Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
J Ethnopharmacol. 2024 Dec 5;335:118644. doi: 10.1016/j.jep.2024.118644. Epub 2024 Jul 31.
Characterized by inflammation of the gastric mucosa, atrophy of gastric gland cells, and intestinal metaplasia, Chronic Atrophic Gastritis (CAG) is a precancerous lesion disease. In traditional Chinese medicine, Rhizoma Coptidis (RC) is extensively used for treating gastrointestinal disorders, mainly because RC alkaloids-based extracts are the main active pharmaceutical ingredients. Total Rhizoma Coptidis extracts (TRCE) is a mixture of Rhizoma Coptidis extracts from Rhizoma Coptidis with alkaloids as the main components. However, the efficacy and mechanism of TRCE on CAG need further study.
To explore the therapeutic effect and underlying mechanisms of action of TRCE on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG) using network pharmacological analysis.
The amelioration effect of TRCE on CAG was evaluated in MNNG-induced CAG mice. The pathological severity of the mice was evaluated through H&E staining. Detection of gastric mucosal parietal cell loss was conducted using immunofluorescence staining, and serum indices were measured using ELISA. Additionally, the active compounds and drug targets of Rhizoma Coptidis were curated from the STP, SEA, and TCMSP databases, alongside disease targets of CAG sourced from PharmGkb, OMIM, and GeneCards databases. By mapping drug targets to disease targets, overlapping targets were identified. A shared protein-protein interaction (PPI) and drug target network were constructed for the overlapping targets and analyzed for KEGG enrichment.
The results of animal experiments demonstrate that TRCE has the potential to improve the CAG process in mice. In conjunction with disease characteristics, cyberpharmacology analysis has identified nine core compounds, 151 targets, 10 core targets, and five significant inflammatory pathways within the compound-target-pathway network. Furthermore, there is a remarkable coincidence rate of 98% between the core compound targets of TRCE and the targets present in the CAG disease database. The accurate search and calculation of literature reports indicate that the coverage rate for 121 predicted core targets related to CAG reaches 81%. The primary characteristic of CAG lies in its inflammatory process. Both predicted and experimental findings confirm that TRCE can regulate ten key inflammation-associated targets (TP53, STAT3, AKT1, HSP90AA1, TNF, IL-6, MAPK3, SRC, JUN, and HSP90AA1) as well as inflammation-related pathways (MAPK, HIF-1, Toll-Like Receptor, IL-17, TNF, and other signaling pathways). These mechanisms mitigate inflammation and reduce gastric mucosal damage in CAG mice.
In conclusion, TRCE was shown to alleviate CAG by modulating TP53, STAT3, AKT1, HSP90AA1, TNF, IL-6, MAPK3, SRC, JUN, and EGFR, as demonstrated by combined network pharmacology and biological experiments. In conclusion, our study provides a robust foundation for future clinical trials evaluating the efficacy of RC in treating CAG.
慢性萎缩性胃炎（CAG）是一种癌前病变疾病，其特征为胃黏膜炎症、胃腺细胞萎缩和肠上皮化生。在中医中，黄连被广泛用于治疗胃肠道疾病，主要是因为黄连生物碱提取物是主要的活性药物成分。黄连总提取物（TRCE）是黄连提取物的混合物，其主要成分是黄连生物碱。然而，TRCE 治疗 CAG 的疗效和机制仍需要进一步研究。
通过网络药理学分析探讨 TRCE 对 N-甲基-N'-硝基-N-亚硝基胍（MNNG）诱导的慢性萎缩性胃炎（CAG）的治疗作用及作用机制。
采用 MNNG 诱导的 CAG 小鼠评价 TRCE 对 CAG 的改善作用。通过 H&E 染色评估小鼠的病理严重程度。采用免疫荧光染色检测胃黏膜壁细胞丢失，采用 ELISA 检测血清指标。此外，从 STP、SEA 和 TCMSP 数据库中提取黄连的活性化合物和药物靶点，并从 PharmGkb、OMIM 和 GeneCards 数据库中提取 CAG 的疾病靶点。将药物靶点映射到疾病靶点，以识别重叠靶点。构建重叠靶点的共享蛋白质-蛋白质相互作用（PPI）和药物靶点网络，并进行 KEGG 富集分析。
动物实验结果表明，TRCE 具有改善 CAG 进程的潜力。结合疾病特征，网络药理学分析鉴定出 9 个核心化合物、151 个靶点、10 个核心靶点和化合物-靶点-通路网络中的 5 个显著炎症通路。此外，TRCE 的核心化合物靶点与 CAG 疾病数据库中的靶点之间的吻合率高达 98%。通过对文献报道的准确搜索和计算，121 个与 CAG 相关的预测核心靶点的覆盖率达到 81%。CAG 的主要特征在于其炎症过程。预测和实验结果均证实，TRCE 可调节 10 个关键炎症相关靶点（TP53、STAT3、AKT1、HSP90AA1、TNF、IL-6、MAPK3、SRC、JUN 和 HSP90AA1）和炎症相关通路（MAPK、HIF-1、Toll 样受体、IL-17、TNF 和其他信号通路）。这些机制减轻了 CAG 小鼠的炎症反应并减轻了胃黏膜损伤。
综上所述，通过网络药理学和生物实验相结合的方法，TRCE 被证明可以通过调节 TP53、STAT3、AKT1、HSP90AA1、TNF、IL-6、MAPK3、SRC、JUN 和 EGFR 来缓解 CAG。综上所述，本研究为进一步评估 RC 治疗 CAG 的疗效提供了可靠的基础。
