# Honey Therapy in Diabetic Foot Ulcers: A Promising Strategy for Effective Wound Healing
## 3 Honey as an Antimicrobial and Anti-Inflammatory Agent  
Honey is considered one of the older wound dressing biomaterials [18]. Gifted with anti-inflammatory, antioxidant, and antibacterial characteristics, honey is a natural substance that is frequently reported as a traditional medicine and has been increasingly investigated [17], especially for chronic wound treatment [68]. The current evidence shows that honey's composition and antimicrobial properties depend on the geographic conditions, the surrounding environment of the hive, and the metabolic activity of the bees, as well as the processing and storage conditions, which will confer distinct characteristics and levels of effectiveness on different microbial strains [18; 69]. For instance, manuka honey, a honey derived from the nectar of the _Leptsospermum scoparium_ (manuka) plant in New Zealand, is recognized for its high concentrations of methylglyoxal (MGO), which confer to pronounced antibacterial activity [70]. The presence of polyphenols is another important factor that contributes to a honey's color, taste, and antioxidant and antimicrobial characteristics, which depend on its floral sources [71]. Despite the differences related to a honey's geographic and botanical origins, almost all types of honey present bactericidal activity as an intrinsic promising property for drug development [72]. Honey is effective against more than 60 bacterial species [73] and has been widely used in the treatment of acute and chronic wounds, ulcers, and burns [74]. Interestingly, honey is also able to inhibit bacterial cell wall synthesis, changing the cell shape and inducing lipopolysaccharide under membrane disintegration [72]. In vitro studies carried out on wound healing have shown the benefits of honey, not only as a general antibacterial medicine [39; 75] but also in the treatment of multidrug-resistant bacteria [76; 77]. Different types of honey, such as buckwheat (_Fagopyrum esculent_), blueberry (_Vactimium corymposium_), and manuka, have shown great effectiveness against _E. coli_ and _Bacillus subtilis_, as well as vancomycin-resistant _Enterococcus facicum_ and _MRSA_[78]. The effectiveness of honey against multidrug-resistant bacteria was shown in a recent review [12] and it has gained increasing attention, especially due to the worldwide antibiotic resistance concerns. In this sense, honey was reported as an effective treatment for chronic wound infections not responding to antibiotics [79]. During the wound healing process, honey has a modulatory role in the inflammatory phase, avoiding a chronic or severe inflammatory state being reached [18]. Importantly, there is some evidence that honey inhibits the nuclear factor kappa B (NF-kB) pathway through NF-kB nuclear translocation attenuation, decreasing the inflammatory mediators, such as cyclooxygenase-2 (COX-2) and TNF-\(\alpha\)[80]. Conversely, the activation of macrophages and the stimulation of COX-2, TNF-\(\alpha\) and prostaglanddams (PGE2) were also observed after treatment with thyme honey [35], suggesting that honey is a immunodulator of wound healing. This means that honey provides pro-inflammatory and anti-inflammatory properties that are activated according to the wound characteristics [81]. A reduction in the reactive oxygen species (ROS) released from infiltrated neutrophiles is another major mechanism by which honey can decrease the cells' oxidative stress levels and reduce the inflammatory status [81; 82]. Japanese honey also showed effectiveness in reducing the wound area during the inflammatory phase [34]. During the proliferative phase, honey is also able to stimulate angiogenesis [83] and wound contraction through fibroblast, myofibroblast, and collagen deposition [18], despite improve the re-epithelialization [84], possibly due to the high osmotic pressure and presence of hydrogen peroxide [83]. During the remodeling phase, honey also shows benefits in decreasing scarring and improving tissue remodeling [85] (Figure 1).