Chen Lisheng, Chang Lei, Wu Wenbin, Jing Manyi, Li Haotian, Niu Cong, Wei Shizhang, Zhu Shishu, Zhao Yanling
College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
J Ethnopharmacol. 2025 Jan 13;339:119151. doi: 10.1016/j.jep.2024.119151. Epub 2024 Nov 22.
Tetradium ruticarpum (A.Juss.) T.G.Hartley is a traditional Chinese medicine with a history of thousands of years, which plays an important role in the relief of gastric pain, indigestion, vomiting and diarrhea. Rutaecarpine (RUT) is one of the major active constituents of Tetradium ruticarpum (A.Juss.) T.G.Hartley with potential therapeutic activity in chronic atrophic gastritis (CAG). However, the mechanism of RUT to improve CAG is not well understood.
This study aimed to evaluate the efficacy of RUT in treating CAG and its underlying mechanism.
The CAG model of SD rats was established by induction with 0.1% ammonia and 20 mmol/L sodium deoxycholate solution, accompanied with irregular fasting cycle. The efficacy of RUT in treating CAG was assessed through pathological examination and serum biochemical indices including PP, IL-6, MTL, TNF-α, PG I, SS, PG II, IL-10 and GAS-17. Following this, network pharmacology, 16s rRNA sequencing, transcriptomics, and broadly targeted metabolomics were conducted to unravel the underlying mechanisms of RUT's action in CAG treatment. Ultimately, molecular docking, western blotting, and immunohistochemistry were employed to validate the critical targets and pathways involved in RUT's therapeutic approach for CAG.
RUT significantly improved body weight, gastric juice pH and gastric histologic injury in CAG rats. The results of serum biochemical indices showed that RUT significantly inhibited the expression levels of SS, GAS-17, IL-6 and TNF-α, and increased the levels of MTL, PP, PGI, PGII and IL-10. In addition, RUT apparently increased the expression of mucosal barrier proteins such as ZO-1, E-cadherin and claudin-4 and occludin. Network pharmacology in combination with transcriptomics revealed that the MAPK signaling pathway was the most important pathway for RUT treatment of CAG. Further analysis suggested that by regulating linoleic acid metabolism, metabolic pathways, etc. mainly related to energy metabolism, RUT intervention effectively ameliorated gastric tissue metabolic disorders in CAG rats. The 16S rRNA gene-based microbiota analysis revealed that RUT altered the composition of the intestinal microbiota and decreased the relative abundance of unclassified_Muribaculaceae. PICRUST analysis suggested that the differential bacteria may be involved in energy metabolism pathway regulation for the improvement of CAG. A comprehensive analysis of the transcriptome and metabolome showed that the RUT improved the differential metabolites through the regulation of TGER2, CBR1 and CTPS1 targets.
These findings indicated that RUT's mechanism of action in treating CAG was related to modulating the gut microbiota, influencing energy metabolism, and inhibiting the MAPK signaling pathway. This provided new insights into how RUT exerts its therapeutic effects on CAG.
吴茱萸是一种有着数千年历史的传统中药，在缓解胃痛、消化不良、呕吐和腹泻方面发挥着重要作用。吴茱萸碱（RUT）是吴茱萸的主要活性成分之一，对慢性萎缩性胃炎（CAG）具有潜在治疗活性。然而，RUT改善CAG的机制尚不清楚。
本研究旨在评估RUT治疗CAG的疗效及其潜在机制。
通过0.1%氨水和20 mmol/L脱氧胆酸钠溶液诱导建立SD大鼠CAG模型，并伴有不规则禁食周期。通过病理检查和血清生化指标（包括PP、IL-6、MTL、TNF-α、PG I、SS、PG II、IL-10和GAS-17）评估RUT治疗CAG的疗效。在此基础上，进行网络药理学、16s rRNA测序、转录组学和广泛靶向代谢组学研究，以揭示RUT在CAG治疗中的作用机制。最终，采用分子对接、蛋白质免疫印迹和免疫组织化学方法验证RUT治疗CAG的关键靶点和途径。
RUT显著改善了CAG大鼠的体重、胃液pH值和胃组织学损伤。血清生化指标结果显示，RUT显著抑制SS、GAS-17、IL-6和TNF-α的表达水平，并提高MTL、PP、PGI、PGII和IL-10的水平。此外，RUT明显增加了紧密连接蛋白1（ZO-1）、E-钙黏蛋白、闭合蛋白4和闭合蛋白等黏膜屏障蛋白的表达。网络药理学与转录组学相结合表明，丝裂原活化蛋白激酶（MAPK）信号通路是RUT治疗CAG的最重要途径。进一步分析表明，通过调节主要与能量代谢相关的亚油酸代谢、代谢途径等，RUT干预有效改善了CAG大鼠胃组织的代谢紊乱。基于16S rRNA基因的微生物群分析显示，RUT改变了肠道微生物群的组成，并降低了未分类毛螺菌科的相对丰度。PICRUST分析表明，差异细菌可能参与能量代谢途径调节以改善CAG。转录组和代谢组的综合分析表明，RUT通过调节TGER2、CBR1和CTPS1靶点改善差异代谢物。
这些发现表明，RUT治疗CAG的作用机制与调节肠道微生物群、影响能量代谢和抑制MAPK信号通路有关。这为RUT对CAG发挥治疗作用的方式提供了新的见解。
