Functional nano-vector boost anti-atherosclerosis efficacy of berberine in Apoe ⁽ mice

Atherosclerosis (AS) is the leading cause of heart attacks, stroke, and peripheral vascular disease. Berberine (BBR), a botanical medicine, has diversified anti-atherosclerotic effects but with poor absorption. The aim of this study was to develop an effective BBR-entrapped nano-system for treating AS in high-fat diet (HFD)-fed Apoe ^(-/-) mice, and also explore the possible underlying mechanisms involved. Three d-α-tocopherol polyethylene glycol (PEG) succinate (TPGS) analogues with different PEG chain lengths were synthesized to formulate BBR-entrapped micelles. HFD-fed Apoe ^(-/-) mice were administered with optimized formula (BBR, 100 mg/kg/day) orally for 5 months. The artery plaque onset and related metabolic disorders were evaluated, and the underlying mechanisms were studied. Our data showed that, BT₁₅₀₀M increased BBR deposition in liver and adipose by 107.6% and 172.3%, respectively. In the Apoe ^(-/-) mice, BT₁₅₀₀M ameliorated HFD-induced hyperlipidemia and lipid accumulation in liver and adipose. BT₁₅₀₀M also suppressed HFD-induced chronic inflammation as evidenced by the reduced liver and adipose levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β); and decreased plasma level of TNF-α, IL-6, IL-1β, interferon-γ (IFN-γ), monocyte chemotactic protein (MCP), and macrophage inflammatory factor (MIP). The mechanism study showed that BT₁₅₀₀M changed Ampk and Nf-κb gene expression, and interrupted a crosstalk process between adipocytes and macrophages. Further investigation proved that BT₁₅₀₀M decreased endothelial lesion and subsequent macrophage activation, cytokines release, as well as cholesteryl ester gathering in the aortic arch, resulting in ameliorated artery plaque build-up. Our results provide a practical strategy for treating AS using a BBR-entrapped nano-system.