半夏泻心汤通过JNK/SIRT1/Foxo3a信号通路防止HT22细胞受高血糖诱导的神经毒性影响

IF 1.5 4区 医学 Q4 CHEMISTRY, MEDICINAL Current computer-aided drug design Pub Date : 2024-01-01 DOI:10.2174/1573409920666230822110258
Yinli Shi, Pei Sheng, Ming Guo, Kai Chen, Yun Zhao, Xu Wang, Mianhua Wu, Bo Li
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引用次数: 0

摘要

背景: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。中药复方半夏泻心汤(BXXXD)在改善胰岛素抵抗、调节内质网应激(ERS)和通过多种途径抑制细胞凋亡方面具有潜力。然而,BXXXD 的具体作用机制和医疗价值仍不清楚:方法: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。利用 Stitch 和 String 数据库,我们将数据导入 Cytoscape 3.8.0 软件,构建了蛋白质-蛋白质相互作用(PPI)网络,随后通过网络拓扑分析确定了核心靶点。对核心靶点进行了基因本体(GO)功能富集和京都基因组百科全书(KEGG)通路分析。结果:结果:网络药理学分析表明,在 BXXXD 中筛选出了 1490 个 DCD 相关靶点和 190 种药物。使用 Cytoscape 软件进行的拓扑分析和富集分析确定了 34 个核心靶点。此外,GO 和 KEGG 通路分析还分别发现了 104 个生物靶点和 97 个通路。BXXXD通过控制突触可塑性和传导、抑制细胞凋亡、减少炎症和作为抗氧化剂等作用,展示了其治疗DCD的潜力。在高糖(HG)环境中,JNK、Foxo3a、SIRT1、ATG7、Lamp2和LC3的表达下调。BXXXD 对 HT22 细胞的干预可能包括抑制过度氧化应激、促进神经元自噬以及提高 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:结论:BXXXD通过多种成分、靶点、水平和途径对DCD产生影响。它能调节 JNK/SIRT1/Foxo3a 信号通路,减轻 HG 诱导的 HT22 细胞自噬抑制和凋亡损伤。这些发现为未来的临床试验和基础研究提供了宝贵的视角和概念。
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Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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来源期刊
Current computer-aided drug design
Current computer-aided drug design 医学-计算机:跨学科应用
CiteScore
3.70
自引率
5.90%
发文量
46
审稿时长
>12 weeks
期刊介绍: Aims & Scope Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design. Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews, original research articles and letter articles written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, theoretical chemistry; computational chemistry; computer and molecular graphics; molecular modeling; protein engineering; drug design; expert systems; general structure-property relationships; molecular dynamics; chemical database development and usage etc., providing excellent rationales for drug development.
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