Ponicidin alleviates atherosclerosis by inhibiting inflammation and oxidative stress through the SIRT۱ and PI۳K/Akt pathway

Objective(s): Atherosclerosis (AS) is caused by dyslipidemia, chronic inflammation, and oxidative stress. Ponicidin, a diterpenoid from Isodon species, has reported anti-inflammatory and antioxidant effects, but its role in AS remains unclear. In this study, we evaluated the therapeutic potential and safety of ponicidin in an experimental AS model.Materials and Methods: ApoE-/- mice were fed a Western diet and treated with ponicidin (۱۰ mg/kg/day, intraperitoneally) for ۱۲ weeks. Hepatic and renal safety were assessed using histological and serum biochemical markers. Aortic plaque burden was quantified using hematoxylin and eosin and Oil Red O staining. Plasma lipids, cytokines, oxidative stress markers, and antioxidant enzymes were measured using biochemical assays and ELISA. The effects on SIRT۱ and PI۳K/Akt/eNOS signaling were analyzed using immunohistochemistry, RT-qPCR, ELISA, and Western blotting.Results: Ponicidin showed no liver or kidney toxicity and moderately altered the body weight. Treatment significantly reduced aortic root plaque coverage and lesion area while improving plasma lipid profiles (↓TG, ↓TC, ↓LDL-C, and ↑HDL-C). Serum cytokine analysis revealed decreased TNF-α, IL-۱β, IL-۶, MCP-۱, and TGF-β۱ levels, with elevated IL-۱۰. Oxidative stress was attenuated, as evidenced by reduced malondialdehyde and myeloperoxidase levels, increased superoxide dismutase, catalase, and glutathione levels, and restored nitric oxide levels. Mechanistically, ponicidin up-regulated SIRT۱ expression and enhanced the phosphorylation of PI۳K, Akt, and eNOS, suggesting improved endothelial function.Conclusion: Ponicidin protects against AS by improving lipid metabolism, reducing vascular inflammation and oxidative stress, and enhancing endothelial signaling.

کلیدواژه ها:

Atherosclerosis ، Inflammation ، Oxidative stress ، Ponicidin ، SIRT۱