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

IF 4.7 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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引用次数: 0

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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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.