Natural products in the treatment of diabetic foot infection

Abstract

Diabetic foot infections (DFIs) are a significant complication in diabetes mellitus, leading to increased morbidity, hospitalizations, and healthcare burdens. The growing prevalence of antibiotic-resistant pathogens has reduced the efficacy of conventional treatments, highlighting the need for alternative therapeutic strategies. Natural products, known for their antimicrobial, anti-inflammatory, and wound-healing properties, have garnered attention as potential treatments for DFIs. This review examines key natural compounds, including eugenol, thymol, carvacrol, curcumin, and Aloe vera, and their mechanisms of action in combating diabetic infections. We analyze the antimicrobial efficacy of these compounds, their ability to inhibit biofilm formation, and their role in wound healing. The review also explores challenges in integrating natural products into clinical practice and the potential for their use alongside or in place of traditional antibiotic therapies. Our findings suggest that natural products could play a crucial role in developing sustainable and effective treatment strategies for DFIs, especially in the face of rising antimicrobial resistance.

Introduction

Diabetes mellitus (DM) is a chronic disease that has been rapidly increasing in prevalence worldwide, impacting millions of people [1]. As of 2021, approximately 485 million people were diagnosed with DM, and this number is projected to rise to 578 million by 2030 [2]. As the number of diabetes cases continues to grow, so does the occurrence of related complications and hospitalizations, creating significant challenges for healthcare systems globally [3]. One of the most severe complications is diabetic foot infections (DFIs), which contribute to a large proportion of diabetes-related hospital admissions [4]. People with diabetes have a 50-fold higher risk of hospitalization due to DFIs compared to non-diabetic individuals [5].

The conventional treatment of DFIs typically involves the use of antibiotics and advanced wound care management [6]. However, the rising threat of antibiotic resistance has made it increasingly difficult to treat these infections effectively [7]. As a result, there is a growing interest in exploring alternative therapies that can either complement or replace conventional antibiotics. Among these alternatives, natural products have shown significant promise due to their antimicrobial, anti-inflammatory, and wound-healing properties [8].

Natural products, derived from plants, microorganisms, and other natural sources, have long been extensively in traditional medicine and are now gaining recognition in modern healthcare for their therapeutic potential [9, 10]. These compounds offer unique mechanisms of action, making them particularly suitable for addressing complex infections such as DFIs [11, 12].

This review aims to explore the current understanding of natural products in the treatment of DFIs, focusing on their antimicrobial, wound healing, and anti-inflammatory properties. We will examine key compounds derived from medicinal plants, essential oils, and other natural sources, as well as their mechanisms of action, clinical efficacy, and potential for integration into modern DFIs management protocols. By highlighting these natural alternatives, this review seeks to provide insights into developing more sustainable and effective strategies for treating DFIs, particularly in the face of the global rise of antibiotic resistance.

Pathophysiology of diabetic foot infections

The development of DFIs is driven by a complex interplay of metabolic dysfunction, neuropathy, angiopathy, and immune system changes (Fig. 1) [13]. These factors contribute to the progression of DFIs and can lead to severe complications such as diabetic neuroarthropathy [14]. The pathophysiology of DFIs involves endothelial dysfunction, ischemia, impaired immune response, and neuroarthropathy, all of which are interlinked through various metabolic and vascular pathways [14]. In particular, metabolic imbalances, diabetic neuropathy, and angiopathy promote DFIs by disrupting the body’s normal defense mechanisms and tissue repair processes [15].

Fig. 1

Pathophysiology of diabetic foot infections (DFIs)

Metabolic dysfunction

In diabetes, metabolic dysfunction affects the nervous system by reducing blood supply to nerves, particularly in the peripheral nervous system, where the long axons are vulnerable to damage [16]. Hyperglycemia, the hallmark of diabetes, leads to several pathological processes, including ATP deficiency, oxidative stress, activation of the polyol pathway, and protein kinase C (PKC) activity [17]. These processes collectively contribute to peripheral nerve damage by impairing axonal transport and inducing axonal degeneration [18]. Excessive oxidative stress and accumulation of harmful by-products like sorbitol and fructose further exacerbate nerve injury, while PKC activation leads to vascular dysfunction and worsens microvascular complications [19].

Diabetic immunopathy

Diabetes also impairs the immune system, reducing the body’s ability to fight infections [20]. Hyperglycemia leads to the overproduction of reactive oxygen species (ROS), which not only damages tissues but also triggers the formation of advanced glycation end-products (AGEs) [20]. These AGEs inhibit nitric oxide (NO) production, crucial for proper wound healing, and contribute to oxidative stress [21]. The excessive ROS in diabetic wounds delays healing and increases vulnerability to infections [21]. In addition, vascular damage from oxidative stress leads to microcirculation issues, further impairing wound repair and creating a favorable environment for infection [21].

Diabetic neuropathy

Neuropathy is one of the most prevalent complications in diabetic patients, significantly impacting sensory, motor, and autonomic functions [22]. More than 60% of diabetic foot ulcers (DFUs) are attributed to underlying neuropathy, with risk increasing proportionally to the duration of diabetes [23]. Damaged nerve endings impair pain perception, allowing unnoticed injuries to progress into ulcers [24]. Motor neuropathy contributes to foot deformities, while autonomic neuropathy results in dry, cracked skin that is more susceptible to injury and infection [25]. The combination of sensory, motor, and autonomic neuropathy leads to biomechanical imbalances in the foot, increasing the risk of ulceration and infection [26].

Diabetic angiopathy

Angiopathy, or vascular damage, is another critical factor in the pathogenesis of DFIs [14]. Hyperglycemia damages endothelial cells, leading to reduce NO production and increased vasoconstriction, platelet aggregation, and atherosclerosis [27]. Peripheral arterial disease, common in diabetic patients, impairs blood flow to the extremities, causing ischemia and delaying wound healing [28]. Atherosclerosis further complicates the condition by promoting vascular smooth muscle proliferation and platelet aggregation, leading to thrombosis and an increased risk of infections in ischemic tissues [29].

Traditional treatments for diabetic foot infections

Antibiotics and their limitations

Antibiotics remain the cornerstone of treatment for DFIs, with the choice of therapy guided by the infection's severity and the involved pathogens. For mild to moderate infections, oral antibiotics such as amoxicillin–clavulanate, clindamycin, or doxycycline are often sufficient to address common gram-positive bacteria like Staphylococcus aureus and Streptococcus species [30, 31]. In more severe cases, intravenous antibiotics, including vancomycin, piperacillin–tazobactam, and carbapenems, are necessary to cover a broader spectrum of pathogens, including gram-negative organisms and anaerobes [32]. Despite their importance, antibiotics face significant limitations. In diabetic patients with poor peripheral circulation, drug delivery to infected tissues is compromised, reducing efficacy [33]. In addition, bacterial biofilm formation, particularly by S. aureus, can shield pathogens from antibiotic action, leading to chronic, hard-to-treat infections [34]. Prolonged antibiotic use also introduces risks of adverse effects, such as gastrointestinal disturbances, nephrotoxicity, and hepatotoxicity, especially in older patients with multiple health issues [35].

The rise of multidrug-resistant bacteria

A major challenge in treating DFIs is the increasing prevalence of multidrug-resistant organisms (MDROs) [36]. Pathogens such as methicillin-resistant S. aureus (MRSA), extended-spectrum beta-lactamase producing gram-negative bacteria, and carbapenem-resistant Enterobacteriaceae are becoming more common [37, 38]. These resistant strains are difficult to treat with standard antibiotics, necessitating the use of more expensive or toxic alternatives like vancomycin, daptomycin, and polymyxins [39]. The rise in MDROs complicates treatment regimens, leading to prolonged hospitalizations, increased risk of severe complications like osteomyelitis and sepsis, and an overall greater healthcare burden [40, 41].

Surgical interventions and wound care

Surgical intervention is crucial in managing DFIs, particularly for infections involving deep tissue or bone, such as osteomyelitis [31]. Debridement, which involves the removal of necrotic tissue, is essential for reducing bacterial load and promoting wound healing [42]. In severe cases, amputation may be necessary to prevent the spread of infection and save the patient's life [43]. While amputation is a last resort, it has been shown to improve life expectancy in severe cases. Efforts to avoid amputation focus on limb-salvage procedures, such as revascularization, which can restore blood flow, enhance wound healing, and reduce complications [44]. Post-operative care is vital to improve mobility and quality of life following amputation [45].

Wound care complements antibiotics and surgical interventions in DFIs management. Specialized dressings, including hydrogels, hydrocolloids, and alginates, maintain a moist environment conducive to healing [46]. Antimicrobial dressings with silver or iodine help control bacterial growth and infection risk [47]. Negative pressure wound therapy applies controlled suction to the wound, promoting blood flow and reducing edema to accelerate tissue regeneration [48]. In addition, offloading devices, such as custom footwear or orthotics, are essential for redistributing pressure on ulcerated areas, particularly for patients with DFUs deformities. These devices prevent further damage and support faster recovery [49].

Despite the advances in surgical interventions and wound care, managing DFIs remains a significant challenge, particularly when deep tissues or bones are involved [50]. Surgical procedures, such as debridement and limb salvage techniques, are often complex and can carry risks, including delayed wound healing and recurrence of infection [51]. Moreover, the reliance on amputation in severe cases underscores the limitations of current treatments and the pressing need for more effective strategies to prevent infections from reaching such critical stages [52].

Natural products with antimicrobial properties

Natural products have long been recognized for their therapeutic potential, especially in combating infections. These products, derived from plants, herbs, and other natural sources, offer diverse chemical compounds that can serve as alternatives or complements to conventional pharmaceuticals (Fig. 2) [53]. Here, we highlight recent studies on the antimicrobial effects of natural products specifically applied to the management of DFIs (Tables 1 and 2).

Fig. 2

Structure and chemical formula of active compounds in natural products

Table 1 Overview of natural products research on bacterial diabetic foot infections

Table 2 Antimicrobial mechanisms of natural products

Eugenol

Eugenol, a phenolic compound primarily found in clove oil, has garnered attention for its potent antimicrobial and anti-inflammatory properties, making it a promising candidate for the treatment of infections, particularly those complicated by antibiotic resistance [54, 55]. Structurally, eugenol features a free hydroxyl group and a hydrophobic aromatic ring, which contribute to its diverse biological activities [56].

The antimicrobial activity of eugenol is attributed to its ability to disrupt bacterial membranes, facilitated by its hydrophobic nature and the presence of a free hydroxyl group in its structure. This disruption compromises membrane integrity, causing leakage of intracellular components and ultimately leading to cell death [56, 57]. Eugenol also interacts with various cellular enzymes, inhibiting critical functions such as protease, amylase, and ATPase activity [58]. In addition, it induces the production of ROS, which can inhibit cell growth, damage membranes, and degrade DNA [59]. These multifaceted mechanisms enhance its effectiveness and also synergize with conventional antimicrobial agents [60].

Several studies have highlighted eugenol’s diverse applications. Ali et al. investigated the efficacy of clove flower extract (CFE), containing eugenol, against multidrug-resistant Proteus mirabilis isolated from DFUs. Their findings demonstrated that topical application of CFE hydrogel improved wound healing parameters, enhanced expression of growth factor signaling pathways, and reduced inflammatory cytokines, oxidative stress, and microbial load, suggesting CFE as a viable alternative to antibiotics for DFU therapy [61]. Gupta et al. developed eugenol-based nanofibers, with a focus on their dual wound-healing and antibiofilm properties. These nanofibers exhibited significant efficacy against Candida albicans, C. tropicalis, and other Candida species biofilms, and notably accelerated wound healing in vivo [62]. Similarly, Obuotor et al. examined the antimicrobial effects of essential oils from turmeric and clove on bacteria implicated in DFUs, including Salmonella paratyphi, S. arizona, Pseudomonas aeruginosa, P. fluorescens, Citrobacter species, Enterococcus faecalis, Enterobacter cloacae, P. mirabilis, P. vulgaris, Escherichia coli, S. aureus, Bacteroides fragilis, and Peptostreptococcus species. Their research revealed that clove oil, which is rich in eugenol, demonstrated the highest inhibitory activity, including against P. mirabilis, thereby highlighting its potential for developing natural antimicrobial agents [63].

Eugenol's anti-inflammatory activity is equally significant. It inhibits several pro-inflammatory mediators, including cytokines such as IL-1β, IL-6, and TNF-α, as well as pathways involving prostaglandins (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and leukotrienes (5-LOX). These actions help reduce inflammation by modulating the immune response and limiting oxidative stress [64]. Eugenol also prevents chemotaxis of neutrophils and macrophages, thereby inhibiting inflammatory neurotransmitter synthesis (Fig. 3) [65].

Fig. 3

Diverse anti-inflammatory mechanisms of seven natural products: eugenol, thymol, carvacrol, curcumin, Aloe vera, neem, and resveratrol

Bioinformatics studies suggest that eugenol's dual inhibition of COX-2 and 5-LOX could make it a promising natural alternative to nonsteroidal anti-inflammatory drugs for managing inflammatory diseases such as osteoarthritis or cancer [64]. Its anti-inflammatory properties further extend to blocking voltage-gated sodium channels in nerve cells, reducing pain perception, and offering potential analgesic benefits [66, 67].

Jiang et al. explored eugenol’s protective role in diabetes-induced muscle dysfunction, demonstrating that oral administration of eugenol at 10 mg/kg significantly reduced inflammation and insulin resistance while enhancing glucose uptake through GLUT4-AMPK signaling pathways [68]. Alharthy et al. evaluated the neuroprotective effects of isoeugenol and eugenol at 20 mg/kg in diabetic polyneuropathy, showing improvements in oxidative stress, inflammation, and behavioral deficits, with synergistic benefits observed in their combined use [69]. Trad et al. reported eugenol’s ability to improve insulin sensitivity, reduce hyperglycemia, and modulate GLUT4 and AMPK protein levels in diabetic rats treated with 10 mg/kg eugenol, supporting its role as a therapeutic agent for type 2 diabetes [70]. Finally, Qar et al. investigated eugenol's potential to mitigate diabetic cardiomyopathy, demonstrating that treatment with eugenol at 20 mg/kg effectively reduced myocardial oxidative stress, inflammation, fibrosis, and hyperglycemia, further establishing its therapeutic versatility [71].

Thymol

Thymol, a naturally occurring monoterpenoid phenol, is one of the primary bioactive components of thyme (Thymus vulgaris) and other aromatic plants [72]. Its chemical structure, characterized by a phenolic hydroxyl group attached to a hydrocarbon ring, underpins its biological activity [73]. Thymol has been extensively studied for its antimicrobial, anti-inflammatory, and antioxidant properties, which contribute to its therapeutic potential in managing infections, inflammatory conditions, and oxidative stress [74]. Beyond its traditional use in herbal medicine, thymol has gained recognition as a potent agent against various pathogens, including antibiotic-resistant strains, making it a valuable natural compound in the era of antimicrobial resistance [75].

The antimicrobial properties of thymol are broad-spectrum, encompassing bacteria, fungi, and even some viruses [76]. A critical mechanism of action is its ability to disrupt the integrity of bacterial cell membranes, attributed to its lipophilic nature [77]. This disruption compromises membrane permeability, causing leakage of intracellular components and leading to cell death. In addition, thymol inhibits biofilm formation, a protective strategy employed by many pathogens to evade antimicrobial agents, and can induce bacterial autolysis, further enhancing its effectiveness [78, 79]. Studies have shown that thymol-rich extracts are highly efficacious at low concentrations, emphasizing its potency [80, 81]. Furthermore, the antimicrobial activity of thyme oil, a primary source of thymol, varies with plant growth stages, correlating with fluctuations in thymol content, suggesting the significance of optimizing harvesting practices to maximize therapeutic efficacy [82].

Thymol has demonstrated anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and MCP-1, in cellular and animal models [83, 84]. It suppresses key inflammatory pathways, including the NF-κB pathway, by inhibiting phosphorylation of mediators like IKK, IκΒα, and NFκΒp65 [84]. These actions decrease downstream inflammatory markers such as PGE2, MCP-1, and IL-6. In clinical studies, thymol-containing varnishes have shown efficacy in reducing gingival inflammation and PGE2 levels [85]. Moreover, combinations of thymol and carvacrol reduce the production of IL-25, IL-33, and TSLP in bronchial epithelial cells, potentially through upregulation of negative regulators like SHIP-1 and SOCS-1 [86].

Salemi et al. synthesized chitosan and zinc oxide nanoparticles with thymol and tested their antimicrobial efficacy against S. aureus isolates from diabetic ulcers. The nanoparticles demonstrated strong antibacterial activity, significantly reducing bacterial growth and virulence gene expression [87]. Yuan et al. investigated the ability of thymol to inhibit biofilm formation and eradicate mature biofilms in MRSA. The study demonstrated that thymol could inhibit biofilm formation and eliminate established biofilms by reducing the production of polysaccharide intracellular adhesin and extracellular DNA (eDNA). The combined treatment of thymol and vancomycin showed greater efficacy in eradicating MRSA biofilms compared to vancomycin alone. Thymol also reduced inflammatory responses in a mouse infection model, lowering white blood cell counts and decreasing serum TNF-α and IL-6 levels [88].

Martirosyan et al. assessed the effects of thymol administration and low-level laser therapy on inflammatory and oxidative indicators in type 2 diabetes patients. In this study, the diabetic group was treated with thymol (25 mg/kg/day for 30 days). The results showed a significant reduction in inflammatory cytokines (TNF-α, IL-1β) and oxidative markers (malondialdehyde, hydrogen peroxide) in the thymol-treated group. In addition, thymol gel (0.5%) was studied for its potential to reduce dermatitis in the feet of diabetic patients, though this effect was not statistically significant. These findings suggest that thymol can aid in controlling diabetes-related complications through its antioxidant and anti-inflammatory properties [89]. Hamed Shosha et al. compared the therapeutic effects of T. vulgaris essential oil, which contains thymol, on peptic ulcers and ulcerative colitis (UC) induced by ethanol in rats. The study found that thymol-rich T. vulgaris essential oil significantly modulated oxidative stress markers, increasing glutathione (GSH) levels by 120.43% in the peptic ulcer model and reducing malondialdehyde levels by 20.05%. In addition, thymol treatment significantly decreased the inflammatory marker (PGE2) and restored stomach and colon function markers in both ulcer and UC models. These results highlight the potential of thymol as an effective treatment for ulcer-related diseases through its antioxidant and anti-inflammatory effects [90]. Oskouei et al. evaluated the positive and protective effects of thymol on streptozotocin-induced (STZ-induced) diabetic rats. In this study, thymol was administered at doses of 20 and 40 mg/kg. The results indicated significant anti-hypoglycemic and anti-hypolipidemic effects, as well as improvements in antioxidant enzyme levels in the liver and kidney. Thymol treatment also resulted in decreased levels of creatinine, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and liver function-related enzymes (AST and ALT), suggesting its potential as a protective agent against diabetic complications in animal models [91].

Carvacrol

Carvacrol, a monoterpenoid phenol derived from the essential oils of oregano (Origanum vulgare) and thyme (T. vulgaris), has garnered significant attention for its therapeutic potential [92]. Its unique structure, characterized by a hydroxyl group attached to a phenolic ring, grants it hydrophobic and reactive properties, enabling interactions with biological membranes and enzymes [93]. Carvacrol has demonstrated potent antimicrobial and anti-inflammatory activities, particularly in the context of chronic wound management, such as diabetic wounds [94]. Its multifaceted mechanisms of action make it a promising candidate for addressing both infections and inflammation associated with such conditions.

Carvacrol exhibits potent antimicrobial activity by interfering with the structural integrity of bacterial cell walls, leading to damage and cell death. It is believed to act by inhibiting the activity of cell wall enzymes, which disrupts the bacterial cell wall, thus inhibiting growth [95]. In addition, carvacrol induces rapid bactericidal effects by causing morphological changes and cytoplasmic leakage, resulting in cell damage [96]. This antimicrobial mechanism is further supported by carvacrol's ability to disrupt the cell membrane, increasing permeability and causing leakage of intracellular contents [96, 97].

In addition to its antimicrobial properties, carvacrol has shown significant anti-inflammatory effects. It protects cells against inflammation, oxidative stress, and apoptosis, particularly under conditions of high glucose levels. This protection is largely attributed to its ability to inhibit the transient receptor potential melastatin 2 (TRPM2) cation channel, which prevents excessive calcium influx and ROS generation [98]. Carvacrol also enhances the activity of antioxidant enzymes like glutathione and glutathione peroxidase, thereby reducing oxidative stress [98]. These anti-inflammatory properties are further evidenced by carvacrol’s ability to suppress the production of pro-inflammatory cytokines and markers such as IL-6, IL-8, ENA-78, GCP-2, PGE2, and COX-2 [99].

Several studies have explored carvacrol's effects in treating diabetic wounds and chronic infections. Altememy et al. evaluated the restorative effect of titanium dioxide nanoparticles (TiO2NPs) synthesized with O. vulgare, carvacrol, and other plant compounds on infected wounds in diabetic rats. The study found that treatment with TiO2NPs synthesized by carvacrol reduced wound microbial load and inflammation, accelerating wound healing compared to the control groups. The bacteria involved in the study was S. aureus (ATCC 12600), and the rats treated with carvacrol showed significant improvements in wound healing, including reduced size and microbial load, highlighting its potential as an effective remedy for chronic diabetic wounds [100]. Mir et al. further demonstrated the antimicrobial potential of carvacrol, especially when formulated into a nanoparticle delivery system for sustained release at infection sites. In their study, carvacrol-loaded poly (caprolactone) nanoparticles (PCL NPs) enhanced antimicrobial activity, with a 2–fourfold increase in efficacy compared to free carvacrol. The system also showed superior skin retention, with carvacrol-PCL NPs maintaining 83.8 ± 5.15% skin retention after 24 h [101].

In another study, Dezfuli et al. examined the use of carvacrol for managing diabetes-related complications. Diabetic rats were treated with 5, 10, or 15 mg/kg body weight/day of carvacrol, which significantly decreased levels of inflammatory markers like IL-1β, IL-6, and TNF-α, and improved antioxidant status by increasing the activities of enzymes such as catalase and superoxide dismutase. Notably, the 15 mg/kg dose showed the most pronounced effects, underscoring carvacrol's potential to mitigate inflammation and oxidative stress in diabetic conditions [102]. Marinelli et al. investigated the use of water-soluble carvacrol prodrugs (WSCPs) combined with hyaluronic acid (HA) to enhance wound healing. Their study demonstrated that WSCPs/HA formulations significantly increased the rate of wound closure compared to individual components. The formulations modulated inflammatory mediators, improving wound repair by regulating macrophage activity and promoting collagen synthesis [103].

Fauzian et al. focused on overcoming the challenges of carvacrol's hydrophobicity and potential skin irritation by formulating it into nanostructured lipid carriers (CAR–NLC). This formulation not only improved carvacrol’s stability and skin penetration but also enhanced its antimicrobial, antioxidant, and anti-inflammatory activities. The CAR–NLC showed superior wound healing in diabetic mice, with a 97.56% wound closure rate by day 15 [104].

Curcumin

Curcumin, a polyphenolic compound classified as a diarylheptanoid, is one of the primary curcuminoids derived from the rhizome of Curcuma longa, a plant commonly known as turmeric [105]. Turmeric has been extensively used in traditional medicine systems, particularly in Asia, due to its diverse therapeutic properties [106]. Curcumin is the most active bioactive component of turmeric, accounting for its characteristic yellow color and a wide range of pharmacological activities [107]. It has attracted significant scientific attention due to its potent antimicrobial, anti-inflammatory, and antioxidant properties, making it a promising candidate for managing various diseases, including chronic wounds such as DFUs [108].

One of its key antimicrobial actions is the disruption of bacterial cell membranes, leading to leakage of cellular contents and subsequent cell death. Curcumin also inhibits quorum sensing, a bacterial communication system that plays a critical role in virulence factor production, thus reducing bacterial pathogenicity [109]. Despite its promising effects, curcumin's therapeutic potential is limited by its poor bioavailability, resulting from rapid metabolism and low absorption [110].

In addition to its antimicrobial activity, curcumin exerts significant anti-inflammatory effects. It is a powerful inhibitor of NF-κB, a transcription factor involved in the regulation of inflammatory responses, by preventing its translocation to the nucleus and blocking the expression of pro-inflammatory mediators [111]. Curcumin also directly inhibits the activity of COX-2 and iNOS, enzymes responsible for the production of inflammatory compounds such as prostaglandins and NO [112]. Furthermore, curcumin demonstrates antioxidant properties by scavenging ROS, thereby protecting cells from oxidative damage and enhancing its antimicrobial effects [113]. It also modulates immune cell function, promoting a shift toward a less inflammatory phenotype, and interferes with key signaling pathways, including the MAPK cascade, involved in the inflammatory process [112].

Recent studies have provided further evidence of curcumin's efficacy in diabetic wound healing and its interaction with antimicrobial therapies. For example, Taghavifar et al. investigated the therapeutic potential of curcumin nanoparticles in diabetic wounds infected with MRSA. Their results indicated that curcumin nanoparticles, when combined with HAMLET (human α-lactalbumin made lethal to tumor cells), significantly improved wound healing in MRSA-infected diabetic wounds. The combination therapy, compared to other treatments, showed a remarkable reduction in bacterial load and improved histological parameters, including granulation tissue formation and collagen deposition [114]. Similarly, Muniz et al. explored the use of photodynamic therapy (PDT) with curcumin for treating MRSA infections in a diabetic mouse model. Their study found that PDT, when combined with curcumin, reduced bacterial load and inflammatory cytokine expression, offering an innovative strategy for managing chronic wound infections [115].

Moreover, Ranjbar-Mohammadi et al. demonstrated the potential of curcumin-loaded poly (ε-caprolactone) (PCL)/gum tragacanth nanofibers for wound healing in diabetic rats. These nanofibers exhibited antibacterial properties against both MRSA and extended-spectrum β-lactamase (ESBL) bacteria. The study highlighted the nanofibers' ability to accelerate wound closure, promote fibroblast proliferation, and enhance collagen deposition, which were not observed in untreated controls [116]. In addition, the study by Tong et al. introduced curcumin-loaded cellulose nanocrystal films as a drug delivery system for diabetic wound healing. These films exhibited sustained antimicrobial effects against various pathogens, including MRSA, and significantly reduced bacterial growth, thus promoting wound healing in diabetic rat models [117]. Finally, Sami et al. investigated the use of a combination of turmeric extract, oregano, and chitosan nanoparticles in wound care formulations for diabetic wound healing. Their findings demonstrated that this combination exhibited significant antibacterial activity against S. aureus and E. coli, with the potential for application in both diabetic and non-diabetic wounds. The ointment and hydrogel formulations, in particular, showed a marked improvement in wound healing compared to commercial dressings [118, 119].

Aloe vera

Aloe vera (L.) Burm. f., a succulent plant belonging to the Asphodelaceae family, has been valued for centuries for its medicinal properties [120]. The gel extracted from its leaves is rich in bioactive compounds, including polysaccharides, glycoproteins, enzymes, vitamins, and anthraquinones, which contribute to its diverse therapeutic effects [121]. In modern medicine, Aloe vera has garnered attention for its potent antimicrobial, anti-inflammatory, and wound-healing properties, making it a promising candidate for managing chronic wounds such as DFUs [122]. The plant's ability to modulate inflammation, combat microbial infections, and promote tissue repair underscores its relevance in addressing the complex pathophysiology of DFUs [123].

The antimicrobial activity of Aloe vera is largely attributed to anthraquinones, particularly aloin and emodin, which disrupt bacterial cell membranes and inhibit protein synthesis [124]. In addition, Aloe vera gel can physically damage bacterial cell walls, enhancing its antimicrobial effects [125]. On the anti-inflammatory front, acemannan, a key polysaccharide in Aloe vera, interacts with immune cells such as macrophages to suppress the production of pro-inflammatory cytokines like TNF-alpha, IL-1beta, and IL-6 [126]. Aloe vera also contains compounds that inhibit COX enzymes, reducing the synthesis of prostaglandins, which are key mediators of inflammation. Furthermore, studies indicate that Aloe vera modulates inflammatory signaling pathways by inhibiting the activation of transcription factors like NF-κB, thereby reducing overall inflammatory responses [127].

Ali et al. investigated the antibacterial activity of Aloe vera leaf aqueous extract against six MRSA strains. They demonstrated that concentrations of 15–20 mg/mL significantly reduced bacterial biomass dry weights after 24 and 48 h, with the strongest effects observed at 20 mg/mL. This concentration also showed inhibition of biofilm formation and produced the largest inhibition zones against S. aureus (LN871241), which was further confirmed using scanning electron microscopy [128]. Similarly, Udgire et al. demonstrated that Aloe vera extracts in various solvents showed antimicrobial activity against a range of gram-positive and gram-negative skin pathogens. Methanol extracts exhibited the highest activity, with zones of inhibition reaching 12 mm against S. aureus and S. epidermidis, followed by 10 mm against E. coli and P. vulgaris. These findings highlight Aloe vera’s potential as a natural antimicrobial agent [129].

Arbab et al. explored the antibacterial effects of Aloe vera gel and leaf extracts against pathogens causing skin infections, including E. coli, Shigella, Salmonella spp., and S. aureus. The study found that ethanol extracts from both the leaves and roots exhibited the highest antibacterial efficacy, showing potential as adjuncts to conventional antibiotics. Notably, the ethanol extracts were more effective than aqueous extracts, suggesting the solvent's role in enhancing bioactivity [130]. Bashir et al. supported these findings, showing that Aloe vera gel extracts displayed robust antibacterial activity against both gram-positive and gram-negative isolates obtained from wounds, burns, and acne patients. This antibacterial efficacy was comparable to or exceeded that of five broad-spectrum antibiotics tested alongside [131].

Valizadeh et al. developed an innovative Aloe vera-based nanoemulsion gel containing erythromycin (AVNE) to enhance topical bioavailability and accelerate wound healing. In diabetic and infected rat models, the AVNE significantly reduced inflammation, increased collagen synthesis, and promoted faster wound closure compared to controls. In addition, the formulation demonstrated potent antibacterial activity against E. coli and S. aureus, supporting its use in diabetic wound care [132].

Neem

Neem (Azadirachta indica), a medicinal plant native to the Indian subcontinent, has been celebrated for centuries in traditional medicine systems like Ayurveda for its wide-ranging therapeutic properties [133]. Modern pharmacological research has substantiated Neem’s efficacy, particularly its potent antimicrobial and anti-inflammatory effects, making it a promising candidate for managing various infections, including challenging conditions such as DFUs [134]. Neem’s diverse bioactive compounds, including nimbidin, nimbin, and azadirachtin, contribute to its multifaceted biological activities, offering both antimicrobial and anti-inflammatory benefits [135].

The antimicrobial efficacy of Neem arises from multiple complementary mechanisms. The bioactive compounds in Neem, including nimbidin, nimbin, and azadirachtin, have been shown to disrupt bacterial cell membranes, leading to cell leakage and eventual cell death [136]. These compounds also interfere with bacterial metabolic processes, inhibiting protein synthesis and enzymatic activity [137]. In addition, Neem has demonstrated the ability to inhibit biofilm formation, a key factor in bacterial virulence, making it effective against bacterial infections that are resistant to traditional antibiotics [138].

Recent studies have further expanded on Neem’s antimicrobial properties. Chaturvedi et al. investigated the antibacterial activities of crude Neem bark and leaf extracts against bacterial species isolated from clinical samples of diabetic individuals. Using the agar well diffusion method, they observed significant activity against both gram-positive and gram-negative bacteria, with coagulase-negative Staphylococcus (CONS) showing the highest inhibition zones. This suggests that Neem extracts, particularly in methanolic form, may hold promise in combating multidrug-resistant bacterial strains associated with diabetic infections [139]. Similarly, Nishat Anzum et al. evaluated the antimicrobial activities of commercially available Neem oil against pathogens such as S. aureus, Klebsiella pneumoniae, Bacillus cereus, and S. typhi. Their results showed that Neem oil exhibited over 99% growth inhibition for these pathogens, even at low concentrations, and was effective against P. aeruginosa using the dilution method. This highlights Neem’s potential as a natural antibiotic for managing infections caused by these bacteria [140].

Sarmiento et al. focused on Neem’s antibacterial efficacy against S. aureus, including MRSA. Neem leaf ethanol extracts exhibited a dose-dependent antibacterial activity, with significant inhibition zones at 100% concentration. While current antibiotics showed greater zones of inhibition, the study confirmed that Neem extracts hold promise as complementary or alternative antibacterial agents, particularly against antibiotic-resistant strains [141].

Neem’s anti-inflammatory mechanism involves inhibiting pro-inflammatory pathways by suppressing the production of inflammatory mediators such as TNF-alpha and IL-6. This is achieved through the modulation of key signaling molecules like NF-κB. In addition, Neem exhibits antioxidant properties by scavenging free radicals, thereby reducing oxidative stress that contributes to inflammation. Active compounds like nimbidin and azadirachtin play a significant role in these anti-inflammatory actions [142].

Thirukumaran et al. explored Neem’s anti-inflammatory and anti-diabetic properties. Their study demonstrated a dose-dependent positive correlation between the concentration of Neem extract and its efficacy in reducing inflammation and regulating blood glucose levels. This dual action makes Neem a potential candidate for managing inflammation and diabetic complications, especially in patients with comorbid conditions [143].

Resveratrol

Resveratrol, a naturally occurring polyphenol classified as a stilbene, is predominantly found in the skin of red grapes, berries, and products derived from these fruits, such as red wine and grape juice [144]. Known for its diverse pharmacological properties, resveratrol has garnered significant attention due to its potent antioxidant, anti-inflammatory, and antimicrobial activities [145]. Its capacity to modulate multiple molecular pathways makes it a promising therapeutic agent, particularly in the context of diabetes and its associated complications, including chronic wounds and infections [146]. The role of resveratrol in managing such complications is underpinned by its ability to target oxidative stress, inflammation, and microbial infection, all of which are critical factors in disease progression [147].

The antimicrobial activity of resveratrol is multifaceted and primarily involves the inhibition of FtsZ, a bacterial protein essential for cell division. By targeting FtsZ, resveratrol disrupts the assembly of the bacterial division machinery, leading to abnormal cell elongation, impaired cell wall synthesis, and eventual cell death. Beyond its effects on cell division, resveratrol compromises bacterial membrane integrity, causing structural damage and leakage of intracellular contents [148]. In addition, it interferes with quorum sensing, the bacterial communication system responsible for coordinating virulence factor production and biofilm formation, thereby diminishing bacterial pathogenicity [149]. Resveratrol’s antimicrobial mechanisms are further enhanced by its capacity to disrupt critical processes such as DNA synthesis and metabolic pathways, which may vary depending on the bacterial species [150, 151].

Resveratrol exerts its anti-inflammatory effects through several mechanisms. It inhibits the production of key inflammatory cytokines, including IL-1α, IL-6, TNF-α, and IL-17, by suppressing lymphocyte activation and macrophage function [152]. Resveratrol also downregulates inflammatory mediators such as COX-2, PGE2, and monocyte chemoattractant protein-1, particularly in response to lipopolysaccharide (LPS) stimulation [153, 154]. Furthermore, resveratrol attenuates the activation of inflammatory signaling pathways, including those involving Toll-like receptors (TLR-4) and NF-κB, thereby reducing the expression of pro-inflammatory proteins [155]. In addition, resveratrol suppresses the generation of ROS and NO, both of which contribute to inflammation, and enhances antioxidant activity, further alleviating inflammatory responses [156]. These actions highlight resveratrol’s potential as a therapeutic agent in controlling inflammation associated with various diseases.

Shevelev et al. investigated resveratrol’s antimicrobial activity against S. aureus and C. albicans in wound healing models. Resveratrol significantly reduced bacterial and fungal growth, promoting faster wound healing [157]. Chan et al. studied resveratrol’s dual antimicrobial and anti-inflammatory effects, demonstrating its efficacy in improving treatment outcomes for infections and inflammatory conditions [158].

Javid et al. examined resveratrol’s impact on diabetes management, noting improvements in glucose control and reduced oxidative stress [159]. Lee et al. explored resveratrol’s effects on inflammatory pathways in diabetic models, highlighting its potential to improve glucose metabolism and reduce diabetic complications [160].

Challenges and considerations in using natural products for treating diabetic foot infections

While natural products show significant promise in treating DFIs, several challenges and considerations must be addressed before they can be fully integrated into clinical practice. These challenges include variability in composition, lack of standardization, potential toxicity, and limited clinical evidence.

Variability in composition

The utilization of natural products in various industries, including pharmaceuticals, cosmetics, and food, presents a significant challenge due to the inherent variability in their chemical composition. This variability stems from a range of factors that can alter the concentration of bioactive compounds, thereby affecting the consistency, efficacy, and safety of natural product-based formulations. For instance, compounds such as thymol and carvacrol exhibit fluctuations in concentration depending on the species, geographical origin, and extraction methods employed [161,162,163]. Such variability complicates the standardization of natural product-derived therapeutics, potentially leading to inconsistent therapeutic outcomes and posing challenges for both regulatory compliance and consumer safety.

The primary source of variability in natural products is dependent on biological and environmental factors. Intra-species genetic variation plays a crucial role in the chemical profile of a plant, fungi, or microorganism, with different genotypes producing differing quantities or types of bioactive compounds [164]. This is exemplified by eugenol which may vary in concentration depending on the genetic lineage of the clove species and its growing conditions [165]. Environmental variables, such as soil composition, climate, and geographic location, further modulate the biosynthesis of secondary metabolites [166]. For example, factors such as temperature, humidity, and light exposure during plant growth can influence the yield and concentration of key compounds such as curcumin [167]. In addition, soil nutrients and mineral content can affect the biosynthesis of bioactive metabolites, leading to substantial differences in their concentrations [168].

Furthermore, the time of harvest and post-harvest processing play pivotal roles in the chemical composition of natural products [169]. The phenological stage at which a plant is harvested can alter the concentration of active compounds, as seen with curcumin, whose levels are influenced by the plant’s growth stage [170]. Post-harvest handling, including drying, storage, and transportation, can also result in the degradation, transformation, or volatilization of active compounds, further contributing to the variability of the final product. Natural products are typically complex mixtures of various bioactive molecules, with some compounds exhibiting higher variability in concentration than others [171]. This complexity presents a challenge for standardizing natural products, as it is difficult to achieve uniformity across different batches and sources of raw material.

To mitigate these challenges, several approaches have been developed. Standardization of natural product extracts, achieved by defining active ingredient levels, is commonly employed to reduce variability. In addition, advanced cultivation techniques, including controlled environmental conditions and optimized breeding programs, are utilized to minimize genetic and environmental influences on product composition. Post-harvest processing techniques, such as controlled drying and storage, can also help stabilize the chemical composition of natural products. In some cases, synthetic analogs or substitutes for natural compounds are developed to replicate the desired bioactivity, ensuring more consistent therapeutic outcomes. Despite these efforts, the inherent variability in natural products remains a significant challenge that requires ongoing research to address to optimize their application in various fields.

Lack of standardization and dosage guidelines

The lack of standardization and dosage guidelines is a significant challenge in the use of natural products, particularly in the treatment of conditions such as DFIs. Unlike conventional pharmaceuticals, which are subject to rigorous clinical trials and regulatory oversight, natural products often do not undergo the same level of scrutiny, leading to inconsistent quality and unclear therapeutic dosing. The absence of well-defined therapeutic doses for natural products complicates their integration into established treatment regimens, as healthcare providers may struggle to determine the appropriate quantity or frequency for safe and effective use. For example, while compounds like curcumin, eugenol, and thymol have demonstrated promising antimicrobial and anti-inflammatory properties, their efficacy is often contingent on factors such as extraction method, concentration, and bioavailability [172, 173]. Without standardized doses, patients may receive insufficient amounts of the active compound, leading to suboptimal therapeutic effects, or excessive amounts, resulting in toxicity or adverse reactions.

Furthermore, the experimental nature of many natural product-based therapies means that clinicians often lack comprehensive clinical guidelines to ensure optimal dosing and safety. Natural products are frequently used in combination with other medications, but the interactions between these compounds and conventional drugs are not always well understood. For example, curcumin may interact with drugs that affect liver enzymes, potentially altering their metabolism and efficacy [174]. The lack of clear guidelines for combining natural products with pharmaceuticals increases the risk of adverse effects, drug interactions, and compromised therapeutic outcomes. As natural products are integrated more into clinical practice, there is an urgent need for more rigorous research, standardized dosages, and comprehensive safety data to guide healthcare providers in their use.

To address these challenges, the development of standardized extracts with well-defined concentrations of active ingredients is essential. For example, standardized curcumin extracts with specified curcumin content have been introduced, enabling more reliable dosing in both clinical trials and therapeutic applications. In addition, dosage recommendations derived from robust clinical evidence would facilitate informed decision-making by healthcare providers regarding the use of natural products in treating DFIs and other conditions. Advances in drug delivery systems, such as nanoparticle-based formulations, may further enhance the bioavailability and precision of natural product administration. However, these innovations require rigorous evaluation to establish their safety and efficacy in clinical settings.

Conclusion

Natural products present a promising avenue for the treatment of DFIs, offering potent antimicrobial, anti-inflammatory, and wound-healing properties. Compounds derived from plants such as curcumin, Aloe vera, neem, and resveratrol have demonstrated significant efficacy in addressing the complex pathophysiology of DFIs, including infection control, inflammation modulation, and tissue regeneration. These properties make natural products a valuable addition to the therapeutic arsenal for managing chronic wounds, particularly in diabetic patients who are susceptible to persistent infections.

However, the integration of natural products into clinical practice is hindered by several challenges, including variability in composition, lack of standardization, and insufficient dosage guidelines. The chemical composition of natural products can vary significantly based on factors such as geographic origin, genetic variation, and extraction methods, which can impact their efficacy and safety. Furthermore, the absence of established therapeutic dosages and the potential for adverse drug interactions complicate their clinical application. Despite these challenges, continued research into standardization techniques, enhanced bioavailability, and clinical trial data will be essential for realizing the full therapeutic potential of natural products in treating DFIs.

Ultimately, while natural products hold considerable promise for advancing wound care in diabetic patients, further studies are needed to establish clear dosing regimens, safety profiles, and optimal formulations. Addressing these concerns will enable the broader adoption of these natural therapies in clinical settings, providing patients with safer, more effective alternatives for managing DFIs and improving overall quality of care.