The present study evaluated the antidiabetic and antioxidant effects of oleanolic acid (OA) from Ligustrum lucidum Ait (LLA) in alloxan-induced diabetic rats. OA in the alloxan-induced diabetic rats showed significant hypoglycemic activity by lowering blood glucose (at doses of 60 and 100 mg/kg for 40 days). The levels of serum total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-c) in the OA-treated diabetic rats were lower, and the high-density lipoprotein cholesterol (HDL-c) level was higher than in the control diabetic rats. A significant reduction in the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels of diabetic rats following OA treatment was also observed. Furthermore, OA treatment decreased the malondialdehyde (MDA) level, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities of the liver and kidney in diabetic rats. These results indicate that OA could protect the liver function avoiding alloxan-induced damage; OA had hypoglycemic, hypolipidemic and antioxidant efficacy in the diabetic rats. The antioxidant ability of OA might be one of the mechanisms of its hypoglycemic and hypolipidemic effects.

Palmitic acid (PA), the main component of dietary saturated fat, has been known to increase in patients with obesity, and PA-induced lipotoxicity may contribute to obesity-related male infertility. Melatonin has beneficial effects on reproductive processes; however, the effect and the underlying molecular mechanism of melatonin's involvement in PA-induced cytotoxicity in the testes are poorly understood. Our findings showed that lipotoxicity was observed in mouse testes after long-term PA treatment and that melatonin therapy restored spermatogenesis and fertility in these males. Moreover, melatonin therapy suppressed PA-induced apoptosis by modulating apoptosis-associated proteins such as Bcl2, Bax, C-Caspase3, C-Caspase12, and CHOP in type B spermatogonial stem cells. Changes in the expression of endoplasmic reticulum (ER) stress markers (p-IRE1, p-PERK, ATF4) and intracellular Ca 2+ levels showed that melatonin relieved PA-induced ER stress. Mechanistically, melatonin stimulated the expression and nuclear translocation of SIRT1 through its receptors and prevented PA-induced ROS production and mitochondrial dysfunction via SIRT1 signaling pathway. Furthermore, melatonin promoted SIRT1-mediated p53 deacetylation, thereby relieving G2/M arrest in response to PA-stimulated DNA damage. Collectively, these findings indicate that melatonin protects the testes from PA-induced lipotoxicity through the activation of SIRT1, which alleviates oxidative stress, ER stress, mitochondrial dysfunction, and DNA damage.

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