Yunnan Branch of Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong, 666100, China.
Heilongjiang University of Chinese Medicine, Haerbin, 150006, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 2):117179. doi: 10.1016/j.jep.2023.117179. Epub 2023 Sep 29.
ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known traditional Chinese medicine, Amomi fructus (A. fructus) (Sharen) has been used therapeutically to treat gastrointestinal illnesses, including gastric ulcer (GU). The mechanism underlying this impact is still not fully known, though. AIM OF THE STUDY: To investigate the hidden mechanism by which A. fructus influences the pathogenesis of GU, we employed network pharmacology approaches and in vivo validated studies. MATERIALS AND METHODS: Multiple public databases were used to compile information on bioactive compounds, potential targets of A. fructus, and associated genes of GU. Then, the STRING database's protein-protein interaction (PPI) data of the drug-disease overlapping gene targets was obtained, and the core targets for A. fructus against GU were discovered. Additionally, molecular docking was done to examine the binding capabilities of the active substances and core targets. Then, the pathways of A. fructus that target GU were examined using the Annotation, Visualization and Integrated Discovery (DAVID)'s Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway studies. In a mouse model of acute stomach mucosal damage brought on by absolute ethanol, the findings of network pharmacology were finally validated. RESULTS: In total, 610 targets derived from the 196 bioactive compounds in A. fructus, were discovered, and along with 115 A. fructus target genes for therapy of GU. Then, ten core targets associated with apoptosis and inflammation were determined based on node degree, and ALB, AKT1, TNF, EGFR, MAPK3, CASP3, MMP9, STAT3, SRC, and HRAS were identified as promising therapeutic targets of A. fructus against GU. The results of molecular docking also revealed that 65 active compounds had strong binding activity with the core targets, with volatile chemicals being the most significant active ingredients. So, for following in vivo tests, A. fructus volatile oils (AVO) were used. The KEGG analysis showed that the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signaling pathway may be crucial for the therapeutic mechanism of GU. In experiments that were validated in vivo, AVO considerably decreased the ulcer area and enhanced the histological appearance of the gastric tissues. In addition, compared to the model group, up-regulated the expression of IGF-1, p-PI3K, and p-AKT and down-regulated the protein levels of TNF-α and Caspase 3 in the stomach tissues. CONCLUSION: According to preliminary findings from this work, A. fructus may influence inflammatory response and apoptosis via regulating the PI3K/AKT signaling pathway and associated gene targets. Importantly, our research might offer a theoretical foundation for future research into the intricate anti-GU mechanism of A. fructus.
民族药理学相关性：作为一种著名的中药，砂仁（A. fructus）（砂仁）已被用于治疗胃肠道疾病，包括胃溃疡（GU）。尽管如此，其影响的机制仍不完全清楚。
研究目的：为了研究砂仁影响 GU 发病机制的潜在机制，我们采用网络药理学方法和体内验证研究。
材料和方法：使用多个公共数据库来编译关于生物活性化合物、砂仁潜在靶点和 GU 相关基因的信息。然后，从 STRING 数据库的药物-疾病重叠基因靶点的蛋白质-蛋白质相互作用（PPI）数据中获得，发现了砂仁治疗 GU 的核心靶点。此外，还进行了分子对接以检查活性物质和核心靶点的结合能力。然后，使用 DAVID 的基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路研究，研究了针对 GU 的砂仁通路。最后，在由绝对乙醇引起的急性胃黏膜损伤的小鼠模型中验证了网络药理学的发现。
结果：总共发现了 196 种砂仁生物活性化合物衍生的 610 个靶点，以及 115 个砂仁治疗 GU 的靶点基因。然后，基于节点度确定了与凋亡和炎症相关的十个核心靶点，并且鉴定 ALB、AKT1、TNF、EGFR、MAPK3、CASP3、MMP9、STAT3、SRC 和 HRAS 作为砂仁治疗 GU 的有前途的治疗靶点。分子对接的结果还表明，65 种活性化合物与核心靶点具有很强的结合活性，挥发性化学物质是最重要的活性成分。因此，对于后续的体内试验，使用了砂仁挥发油（AVO）。KEGG 分析表明，磷脂酰肌醇 3-激酶/蛋白激酶 B（PI3K/AKT）信号通路可能是 GU 治疗机制的关键。在体内验证实验中，AVO 显著降低了溃疡面积并改善了胃组织的组织学外观。此外，与模型组相比，AVO 在上调胃组织中 IGF-1、p-PI3K 和 p-AKT 的表达和下调 TNF-α和 Caspase 3 的蛋白水平方面具有统计学意义。
结论：根据这项工作的初步发现，砂仁可能通过调节 PI3K/AKT 信号通路和相关基因靶点来影响炎症反应和细胞凋亡。重要的是，我们的研究可能为未来研究砂仁复杂的抗 GU 机制提供理论基础。
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