The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
Southeast University, Zhongda Hospital Southeast University, Nanjing, China.
Curr Comput Aided Drug Des. 2024;20(6):911-927. doi: 10.2174/1573409920666230822110258.
Type 2 diabetes-associated cognitive dysfunction (DCD) is a chronic complication of diabetes that has gained international attention. The medicinal compound Banxia Xiexin Decoction (BXXXD) from traditional Chinese medicine (TCM) has shown potential in improving insulin resistance, regulating endoplasmic reticulum stress (ERS), and inhibiting cell apoptosis through various pathways. However, the specific mechanism of action and medical value of BXXXD remain unclear.
We utilized TCMSP databases to screen the chemical constituents of BXXXD and identified DCD disease targets through relevant databases. By using Stitch and String databases, we imported the data into Cytoscape 3.8.0 software to construct a protein-protein interaction (PPI) network and subsequently identified core targets through network topology analysis. The core targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The results were further validated through in vitro experiments.
Network pharmacology analysis revealed the screening of 1490 DCD-related targets and 190 agents present in BXXXD. The topological analysis and enrichment analysis conducted using Cytoscape software identified 34 core targets. Additionally, GO and KEGG pathway analyses yielded 104 biological targets and 97 pathways, respectively. BXXXD exhibited its potential in treating DCD by controlling synaptic plasticity and conduction, suppressing apoptosis, reducing inflammation, and acting as an antioxidant. In a high glucose (HG) environment, the expression of JNK, Foxo3a, SIRT1, ATG7, Lamp2, and LC3 was downregulated. BXXXD intervention on HT22 cells potentially involved inhibiting excessive oxidative stress, promoting neuronal autophagy, and increasing the expression levels of JNK, SIRT1, Foxo3a, ATG7, Lamp2, and LC3. Furthermore, the neuroprotective effect of BXXXD was partially blocked by SP600125, while quercetin enhanced the favorable role of BXXXD in the HG environment.
BXXXD exerts its effects on DCD through multiple components, targets, levels, and pathways. It modulates the JNK/SIRT1/Foxo3a signaling pathway to mitigate autophagy inhibition and apoptotic damage in HT22 cells induced by HG. These findings provide valuable perspectives and concepts for future clinical trials and fundamental research.
2 型糖尿病相关认知功能障碍（DCD）是糖尿病的一种慢性并发症，已引起国际关注。来自中药（TCM）的复方半夏泻心汤（BXXXD）已显示出通过多种途径改善胰岛素抵抗、调节内质网应激（ERS）和抑制细胞凋亡的潜力。然而，BXXXD 的具体作用机制和医学价值尚不清楚。
我们利用 TCMSP 数据库筛选 BXXXD 的化学成分，并通过相关数据库确定 DCD 疾病靶点。我们使用 Stitch 和 String 数据库将数据导入 Cytoscape 3.8.0 软件，构建蛋白质-蛋白质相互作用（PPI）网络，然后通过网络拓扑分析确定核心靶点。对核心靶点进行基因本体（GO）功能富集和京都基因与基因组百科全书（KEGG）通路分析。通过体外实验进一步验证。
网络药理学分析显示，筛选出 1490 个 DCD 相关靶点和 190 种 BXXXD 中的药物成分。使用 Cytoscape 软件进行拓扑分析和富集分析，确定了 34 个核心靶点。此外，GO 和 KEGG 通路分析分别得到 104 个生物靶点和 97 条通路。BXXXD 通过控制突触可塑性和传导、抑制细胞凋亡、减轻炎症和发挥抗氧化作用，显示出治疗 DCD 的潜力。在高葡萄糖（HG）环境下，JNK、Foxo3a、SIRT1、ATG7、Lamp2 和 LC3 的表达下调。BXXXD 对 HT22 细胞的干预可能涉及抑制过度氧化应激、促进神经元自噬以及增加 JNK、SIRT1、Foxo3a、ATG7、Lamp2 和 LC3 的表达水平。此外，SP600125 部分阻断了 BXXXD 的神经保护作用，而槲皮素增强了 BXXXD 在 HG 环境中的有利作用。
BXXXD 通过多种成分、靶点、水平和途径对 DCD 发挥作用。它调节 JNK/SIRT1/Foxo3a 信号通路，减轻 HG 诱导的 HT22 细胞自噬抑制和细胞凋亡损伤。这些发现为未来的临床试验和基础研究提供了有价值的观点和概念。
