Mechanisms of Nrf2 and NF-κB pathways in diabetic wound and potential treatment strategies

The issue of delayed wound healing or nonhealing in diabetic patients presents a challenge for modern medicine. A number of attempts have been made to understand the mechanisms behind diabetic wound. In a hyperglycemic environment, increased intracellular reactive oxygen species (ROS) disturb the balance between oxidation and antioxidant, causing the wound environment to deteriorate. It has been established that the nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) pathways play an important role in regulating inflammation and oxidative stress. Several potential treatment strategies involving Nrf2 and/or NF-κB pathways have been explored in previous studies. Hence, we analyzed mechanisms and changes in Nrf2 and NF-κB pathways in response to oxidative stress and inflammation in diabetic environment. Additionally, we reviewed potential treatment strategies from the past five years for diabetic wound by Nrf2 and/or NF-κB pathways, including receptor agonists, vitamins, hormones, exosomes, drugs, plants, and biomaterials. It may be useful to develop drugs to promote diabetic wound healing.


Introduction
Type II Diabetes (T2DM) is characterized by chronic hyperglycemia and is associated with complications related to neuropathy and vasculopathy [1]. Globally, T2DM is becoming more prevalent. World diabetes statistics indicate that 463 million people have diabetes, accounting for about 9.3% of the world's population [2,3]. Furthermore, about 6.3% of these diabetic patients suffered from wound ulcers [2,3]. However, wound healing is the precise interplay of complex biological and molecular events and influenced by the functions of many cells and cytokines, including migration, proliferation, differentiation, polarization, secretion, and metabolism [4][5][6]. Hemostasis, inflammation, proliferation and remodeling are four stages of wound healing that require the combined action of various cells, including platelets, monocytes, macrophages, neutrophils, endothelial cells, glial forming cells, fibroblasts, and myofibroblasts [4][5][6][7][8][9]. Hyperglycemia, however, causes wounds to exhibit excessive oxidative stress, breaking the balance between oxidative and antioxidative activities [10,11]. As the oxidative activity increases, a large number of inflammatory mediators are released, cells are inhibited from functioning normally, and the natural healing process is hindered [10]. It is well known that the important regulators of nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) pathways play the key role in oxidative stress in diabetic wounds [10,12]. A promising strategy for treating diabetic wounds is to regulate the balance between excessive oxidative stress and antioxidative activity. In this review, we analyzed mechanisms and changes in cells, cytokines, Nrf2 and NF-κB pathways in response to oxidative stress in hyperglycemic environment. Additionally, the potential studies from the past five years were reviewed for diabetic wound treatment vie Nrf2 and/or NF-κB pathway, including receptor agonists, vitamins, hormones, exosomes, drugs, plants, and biomaterials. It may be useful to develop drugs to promote diabetic wound healing.

Oxidative stress generation and regulation
Reactive oxygen species (ROS), the crucial regulators in the wound healing process, were significantly increased during the body's exposure to a hyperglycemic environment [13,14]. It is important to note that diabetic patients are more likely to develop delayed or uncompleted wound healing due to dysregulation of ROS levels compared with healthy people [13]. Indeed, low levels of ROS are necessarily needed to resist external damage [13]. However, in a hyperglycemic environment (for example T2DM), the redox balance can be disturbed due to the excessive oxidative stress and the decreased antioxidant ability, which may contribute to excessive production of ROS and cause unhealed diabetic wounds ( Fig. 1) [13,15]. Excessive ROS activates intracellular metabolic pathways, such as Nrf2, NF-κB, polyol, and protein kinase C (PKC), which is associated with increased release of inflammatory cytokines and decreased activity of antioxidant enzymes [10,12,16,17]. Additionally, advanced glycation end products (AGEs), the powerful prooxidants, are made when glucose reacts with amino groups in protein [14,18,19], which can delay wound shrinkage, induce excessive inflammation, damage the extracellular matrix (ECM), and promote the accumulation of excessive ROS [14,18,19]. Excessive ROS can also promote the generation of matrix metalloproteinases (MMPs), followed by the damage of the ECM remodeling [20]. During this complex process, oxidative stress can hinder the wound healing process by causing skin lesions, local infections, neuropathy, and vascular lesions (Fig. 1).

Oxidative stress promotes wound inflammation
In the inflammatory phase of wound healing, the stable function of neutrophils and macrophages is essential for the transformation of the wound healing process from the inflammatory phase to proliferation [4,[21][22][23]. However, their function can be disturbed by excessive oxidative stress that may be caused by local blood circulation disorders in wounds due to hyperglycemia [24]. During this process, the dramatic proliferation of neutrophils produces numerous ROS, causes excessive oxidative stress, and damages the nearby cells and tissues [24]. Additionally, oxidative stress can also inhibit wound healing by influencing macrophage differentiation and polarization. The presence of hyperglycemia can induce pathological hematopoietic stem cells (HSCs) oxidative stress that can result in a decrease in the number and function of terminal differentiation into inflammatory cells as a result [25]. Hyperglycemia induces oxidative stress in HSC and is associated with a Nox-2-dependent mechanism, decreased microRNA let-7d-3p, and upregulated expression of Dnmt1 [25]. In the presence of increased expression of Dnmt1, HSC differentiation into monocytes/ macrophages can be prevented through downregulation of related genes and macrophage infiltration can be reduced consequently [26,27]. These changes drive polarization toward M1 macrophages that display a pro-inflammatory function, which causes excessive inflammation and delayed wound healing [26, 27].

Oxidative stress hinders migration and proliferation of cells
In the migration and proliferation phases, migration, differentiation, and proliferation are impacted by oxidative stress in various cells, such as endothelial cells, keratinocytes, and fibroblasts [23,[28][29][30]. The pathological basis of diabetic microangiopathy is endothelial dysfunction that can lead to wound angiogenesis and vascular disorders, resulting in a wound with insufficient blood supply and support that will fail to angiogenic and heal [31]. In the process, the oxidative stress process alters endothelial nitric oxide synthase (eNOS) functions and directly degrades vaso-protective nitric oxide (NO) by increasing ROS, resulting in reduced bioavailability of NO and endothelial dysfunction [32]. Moreover, it is well known that the migration of keratinocytes is essential for wound healing and epithelization. Research has shown that keratinocyte migration was associated with the activation of focal adhesion kinase p125FAK and its phosphorylation [33]. Additionally, the research also demonstrated that keratinocyte migration ability may be reduced due to the downregulation of p125FAK expression in a hyperglycemic environment [33]. Interleukin-8 (IL-8) is produced more readily in keratinocytes under oxidative stress, inhibiting wound healing by recruiting neutrophil aggregates [34]. Oxidative stress also promotes antiangiogenic molecule thrombospondin-1 (TSP-1) DNA methylation in keratinocytes, impairing normal wound healing by overexpressing TSP-1 [35]. Furthermore, oxidative stress also negatively affects fibroblasts in wound healing. In excessive oxidative stress, the proliferation of fibroblasts can be negatively affected by the production of free radicals and the lack of antioxidant defense [36], and differentiation can be decreased due to the stimulation of growth factors that are produced in the process of wound healing [37]. to the nucleus where it forms heterodimers with the Maf protein that bind antioxidant response element (ARE) [44]. A series of key genes are activated by Nrf2 in response to oxidative stress, such as NAD(P)H quinone oxidoreductase 1 (NQO1), manganese superoxide dismutase (MnSOD), heme oxygenase 1 (HO-1), glutamate cysteine ligase (GCL), and glutathione S-transferases (GSTs) (Fig. 2) [45,46].

NF-κB pathway
In oxidative stress, NF-κB signaling is a master switch system for activating pro-inflammatory and pro-oxidant responses [47]. It has been suggested that overexpression of NF-κB genes or proteins can lead to enhanced oxidative stress, thereby affecting wound healing in diabetics [48]. NF-κB is a transcription factor that is commonly found in the cytoplasm as a heterodimer of p50/p65 [49]. Interacting

Nrf2 pathway
As a central defense mechanism, the Nrf2/kelch-like erythroid cell-derived protein 1 (Keap1) pathway maintains redox equilibrium, but the pathway can be disrupted in T2DM [38,39]. In Nrf1/Keap1 pathway, an essential transcription factor for maintaining redox balance, metabolism, and repairing DNA, Nrf2 regulates a wide range of genes [40]. However, Keap1 is responsible for regulating Nrf2 turnover and ensuring that Nrf2 can translocate to the nucleus and activate cellular antioxidant defenses [41]. Generally, a cell's actin cytoskeleton interacts with Keap1 to sequester Nrf2 to the cytoplasm, promoting its ubiquitination and degradation under unstressed conditions [42,43]. However, because of oxidative stress, certain cysteinerich oxidant and electrophile sensing regions of Keap1 are covalently modified, preventing Nrf2's ubiquitination. Subsequently, after dissociation from Keap1, Nrf2 translocates inflammatory cytokines by upregulating the NF-κB pathway, which delays diabetic wound healing [51]. Thus, NF-κB is crucial to regulating oxidative stress and inflammation in diabetic wounds and promoting wound healing. Therefore, further research strategies should be performed to promote diabetic wound healing by targeting the NF-κB pathway.

Crosstalk between Nrf2 and NF-κB pathways
In healthy cells, it is imperative that Nrf2 and NF-κB pathways work together to maintain redox homeostasis. As shown in Nrf2-deficient mice, Nrf2 activation inhibits the pro-inflammatory effects of NF-κB [52]. In the mice, the HF-κB pathway was significantly promoted and exhibited the greater pro-inflammatory reaction [52]. Previous study with NF-κB, inhibitory κB (I-κB) protein blocks NF-κB's nuclear localization signal, stabilizes p65 in cytoplasm and inhibits NF-κB's transcriptional activity. NF-κB protein is removed from the nucleus by nuclear export signals expressed by I-κB, preventing its targeted activation. However, the inflammation signals (such as TNF-α) phosphorylate I-κB proteins by upstream kinases (IKK) and PI3K/ AKT/NF-κB pathway, and ultimately lead to ubiquitination and degradation of I-κB [50]. The activated NF-κB is translocated to the nucleus after I-κB inhibition is lost, where it binds to targeted genes and releases inflammatory cytokines [51], such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), and NADPH oxidase (NOX-2) (Fig. 3). Through observation of diabetic mouse models, research demonstrated that hyperglycemia causes the release of a large number of Fig. 3 The mechanism of NF-κB pathway and oxidative stress. As inflammation signals (such as TNF-α) phosphorylate I-κB proteins via the IKK/PI3K/AKT/NF-κB pathway, I-κB proteins become ubiquitinated and degraded. When I-κB inhibition is lost, activated NF-κB translocates to the nucleus, where it binds to target genes and releases inflammatory cytokines. Through targeted inhibition of tumor necrosis factor receptor-associated factor 6 (TRAF6), miRNA-146a can regulate the phosphorylation of I-κB, thereby reducing the expression level of NF-κB and inflammation. Silent information regulator 1 (SIRT1) can inhibit transferring of NF-κB to the nucleus and prevent the binding of NF-κB to inflammation-related gene promoters. (P: phosphorylation; Up: ubiquitination) (The figure is drawn by photoshop) ARE-linked gene expression through several mechanisms [54]. Furthermore, by increasing nuclear Keap1 levels and promoting nuclear transocation of Keap1, p65 can inhibit the beneficial effects of Nrf2 [55]. All in all, both Nrf2 and NF-κB contribute to redox homeostasis through numerous signaling cascades (Fig. 4). As redox modulators, they interact and further modulate the levels of key redox mediators in diabetic wound.
showed that the TNF-α dependent activation of NF-κB can be inhibited by HO-1 that can be released via the Nrf2 activation [53]. The action sites of HO-1 in inhibition of the NF-κB pathway include IκB phosphorylation, degradation, and nuclear translocation [53]. Hence, HO-1 was considered as one of the hubs for crosstalk between Nrf2 and NF-κB pathways. Additionally, it has been proved that the transcriptional activity of Nrf2 can be suppressed NF-κB. The canonical NF-κB subunit p65 can negatively affect

Exosomes (EXOs)
Moreover, multifunctional vesicles, exosomes (EXO), are released by cells into body fluids through paracrine processes and contribute significantly to cell function. EXO is an important secretory cell that is composed of proteins, lipids, nucleic acids, and carbohydrates [65]. It plays an important role in intercellular signaling and remodeling of the extracellular matrix [65]. Additionally, EXO also reduced oxidative stress and inflammation caused by hyperglycemia. A study found that adipose-derived stem cells (ADSCs)-EXOs with Nrf2 overexpression significantly reduced oxidative stress and inflammation in diabetic foot ulcers in rats with a positive angiogenesis and proliferation of endothelial progenitor cells [66].

Ameliorate nerve lesions
As a consequence of oxidative stress, peripheral nerve function is affected, which contributes to the difficulty of healing diabetic wounds [6]. Diabetic peripheral neuropathy (DPN) is induced and aggravated by the increased production of AGEs, PKC, and ROS in diabetes, which is bad for wound healing [67]. Inosine which is often taken as a dietary supplement is a purine nucleoside resulting from adenosine deamination and is abundant in fish and meat [68]. A study demonstrated that inosine inhibited NF-κB p65 and enhanced Nrf2 transcriptional activity [69]. By inhibiting the AGE/RAGE axis, inosine has the ability to reduce oxidative stress, which in turn results in NF-κB p65 phosphorylation being reduced, Nrf2 and OH-1 being increased, and the expression of antioxidant molecules being increased such as superoxide dismutase (SOD) and catalase (CAT) [69]. Hence, inosine has important benefits for DPN and wound healing. Additionally, it has been confirmed that by covalently modifying Keap1, Xanthohumol (XN, a hopderived prenylated dietary flavonoid) can stabilize Nrf2 and facilitate its transfer to the nucleus, thereby promoting the expression of antioxidant genes [70]. As a result of the above findings, potential food or drugs for diabetic skin ulcers and wound healing may be developed.

Ameliorate vascular lesions
In addition, hyperglycemia and Nrf2 pathway involvement in vascular lesions are of concern [71,72]. In diabetic wounds, excessive ROS can damage microvascular endothelial cells and cause microcirculation disorders, which greatly contribute to delay wound healing or non-healing [73,74]. Increased production in ROS triggers Nrf2 dissociation from Keap1, allowing it to bind to ARE and releases antioxidant genes (such as NQO1, SOD, and OH-1),

Antioxidant therapy and Nrf2 pathway
In vitro studies have shown that hyperglycaemia inhibits Nrf2 activation, resulting in oxidative stress in rat macrophages [56]. In this process, the antioxidant factor gene HQO1 is overexpressed, which can partially reduce oxidative stress, but it is difficult to achieve a good result [56]. In this study, dimethyl fumarate (DMF), a Nrf2 activator, was used to treat diabetic wounds and the result shown that DMF effectively alleviated inflammation and oxidative stress [56]. In this study, Nrf2 was confirmed as an essential antioxidant in diabetic wound treatment.

Natural extracts
Betulinic acid (BA) is a pentacyclic triterpene product purified from natural products including Pulsatilla Chinensis [57]. According to reports, BA counteracts oxidative stress through the Nrf2 pathway [58][59][60]. In this process, a significant increase in transcriptional activity of Nrf2 was observed after BA treatment [58][59][60]. The antioxidant property of BA decreases the production of ROS, 8-oxo-dG, and methylglyoxal (MG) that are mediated by hyperglycemia, and it can reduce the Glutathione/Glutathione disulfide (GSH/GSSG) ratio in the blood by stimulating Nrf2 [61]. Further, BA ameliorated hyperglycemia-mediated increased NF-κB p65 activity and reduced proinflammatory cytokines such as IL-1, IL-6, and MCP-1 [61]. Additionally, traditional Chinese medicine has made significant contributions to research on wound healing and antioxidants. Huangbai liniment (HB), a traditional Chinese medicine, comprises Cortex Phellodendri, Forsythia suspensa, and Lonicera japonica Thunb, and is used to treat wounds, usually in clinical settings [62]. In excessive ROS, HB can restore blocked Nrf2 activity, and repair damaged antioxidant genes, such as NQO1, Sod1, and Sod2 [63]. Additionally, HB has been found to improve ECM remodeling by significantly increasing TGF-β1 levels and reducing MMP9 levels, which is beneficial to wound healing [63]. Another promising substance, theaflavin (TF, a principal constituent of black tea) was found to have a satisfactory antioxidant effect. When TF was used to treat Human Umbilical Vein Endothelial Cells (HUVECs), oxidative stress was significantly reduced, tert-butyl hydroperoxide (TBHP)-induced apoptosis was decreased, and HUVEC dysfunction was improved, which changes were associated with the activated Nrf2/HO-1 axis [64]. TF was also used to treat diabetic wound models in rats with an intragastric administration and the result demonstrated that TF can significantly increase new capillaries located in wounds and short time of wound healing by activating the PI3K/AKT/Nrf2 pathway.

Non-coding RNA
Non-coding RNA has also been shown to have an antioxidant effect [87,88]. Research reported that miRNA-146a, an anti-inflammatory micro-RNA, improves diabetic wound healing by inhibiting the NF-κB pathway [89]. Through targeted inhibition of tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), miRNA-146a can regulate the phosphorylation of I-κB, thereby reducing the expression level of NF-κB and inflammation [90,91]. Furthermore, compared to wild-type diabetic mouse, miRNA-146a knockout diabetic mouse were found to have increased inflammation and delayed wound healing, which phenomenon was closely associated to the activity of the NF-κB pathway [92]. According to study, CNP-miRNA-146a, which is formed by coupling cerium oxide nanoparticles (CNP) and miRNA-146a, promotes wound healing in diabetic wounds by decreasing inflammation and oxidative stress [93].

Matrix metalloproteinases (MMPs)
It has been mentioned that MMP can be upregulated by the activated NF-κB at high levels of ROS [20]. However, it should be emphasized that upregulation of MMP-9 increases inflammation and decreases angiogenesis, whereas MMP-8 has been shown to be protective against diabetic foot ulcers [94]. Therefore, in order to achieve optimal therapeutic results, it is essential to selectively inhibit harmful MMP-9 without affecting beneficial MMP-8. Research found that lead optimization of the thiirane class of inhibitors led to the discovery of (R)-ND-336, a potent (19 nM) and selective (450-fold) MMP-9 inhibitor, which (R)-ND-336 reduced inflammation and promoted angiogenesis by reducing ROS and NF-κB in diabetic mice [94]. Moreover, (R)-ND-336 in combination with the antibiotic linezolid could improve wound healing by inhibiting MMP-9 [94]. Additionally, there is a close link between the NF-κB signal and the differentiation of macrophages. Under the induction of hyperglycemia, the macrophage is polarized into the M1 type and promotes inflammation, and the transformation of it from the M1 to the M2 type is inhibited, which results in prolonged inflammation [4,23,95]. Furthermore, hyperglycemia activates the NF-κB pathway and releases a large number of inflammatory factors, including IL-1 and iNOS, resulting in macrophage polarization to the M1 type [96]. Some studies reported a satisfactory outcome in diabetic wound treatment using insulin or stem cells and demonstrated that improving macrophage function and decreasing MMP levels can be achieved by regulating NF-κB pathways, which results were beneficial for the development of targeted drugs [96,97].
preventing excessive oxidation and improving microvascular endothelial function [75]. However, it is inadequate to rely solely on these genes. Research shown that carnosol improves microangiopaplasia caused by oxidative stress, which is conducive to vascular repair, and the mechanism of action is closely tied to Nrf2 activation [76]. In addition, CXC Chemokine Receptor 7 (CXCR7) is one of the most important ligand receptors for Stromal-Derived Factor-1 (SDF-1, also called CXCL12) and is expressed by endothelial progenitor cells (EPCs) [77,78]. The proliferation and adhesion of EPCs are regulated by the SDF-1/CXCR7 axis, which affects angiogenesis as well [77,78]. A study has shown that decreased CXCR7 expression may damage the self-healing ability of EPCs in a hyperglycemic environment [79]. Furthermore, this study confirmed that SDF-1/ CXCR7's downstream signaling target, Akt/Keap1/Nrf2, plays an important role in EPC functionality [79]. The upregulation of CXCR7 can stimulate the phosphorylation of Akt, the inactivation of Keap1, and the accumulation of Nrf2, as well as the expression of HO-1 and NQO-1, which may benefit antioxidant therapy and functional recovery of EPC [79].

Antioxidant therapy and NF-κB pathway
As previously mentioned, EPCs are essential for promoting angiogenesis, resisting oxidative stress, and promoting diabetic wound healing. However, when NF-κB is overexpressed, numerous inflammatory cytokines are released into the body fluid, such as TNF-α, IL-1β, and IL-6, which cytokines may significantly damage the EPC function. Silent information regulator 1 (SIRT1), a NAD-dependent class III histone deacetylase, inhibits transferring of NF-κB to the nucleus and prevents the binding of NF-κB to inflammation-related gene promoters, which process is associated with deacetylating the p65 subunit at lysine [80,81]. By inhibiting the expression of the NF-κB signal, SIRT1 can reduce the release of inflammatory factors and improve wound healing.

Natural extracts
Resveratrol (RES), a phytoalexin, occurs naturally in mulberries, Polygonum cuspidatum, grapes, and red wine [82]. Various researchers have studied and confirmed the important role of RES in antioxidant functions as an important agonist of SIRT1 [83][84][85]. It has also been shown that RES inhibits forkhead box O1 (FOXO1) expression, relieves the inhibition of c-Myc, and promotes the proliferation of EPCs by activating SIRT1 [86].
agonists, vitamins, hormones, exosomes, drugs, plants, and biomaterials, have been shown to significantly reduce oxidative stress, decrease inflammation, and enhance diabetic wound closure in these studies [56, 61-66, 69, 70, 76, 79, 86, 93-101]. However, the majority of these encouraging findings have been only confirmed in laboratory animals. For patients with diabetic wounds, conventional wound care remains the main treatment option. Natural extracts and EXOs have been studied extensively in recent years for their ability to regulate oxidative stress. Hence, it is possible to use natural extracts or EXOs on biological materials (such as hydrogel) for diabetic patients as a potential research area. Additionally, although the effect of Nrf2 and NF-κB pathways have been widely studied, further research is needed to determine how to regulate their balance between oxidation and antioxidant in diabetic wound healing.

Conclusion
Delay wound healing and non-healing in diabetic patients are challenging for clinicians. Various studies have verified that in a hyperglycemic environment excessive oxidative stress significantly damages the normal process of wound healing via a series of physiological changes, such as injured neurotrophic function, decreased angiogenesis, and increased inflammation. To solve this challenge, numerous researchers highlighted the promising potential of antioxidant therapy in diabetic wounds. They explained the mechanisms of antioxidant therapies that promote diabetic wound healing by influencing the activity of Nrf2 and/or NF-κB pathways. This review summarizes the antioxidant strategy associated with Nrf2 and/or NF-κB pathways and published in the past 5 years. Antioxidant effects that can significantly downregulate oxidative stress, decrease inflammation, and promote diabetic wound closure were verified in various substances. The rapid and satisfactory development in the field of antioxidant and anti-inflammatory therapy for diabetic wounds in cell or animal experiments, but fewer results were satisfactorily demonstrated in humans. Hence, the scope of future studies should more focus on the application of antioxidant strategies to humans.

Regulate macrophage polarization and inflammatory cytokine release
Other hand, the production of uric acid (UA) in wounds can increase inflammation through the overproduction of IL-1β, which process may be associated with the direct action of nod-like receptor protein-3 NLRP3 inflammasome [98,99]. Setdb2 regulates xanthine oxidase and hence the UA pathway of purine catabolism in macrophages, explaining the higher levels of UA seen in diabetic tissue [100]. Research shown that Setdb2 can directly regulate UA metabolism via H3K9me3 (Setdb2 specifically trimethylates lysine 9 (K9) on histone 3 (H3)) at the NF-κB binding site on the gene promoter of xanthine dehydrogenase (Xdh) [100]. Because the Xdh gene encodes XO, a decrease in H3K9me3 leads to an increase in XO, greater substrate drive across the purine UA pathway, and excess UA production [100]. A potential therapy was found and confirmed that interferon (IFN) regulates Setdb2 expression in wound macrophages via type 1 interferon/janus kinase/signal transducer and activator of transcription 1 (IFN-1/JAK/STAT1) signaling, which promotes the transformation of macrophages from inflammation to repair and is beneficial for wound healing [100]. Interestingly, another study found that the increased expression of inflammatory genes was associated with the Jumonji domain-containing protein D3 (JMJD3) production in macrophages from diabetic wounds [101]. During the late stage of wound injury, IL-6 increases, regulating JMJD3 expression in macrophages through JAK1, while the increase expression of 3/STAT3 pathway and JMJD3 in late process can induce the NF-κB mediated transcription of inflammatory genes in macrophages by influencing H3K27me3 [101]. Further, the study showed that macrophage-specific nanoparticles were effective at inhibiting JMJD3 in diabetic wounds, as well as reducing inflammation and accelerating wound healing [101]. In conclusion, macrophages and NF-κB -mediated inflammation offer important therapeutic targets for diabetic wounds.

Discussion
Diabetes wound repair has always been an urgent clinical and scientific issue. Through the Nrf2 and NF-κB pathways, excessive ROS result in disruption of the oxidation-antioxidant balance during wound healing, impairing normal cellular function and cytokine secretion, thus contributing to the delayed healing process [23, 28-37]. There has been a significant amount of research conducted on finding potential treatments for diabetes wounds that are subject to excessive oxidative stress caused by ROS during healing [6,56,. Numerous therapeutic strategies, including receptor

Declarations
Compliance with ethical standards This article does not contain any studies with human participants performed by any of the authors.

Conflicts of interest
The authors declare that they have no conflict of interest.