Hesperidin enhances angiogenesis via modulating expression of growth and inflammatory factor in diabetic foot ulcer in rats

One of the most devastating consequences of diabetes mellitus is a chronic condition, diabetic foot ulcer. Numerous investigations are being targeted to explore newer compounds for treatment of diabetic foot ulcer wounds in diabetic patients. Hesperidin (HSP), an isoflavone glycoside has been established to exhibit antidiabetic and antioxidant potential. In the current investigation, diabetes was induced in rats by administration by streptozotocin (STZ) intraperitoneally (50 mg/kg). Wound-healing capacity was estimated in hind paw of rats by artificially initiating wound injury on the paw dorsal surface. The injured animals were administered with incremental doses of HSP suspension orally (10, 20, 40, 60, and 80 mg/kg) and insulin subcutaneously (10 IU/kg). Parameters such as wound area were estimated every 2 days, and at the end of 20 days of study, biochemical estimations in serum and histopathological observations of the wound were made. HSP (60 and 80 mg/kg) revealed statistically significant (P < 0.05) improvement in wound dimension, glucose and insulin concentration, and glycated hemoglobin (HbA1C). Administration of HSP indicated significant (P < 0.05) modulation of mRNA associated with expression of vascular endothelial growth factor (VEGF), whereas the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels were lowered compared to the control group of animals. Real-time quantitative polymerase chain reaction (RT-qPCR) indicated expression of vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) compared to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Histological observations indicated higher expression of VEGF in the groups receiving HSP, indicative of angiogenesis stimulation in the diabetic wound. The results advocate angiogenesis activity of HSP was enhanced owing to reduction in hyperglycemia and oxidative stress-induced damage, reduced expression of inflammatory mediators, and enhanced expression of growth-related factors, thereby promoting healing of diabetic foot ulcer.