Eriodictyol alleviates diabetic limb ischemia/reperfusion injury via the Nrf2/HO-1 pathway-mediated antioxidant, antiapoptotic and mitochondrial protective effects

Objective: Accumulating evidence suggests that diabetes mellitus (DM) aggravates the incidence and severity of ischemia reperfusion injury (IRI). Eriodictyol (EDT), a natural flavonoid with reported nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant and anti-diabetic abilities, has been shown to mitigate IRI in various experimental models. However, its potential effect in diabetic IRI models remains unidentified. This study is aiming to explore the protective role of EDT against hyperglycemia-aggravated IRI and its underlying mechanism.

Methods: High-fat-high-sugar diets and low-dose streptozotocin (STZ) injection, followed by orthodontic rubber bands (ORBs) wrapping, were utilized to induce the diabetic limb IRI model. C2C12 myoblasts were subjected to hypoxia/reoxygenation (H/R) with or without high-glucose induction. Treatment with intraperitoneal injection of EDT was performed in vivo. Administration with EDT and the Nrf2 inhibitor, ML385, was applied in vitro.

Results: EDT treatment dose-dependently alleviated skeletal muscle histopathological damage, reduced tissue oxidative injury and Apoptosis in IRI-induced diabetic mice. Concurrently, EDT upregulated Nrf2 and its downstream Enzymes such as hemeoxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). In C2C12 cells, EDT activated the Nrf2/HO-1 signaling, which enhanced antioxidant resistance, preserved mitochondrial function, and inhibited Apoptosis. Notably, ML385 administration effectively blocked these protective effects, demonstrating their dependence on Nrf2 signaling.

Conclusion: Eriodictyol mitigates diabetic muscle IRI by means of Nrf2/HO-1 pathway activation, highlighting its potential for managing this severe complication in diabetic patients undergoing orthopedic surgery.