Yang Yang, Chen Shengxiang, Shi Guanjin, Huang Shanshan, Cui Ningning, Tan Le, Yang Xuefeng
Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
Hubei YouTang Health Management Co. Ltd, Wuhan, Hubei, 430000, PR China.
Phytomedicine. 2025 May;140:156572. doi: 10.1016/j.phymed.2025.156572. Epub 2025 Feb 25.
Diabetes mellitus promotes atherosclerosis (AS), a major cause of cardiovascular disease. Statins, clinical drugs for AS treatment, may increase the risk of diabetes and induce hepatotoxicity. Polyphenols can alleviate AS by exerting anti-inflammatory and antioxidant effects, and play a role in liver protection. However, the effects of polyphenol extract (PE) on diabetic AS and whether PE can assist atorvastatin in managing diabetic AS with additional benefits remain poorly understood.
This study aims to investigate the synergistic effects of a type of PE with atorvastatin on diabetic AS, as well as explore the anti-atherogenic mechanisms of PE.
Polyphenol constituents in PE were identified using UPLC-MS/MS. Streptozocin -induced diabetic ApoE mice were orally administered 350 and 700 mg/kg of PE, 10 mg/kg of atorvastatin, or 5 mg/kg of atorvastatin+700 mg/kg of PE for 10 weeks. Atherosclerotic lesions and plaque stability were evaluated using Oil Red O staining, Sirius red staining, and immunofluorescence. Inflammation and oxidative stress were determined using the corresponding markers. Hepatic pathological changes were assessed using hematoxylin and eosin staining. Network pharmacology prediction, molecular docking, microscale thermophoresis (MST) and western blotting were used to explore the anti-atherosclerotic mechanisms of PE.
The polyphenolic constituents of PE mainly consist of flavonoids and phenolic acids. PE treatment effectively mitigated atherosclerotic lesions in diabetic mice, particularly at high dose. Co-treatment with a half-dose of atorvastatin and PE did not restrain the anti-atherosclerotic effects of atorvastatin treatment, whereas the combination better relieved hyperglycemia, inflammation, oxidative stress, and liver damage in diabetic AS compared to that with atorvastatin alone. In addition, network pharmacology, molecular docking, MST and western blotting results indicated that PE ameliorated diabetic AS, possibly by targeting the AKT/mTOR/HIF-1 signaling pathway.
The PE demonstrated efficacy against diabetic AS and cooperated with atorvastatin for some additional benefits, especially in liver protection, indicating that PE has the potential to be developed as a supplement for the management of diabetes-related AS.
糖尿病会促进动脉粥样硬化（AS），这是心血管疾病的主要病因。他汀类药物是治疗AS的临床药物，可能会增加糖尿病风险并引发肝毒性。多酚可通过发挥抗炎和抗氧化作用来减轻AS，并在肝脏保护中发挥作用。然而，多酚提取物（PE）对糖尿病性AS的影响以及PE是否能辅助阿托伐他汀治疗糖尿病性AS并带来额外益处仍知之甚少。
本研究旨在探讨一种PE与阿托伐他汀对糖尿病性AS的协同作用，并探索PE的抗动脉粥样硬化机制。
采用超高效液相色谱-串联质谱法（UPLC-MS/MS）鉴定PE中的多酚成分。将链脲佐菌素诱导的糖尿病ApoE小鼠分别口服给予350和700 mg/kg的PE、10 mg/kg的阿托伐他汀或5 mg/kg的阿托伐他汀+700 mg/kg的PE，持续10周。采用油红O染色、天狼星红染色和免疫荧光评估动脉粥样硬化病变和斑块稳定性。使用相应标志物测定炎症和氧化应激。采用苏木精和伊红染色评估肝脏病理变化。运用网络药理学预测、分子对接、微量热泳动（MST）和蛋白质免疫印迹法探索PE的抗动脉粥样硬化机制。
PE中的多酚成分主要由黄酮类和酚酸类组成。PE治疗有效减轻了糖尿病小鼠的动脉粥样硬化病变，高剂量时尤为明显。半剂量的阿托伐他汀与PE联合治疗并未抑制阿托伐他汀治疗的抗动脉粥样硬化作用，而与单独使用阿托伐他汀相比，该组合能更好地缓解糖尿病性AS中的高血糖、炎症、氧化应激和肝损伤。此外，网络药理学、分子对接、MST和蛋白质免疫印迹结果表明，PE可能通过靶向AKT/mTOR/HIF-1信号通路改善糖尿病性AS。
PE对糖尿病性AS具有疗效，并与阿托伐他汀协同作用带来一些额外益处，尤其是在肝脏保护方面，表明PE有潜力被开发为糖尿病相关AS管理的补充剂。
