Li Rui, Lou Qi, Zhu Yu, Si Min, Zhu Xiaoyu, Jia Huiyu, Yang Haoran, Ji Tingting, Xu Dongrui, Yang Wulin, Luo Shengyong, Wang Yijun
Anhui Medical College (Anhui Academy of Medical Sciences), 15 Yonghong Road, Hefei 230061, China.
Department of Pharmacology, School of Basic Medicine, Anhui Medical University, 81 Meishan Road, Hefei 230031, China.
Phytomedicine. 2025 Aug;144:156923. doi: 10.1016/j.phymed.2025.156923. Epub 2025 Jun 7.
Diabetic cognitive dysfunction (DCD) is a prevalent complication of diabetes, characterized by progressive cognitive decline. Current pharmacological interventions have limited therapeutic efficacy in managing this condition. Huoshan large - leaf yellow tea (HLYT), derived from Camellia sinensis leaves, has demonstrated dual pharmacological properties in both glycemic regulation and cognitive enhancement, suggesting its potential as a preventive and therapeutic agent for DCD.
The main purpose of this study was to clarify the regulatory effect of HLYT on DCD and explore its underlying mechanisms.
The research encompassed a comprehensive multi-phase investigation. Network pharmacological analysis identified HLYT's key target genes for DCD. Molecular docking screened hub target genes, which were further verified by molecular dynamic (MD) simulations. High-performance liquid chromatography (HPLC) quantified HLYT's active components for setting animal experiment dosages. A DCD model was established in rats by feeding them a high - fat diet and injecting streptozotocin (STZ). Subsequently, HLYT was administered to the rats via intragastric gavage for intervention. The results of this intervention were then verified through relevant animal experiments.
Utilizing an integrated approach of network pharmacology and molecular docking, five pivotal target genes (Adora2a, Mapk8, Stat3, Vcam1, Edn1) were identified as the primary molecular targets of HLYT in DCD pathogenesis. Quercetin, kaempferol, caffeine, theobromine, and EGCG in HLYT exhibited significant binding affinities with these targets. The results of animal experiment have shown that HLYT can alleviate neuronal damage and cognitive dysfunction, reduce the levels of IL-6 and IL-1β in the serum and brain tissue in DCD rats. Furthermore, it can also inhibit the expression of Adora2a, Mapk8, Stat3, Vcam1, and Edn1 mRNA as well as the expression of STAT3, ADORA2A, JNK1, ET1, and VCAM1 proteins.
HLYT has a significant protective effect on DCD in rats by regulating Adora2a, Mapk8, Stat3, Vcam1, and Edn1 genes, suggesting that it has remarkable clinical potential in the treatment of DCD.
糖尿病认知功能障碍（DCD）是糖尿病常见的并发症，其特征为进行性认知功能衰退。目前的药物干预在治疗这种疾病方面疗效有限。源自茶树叶片的霍山大叶黄茶（HLYT）在血糖调节和认知增强方面均显示出双重药理特性，表明其具有作为DCD预防和治疗药物的潜力。
本研究的主要目的是阐明HLYT对DCD的调节作用并探索其潜在机制。
该研究涵盖了全面的多阶段调查。网络药理学分析确定了HLYT对DCD的关键靶基因。分子对接筛选出枢纽靶基因，并通过分子动力学（MD）模拟进一步验证。高效液相色谱法（HPLC）对HLYT的活性成分进行定量，以确定动物实验剂量。通过给大鼠喂食高脂饮食并注射链脲佐菌素（STZ）建立DCD模型。随后，通过灌胃给大鼠施用HLYT进行干预。然后通过相关动物实验验证该干预的结果。
利用网络药理学和分子对接的综合方法，确定了五个关键靶基因（Adora2a、Mapk8、Stat3、Vcam1、Edn1）是HLYT在DCD发病机制中的主要分子靶点。HLYT中的槲皮素、山奈酚、咖啡因、可可碱和表没食子儿茶素没食子酸酯（EGCG）与这些靶点表现出显著的结合亲和力。动物实验结果表明，HLYT可以减轻神经元损伤和认知功能障碍，降低DCD大鼠血清和脑组织中IL-6和IL-1β的水平。此外，它还可以抑制Adora2a、Mapk8、Stat3、Vcam1和Edn1 mRNA的表达以及STAT3、ADORA2A、JNK1、ET1和VCAM1蛋白的表达。
HLYT通过调节Adora2a、Mapk8、Stat3、Vcam1和Edn1基因对大鼠DCD具有显著的保护作用，表明其在治疗DCD方面具有显著的临床潜力。
