## 4 Discussion  
Propolis has been suggested to exert immunomodulatory, antiulcer, antidiabetic [27], and tissue healing/improvement effects [28; 29; 30; 31]. The constituent compounds of propolisis are apigenin, galangin, kaempfer, myricetin, pinocembrin, quercetin, and CAPE [15]. Among these, CAPE has been identified as the principal compound of propolisis and has been reported to have anti-inflammatory, antibacterial, and tissue-repair properties [17; 18; 19; 20]. CAPE has also been proposed to improve diabetic wound healing. Furthermore, several studies have suggested that CAPE attenuated the inflammatory response to periodontal pathogens via NF-kB inhibition [32], and that it exerted positive effects on gingival wound healing in nondiabetic Wistar albino rats [33]. In diabetic rats induced by streptozotocin, CAPE also diminished pancreatic oxidative stress by acting as a heme oxygenase-1 inducer [34] and had beneficial effects on the brain by decreasing oxidative damage and inflammation [35]. Figure 4: The effect of a single and simultaneous application of CAPE on cutaneous wound areas in diabetic and nondiabetic mice treated with either saline containing 35% EtOH as control or 5 mM CAPE or 20 \(\upmu\)L in saline containing 35% EtOH. (**a**) Representative photos of wounds in diabetic mice. (**b**) Group data of wound area expressed as a percentage of the initial wound area. Although the injury in one nondiabetic mice group was untreated, another group was treated with saline containing 35% EtOH. Alternatively, while the wounds in one group of diabetic mice were treated with saline containing 35% EtOH as control, another group was treated with CAPE in saline containing 35% EtOH. The values are presented as the mean \(\pm\) SEM (n = 3) per group. * \(p\) < 0.05 vs. 35% EtOH of the m+/m+ group and \(p\) < 0.05 vs. 35% EtOH of the db/db group. Foot ulceration is a major complication in patients with diabetes [4; 5; 6]. The problem occurs in at least 15% of these patients, making it the reason for 50-70% of nontraumatic amputations. Foot ulceration has also been associated with increased morbidity, mortality, and decreased quality of patients' lives [7; 8]. Thus, developing therapies for foot ulcers in patients with diabetes is imperative [11]. This investigation is the first to identify the effects of CAPE on cutaneous wound healing in a diabetic mouse model. In this study, we observed that CAPE accelerated cutaneous diabetic wound healing. This protective effect was associated with, at least in part, the induction of VEGF release in VSMCs and the relaxation of the artery via the NO/cGMP pathway. Furthermore, angiogenesis is essential for wound healing as it helps in the delivery of nutrients, oxygen, and other molecules, thereby participating in the wound healing process [36]. In patients with diabetes, ECs are seriously defective in angiogenesis and cause an ischemic limb, which impairs wound healing [37]. Therefore, inducing angiogenesis in an ischemic limb can be key to improving the blood flow to the limb, consequently leading to healed limb wounds, which are delayed by diabetes-induced ischemia [38]. Additionally, VEGF is an important component that induces angiogenesis [39], produced by different cell types, such as VSMCs, fibroblasts, tumor cells, macrophages, and ECs [40; 41; 42; 43; 44; 45; 46; 47]. VEGF is involved in the angiogenic process, enhances microvascular permeability, and promotes EC survival, migration, proliferation, and matrix metalloproteinases secretion [48]. However, CAPE has a double aspect regarding VEGF. It has considerably been reported that CAPE inhibits the expression of VEGF and VEGF-induced angiogenesis [49]. Nevertheless, these findings have not been completely assessed in cancer cells. Our study showed that VEGF in cultured human VSMC-conditioned medium increased when CAPE was administered to the cells. According to our result, in the cells that are not cancerous or under insufficient VEGF or ischemia conditions, CAPE rather induces VEGF expression.