Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets

INTRODUCTION

The process of wound healing is complex and requires spatial as well as temporal synchronization between different types of cells with specific functions. Hemostasis, inflammatory phase, proliferative phase, re-epithelialization, and remodelling phase are the four major phases of wound healing process,which result in the restoration of functional integrity of tissues[1-3]. Alteration in the microenvironment due to diabetes mellitus (DM) results in a change in the level of oxygen, chemokines, synthesis of growth factors, extracellular matrix, oxidative stress that in turn alter normal cellular recruitment and activation, and induce impaired or delayed wound healing[1,3]. Ageing, genetic disorders, obesity, and metabolic disorders including DM, are responsible for the abnormal wound healing process, that enhances the risk of developing chronic wound[1,3,4]. It was estimated that chronic wounds directly affect the quality of life of about 2.5% population of the United States, and the medicare cost for management of all wounds and the related situation was projected between $28.1 to $96.8 billion[5].Management of wounds in the diabetic individual is a major clinical and social concern. The hyperglycaemic environment in diabetic people causes impaired and delayed wound healing[4],making the situation more perilous as the number of diabetic people is increasing day by day. It was also found that treatment and management of diabetic ulcers and surgical wounds were the most expensive[5]. The IDF Diabetes Atlas estimated that the prevalence of DM in 2021 was 10.5% (536.6 million people in the 20-79 year age group), which will increase to 12.2% (783.2 million in the 20-79 year age group) by 2045. Global health expenditures related to the management of DM and its complications are expected to reach $966 billion in 2021[6]. It was also predicted that almost half of the adult population (44.7%; 239.7 million of 20-79 years old) were unaware of their diabetic condition. People may develop micro and macrovascular complications during an asymptomatic diabetic state[7].Impaired or delayed wound healing affects about 25% of diabetic people. A study suggested that 1 in 3 to 1 in 5 diabetic individuals are at risk of chronic non-healing wounds, including diabetic foot (with a very high recurrence rate) in their lifetime[8]. Zhang

[9] estimated that the global prevalence of diabetic foot is 6.3%, which usually affects type 2 diabetic people, older people, and people with a longer duration of DM.

Both the extrinsic and intrinsic factors are responsible for delay in the wound healing process in diabetic patients. Repeated trauma or mechanical stress in the diabetic foot can lead to neuropathy and ischemic situation. Glucose-rich environment results in increased generation of advanced glycation endproducts (AGEs) and elevated levels of inflammatory cytokines [

, interleukin (IL)-1β and tumor necrosis factor α (TNF-α)] for a persistent period that hinders the normal process of wound healing[10,11]. In turn, hyperglycemia reduces collagen synthesis, growth factor production, macrophage function,angiogenic response, migration and proliferation of fibroblast and keratinocyte, epidermal nerve count,and the balance between extracellular matrix (ECM) component accumulation and matrix metalloproteinase (MMP) induced remodelling [4,12]. The normal wound healing process and effect of the hyperglycemic condition are depicted in Figure 1.

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Despite the presence of protocols to standardize care in the diabetic wounds, as well as numerous advancements in scientific research and in clinical fronts, DM remains a problematic situation for wound healing. This paper is an attempt to highlight the mechanistic insights, plausible therapeutic targets, and pharmacotherapeutic approaches, particularly the role of phytochemicals in the management of diabetic wounds, in light of recent shreds of evidence.

MECHANISTIC INSIGHTS OF DIABETIC WOUND

Wound healing, being an evolutionary conservation process, restores impaired epithelial barriers through a cascade of events including inflammatory responses, proliferation, cellular migration,angiogenesis, and remodeling of tissues[13]. DM interferes with the normal healing process to provoke non-healing wound, and leads to complications including walking difficulty and infections like septicemia, abscess, cellulitis, osteomyelitis, and gangrene[4]. Acute diabetic wounds with an impaired healing process of unknown aetiology are the first signs of chronic diabetic wounds. Hyperglycemia,hypoxia, chronic inflammation, neuropathy, circulatory dysfunctions, alteration in neuropeptide signalling, and infections impede the diabetic wound healing process. Importantly, due to the heterogeneous nature of the diabetic wound, there exist no clear implications from the pathogenic vantage.The following subsections discuss the potential factors underlying the pathogenesis of diabetic wound.

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Molecular implications

Impaired wound healing associated with diabetes remains inconclusive. However, the alterations in cellular factors and biochemical mediators have been believed to be involved in the development and progression of diabetic wound (Figure 2). Factors like hyperglycemia and oxidative stress in diabetic patients result in dysregulated macrophage polarization through modulation of epigenetic codes to delay the process of wound healing[14,15]. Hyperglycemia is implicated in impaired wound closure in diabetic foot ulcers (DFUs), with reduced skin cell function and the formation of atherosclerosis and neuropathy as possible contributors[8]. The development of atherosclerosis leads to alteration in the physiology of endothelial cells along with deprivation of nutrients in the wound site, critically affecting the healing process. Patients with type 1 DM are more prone to macrovascular diseases, especially affecting femoral and metatarsal arteries[16,17]. DM associated early microvascular deficiencies include decreased capillary size, basement membrane thickening, and arteriolar hyalinosis. Thickening of the membrane disrupts the physiological exchanges and causes altered leucocyte migration, and thereby increasing the risk of microbial infections[18,19]. Hyperglycemia disrupts protein translation as well as the migration and proliferation of fibroblasts and keratinocytes involved in the process of re-epithelialization[20-22]. For instance, altered expression of proteins like cytoskeletal keratin proteins(K2/K6/K10) associated with keratinocyte differentiation, and LM-3A32, a laminin-5 α3 chain precursor protein that regulates epithelial cell binding to the basement membrane, was reported in subjects with DFUs[23]. As LM-3A32 is required for the survival and differentiation of keratinocytes, reduction in this protein affects the re-epithelialization process[24]. Interestingly, the expression of mRNA and microRNA was found to be non-significant in diabetic and non-diabetic foot skin fibroblasts[25].However, fibroblasts from DFUs were reported to exhibit altered morphology, growth factor unresponsiveness, ECM deposition, and reduced proliferation and migration[26-29]. Impaired vasculogenesis and angiogenesis due to deregulation of the growth factors and receptors leads to impaired wound healing. Dysfunctional endothelial progenitor cells (EPC) or reduction in their numbers and transition to proinflammatory EPC phenotypes have been implicated in DM[30,31]. Notably, EPC dysfunction and altered recruitment are contributed by hyperglycemia, chronic inflammation, oxidative stress, and activation of NADPH oxidase associated with diabetes pathogenesis[32]. Prolonged IL-1β production and reduced expression of peroxisome proliferator-activated receptor-γ are also involved in the impairment of wound healing in DM[33]. Higher expression of MMPs including MMP-1, 2, 8, 9, 14,and 26, and lower expression of their tissue inhibitors were also reported in diabetes[34,35]. In patients with DFUs, it was reported that there is an increase in MMPs and a decrease in tissue inhibitor of metalloproteinase (TIMP)-2, which supports the fact that in a proteolytic environment, diabetic wound fails to heal due to reduction in ECM formation[36]. An increase in MMPs also contributes to matrix degradation, delayed cell migration, and inhibition of collagen deposition[36]. Oxidative stress resulting due to decrease action of enzymes like superoxide dismutase and glutathione peroxidase augment diabetic wound. Overproduction of reactive oxygen species (ROS) from hexosamine, polyol, and AGE pathways affects the later stages of diabetic wound healing, particularly by damaging the peripheral nerves. Consequently, the detrimental effect on the structure, supply, and metabolism of peripheral nerves (neuropathy) increases the risk of DFU development[37]. Hyperglycemia not only contributes to impaired healing but also makes skin prone to injury. Decrease in nuclear factor erythroid factor 2-related factor 2 (Nrf2) in diabetic patients increases the oxidized proteins and ROS generation[38,39]. In Nrf2 knockout mice, delayed wound healing was reported when compared to a Nrf2

mice, possibly due to oxidative DNA damage, elevated MMP-9 expression, and lower level of transforming growth factor-beta 1 (TGF-β1) expression[40]. Hyperglycemia also leads to an increase in neutrophil extracellular traps release, which has been implicated in delayed wound healing in both murine and human models[13,41].

The formation of a diabetic wound is also linked to several forms of neuropathy, including sensory,motor, and autonomic. Sensory deficits, for example, cause a loss of protective symptoms, whereas motor neuropathy causes anatomical deformities and ischemic death in the plantar region of the foot[42], and autonomic neuropathy reduces sweat secretion from the glands, making skin dry and increasing the risk of infection and pruritus[43]. Furthermore, neuropathy causes a decrease in neuron density, causing impairment in wound healing. Primarily, diabetic neuropathy occurs in nerves that are dependent on nerve growth factor[8]. Impaired microvascular processes along with autonomic neuropathy and denervation of sympathetic nerves disrupt the blood flow. Cellular necrosis and microvascular reactivity are also triggered by Poly (ADP-ribose) polymerase enzyme

oxidative DNA damage[16,44]. In diabetic neuropathy, impairment of C-fibre dependent neurovascular responses leads to abnormality in the release of histamine, substance P, and calcitonin related peptide, thus exhibiting altered vasodilatation in case of stress like pressure or trauma[44]. However, the direct link between neuropathic abnormalities and glucose control is yet to be proven.

Epigenetic mechanisms

Despite the fact that epigenetic pathways have a role in a variety of diabetic complications, evidence of epigenetics in diabetic wound or impaired wound healing is still emerging. The role of microRNA in diabetic wound was first highlighted by a study that revealed up-regulation of miR-503 in plasma obtained from DFUs and in human umbilical vein endothelial cells (HUVEC).

experiment suggested the detrimental effect of forced miR-503 expression on function of HUVEC cells resulting due to impaired migration, proliferation, and formation of blood vessels[45]. Blockage of miR-503 expression showed improvement in angiogenesis in diabetic animals with limb ischemia[45,46]. Another study demonstrated that diabetic mice had a distinct microRNA signature, with differential expression of fourteen microRNAs[47]. Of these, expression of miR-146b was found to be up-regulated by 30 fold.Though miR-21 was up-regulated in diabetic skin, it was reduced in diabetic wound healing. This study suggested the necessity of miR-21 expression for fibroblast migration and miR-21 knock-down results in altered cellular migration. Similarly, another study showed the stabilisation of hypoxia-inducible factor α leads to miR210 expression, which silences the expression of E2F3, an important element of wound healing[46]. This implies the fact that epigenetic changes in miR-210 lead to impaired wound re-epithelialization and reduced proliferation. The involvement of DNA methylation in impaired diabetic wound healing is being studied in many experiments. A study reported inhibition of DNA methyltransferase 1(DNMT1), an enzyme that transfers a methyl group to the cytosine ring to produce 5-methylcytosine associated with transcriptional repression, suppresses inflammatory signals in bone marrow derived macrophages and also promotes M2-like macrophage formation[48]. This finding was supported by DNMT1 knockdown in db/db mice showing improvement in wound healing[49]. In contrast to that,demethylation of MMP-9 promoter in keratinocytes was reported to be involved in the induction of diabetic wound[50,51]. Apart from the role of DNA methylation in wound healing, it is also associated with metabolic memory, insulin resistance, and other diabetic complications[52,53]. Unlike DNA methylation, histone methylation does not always lead to transcriptional repression. Instead, it silences or promotes transcription based on the target residue and methyl groups. Methylation of histone H3K4 is regulated by SET domain containing protein family, particularly MLL1 that promotes inflammatory gene expression in nuclear factor kappa B-dependent manner[54-56]. A study reported the role of mixed-lineage leukemia-1 (MLL1) is to catalyze H3K4me3 deposition in macrophages during the process of wound healing[57]. Delayed wound healing and reduced pro-inflammatory cytokine generation were reported in a myeloid-specific MLL1 deletion in mice. Monocytes isolated from patients with type-2 DM demonstrated higher MLL1 expression, indicating dynamic regulation of MLL1 expression during diabetic wound healing. In diet-induced obesity model of diabetes, increased expression of histone demethylase (

, lysine-specific demethylase 6B or JMJD3) that targets H3K27me3 was seen in wound macrophages[58,59]. Epigenetic regulation of IL-6 expression in neutrophils was believed to be impacted by toll-like receptor (TLR) activation associated with increased H3K27ac,H3K4me3, and acetylated histone H4[60]. Re-epithelialization is also promoted by JMJD3 expression,which induces keratinocyte migration to the wound site[61]. Similar report suggests upregulation of JMJD3 expression on the wound site is necessary for early onset of the wound healing process, which is absent in diabetic wound[62]. However, it will be too oversimplified interpolation as most of these findings are limited to normal wounds; thus, further studies are warranted. Other histone modifications including histone acetylation or deacetylation, histone phosphorylation, histone-arginine demethylation or methylation, and ATP-dependent chromatin remodelling are also being studied for their potential role in diabetic wound healing[62].

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Microbiological perspectives

Growth factors are biologically active polypeptides that play an important role in the onset and maintenance of wound healing[97]. In diabetics, any change,

, down-regulation of growth factor receptors and rapid degradation of growth factors, causes wound healing to be delayed. Factors such as VEGF, IGF, TGF-β, KGF24, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), TNF-α, and IL-6 are significantly reduced in diabetes patients, and several of them have been demonstrated to significantly enhance wound healing in many studies.Growth factors that cause a molecular alteration in the wound micro-environment may help patients with non-responsive wounds. PDGF is a major serum mitogen that promotes fibroblast proliferation,matrix formation, and connective tissue maturation[98]. They attract fibroblasts and inflammatory cells and aid in the production of glycosaminoglycans, proteoglycans, and collagen. During the healing process, it is a critical mediator in fibroblast migration and proliferation, the formation of granulation tissue proteins and provisional extracellular matrix, and angiogenesis[99]. The expression of PDGF and its receptors is reduced in diabetic wounds, and many clinical studies employing PDGF have shown improved healing time[100,101]. It is indicated for the treatment of infections that have spread to deeper subcutaneous tissues or beyond areas with a sufficient blood supply[102]. Another growth factor, bFGF,has a stimulatory effect on fibroblast growth and differentiation, as well as the proliferation of vascular smooth muscle cells, endothelial cells, ECM metabolism, growth, and movement of mesodermally derived cells, all of which speed up the formation of granulation tissue and promote wound healing[103]. Angiogenesis, cell proliferation, migration, differentiation, neo-vascularization, re-epithelialization, and collagen disposition were all stimulated by the clinical application of bFGF, all of which contribute to wound healing[104]. It promotes mesodermal cell chemotaxis and extracellular matrix growth and expedites both acute and chronic wound healing, which gives a scar-free cure[105]. VEGF is a potent angiogenic cytokine that has a substantial impact on healing and promotes rate-limiting processes in vasculogenesis and angiogenesis[106]. Low VEGF levels cause impaired wound healing and aberrant VEGF receptor patterns in diabetics. Decreased VEGF mRNA levels, increased VEGF receptor (VEGFR)-1 Levels, and decreased VEGFR-2 Level are some of the key causes of wound nonhealing[107]. In diabetic wounds, VEGF leads to an increase in capillary density, which enhances blood perfusion and metabolism in the wounded tissue[108]. VEGF causes an increase in capillary density,which improves blood perfusion and metabolism in the wounded tissue. This leads to the facilitation of the supply of oxygen and nutrients to assist the growth and function of reparative cells. It is the primary regulator of wound revascularization and permeability and participates in the formation of granulation tissue. On binding with the EGF receptors, EGF causes an increase in epidermal cell, cell motility,cellular migration, mesenchymal regeneration, angiogenesis and cell proliferation[109]. Application of EGF into the wound site results in a greater pharmacodynamic response in terms of granulation tissue growth and wound closure. IGF-1 promotes wound healing by assisting in cell granulation and reepithelisation, promoting endothelial cell chemotaxis and keratinocyte and fibroblast proliferation,while lower levels of both IGF-1 and TGF-β in wound tissue cause wound healing to be delayed[110,111]. TGF-β attracts and stimulates inflammatory cells such as neutrophils, macrophages, lymphocytes,keratinocytes, and fibroblasts, as well as the synthesis of growth factors, which speed up vascularisation, angiogenesis, and ECM synthesis while slowing down ECM degradation[112]. Therapeutic agents or strategy, which can ameliorate this positively, are useful in diabetic wound condition. Several drugs and phytoconstituents have shown their positive effect in diabetic wounds targeting these biomolecules. The use of platelet-rich plasma (PRP), EGF, PDGF, and FGF has shown promising effects in the treatment of diabetic wound in a better way.

to be the most common colonizers in DFUs[64]. Stratification of DFUs as per infection severity revealed higher bacterial diversity in severely infected DFUs, while

and

were found to be the most abundant in mild-to-moderate DFUs[65]. It was similar to a previous finding that found diverse microbiota (with higher incidence of anaerobic and Proteobacteria infection) in deep chronic ulcers, while

was found to be abundant in acute and superficial ulcers[66]. However,contrary to these reports, another study reported

spp. to be the primary culture detected in the microbiome in diabetic foot osteomyelitis[67]. A higher prevalence of

colonization in DFUs and intact diabetic skin lead to systemic infection and osteomyelitis[63]. Indeed, in a Nigerian observational multi-center study, it was reported that the presence of osteomyelitis is an important predictor of wound healing in hospitalized patients with DFUs[68]. The expression of proteolytic factors by

and

are believed to be the disruptor of skin barrier. For example, SpeB released by

leads to cleavage of desmoglein 1 and 3 that causes epidermal barrier damage[69]. The alkaline environment of DFUs contributes to the formation of bacterial biofilm, leading to complex host–microbiome interaction[70]. The formation of bacterial biofilm along with alkaline pH affects drug action and is responsible for antibiotic resistance[71]. One should appreciate various other factors influencing this intricate microbiome network and its potential correlation with clinical significance. Keeping all this evidence in sight, more longitudinal studies are anticipated for an adequate understanding of the probable relevance of the microbiome to clinical outcomes.

PLAUSIBLE DRUG TARGETS

They were to eat peaches, as planned, after her nap, and now she sat across from the man who would have been a total stranger except that he was in fact her father. They had been together again (although she couldn t quite remember when they had been together before) for almost a hundred years now, or was it only since day before yesterday? Anyhow, they were together again, and he was kind of funny. First, he had the biggest mustache she had ever seen on anybody, although to her it was not a mustache at all; it was a lot of red and brown hair under his nose and around the ends of his mouth. Second, he wore a blue-and-white striped jersey1（） instead of a shirt and tie, and no coat. His arms were covered with the same hair, only it was a little lighter2 and thinner. He wore blue slacks3 , but no shoes and socks, He was barefoot, and so was she, of course.

There were many pictures of my mother in those books, given to me by my father before he died an old man just a few years ago. I had barely known the woman on those pages and only imagined that she must have loved me. She, too, had died, when I was very little, leaving me to miss the presence of a relationship that seemed so innate18, so necessary.

As a result of elevated blood sugar levels in diabetic conditions, damage to nerve fiber occurs, leading to diabetic neuropathy, which can be sensory, motor or autonomic[72]. Sensory neuropathy can result in one of two outcomes: a painful foot or a foot that is devoid of sensation[12]. Motor neuropathy is accompanied by muscle weakening, atrophy, and paresis. The inability of an intrinsic muscle to keep the foot in its normal state resulting because of weakening of inter-osseous muscles in the foot, which contributes to foot deformity. When the foot deforms, the pressure distribution throughout the foot changes, and aberrant pressure develops at various locations on the foot[73]. Keratosis and callus development occur as a result of repeated pressure, which leads to damage to callused areas and induces ulcer formation beneath the callus that further causes cracks on the foot[74-77]. Malfunctioning of the sympathetic nerves supplying the sweat glands in the foot reduces the sweat and moisture in the feet, which leads to the development of cracks[78]. Inflammation, necrosis, and ulceration result when an unnoticed injury is combined[16,79]. Currently, duloxetine, anticonvulsant pregabalin and opioid tapentadol are being prescribed for diabetic peripheral neuropathy. Besides these, a substance like αlipoic acid has shown effectiveness in delaying or reversing peripheral diabetic neuropathy through its multiple antioxidant properties[80]. Neuropeptides such as substance-P and neuropeptide-Y are also been found to be effective in diabetic neuropathy and associated wound[81,82].

Peripheral vascular dysfunction is another major cause of diabetic wound in a majority of diabetic patients. The wound healing process in the diabetic condition is hampered by the altered physiological response due to glycation of hemoglobin, alteration of the red blood cell membrane and narrowing of blood vessels which cause the decreased supply of nutrients and oxygen to tissues[12]. The development of atherosclerotic plaque in diabetic patients also leads to the development of non-healing wound. Therefore, pharmacotherapeutic agents like antioxidant phytochemicals that can avert oxidative stress and formation of AGEs could be useful in treating diabetic wound.

Bacterial infection is one of the most common causes of wounds, and diabetic individuals are more vulnerable to it because of delayed wound healing and immunosuppression[83,84]. The biofilms created by microorganisms protect them from antimicrobial agents and the immune system while also interfering with the healing process, which is one of the most prevalent reasons for amputation of lower limbs in diabetic wounds[14]. Therefore, empiric therapy should include broad-spectrum antibiotics. In recent times, drug resistance is a bigger problem and several drugs are in use in the treatment of DFU.

Neutrophils, monocytes, macrophages, keratinocytes, fibroblasts, T cells, B cells, mast cells, and endothelial cells are all involved in wound healing and are responsible for the formation and modulation of pro-inflammatory cytokines and growth factors such IL-1, TNF-α, IL-6, vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), and TGF-β. Hyperglycemia and oxidative stress lead to dis-regulation of these cells, resulting in delayed wound healing[85-87].Increased amounts of pro-inflammatory cytokines cause an inflammatory cascade to be disrupted,resulting in hyper-inflammation and insulin resistance. These also lead to reduced angiogenesis and microvascular issues, impaired macrophage and neutrophil function, impaired keratinocyte and fibroblast migration and proliferation, and impaired growth factor generation[15,88-90]. Many of these cells play a vital role in the immune response, which is also important for wound healing. Various chemokines whose expression can regulate the function of immune cells have the potential to enhance wound healing. Mast cells with close coordination with macrophages, endothelial cells, and fibroblasts,play a key role in matrix remodeling and disrupt the balance of pro- and anti-angiogenic molecules in wound tissues, affecting angiogenesis and vascular regression in the proliferative and remodeling phases, respectively[91-93]. As a result, mast cell degranulation inhibitors such as disodium cromoglycate, quercetin, and luteolin may be promising options for improving diabetic wound healing[92]. Heat shock proteins (HSPs) aid wound healing by attracting dermal fibroblasts, stimulating cell proliferation and keratinocyte differentiation, reducing oxidative stress, ameliorating actin microfilaments, aiding endothelial cell migration, and enhancing pro-collagen synthesis and protein homeostasis[94,95]. Reduced levels of HSPs and their downstream components TLR4 and p38-MAPK(mitogen-activated protein kinases) in diabetic patients are responsible for the slowed healing process[96]. Therefore, targeting this as a therapeutic target could be useful in diabetic wound conditions.

At last his confidants searched his heart and lifted the veil from the face of his love, and then set the matter before his father, King Saman-lal-posh

Certainly, pathogenic infections are not directly associated with the pathophysiology of diabetic wounds but are critical from the vantage of impaired wound healing, hospitalization, morbidity, and amputation. However, the role in the initiation of diabetic wound in case of trauma remains unclear.The rapid spreading of infections and high microbial burden exhibit detrimental effect on the wound healing process. Injury to the superficial skin layer allows polymicrobial contamination and colonization, affecting diabetic wound. Particularly, infections like cellulitis, osteomyelitis, and abscesses are of major concern[16]. The advent of high-throughput sequencing technologies like microarray, 16S rRNA sequencing, and whole-genome sequencing have enabled the expansion of diabetic wound microbiome. Diabetic wound has demonstrated higher colonization of

and

[63]. Another study reported

,

, and

Infection caused by microbes is a major problem in DFU. Antimicrobial therapy targeting Gram -ve,Gram +ve, anaerobic bacteria, and certain fungi, contributing to the pathophysiology of DFU, is also a key approach. Povidone iodine solution (10%), chlorhexidine, acetic acid (5%), and silver compounds can be used to treat the mild wound. Antibiotics like amoxicillin + clavulanate, ampicillin, dicloxacilline,cephalosporin (

, cephalexin, cefoxitin, ceftriaxone, and ceftazidime), quinolones (

, ciprofloxacin,levofloxacin), metronidazole, and clindamycin used to cure moderate DFU[126]. Drugs like piperacillin/tazobactam + clindamycin, meropenem, imipenem, ertapenem, ampicillin + sulbactam are used to cure severe infections caused by different Gram +ve and Gram -ve bacteria, anaerobes, MRSA,

, while vancomycin, linezolid, and daptomycin can cure MRSA[11]. Cefepime, ceftazidime,meropenem, and piperacillin/tazobactam are recommended to use against

Metronidazole and clindamycin are used to manage infection caused by anaerobes, while osteomyelitis can be managed with quinolones and linezolid. Further, the effectiveness of different drugs like penicillin,cephalosporin (ceftazidime, ceftriaxone, and cefuroxime), dicloxacillin, vancomycin aztreonam,cefalotin, clindamycin, cefoxitin, gentamicin, imipenem, piperacillin/tazobactam, imipenem,metronidazole, amikacin, levofloxacin, and cefalotin against microbes contributing in DFU infection also established[126]. Dressings with hydrogels, acrylics, hydrofibers, films, hydrocolloids, calcium alginates, polyurethane foam and ciprofloxacin-loaded calcium alginate wafer are also used to control the infection[126,127].

Autologous stem cells capable of self-renewal and multi-lineage differentiation have been used in diabetic wound. Clinically, bone marrow-derived mononuclear cells and mesenchymal stem cells are the most successful stem cell therapies[116,117]. Besides these, several other targets to promote diabetic wound healing include stimulation of nitric oxide production and up-regulation of endothelial NO synthase and nitric oxide (NO) expression[118-120], a decrease of AGE receptors[121], collagen generation and epitheliazation

[122-124]

Figure 3 represents plausible drug targets for diabetic wound.

The prince accepted gladly, and they went back to the palace, where the bald-headed king s daughter, who was still more beautiful than the other princess, welcomed them at the door and led the way into a large hall and to a table covered with silver dishes

Then all too soon the garden was harvested, the vegetables canned and stored, and the school reopened. Soon the leaves fell and the winds blew cold and gusty12 from the bay. Reuben wandered the streets, diligently13 searching for his hessian（） treasures.

MANAGING DFU: PHARMACOTHERAPY

Hyperglycemic environments worsen the wound situation and delay the wound healing process, thus controlling blood sugar levels is important for the wound healing process. Several antidiabetic medications [

, insulin, metformin, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors,thiazolidinediones] found effective in controlling not only blood sugar levels but also promoting the healing of a wound. Metformin was found to be effective in wound healing, which may act by improving epidermis and deposition of collagen, and increasing TGF-β production that may link with angiogenesis process, inflammatory reaction, re-epithelization, and remodeling process. DPP-4 inhibitors may act by increasing the generation of SDF1α, which is crucial for wound repair process[11,125]. Drugs like simvastatin (enhance VEGF and NO content at wound site) and phenytoin (enhance VEGF and FGF in wound area) have also shown some positive effects in wound healing[11,125].

MMPs are a class of endopeptidase that play a key part in wound debridement, as well as angiogenesis, epithelialization, and extracellular matrix remodeling[113]. Matrix proteins such as collagens, basement membrane collagens, proteoglycans, elastin, and fibronectin are digested by the MMPs. TIMPs form a complex with MMPs, limiting interaction with the active site. A balance between MMPs and TIMPs is required for wound healing, which is impaired in diabetes patients[114]. Increased protease activity caused by high MMP levels in diabetic wounds causes tissue damage and slows down normal repair processes[115]. This is due to altered MMP expression and decreased TIMP expression in diabetic conditions, which results in high levels of pro-inflammatory and pro-fibrotic cytokines due to increased inflammatory cell activation and invasion, and indirectly affects MMPs through the formation of advanced glycation products which leads to the loss of growth factors, receptors, and matrix proteins essential for wound healing[111,114]. Drugs, therapy that is useful in diabetic wounds are found to act by enhancing collagen synthesis, decreasing inflammatory cytokines, AGEs

Further, identifying the therapeutic agents that can inhibit MMPs,

, MMP-1, MMP-8, and MMP-9 could be important in the management of diabetic wounds.

Debridement (elimination of bacterial biofilm and necrotic tissue from wound site), offloading(complete/partial removal of pressure), PRP, EGF, PDGF, FGF, oxygen therapy, negative pressure wound therapy (NPWT), low-level laser therapy (LLLT), extracorporeal shock wave therapy (ESWT),bio-engineered skin substitutes/ soft tissue substitutes (amniotic membrane, autologous stem cell therapy, bi-layered bio-engineered skin substitute, human fibroblast-derived dermis, porcine small intestine submucosa), and maggot therapy are also used successfully to cure DFU[127-129].

In clinical practice, control of blood glucose level, periodical foot screening, patient education, use of therapeutic footware by susceptible people, prophylactic arterial revascularization are important in prevention of DFU[130]. Off-loading in different grades of DFUs (grade 1B, 1C), and diagnosis of diabetic foot osteomyelitis are recommended in grade 1B, 1C, 2C DFU using different screening methods by Society of Vascular Surgery[130]. Surgical debridement to remove necrotic and devitalized tissue, use of proper dressing to create and maintain moist environment, reducing plantar pressure and shear stress (off-loading), vascular assessment in patient with peripheral arterial disease are the vital part of wound care in diabetic people[130,131]. Microbial infection is a major concern in DFU, and in such cases, use of antimicrobial agents is advised conserving extent of infection[131]. A number of adjuvant therapy as discussed in previous section are also used for effective wound healing. Further,adequate glycemic control is important also in acceleratd healing of DFU’s[130,131].

RECENT APPROACHES IN CLINICAL TRIALS

PRP is an important treatment approach investigated in DFU. A systematic review with metaanalyses of 10 studies reported that PRP promotes chronic diabetic wound healing (RR = 1.32; 95%CI:1.11-1.57,

= 15%) by reducing the volume and time of wound healing[160]. PRP may act

promoting the proliferation of wound cells, upregulation of cyclin A and cyclin-dependent kinase 4 proteins,modification of macrophage phenotype, reduction of TNF-α, enhancement of TGF-β and VEGF,increased secretion of fibroblast of collagen type I and III[161].

Several treatments /medicines have been successfully investigated clinically for their beneficial effects on the diabetic wound, especially in DFUs which was tabulated in Table 1[132-159].

A systematic review of 26 randomized controlled trials (RCTs) examined the usefulness of different recombinant proteins and growth factors in the treatment of DFU. EGF can be used as intralesional injection, topical cream, or gel. This meta-analysis reported that EGF significantly improves wound healing and the study failed to find a significant effect of EGF in reducing the risk of amputation[162].Decreasing the level of circulating C-reactive protein, decreasing NFκB1, TNF-α, and IL-1a expression,and increasing the wound expression of platelet-derived growth factors (PDGF)-B, cyclin-dependent kinase 4, P21, TP53, angiopoietin 1, collagen 1A1, MMP-2, and TIMP-2 after the treatment with hEGF may be linked to its beneficial effect[161]. Recombinant human PDGF (rhPDGF) also exhibits their beneficial effect in several clinical studies[143,144], but few clinical studies also failed to find statistically significant effects of rhPDGF compared to the control group[163,164] when used to cure DFU. The effectiveness of PDGF may be related to the promotion of fibroblast and leukocyte migration, and synthesis of extracellular matrix[161]. FGF, a family of cell signaling proteins, is found to stimulate angiogenesis, induce fibroblasts proliferation, and promote wound healing. About 23 subtypes of FGF from 7 subfamilies were identified[165]. Some clinical studies have reported the beneficial effect of FGF in diabetic wound[145], some studies failed to report the advantageous effect of FGF over the placebo group[166], while clinical studies reported the beneficial effect of combined use of human EGF and acidic FGF on wound healing in the later stage[167]. Very few clinical studies evaluated the effectiveness of granulocyte-colony-stimulating factor, topical telbermin, epoetin-β, talactoferrin, TGF-β2 in the diabetic wound. But the results are inconsistent[162].

LLLT was found to increase blood flow and regulation of the autonomic nervous system in patients suffering from DFU[151]. Reduce wound inflammation, enhance fibroblasts and angiogenesis[161],which may play an important role in diabetic wound healing. A metanalysis of 13 RCTs that included 413 patients concluded that LLLT significantly enhanced complete healing rate (RR = 2.10, 95%CI: 1.56-2.83,

< 0.00001), decreased wound ulcer area, and reduce mean healing time of wound healing in patients suffering from DFU[171].

It was evaluated that NPWT results in macro- and micro-deformation that stimulate different wound healing cascade like promotion of tissue granulation, epithelialization, proliferation of vessel, neoangiogenesis, pro-angiogenic condition, removal of surplus extracellular fluid, anti-inflammatory effect,increase expression of VEGF, FGF2, modification of circulating micro-RNAs, alteration of DNA methylation of genes linked with wound repair[161,168]. Liu

[169] in their study (meta-analysis of 11 RCTs) concluded that NPWT is a safe, cost-effective and effective strategy in the treatment of DFU,while Liu also evaluated 11 RCTs and found that compared with wound dressings NPWT may enhance the proportion of wounds healed, decrease the time of postoperative foot wound healing[170].

Oxygen therapy is found to improve cell metabolism and energy, decrease proinflammatory cytokines and ROS, and promote the synthesis of matrix and wound repair[161]. Few clinical studies confirmed the beneficial effect of hyperbaric as well as topic oxygen therapy in promoting diabetic wound[146,147]. A systematic review and meta-analysis of 20 RCTs and 1263 trials analysed that hyperbaric oxygen therapy confer benefits in DFU treatment by increasing the healing of ulcers (relative risk, 1.901; 95%CI: 1.484-2.435,

< 0.0001), reducing healing time, and also decrease the risk of major amputation[148].

In recent studies, neuropathy, peripheral vascular disease, and impaired wound healing have all been identified as key contributors to diabetic wounds and have all become critical targets in improving wound healing in diabetic patients. But despite of this well-established knowledge, comparatively fewer treatment options are being implemented in routine practice. The expression of cellular components of participating cells, as well as cytokines, growth factors, and other molecular factors required for coordinating the normal healing process, is impaired in diabetic wounds, and as a result, they are unable to progress in synchrony and are primarily checked in the inflammatory phase. Therapeutic strategy targeting such cellular and molecular pathway could be useful for effective management of diabetic wound.

Huang

[172] performed a meta-analysis of 8 RCTs and concluded that ESWT treatment reduced wound surface area in greater proportion, enhances re-epithelialization and can reduce treatment inefficiency. ESWT is useful as an adjuvant strategy in the management of DFUs, which can improve the complete wound cure rate and reduce the healing period of DFUs. ESWT may enhance the angiogenesis process, decrease macrophage number, and enhance the production of macrophage of growth factors from macrophages that help in the healing of wound[161].

In light of current evidence, it can be suggested that stem cell-based therapy (delivery through both local and systemic route is effective to heal DFU and considered a promising regenerative medicine, and mechanisms of stem cell therapy include improved angiogenesis, decrease inflammation, ameliorating neuroischemia, improved collagen deposition,

[173].

Wound healing in diabetic people can be promoted by providing endogenous or exogenous NO.Products (

, patches/ matrices) that release NO are used to treat diabetic wounds by different mechanisms like enhancement of angiogenic activity, endothelial cell proliferation, conferring antimicrobial substances, and promoting cell migration to the injured site[174]. Only a few clinical studies have reported the beneficial effects of NO-releasing devices, and several products are in the clinical trial.

Homeopathic medicines (like silicea, sulphur, lycopodium, and arsenic) were also investigated in the clinical trial and concluded that homeopathic medicine may be useful in the management of diabetic wounds[132,133]. Several other products, like honey, fish skin grafts,

were also clinically investigated for their beneficial effects against DFU[158,159]. Further, several herbal products were also successfully investigated in the treatment of diabetic wound[134,135,136-138].

MEDICINAL PLANTS AND PHYTOCONSTITUENTS IN DIABETIC WOUND

Medicinal plants and phytoconstituents always represent an important, effective and alternative treatment strategy to cure diseases. Phytochemicals have showed their effectiveness in different diabetes complications. Anti-inflammatory mechanism of phytochemicals is considered important in the management of diabetes wound. Epigallocatechin gallate in pre-clinical investigation was found to reduce reduced levels of IL-1β, TNF-α and IL-6, producing inhibition of Notch signaling and accumulation of macrophage at a wound site. Kaempferol, is an important dietary flavonoid found to exert different pharmacological activities, including antioxidant, anti-inflammatory and cardioprotective activity. An ointment containing Kaempferol was found effective in diabetic excisional and non-diabetic incisional wounds in experimental animals[175]. Flavonoids an important class of phytoconstituents,exerted anti-inflammatory and antioxidant effect, and also enhances angiogenesis and re-epithelialization. Preclinical trials found the effectiveness of isoliquiritin, isoflavonoid, naringenin,dihydromyricetin, dihydroquercetin, quercetin, hesperidin, kaempferol, proanthocyanidins, icariin,puerarin, rutin, genistein, luteolin, rutoside, silymarin, daidzein, genistein, and epigallocatechin gallate to cure wound[174]. Flavonoids positively regulate MMP-2, MMP-8, MMP-9, MMP-13, Ras/Raf/MEK/ERK, PI3K/Akt, and NO pathways. Phytochemicals are found to reduce oxidative stress,expression/release of proinflammatory/inflammatory cytokines,

, TNF-α, IL-1β, IL-6, NF-κB and upregulate IL-10 and antioxidant enzymes. Flavonoids also act on macrophages, fibroblasts and endothelial cells by facilitating expression/release of TGF-β1, VEGF, angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains, and small mothers against decapentaplegic 2 and 3[176]. Oguntibeju[177] in his paper highlighted different medicinal plants like

,

,

,

,

,

,

,

,

,

, and

that has been investigated in the treatment of diabetic wound. Benefits of the plants may link to different mechanisms like an increase in fibroblast cell, fibroplasia, increase in collagen formation, enhancement of tissue regeneration, angiogenesis, antimicrobial, anti-inflammatory and antioxidant effect. A recent clinical study established the effectiveness and safety of nano-hydrogel embedded with quercetin and oleic acid when used in the management of lower limb skin wound in diabetic patients. The formulation effectively treated the wound and reduce the wound healing time compared to the control group[178].Infections caused by different microbes like

,

β-hemolytic

,

,

,

,

,

. and anaerobes are posing a serious situation in diabetic people[126]. Medicinal plants and phytochemicals with antimicrobial activity may also play an important role in the management of diabetic wound.Several plants have shown their potential against the microbial strain responsible for infection in the diabetic wound[126]. Formulation designed with

,

,

,

,

,

,

, and

has shown their potential in the treatment of diabetic wound[126]. Isoflavones isolated from plant sources were also found to be effective against DFU bacteria[179] Phytofabricated silver nanoparticles (

reduced silver nanoparticles) at 20 μg/mL were found highly effective against multi antibiotic-resistant DFU isolates like

,

,

. Identified phytochemicals of

include rutin,quercetin, kaempferol, gallic acid and ellagic acid[180]. The use of phytoextracts/active compounds may be considered as an important strategy for addressing the wound problem associated with DM in a better way.

CONCLUSION

Diabetes adversely acts on the phases of normal wound healing phases, i.e., hemostasis, inflammatory phase, proliferative phase, re-epithelialization and remodeling phase, and poses a big burden on the quality of life of a diabetic individual. Hyperglycemia can trigger oxidative stress, increase inflammatory cytokines, interrupt angiogenesis, decrease the functioning of fibroblast and keratinocyte,induce neuropathy associated events, increase MMPs, and reduce TIMPs that is responsible for impaired states of wound healing. An understanding sequence of the molecular and cellular cascade,epigenetic mechanisms, microbial perspective, complexity and plasticity of impaired wound healing in diabetic conditions is required for targeted research focusing on treatment of diabetic wound. Pharmacotherapy/strategy involving angiogenesis stimulation, growth factors, cytokines modulators, MMP inhibitors, ECM stimulators, anti-inflammatory drugs, antidiabetic agents, antimicrobial drugs,debridement, offloading, PRP, oxygen therapy, NPWT, LLLT, ESWT, stem cells, bio-engineered substitutes, and various natural-based products have shown their benefit. There has been a lack of quality-based evidence of efficacy of different adjuvant therapies tested through different clinical trials,thus more structured and quality studies are required. Indeed, the utilisation of medicinal plants/products in diabetic wound care holds prodigious potential in the future, and the development of innovative pharmaceutical formulations for advanced wound care is equally critical. Effective diabetic wound management necessitates a combination of techniques, including medication and nonpharmacological intervention. Hence, the treatment strategy of the future can only succeed if research concentrated on plausible drug targets after comprehending the inherent pathological complexities,evaluating non-pharmacological approaches through well-designed clinical trials, and targeting natural sources for new drug development.

The whole court applauded her with hands and tails; and for a moment her heart felt quite gay, for she knew she had the loveliest voice25 of any on earth or in the sea

FOOTNOTES

Chakraborty R, Borah P, Sen S, Dutta PP performed data accusation and writing; Borah P,Dutta PP prepared the figures; Chakraborty R provided the input in writing the paper; Sen S designed the outline and coordinated the writing of the paper.

There is no conflict of interest associated with any of the authors contributed their efforts in this manuscript.

I tried to be invisible within a sea of faces. I wanted to run away. Disappear. Most of all I wanted no one to guess whose kid I was. I was betrayed by my last name, which began with the letter A, so I was the first graduate on the first row; Being a red-head gave me even more exposure, and the baccalaureate（） speaker, who had never met me, decided6 to use me as his audio-visual aid.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

India

Raja Chakraborty 0000-0002-2097-9178; Pobitra Borah 0000-0003-1047-4552; Partha Pratim Dutta 0000-0003-0907-3030; Saikat Sen 0000-0002-5279-1532.

Halloa! you Turkish nurse, said he, what is that great castle there close to the town? The one with the windows so high up? The sultan s daughter lives there, she replied

Chang KL

A

Chang KL

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