Network Pharmacology and Experimental Validation Reveal Sishen Pill's Efficacy in Treating NSAID-Induced Small Intestinal Ulcers.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-03-19 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S502193

Jiaying Zhou, Fengting Zhu, Huixian Liang, Leimin Sun

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Abstract

Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used but often cause small intestinal ulcers (SIUs), for which effective therapies are lacking. Sishen Pill (SSP), a traditional Chinese medicine, shows therapeutic promise, yet its mechanisms remain unclear. This study integrates network pharmacology, molecular docking, and experimental validation to systematically investigate SSP's protective mechanisms against NSAID-induced SIUs.

Patients and methods: Active SSP ingredients were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopedia of Traditional Chinese Medicine (ETCM) databases. SIU-related targets were retrieved from GeneCards and DisGeNET. Protein-protein interaction (PPI) networks were constructed via STRING and Cytoscape, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking (AutoDock Vina, PyMOL) validated ligand-target interactions. In vivo validation employed an indomethacin-induced SIU rat model to assess SSP's effects on ulcer severity, inflammation, oxidative stress, and PI3K/AKT signaling.

Results: We identified 66 bioactive SSP ingredients, 222 drug targets, and 144 SIU-related targets. Molecular docking revealed high binding affinity of SSP components (quercetin, bavachinin, rutaecarpine, evodiamine) to key targets (AKT1, HSP90AA1, IL6, MAPK1, BCL2). KEGG analysis highlighted the PI3K/AKT pathway as central. In vivo, SSP reduced ulcer indices, suppressed pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and attenuated oxidative stress. SSP also downregulated PI3K and AKT1 mRNA expression, confirming pathway modulation.

Conclusion: This study elucidates SSP's multi-target mechanism against NSAID-induced SIUs, emphasizing its role in suppressing inflammation, oxidative stress, and PI3K/AKT signaling. These findings provide a scientific foundation for SSP's clinical application and highlight its potential as a safe, effective alternative to conventional therapies.

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网络药理学和实验验证表明四肾丸治疗非甾体抗炎药致小肠溃疡的疗效。

目的：非甾体抗炎药（NSAIDs）被广泛使用，但常引起小肠溃疡（SIUs），缺乏有效的治疗方法。四神丸（SSP）是一种传统的中药，具有良好的治疗前景，但其作用机制尚不清楚。本研究结合网络药理学、分子对接、实验验证等方法，系统探讨了SSP对非甾体抗炎药诱导的SIUs的保护机制。患者和方法：采用中药系统药理学（TCMSP）和中国中医百科全书（ETCM）数据库筛选SSP的有效成分。从GeneCards和DisGeNET中检索与siu相关的靶标。通过STRING和Cytoscape构建蛋白-蛋白相互作用（PPI）网络，随后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）途径富集分析。分子对接（AutoDock Vina, PyMOL）验证了配体-靶标相互作用。体内验证采用吲哚美辛诱导的SIU大鼠模型来评估SSP对溃疡严重程度、炎症、氧化应激和PI3K/AKT信号传导的影响。结果：共鉴定出66种SSP活性成分，222个药物靶点，144个siu相关靶点。分子对接显示，SSP成分（槲皮素、巴伐齐素、芦果卡果素、evodiamine）与关键靶点（AKT1、HSP90AA1、IL6、MAPK1、BCL2）具有较高的结合亲和力。KEGG分析强调PI3K/AKT通路为中心。在体内，SSP可降低溃疡指数，抑制促炎因子（TNF-α、IL-1β、IL-6），减轻氧化应激。SSP还下调了PI3K和AKT1 mRNA的表达，证实了途径的调节。结论：本研究阐明了SSP抗nsaid诱导的SIUs的多靶点机制，强调了其在抑制炎症、氧化应激和PI3K/AKT信号传导中的作用。这些发现为SSP的临床应用提供了科学基础，并突出了其作为一种安全、有效的替代传统疗法的潜力。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.