Bee venom improves diabetic wound healing by protecting functional macrophages from apoptosis and enhancing Nrf2, Ang-1 and Tie-2 signaling.

Impaired wound healing is a serious complication of diabetes that negatively affects the patient's socioeconomic life. Multiple mechanisms contribute to impaired diabetic wound healing including deficient recruitment of wound macrophages/neutrophils and impaired neovascularization. Bee venom (BV) has been used as an anti-inflammatory agent for the treatment of several diseases. Nevertheless, the impacts of BV on the diabetic wound healing have been poorly studied. In the present study, we investigated the molecular mechanisms underlying BV treatment on diabetic wound healing in a type I diabetic mouse model. Three experimental groups were used: group 1, non-diabetic control mice; group 2, vehicle-diabetic mice; and group 3, BV-treated diabetic mice. We found that the diabetic mice exhibited impaired wound closure characterized by a significant decrease in collagen and ß-defensin-2 (BD-2) expression compared to control non-diabetic mice. The impairment of diabetic wound healing is attributed to increased ROS levels and abolished antioxidant enzymes activity in the wounded tissues. Additionally, wounded tissue in diabetic mice revealed aberrantly decreased levels of Ang-1 and Nrf2 (the agonist ligands of Tie-2) followed by a marked reduction in the phosphorylation of Tie2 and downstream signaling eNOS, AKT and ERK. Impaired diabetic wound healing was also characterized by a significant reduction in activities of total antioxidant enzymes followed by a marked reduction in the levels of CCL2, CCL3 and CXCL2; which led to impaired recruitment and functions of wound macrophages/neutrophils; and significant reduction in the expression of CD31, a marker for neovascularization and angiogenesis of the injured tissue. Interestingly, BV treatment significantly enhanced wound closure in diabetic mice by increasing collagen and BD-2 expression and restoring the levels of Ang-1 and Nrf2 and hence enhancing the Tie-2 downstream signaling. Most importantly, treatment of diabetic mice with BV significantly restored the activities of wounded tissue antioxidant enzymes and the levels of chemokines, and subsequently rescued wound macrophages from mitochondrial membrane potential-induced apoptosis. Our findings reveal the immune-enhancing effects of BV for improving healing process of diabetic wounds and provide the first insight concerning the underlying molecular mechanisms.

Oral supplementation of diabetic mice with propolis restores the proliferation capacity and chemotaxis of B and T lymphocytes towards CCL21 and CXCL12 by modulating the lipid profile, the pro-inflammatory cytokine levels and oxidative stress.

BACKGROUND: Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the selective destruction of pancreatic ß cells, followed by hyperglycemia, oxidative stress and the subsequent extensive impairment of immune cell functions, a phenomenon responsible for the development of chronic diabetic complications. Propolis, a natural bee product that is extensively used in foods and beverages, significantly benefits human health. Specifically, propolis exerts antioxidant, anti-inflammatory and analgesic effects that may improve diabetic complications. To further elucidate the potential benefits of propolis, the present study investigated the effect of dietary supplementation with propolis on the plasma cytokine profiles, free radical levels, lipid profile and lymphocyte proliferation and chemotaxis in a streptozotocin (STZ)-induced type I diabetic mouse model. METHODS: Thirty male mice were equally distributed into 3 experimental groups: group 1, non-diabetic control mice; group 2, diabetic mice; and group 3, diabetic mice supplemented daily with an ethanol-soluble derivative of propolis (100 mg/kg body weight) for 1 month. RESULTS: First, the induction of diabetes in mice was associated with hyperglycemia and significant decreases in the insulin level and the lymphocyte count. In this context, diabetic mice exhibited severe diabetic complications, as demonstrated by a significant decrease in the levels of IL-2, IL-4 and IL-7, prolonged elevation of the levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and reactive oxygen species (ROS) and altered lipid profiles compared with control non-diabetic mice. Moreover, antigen stimulation of B and T lymphocytes markedly reduced the proliferative capacity and chemotaxis of these cells towards CCL21 and CXCL12 in diabetic mice compared with control mice. Interestingly, compared with diabetes induction alone, treatment of diabetic mice with propolis significantly restored the plasma cytokine and ROS levels and the lipid profile to nearly normal levels. Most importantly, compared with untreated diabetic mice, diabetic mice treated with propolis exhibited significantly enhanced lymphocyte proliferation and chemotaxis towards CCL21 and CXCL12. CONCLUSION: Our findings reveal the potential immuno-modulatory effects of propolis, which acts as a natural antioxidant to enhance the function of immune cells during diabetes.