Protective mechanisms of loquat leaf extract and ursolic acid against diabetic pro-inflammation

The pharmacological effectiveness of loquat leaf extract (LE) and its important component, ursolic acid (UA), in the treatment of diabetes mellitus, has been well established in traditional medicine; however, the mechanism underlying their action is still unclear. We evaluated the protective effects of LE and UA against hyperglycemia-induced advanced glycation end product (AGE) formations and hepatic pro-inflammation. Oral administration of UA and LE at a dose of 50 mg/kg/day for 15 days yielded no significant hypoglycemic effect in diabetic db/db mice. UA and LE suppressed hepatic oxidative stress and AGE formation in diabetic mice, and this was followed by the downregulated mitogen-activated protein kinase signaling and nuclear factor κ B (NF-κB) activity. To identify the molecular target of LE and UA, a docking simulation was performed, and this predicted UA to bind to liver kinase B1 (LKB1), an upstream of AMP-activated protein kinase (AMPK)/transcription factor forkhead box O3 (FOXO3) axis. UA reversed the high-glucose-induced downregulation of LKB1-AMPK1-FOXO3 activation and antioxidant gene transcription. These findings demonstrated the antioxidant and anti-inflammatory effects of UA and LE against hyperglycemia-induced hepatic inflammation. Furthermore, we speculate that the LKB1/AMPK/FOXO3 pathway is a potential target responsible for these beneficial effects of LE and UA.