Krarup et al. 2017).

On mouse models, it was shown that MMP-1, MMP-7, MMP-9 are involved in re-epithelialization (Pilcher et al. 1997; Kyriakides et al. 2009; Hayden et al. 2011), and MMP-9 activation occurred during wound healing (Kang et al. 2017); in superficial human wounds, MMP-1 expression and activities are upregulated 100-fold.

MMPs are able to hydrolyze almost all ECM proteins, including elastin and collagen, and determine structural organization and regeneration of dermis and epidermis (Sternlicht and Werb 2001; Maret 2013; Rohani and Parks 2015). MMPs are involved in vascular tissue remodeling, cell growth, migration and differentiation, and also in tissues invasion and vascularization (Jablonska-Trypuc et al. 2016).

Besides, MMPs could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction (Cui et al. 2017; Wang and Khalil 2018).

MMP activation is triggered by such processes as tissue damage, oxidative stress, inflammatory cytokines, hormones, growth factors, and UV-radiation.

MMP family main enzymes are collagenases capable of hydrolyzing native collagen. Collagenolytic enzymes are effective proteolytic complexes due to their ability to break down collagen, which is the main component of wounds and scars. Studies have shown that collagenases affect the reparation process, for instance, they activate cellular migratory, proliferative and angiogenic responses to injury in vitro, and promote wound closure in vivo (Sheets et al. 2016). In relation to collagenases, apart from proreparative activity, there has been shown a decrease in pro-inflammatory polarization, for instance, increased production of anti-inflammatory cytokines IL-10 and TGF-p, and decreased levels of pro-inflammatory cytokines TNF-a and IL-1p.

During the remodeling phase, wound re-epithelialization takes place, and the dermis regains its strength.

Oxidative stress

ROS play a morbid role at all stages of wound regeneration. For instance, during the inflammatory phase, not only pro-inflammatory cytokines and proteolytic enzymes, but also neutrophils and macrophages start to release large amounts of ROS. To date, the role of ROS signals in angiogenesis has been well studied (Bretón-Romero and Lamas 2014). Moderate levels of H2O2 regulate production of VEGF, a key angiogenic growth factor in keratinocytes, and make angiogenesis speed up. ROS are also involved in epithelialization; they trigger activation of EGF and keratinocytes growth factor (KGF) receptors and induce TGFa production in fibroblasts. At the same time, an excessive amount of ROS slows angiogenesis down. Some enzymes involved in signaling pathways, such as phosphotyrosine phosphatase, have sulfhydryl residues that are very sensitive to oxidative modification and undergo oxidative inactivation. Thus, an excessive amount of ROS indicates an unbalanced redox homeostasis and impairs wound healing.

Antioxidant effect of zinc is manifested through various mechanisms: competition with iron (Fe) and copper (Cu) ions for binding to cell membranes and proteins that displace these redox metals; binding to SH sulfhydryl groups of bio-molecules protecting them from oxidation; activation of antioxidant proteins, molecules and enzymes, for example, glutathione, catalase, SOD; binding to MT, which is very rich in cysteine and is an excellent exchanger of OH ions (Prasad 2014).

Zinc treatment of wounds

Currently, zinc-containing preparations (zinc sulfate, zinc oxide, zinc hyaluronate, zinc pyrition) are widely used in skin lesions of various types. Zinc sulfate is known to have antiseptic, astringent, drying, antimicrobial effects. However, experimental studies show that, exhibiting anti-inflammatory and antibacterial activity, this drug does not affect re-epithelialization (Larsen et al. 2017).

FDA-approved microbicidal zinc pyrithione agent (ZnPT) is used worldwide in antiseptic products, local antimicrobials and cosmetics. However, a study of epidermal keratinocyte and human melanocyte cultures demonstrated the vulnerability of cells to zinc pyrithione with strong expression of shock response genes and depletion of ATP levels (Lamore et al. 2010).

Almost 30 years ago, it was shown that topical administration of ZnO to murine skin increases keratinocyte mitosis (Jin et al. 1994) and the ability of MMPs to enhance collagen degradation in necrotic wounds (Agren 1993; Mirastschijski et al. 2004), which is beneficial in wound healing.

By present, it has been demonstrated that topical zinc treatment reduces the size of wounds and enhances epithelialization in surgical wounds in rabbits and rats (Abdullah et al. 2019). A rat study proved a positive (biochemical, biomechanical and histological) effect of cream with zinc oxide and composite silver nanoparticles on wound healing (Kantipudi et al. 2018).

The above-mentioned low-molecular zinc compounds due to their low bioavailability cannot provide the necessary microelement concentration in the right place, but they require a long take-up time and have pronounced side effects. Recent advances in drug delivery with zinc oxide nanoparticle (ZnO-NPs) technology has received considerable attention for the treatment of wounds due to their effective cell penetration, immunomodulation and antimicrobial ability (Xiong 2013; Oyarzun-Ampuero et al. 2015).

Currently, hydrogel membranes were developed based on poly vinyl alcohol, starch, and chitosan hydrogels with ZnO-NPs (Baghaie et al. 2017). Bioactive films with zinc oxide based on p-glucans and proteins extracted from barley are used for wound healing (Cleetus et al. 2020; Razzaq et al. 2021). Innovative ZnO-NPs also based on unprocessed human

amniotic membrane antimicrobial proteins/peptides, growth factors, and signaling molecules, metabolites nanofiber mats composed of a combination of chitosan, polyvinyl alcohol and zinc oxide have great promise for applications in chronic wounds (Ahmed et al. 2018).

ZnONPs are biocompatible, permeable to the dermis and epidermis, and have exhibited remarkable regenerative abilities in vivo through re-epithelialization, keratinocyte migration along with collagen fiber deposition, and tissue granulation (Mendes et al. 2022).

The preparation of ZnONPs exhibits antimicrobial activity against Gram-negative and Gram-positive bacteria (Augustine et al. 2014; Diez-Pascual and Diez-Vicente 2015). One of the main mechanisms of action of ZnONPs is a slight increase in the production of ROS (especially H2O2), which stimulates the migration and proliferation of fibroblasts (Augustine et al. 2014; Sharma et al. 2016). When in ideal doses and size, ZnONPs demonstrated anti-inflammatory and antioxidant properties (Manuja et al. 2020). ZnONPs are highly compatible with fibroblast cells and enhance the growth of these cells, promoting cell adhesion and migration (Kaushik et al. 2019). However, in-depth pharmacodynamic and toxicological studies are needed for wider use of zinc nanoparticles (Pati et al. 2016; Lin et al. 2017).

Conclusion

Wound healing is a complex multi-phase process consisting of several phases, each involving metal ions, primarily zinc. Topical zinc may stimulate re-epithelialization, decrease inflammation and bacterial growth. The use of known zinc drugs is accompanied by side effects and low efficacy due to low skin absorption, which significantly limits their use and highlights the urgency of finding new, more effective and safe drugs. The emerging field of nanobiotechnology may provide an alternative platform to develop new therapeutic agents for the wound healing process.

Conflict of interests

The authors have no conflict of interests to declare.

References

Abdullah BJ, Atasoy N, Omer AK (2019) Evaluate the effects of platelet rich plasma (PRP) and zinc oxide ointment on skin wound healing. Annals of Medicine and Surgery (2012) 37: 30-37. https://doi.org/10.1016/j.amsu.2018.11.009 [PubMed] [PMC]

Adjepong M, Agbenorku P, Brown P, Oduro I (2016) The role of antioxidant micronutrients in the rate of recovery of burn patients: a systematic review. Burns & Trauma 4: 18. https://doi.org/10.1186/s41038-016-0044-x [PubMed] [PMC] Agren MS (1993) Zinc oxide increases degradation of collagen in necrotic wound tissue. British Journal of Dermatology 129(2): 221-222. https://doi.org/10.1111/j .1365-2133.1993.tb03533.x [PubMed]

Agren MS, Auf dem Keller U (2020) Matrix metalloproteinases: How much can they do? International Journal of Molecular Sciences 21(8): 2678. https://doi.org/10.3390/ijms21082678 [PubMed] [PMC] Ahmed NS, Lopes-Pires M, Pugh N (2021) Zinc: an endogenous and exogenous regulator of platelet function during hemostasis and thrombosis. Platelets 32(7): 880-887. https://doi.org/10.1080/09537104.2020.1840540 [PubMed] Ahmed NS, Lopes Pires ME, Taylor KA, Pugh N (2019) Agonist-evoked increases in intra-platelet zinc couple to functional responses. Thrombosis and Haemostasis 119(1): 128-139. https://doi.org/10.1055/s-0038-1676589 [PubMed] [PMC]

Ahmed R Tariq M, Ali I, Asghar R, Noorunnisa Khanam P, Augustine R Hasan A (2018) Novel electrospun chitosan/polyvinyl alcohol/zinc oxide nanofibrous mats with antibacterial and antioxidant properties for diabetic wound healing. International Journal of Biological Macromolecules 120(Pt A): 385-393.

https://doi.org/10.1016/j.ijbiomac.2018.08.057 [PubMed] Apgar J (1968) Effect of zinc deficiency on parturition in the rat. The American Journal of Physiology 215(1): 160-163. https://doi.org/10.1152/ajplegacy. 1968.215.1.160 [PubMed] Augustine R, Dominic EA, Reju I, Kaimal B, Kalarikkal N, Thomas S (2014) Investigation of angiogenesis and its mechanism using zinc oxide nanoparticle-loaded electrospun tissue engineering scaffolds. RSC Advances 4: 51528-51536. https://doi.org/10. 1039/C4RA07361D Baghaie S, Khorasani MT, Zarrabi A, Moshtaghian J (2017) Wound healing properties of PVA/starch/chitosan hydrogel membranes with nano Zinc oxide as antibacterial wound dressing material. Journal of Biomaterials Science, Polymer Edition 28(18): 2220-2241.

https://doi.org/10.1080/09205063.2017.1390383 [PubMed] Bin B-H, Seo J, Kim ST (2018) Function, structure, and transport aspects of ZIP and ZnT zinc transporters in immune cells. Journal of Immunology Research 2018: 9365747. https://doi.org/10.1155/2018/9365747 [PubMed] [PMC] Bin B-H, Bhin J, Kim N-H, Lee S-H, Jung H-S, Seo J, Kim DK, Hwang D, Fukada T, Lee A-Y, Lee TR, Cho E-G (2017) An acrodermatitis enteropathica-associated Zn transporter, ZIP4, regulates human epidermal homeostasis. The Journal of Investigative Dermatology 137(4): 874-883. https://doi.org/10.1016/jjid.2016.11.028 [PubMed] Breton-Romero R Lamas S (2014) Hydrogen peroxide signaling in vascular endothelial cells. Redox Biology 2: 529534. https://doi.org/10.1016Zj.redox.2014.02.005 [PubMed] [PMC]

von Bulow V, Dubben S, Engelhardt G, Hebel S, Plumakers B, Heine H, Rink L, Haase H (2007) Zinc-dependent suppression of TNF-alpha production is mediated by protein kinase A-induced inhibition of Raf-1, I kappa B kinase beta, and NF-kappa B. Journal of Immunology 179(6): 4180-4186. https://doi.org/10.4049/jimmunol.179.6.4180 [PubMed]

Chaudhry SA, Serrata M, Tomczak L, Higgins S, Ryu J, Laprise D, Enjyoji K, Bekendam R, Kaushik V, Flaumenhaft R Bendapudi PK (2020) Cationic zinc is required for factor XII recruitment and activation by stimulated platelets and for thrombus formation in vivo. Journal of Thrombosis and Haemostasis 18(9): 2318-2328.

https://doi.org/10.1111/jth.14964 [PubMed] [PMC] Cho JG, Park S, Lim CH, Kim HS, Song SY, Roh T-Y, Sung J-H, Suh W, Ham S-J, Lim K-H, Park SG (2016) ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a. Oncotarget 7(21): 31177-31190. https://doi.org/10.18632/oncotarget.8870 [PubMed] [PMC] Cleetus CM, Alvarez Primo F, Fregoso G, Lalitha Raveendran N, Noveron JC, Spencer CT, Ramana CV, Joddar B (2020) Alginate hydrogels with embedded ZnO nanoparticles for wound healing therapy. International Journal of Nanomedicine 15: 5097-5111. https://doi.org/10.2147/IJN.S255937 [PubMed] [PMC]

Coger V, Million N, Rehbock C, Sures B, Nachev M, Barcikowski S, Wistuba N, Strauß S, Vogt PM (2019) Tissue concentrations of zinc, iron, copper, and magnesium during the phases of full thickness wound healing in a rodent model. Biological Trace Element Research 191(1): 167-176. https://doi.org/10.1007/s12011-018-1600-y [PubMed] [PMC] Cui N, Hu M, Khalil RA (2017) Biochemical and biological attributes of matrix metalloproteinases. Progress in Molecular Biology and Translational Science 147: 1-73. https://doi.org/10.1016/bs.pmbts.2017.02.005 [PubMed] [PMC]

Diegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Frontiers in Bioscience: A Journal and Virtual Library 9: 283-289. https://doi.org/10.2741/1184 [PubMed] Diez-Pascual AM, Diez-Vicente AL (2015) Wound healing bionanocomposites based on castor oil polymeric films reinforced with chitosan-modified ZnO nanoparticles. Biomacromolecules 16(9): 2631-2644.

https://doi.org/10.1021/acs.biomac.5b00447 [PubMed] Dudev T, Lim C (2003) Principles governing Mg, Ca, and Zn binding and selectivity in proteins. Chemical Reviews 103(3): 773-788. https://doi.org/10.1021/cr020467n [PubMed] Emery MP, Browning JD, O'Dell BL (1990) Impaired hemostasis and platelet function in rats fed low zinc diets based on egg white protein. The Journal of Nutrition 120(9): 1062-1067. https://doi.org/10.1093/jn/120.9.1062 [PubMed] Feng X, Zhou S, Cai W, Guo J (2021) The miR-93-3p/ZFP36L1/ZFX axis regulates keratinocyte proliferation and migration during skin wound healing. Molecular Therapy. Nucleic Acids 23: 450-463.

https://doi.org/10.1016/j.omtn.2020.11.017 [PubMed] [PMC] Fukada T, Kambe T (2011) Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics: Integrated Biometal Science 3(7): 662-674. https://doi.org/10.1039/c1mt00011j [PubMed] Gladka MM, Kohela A, Molenaar B, Versteeg D, Kooijman L, Monshouwer-Kloots J, Kremer V, Vos HR, Huibers MMH, Haigh JJ, Huylebroeck D, Boon RA, Giacca M, van Rooij E (2021) Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner. Nature Communications 12(1): 84. https://doi.org/10.1038/s41467-020-20361-3 [PubMed] [PMC]

Gupta M, Mahajan VK, Mehta KS, Chauhan PS (2014) Zinc therapy in dermatology: a review. Dermatology Research and Practice 2014: 709152. https://doi.org/10.1155/2014/709152 [PubMed] [PMC]

Gupta M, Mahajan VK, Mehta KS, Chauhan PS, Rawat R (2015) Peroxisome proliferator-activated receptors (PPARs)

and PPAR agonists: the "future" in dermatology therapeutics? Archives of Dermatological Research 307(9): 767-780. https://doi.org/10.1007/s00403-015-1571-1 [PubMed] Haase H, Ober-Blobaum JL, Engelhardt G, Hebel S, Heit A, Heine H, Rink L (2008) Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes. Journal of Immunology 181(9): 6491-6502. https://doi.org/10.4049/j immunol .181.9.6491 [PubMed]

Hara T, Takeda T-A, Takagishi T, Fukue K, Kambe T, Fukada T (2017) Physiological roles of zinc transporters: molecular and genetic importance in zinc homeostasis. The Journal of Physiological Sciences 67(2): 283-301.

https://doi.org/10.1007/s12576-017-0521-4 [PubMed] Hayden DM, Forsyth C, Keshavarzian A (2011) The role of matrix metalloproteinases in intestinal epithelial wound healing during normal and inflammatory states. The Journal of Surgical Research 168(2): 315-324.

https://doi.org/10.1016/jjss.2010.03.002 [PubMed] Hershfinkel M (2018) The zinc sensing receptor, ZnR/GPR39, in health and disease. International Journal of Molecular Sciences 19(2): 439. https://doi.org/10.3390/ijms19020439 [PubMed] [PMC]

Hoch E, Levy M, Hershfinkel M, Sekler I (2020) Elucidating the H+ coupled Zn2+ transport mechanism of ZIP4; Implications in acrodermatitis enteropathica. International Journal of Molecular Sciences 21(3): 734. https://doi.org/10.3390/ijms21030734 [PubMed] [PMC] Hojyo S, Fukada T (2016) Zinc transporters and signaling in physiology and pathogenesis. Archives of Biochemistry and Biophysics 611: 43-50.

https://doi.org/10.1016/j.abb.2016.06.020 [PubMed] Hopmeier P, Halbmayer M, Fischer M, Marx G (1990) Zinc modulates thrombin adsorption to fibrin. Thrombosis Research 58(3): 293-301. https://doi.org/10.1016/0049-3848(90)90099-x [PubMed]

Jablonska-Trypuc A, Matejczyk M, Rosochacki S (2016) Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. Journal of Enzyme Inhibition and Medicinal Chemistry 31: 177-183.

https://doi.org/10.3109/14756366.2016.1161620 [PubMed] Jin L, Murakami TH, Janjua NA, Hori Y (1994) The effects of zinc oxide and diethyldithiocarbamate on the mitotic index of epidermal basal cells of mouse skin. Acta Medica Okayama 48(5): 231-236. https://doi.org/10.18926/AMO/31117 [PubMed]

Kambe T (2012) Molecular architecture and function ofZnT transporters. Current Topics in Membranes 69: 199-220. https://doi.org/10.1016/B978-0-12-394390-3.00008-2 [PubMed]

Kambe T, Matsunaga M, Takeda T (2017) Understanding the contribution of zinc transporters in the function of the early secretory pathway. International Journal of Molecular Sciences 18(10): 2179. https://doi.org/10.3390/ijms18102179 [PubMed] [PMC]

Kang SU, Choi JW, Chang JW, Kim KI, Kim YS, Park JK, Kim YE, Lee YS, Yang SS, Kim C-H (2017) N2 non-thermal atmospheric pressure plasma promotes wound healing in vitro and in vivo: Potential modulation of adhesion molecules and matrix metalloproteinase-9. Experimental Dermatology 26(2): 163-170. https://doi.org/10.1111/exd.13229 [PubMed] Kantipudi S, Sunkara JR, Rallabhandi M, Thonangi CV, Cholla RD, Kollu P, Parvathaneni MK, Pammi SVN (2018) Enhanced wound healing activity of Ag-ZnO composite NPs in Wistar Albino rats. IET Nanobiotechnology 12(4): 473478. https://doi.org/10.1049/iet-nbt.2017.0087 [PubMed] [PMC]

Kaushik M, Niranjan R, Thangam R, Madhan B, Pandiyarasan V, Ramachandran C, Oh D-H, Venkatasubbu GD (2019) Investigations on the antimicrobial activity and wound healing

potential of ZnO nanoparticles. Applied Surface Science 479: 1169-1177. https://doi.Org/10.1016/j.apsusc.2019.02.189 [PubMed]

Kimura T, Kambe T (2016) The functions of metallothionein and ZIP and ZnT transporters: An overview and perspective. International Journal of Molecular Sciences 17(3): 336. https://doi.org/10.3390/ijms17030336 [PubMed] [PMC] Kiran Gotru S, van Geffen JP, Nagy M, Mammadova-Bach E, Eilenberger J, Volz J, Manukjan G, Schulze H, Wagner L, Eber S, Schambeck C, Deppermann C, Brouns S, Nurden P, Greinacher A, Sachs U, Nieswandt B, Hermanns HM, Heemskerk JWM, Braun A (2019) Defective Zn2+ homeostasis in mouse and human platelets with a- and S-storage pool diseases. Scientific Reports 9: 8333. https://doi.org/10.1038/s41598-019-44751-w [PubMed] [PMC]

Klein C, Heyduk T, Sunahara RK (2004) Zinc inhibition of adenylyl cyclase correlates with conformational changes in the enzyme. Cellular Signalling 16(10): 1177-1185. https://doi.org/10.1016/j.cellsig.2004.03.008 [PubMed] Kogan S, Sood A, Garnick MS (2017) Zinc and wound healing: A review of zinc physiology and clinical applications. Wounds 29(4): 102-106. [PubMed]

Komi DEA, Khomtchouk K, Santa Maria PL (2020) A review of the contribution of mast cells in wound healing: involved molecular and cellular mechanisms. Clinical Reviews in Allergy & Immunology 58(3): 298-312. https://doi .org/10.1007/s 12016-019-08729-w [PubMed] Korbecki J, Bobinski R, Dutka M (2019) Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflammation Research 68(6): 443-458. https://doi .org/10.1007/s00011-019-01231-1 [PubMed]

[PMC]

Krarup P-M, Eld M, Jorgensen LN, Hansen MB, Agren MS (2017) Selective matrix metalloproteinase inhibition increases breaking strength and reduces anastomotic leakage in experimentally obstructed colon. International Journal of Colorectal Disease 32(9): 1277-1284.

https://doi .org/10.1007/s003 84-017-2857-x [PubMed] Krishnaswamy VR, Mintz D, Sagi I (2017) Matrix metalloproteinases: The sculptors of chronic cutaneous wounds. Biochimica Et Biophysica Acta. Molecular Cell Research 1864: 2220-2227.

https://doi.org/10.1016/j.bbamcr.2017.08.003 [PubMed] Kurmis R, Greenwood J, Aromataris E (2016) Trace element supplementation following severe burn injury: A systematic review and meta-analysis. Journal of Burn Care & Research: Official Publication of the American Burn Association 37(3): 143-159. https://doi.org/10.1097/BCR.0000000000000259 [PubMed]

Kuzmicka W, Manda-Handzlik A, Cieloch A, Mroczek A, Demkow U, Wachowska M, Ciepiela O (2020) Zinc supplementation modulates nets release and neutrophils' degranulation. Nutrients 13(1): 51.

https://doi.org/10.3390/nu13010051 [PubMed] [PMC] Kyriakides TR, Wulsin D, Skokos EA, Fleckman P, Pirrone A, Shipley JM, Senior RM, Bornstein P (2009) Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis. Matrix Biology: Journal of the International Society for Matrix Biology 28(2): 65-73. https://doi.org/10.1016/j.matbio.2009.01.001 [PubMed]

[PMC]

Lamore SD, Cabello CM, Wondrak GT (2010) The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells. Cell Stress & Chaperones 15(3): 309322. https://doi.org/10.1007/s12192-009-0145-6 [PubMed] [PMC]

Larsen HF, Ahlström MG, Gjerdrum LMR, Mogensen M,

Ghathian K, Calum H, S0rensen AL, Forman JL, Vandeven M, Holerca MN, Du-Thumm L, Jorgensen LN, Agren MS (2017) Noninvasive measurement of reepithelialization and microvascularity of suction-blister wounds with benchmarking to histology. Wound Repair and Regeneration 25(6): 984-993. https://doi.org/10.1111/wrr.12605 [PubMed] Lee S, Eskin SG, Shah AK, Schildmeyer LA, McIntire LV (2012) Effect of zinc and nitric oxide on monocyte adhesion to endothelial cells under shear stress. Annals of Biomedical Engineering 40(3): 697-706. https://doi.org/10.1007/s10439-011-0434-y [PubMed] [PMC]

Lin P-H, Sermersheim M, Li H, Lee PHU, Steinberg SM, Ma J (2017) Zinc in wound healing modulation. Nutrients 10(1): 16. https://doi.org/10.3390/nu10010016 [PubMed] [PMC] Liu T, Zhang L, Joo D, Sun S-C (2017) NF-kB signaling in inflammation. Signal Transduction and Targeted Therapy 2: 17023. https://doi.org/10.1038/sigtrans.2017.23 [PubMed] [PMC]

Lopes-Pires ME, Ahmed NS, Vara D, Gibbins JM, Pula G, Pugh N (2021) Zinc regulates reactive oxygen species generation in platelets. Platelets 32(3): 368-377. https://doi.org/10.1080/09537104.2020.1742311 [PubMed] Mammadova-Bach E, Braun A (2019) Zinc homeostasis in platelet-related diseases. International Journal of Molecular Sciences 20(21): 5258. https://doi.org/10.3390/ijms20215258 [PubMed] [PMC]

Manuja A, Raguvaran R Kumar B, Kalia A, Tripathi BN (2020) Accelerated healing of full thickness excised skin wound in rabbits using single application of alginate/acacia based nanocomposites of ZnO nanoparticles. International Journal of Biological Macromolecules 155: 823-833. https://doi.org/10.1016/j.ijbiomac.2020.03.221 [PubMed] Maret W (2013) Zinc biochemistry: from a single zinc enzyme to a key element of life. Advances in Nutrition 4(1): 82-91. https://doi.org/10.3945/an.112.003038 [PubMed] [PMC] Marx G, Hopmeier P (1986) Zinc inhibits FPA release and increases fibrin turbidity. American Journal of Hematology 22(4): 347-353. https://doi.org/10.1002/ajh.2830220403 [PubMed]

Maxfield L, Shukla S, Crane JS (2022) Zinc Eficiency. In: StatPearls. StatPearls Publishing, Treasure Island (FL). Available at:

http://www.ncbi.nlm.nih.gov/books/NBK493231/ (January 5, 2023)

Maywald M, Rink L (2017) Zinc supplementation induces CD4+CD25+Foxp3+ antigen-specific regulatory T cells and suppresses IFN-y production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1. European Journal of Nutrition 56(5): 1859-1869. https://doi.org/10.1007/s00394-016-1228-7 [PubMed]

Maywald M, Meurer SK, Weiskirchen R Rink L (2017) Zinc supplementation augments TGF-ß1-dependent regulatory T cell induction. Molecular Nutrition & Food Research 61(3). https://doi.org/10. 1002/mnfr.201600493 [PubMed] Mendes C, Thirupathi A, Correa MEAB, Gu Y, Silveira PCL (2022) The use of metallic nanoparticles in wound healing: New perspectives. International Journal of Molecular Sciences 23(23): 15376. https://doi.org/10.3390/ijms232315376 [PubMed] [PMC]

Mirastschijski U, Haaksma CJ, Tomasek JJ, Agren MS (2004) Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Experimental Cell Research 299(2): 465-475. https://doi.org/10.1016Zj.yexcr.2004.06.007 [PubMed]

Mirastschijski U, Martin A, Jorgensen LN, Sampson B, Agren MS (2013) Zinc, copper, and selenium tissue levels and their relation to subcutaneous abscess, minor surgery, and wound healing in humans. Biological Trace Element Research 153(1-3): 76-83. https://doi.org/10.1007/s12011-013-9658-z [PubMed]

Nakano Y, Arima T, Tobita Y, Uchiyama M, Shimizu A, Takahashi H (2020) Combination of peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists prevents corneal inflammation and neovascularization in a rat alkali burn model. International Journal of Molecular Sciences 21(14): 5093. https://doi.org/10.3390/ijms21145093 [PubMed] [PMC]

Nishida K, Uchida R (2017) [Regulatory Mechanism of Mast Cell Activation by Zinc Signaling]. Yakugaku Zasshi 137(5): 495-501. https://doi.org/10.1248/yakushi.16-00239-1

[PubMed] [in Japanese]

Nishida K, Uchida R (2018) Role of zinc signaling in the regulation of mast cell-, basophil-, and T cell-mediated allergic responses. Journal of Immunology Research 2018: 5749120. https://doi.org/10.1155/2018/5749120 [PubMed] [PMC]

Nishida K, Hasegawa A, Yamasaki S, Uchida R, Ohashi W, Kurashima Y, Kunisawa J, Kimura S, Iwanaga T, Watarai H, Hase K, Ogura H, Nakayama M, Kashiwakura J-I, Okayama Y, Kubo M, Ohara O, Kiyono H, Koseki H, Murakami M, Hirano T (2019) Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis. Scientific Reports 9(1): 10842. https://doi.org/10.1038/s41598-019-47132-5 [PubMed] [PMC]

Nosbaum A, Prevel N, Truong H-A, Mehta P, Ettinger M, Scharschmidt TC, Ali NH, Pauli ML, Abbas AK, Rosenblum MD (2016) Cutting edge: Regulatory T cells facilitate cutaneous wound healing. Journal of Immunology 196(5): 2010-2014. https://doi.org/10.4049/jimmunol.1502139

[PubMed] [PMC]

O'Dell BL, Reynolds G, Reeves PG (1977) Analogous effects of zinc deficiency and aspirin toxicity in the pregnant rat. The Journal of Nutrition 107(7): 1222-1228. https://doi.org/10.1093/jn/107.7.1222 [PubMed] Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harbor Perspectives in Biology 1(4): a000034. https://doi.org/10.1101/cshperspect.a000034 [PubMed] [PMC] Oyarzun-Ampuero F, Vidal A, Concha M, Morales J, Orellana S, Moreno-Villoslada I (2015) Nanoparticles for the treatment of wounds. Current Pharmaceutical Design 21(29): 43294341. https://doi.org/10.3390/molecules23092392 [PubMed] Pati R, Das I, Mehta RK, Sahu R Sonawane A (2016) Zinc-oxide nanoparticles exhibit genotoxic, clastogenic, cytotoxic and actin depolymerization effects by inducing oxidative stress responses in macrophages and adult mice. Toxicological Sciences 150(2): 454-472.

https://doi.org/10.1093/toxsci/kfw010 [PubMed] Pawlak K, Mysliwiec M, Pawlak D (2012) The alteration in Cu/Zn superoxide dismutase and adhesion molecules concentrations in diabetic patients with chronic kidney disease: the effect of dialysis treatment. Diabetes Research and Clinical Practice 98(2): 264-270. https://doi.org/10.1016/j.diabres.2012.09.012 [PubMed] Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. The Journal of Cell Biology 137(6): 1445-1457. https://doi.org/10.1083/jcb.137.6.1445 [PubMed] [PMC] Posthauer ME (2014) Nutrition: fuel for pressure ulcer prevention and healing. Nursing 44(12): 67-69. https://doi.org/10.1097/01.NURSE.0000456389.22724.ef [PubMed]

Prasad AS (2014) Zinc is an antioxidant and antiinflammatory agent: Its role in human health. Frontiers in Nutrition 1: 14. https://doi.org/10.3389/fnut.2014.00014 [PubMed] [PMC]

Prasad AS (2020) Lessons learned from experimental human model of zinc deficiency. Journal of Immunology Research 2020 : 9207279. https://doi.org/10.1155/2020/9207279 [PubMed] [PMC]

Prasad AS, Bao B, Beck FW, Sarkar FH (2001) Zinc activates NF-kappaB in HUT-78 cells. The Journal of Laboratory and Clinical Medicine 138(4): 250-256.

https://doi.org/10.1067/mlc.2001.118108 [PubMed] Razzaq HAA, Gomez d'Ayala G, Santagata G, Bosco F, Mollea C, Larsen N, Duraccio D (2021) Bioactive films based on barley ß-glucans and ZnO for wound healing applications. Carbohydrate Polymers 272: 118442.

https://doi .org/10.1016/j .carbpol.2021.118442 [PubMed] Rohani MG, Parks WC (2015) Matrix remodeling by MMPs during wound repair. Matrix Biology 44-46: 113-121. https://doi.org/10.1016/j.matbio.2015.03.002 [PubMed] Roohani N, Hurrell R, Kelishadi R, Schulin R (2013) Zinc and its importance for human health: An integrative review. Journal of Research in Medical Sciences 18(2): 144-157. [PubMed] [PMC]

Rosenkranz E, Hilgers R-D, Uciechowski P, Petersen A, Plümäkers B, Rink L (2017) Zinc enhances the number of regulatory T cells in allergen-stimulated cells from atopic subjects. European Journal of Nutrition 56(2): 557-567. https://doi.org/10.1007/s00394-015-1100-1 [PubMed] Rosenkranz E, Metz CHD, Maywald M, Hilgers R-D, Weßels I, Senff T, Haase H, Jäger M, Ott M, Aspinall R, Plümäkers B, Rink L (2016) Zinc supplementation induces regulatory T cells by inhibition of Sirt-1 deacetylase in mixed lymphocyte cultures. Molecular Nutrition & Food Research 60(3): 661671. https://doi.org/10.1002/mnfr.201500524 [PubMed] Rousselle P, Braye F, Dayan G (2019) Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. Advanced Drug Delivery Reviews 146: 344-365. https://doi .org/10.1016/j .addr.2018.06.019 [PubMed] Ruttkay-Nedecky B, Nejdl L, Gumulec J, Zitka O, Masarik M, Eckschlager T, Stiborova M, Adam V, Kizek R (2013) The role of metallothionein in oxidative stress. International Journal of Molecular Sciences 14(3): 6044-6066. https://doi.org/10.3390/ijms14036044 [PubMed] [PMC] Sabino F, Keller U auf dem (2015) Matrix metalloproteinases in impaired wound healing. Metalloproteinases in Medicine 2: 1-8. https://doi.org/10.2147/MNM.S68420 Satianrapapong W, Pongkorpsakol P, Muanprasat C (2020) A G-protein coupled receptor 39 agonist stimulates proliferation of keratinocytes via an ERK-dependent pathway. Biomedicine & Pharmacotherapy 127: 110160.

https://doi .org/10.1016/j .biopha.2020.110160 [PubMed] Sharma DK, Sharma KK, Kumar V, Sharma A (2016) Effect of Ce doping on the structural, optical and magnetic properties of ZnO nanoparticles. Journal of Materials Science: Materials in Electronics 27: 10330-10335.

https://doi.org/10.1007/s10854-016-5117-x Sheets AR, Demidova-Rice TN, Shi L, Ronfard V, Grover KV, Herman IM (2016) Identification and characterization of novel matrix-derived bioactive peptides: A role for collagenase from Santyl® ointment in post-debridement wound healing? PloS One 11(7): e0159598. https://doi.org/10.1371/journal.pone.0159598 [PubMed] [PMC]

Shembade N, Ma A, Harhaj EW (2010) Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327(5969): 1135-1139. https://doi.org/10.1126/science.1182364 [PubMed] [PMC] Shi Y, Zou Y, Shen Z, Xiong Y, Zhang W, Liu C, Chen S (2020) Trace elements, PPARs, and metabolic syndrome. International Journal of Molecular Sciences 21(7): 2612. https://doi.org/10.3390/ijms21072612 [PubMed] [PMC] Sobczak AIS, Pitt SJ, Stewart AJ (2018) Influence of zinc on glycosaminoglycan neutralisation during coagulation. Metallomics 10(9): 1180-1190.

https://doi.org/10.1039/c8mt00159f [PubMed] [PMC] Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annual Review of Cell and Developmental Biology 17: 463-516.

https://doi .org/10.1146/annurev .cellbio.17.1.463 [PubMed] [PMC]

Taylor KA, Pugh N (2016) The contribution of zinc to platelet behaviour during haemostasis and thrombosis. Metallomics 8(2): 144-155. https://doi.org/10.1039/c5mt00251f [PubMed] Thingholm TE, Rönnstrand L, Rosenberg PA (2020) Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation. Cellular and Molecular Life Sciences 77(16): 3085-3102. https://doi.org/10.1007/s00018-020-03473-3 [PubMed]

[PMC]

Tobita Y, Arima T, Nakano Y, Uchiyama M, Shimizu A, Takahashi H (2020) Peroxisome proliferator-activated receptor beta/delta agonist suppresses inflammation and promotes neovascularization. International Journal of Molecular Sciences 21(15): 5296.

https://doi.org/10.3390/ijms21155296 [PubMed] [PMC] Tobita Y, Arima T, Nakano Y, Uchiyama M, Shimizu A, Takahashi H (2021) Effects of selective peroxisome proliferator activated receptor agonists on corneal epithelial wound healing. Pharmaceuticals 14: 88. https://doi.org/10.3390/ph14020088 [PubMed] [PMC] Vereecke L, Beyaert R, van Loo G (2009) The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends in Immunology 30(8): 383-391. https://doi.org/10.1016/).it.2009.05.007 [PubMed] Voelkl J, Tuffaha R, Luong TTD, Zickler D, Masyout J, Feger M, Verheyen N, Blaschke F, Kuro-O M, Tomaschitz A, Pilz S, Pasch A, Eckardt K-U, Scherberich JE, Lang F, Pieske B, Alesutan I (2018) Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB. Journal of the American Society of Nephrology 29(6): 1636-1648. https://doi.org/10.1681/ASN.2017050492

[PubMed] [PMC]

Wang X, Khalil RA (2018) Matrix metalloproteinases, vascular remodeling, and vascular disease. Advances in Pharmacology 81: 241-330.

https://doi.org/10.1016/bs.apha.2017.08.002 [PubMed] [PMC] Wang Y, Ivanov I, Smith SA, Gailani D, Morrissey JH (2019) Polyphosphate, Zn2+ and high molecular weight kininogen modulate individual reactions of the contact pathway of blood clotting. Journal of Thrombosis and Haemostasis 17(12): 2131-2140. https://doi.org/10.1111/jth.14612 [PubMed] [PMC]

Wätjen W, Benters J, Haase H, Schwede F, Jastorff B, Beyersmann D (2001) Zn2+ and Cd2+ increase the cyclic GMP level in PC12 cells by inhibition of the cyclic nucleotide phosphodiesterase. Toxicology 157(3): 167-175. https://doi.org/10.1016/s0300-483x(00)00370-x [PubMed] Watson BR, White NA, Taylor KA, Howes J-M, Malcor J-DM, Bihan D, Sage SO, Farndale RW, Pugh N (2016) Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner. Metallomics 8(1): 91-100. https://doi.org/10.1039/c5mt00064e [PubMed] Weisel JW, Litvinov RI (2017) Fibrin formation, structure and properties. Sub-Cellular Biochemistry 82: 405-456. https://doi.org/10.1007/978-3-319-49674-0_13 [PubMed] [PMC]

Wessels I, Haase H, Engelhardt G, Rink L, Uciechowski P (2013) Zinc deficiency induces production of the proinflammatory cytokines IL-1ß and TNFa in promyeloid cells via epigenetic and redox-dependent mechanisms. The Journal of Nutritional Biochemistry 24(1): 289-297. https://doi.org/10.1016/jjnutbio.2012.06.007 [PubMed] Xiong H-M (2013) ZnO nanoparticles applied to bioimaging and drug delivery. Advanced Materials 25(37): 5329-5335. https://doi .org/10.1002/adma.201301732 [PubMed] Yu M, Lee W-W, Tomar D, Pryshchep S, Czesnikiewicz-Guzik M, Lamar DL, Li G, Singh K, Tian L, Weyand CM, Goronzy JJ (2011) Regulation of T cell receptor signaling by activation-induced zinc influx. The Journal of Experimental

Medicine 208(4): 775-785.

https://doi.org/10.1084/jem.20100031 [PubMed] [PMC]

■ Zabel U, Schreck R, Baeuerle PA (1991) DNA binding of purified transcription factor NF-kappa B. Affinity, specificity, Zn2+ dependence, and differential half-site recognition. The Journal of Biological Chemistry 266(1): 252-260. https://doi.org/10.1016/S0021-9258(18)52428-5 [PubMed]

■ Zhang T, Kuliyev E, Sui D, Hu J (2019) The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and plays

a role in zinc transport. The Biochemical Journal 476(12): 1791-1803. https://doi.org/10.1042/BCJ20190108 [PubMed] [PMC]

■ Zheng J, Lang Y, Zhang Q, Cui D, Sun H, Jiang L, Chen Z, Zhang R, Gao Y, Tian W, Wu W, Tang J, Chen Z (2015) Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation. Genes & Development 29(14): 1524-1534. https://doi.org/10.1101/gad.261792.115 [PubMed] [PMC]

Author contributions

■ Svetlana A. Lebedeva, Holder of an Advanced Doctorate (Doctor of Science) in Biological Sciences, Professor, Department of Pharmacology of Institute of Pharmacy, e-mail: Lebedeva502@yandex.ru, ORCID ID https://orcid.org/0000-0003-0325-6397. The author contributed to the concept review, drafting the article, its critical revision, approval of the final stage of the article preparation - admission of responsibility for all stages of the research, finalizing the article and preparing its final draft.

■ Pavel A. Galenko-Yaroshevsky (Jr.), degree student of the Department of Pharmacology of Institute of Pharmacy, Surgeon-Oncologist, Deputy Chief Physician for the Polyclinic section of work, e-mail: Pavelgalenko@bk.ru, ORCID ID https://orcid.org/0000-0002-6279-0242. The author was engaged in collecting information and writing the article.

■ Mikhail Yu. Samsonov, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology of Institute of Pharmacy, e-mail: samsonov@rpharm.ru,_ORCID ID https://orcid.org/0000-0003-2685-1623. The author was engaged in collecting information and writing the article.

■ Arkadiy B. Erlich, master degree of Sechenov University, e-mail: ursamonster@yandex.ru. The author was engaged in developing the concept and conducting the literature analysis and drawing figures.

■ Anait V. Zelenskaya, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology, e-mail: anait_06@mail.ru, ORCID ID https://orcid.org/0000-0001-9512-2526. The author was engaged in structuring the article and arranging the references.

■ Arus G. Margaryan, graduate degree student of the Department of Pharmacology of Institute of Pharmacy, e-mail: arusyam@mail.ru, ORCID ID https://orcid.org/0000-0002-2150-756X. The author was engaged in structuring the article and arranging the references.

■ Maria Yu. Materenchuk, 4th year student of Medical Biochemistry, Institute of Biodesign and Complex System Modellin, ORCID ID https://orcid.org/0000-0002-0711-4153. The author was engaged in drawing figures.

■ Iaroslav R. Arshinov, postgraduate student of the Department of Pharmacology, Institute of Pharmacy, email: yarik0707@list.ru, ORCID ID https://orcid.org/0000-0003-4213-4683. The author was engaged in structuring the article and arranging the references.

■ Yuriy V. Zharov, graduate degree student of the Department of Pharmacology of Institute of Pharmacy, email: yurazharov@mail.ru, ORCID ID https://orcid.org/0000-0002-6259-3708. The author was engaged in structuring the article and arranging the references.

■ Olga V. Shelemekh, postgraduate student of the Department of Dentistry 4, e-mail: lioli777@yandex.ru, ORCID ID https://orcid.org/0000-0003-3488-9971. The author was engaged in collecting data and drafting the article.

■ Izabella G. Lomsadze, 3rd year student of the Faculty of Medicine, e-mail: izabella.lomsadze@yandex.ru, ORCID ID https://orcid.org/0009-0007-5584-3397. The author was engaged in structuring the article and arranging the references.

■ Tatiana A. Demura, Holder of an Advanced Doctorate (Doctor of Science) in Medical Sciences, Director of Institute for Clinical Morphology and Digital Pathology, e-mail: demura-t@yandex.ru, ORCID ID https://orcid.org/0000-0002-6946-6146. The author was engaged in concept review, data collection and interpretation, and manuscript preparation.