Integrating network pharmacology and Mendelian randomization to explore potential targets of matrine against ovarian cancer.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-01-01 DOI:10.3233/THC-231051

Xiaoqun Chen, Yingliang Song

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引用次数: 0

Abstract

Background: Matrine has been reported inhibitory effects on ovarian cancer (OC) cell progression, development, and apoptosis. However, the molecular targets of matrine against OC and the underlying mechanisms of action remain elusive.

Objective: This study endeavors to unveil the potential targets of matrine against OC and to explore the intricate relationships between these targets and the pathogenesis of OC.

Methods: The effects of matrine on the OC cells (A2780 and AKOV3) viability, apoptosis, migration, and invasion was investigated through CCK-8, flow cytometry, wound healing, and Transwell analyses, respectively. Next, Matrine-related targets, OC-related genes, and ribonucleic acid (RNA) sequence data were harnessed from publicly available databases. Differentially expressed analyses, protein-protein interaction (PPI) network, and Venn diagram were involved to unravel the core targets of matrine against OC. Leveraging the GEPIA database, we further validated the expression levels of these core targets between OC cases and controls. Mendelian randomization (MR) study was implemented to delve into potential causal associations between core targets and OC. The AutoDock software was used for molecular docking, and its results were further validated using RT-qPCR in OC cell lines.

Results: Matrine reduced the cell viability, migration, invasion and increased the cell apoptosis of A2780 and AKOV3 cells (P< 0.01). A PPI network with 578 interactions among 105 candidate targets was developed. Finally, six core targets (TP53, CCND1, STAT3, LI1B, VEGFA, and CCL2) were derived, among which five core targets (TP53, CCND1, LI1B, VEGFA, and CCL2) differential expressed in OC and control samples were further picked for MR analysis. The results revealed that CCND1 and TP53 were risk factors for OC. Molecular docking analysis demonstrated that matrine had good potential to bind to TP53, CCND1, and IL1B. Moreover, matrine reduced the expression of CCND1 and IL1B while elevating P53 expression in OC cell lines.

Conclusions: We identified six matrine-related targets against OC, offering novel insights into the molecular mechanisms underlying the therapeutic effects of matrine against OC. These findings provide valuable guidance for developing more efficient and targeted therapeutic approaches for treating OC.

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整合网络药理学和孟德尔随机法，探索马特林抗卵巢癌的潜在靶点。

背景：据报道，马特林对卵巢癌（OC）细胞的进展、发育和凋亡具有抑制作用。然而，马屈菜碱抗卵巢癌的分子靶点及其作用机制仍不明确：本研究旨在揭示马屈菜红碱抗 OC 的潜在靶点，并探讨这些靶点与 OC 发病机制之间错综复杂的关系：方法：通过CCK-8、流式细胞术、伤口愈合和Transwell分析，分别研究了马钱子碱对OC细胞（A2780和AKOV3）活力、凋亡、迁移和侵袭的影响。接着，从公开数据库中获取了与Matrine相关的靶点、与OC相关的基因和核糖核酸（RNA）序列数据。通过差异表达分析、蛋白质-蛋白质相互作用（PPI）网络和维恩图，揭示了马钱子碱抗OC的核心靶点。利用GEPIA数据库，我们进一步验证了这些核心靶点在OC病例和对照组之间的表达水平。我们实施了孟德尔随机化（MR）研究，以探讨核心靶点与 OC 之间的潜在因果关系。使用AutoDock软件进行分子对接，并在OC细胞系中使用RT-qPCR进一步验证其结果：结果：Matrine降低了A2780和AKOV3细胞的活力、迁移和侵袭，增加了细胞凋亡（P< 0.01）。在105个候选靶点之间建立了一个包含578个相互作用的PPI网络。最后得出了6个核心靶点（TP53、CCND1、STAT3、LI1B、VEGFA和CCL2），并进一步挑选了其中5个在OC和对照样本中差异表达的核心靶点（TP53、CCND1、LI1B、VEGFA和CCL2）进行磁共振分析。结果显示，CCND1和TP53是OC的风险因素。分子对接分析表明，matrine与TP53、CCND1和IL1B有很好的结合潜力。此外，在降低CCND1和IL1B表达的同时，提高了P53在OC细胞系中的表达：结论：我们发现了六个针对OC的与马钱子碱相关的靶点，为马钱子碱治疗OC的分子机制提供了新的见解。这些发现为开发更高效、更有针对性的OC治疗方法提供了宝贵的指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.