The therapeutic intervention of Chinese herbal formula SQQT on gastric mucosal spasmolytic polypeptide-expressing metaplasia cells and its systematic biological mechanism analysis
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摘要: 目的 研究中药复方SQQT对胃黏膜解痉多肽表达化生(SPEM)细胞病理表型的影响，探讨其干预SPEM细胞病理演变的可能效应机制。方法 回顾性分析以SQQT为主方的中药辨证方对临床不同部位胃黏膜癌前病变的干预效果和SPEM细胞分布情况；评估SQQT对小鼠模型SPEM细胞病理表型的影响；利用超高效液相色谱、单细胞RNA转录数据挖掘和网络药理学分析等系统生物学方法构建“成分-靶点”网络图谱，并进行拓扑分析。结果 ①中药辨证方可有效减轻胃癌前病变患者胃体黏膜萎缩、肠化、异型增生的程度，抑制胃体黏膜基底部SPEM细胞的形成；②SQQT可显著降低他莫昔芬复合法诱导的增殖型SPEM小鼠胃体黏膜SPEM细胞数量，并有效抑制SPEM细胞Ki67和CD44v9标记蛋白的异常表达；③本研究从复方中共鉴定出27种成分和118个靶点与增殖型SPEM细胞的病理转变密切关联。拓扑分析显示，SQQT主要通过调控细胞能量代谢、核糖体功能、细胞通讯、凋亡信号通路等，影响SPEM细胞的增殖和分化功能。有6种化学成分(柠檬酸、根皮酚、去甲基吴茱萸酰胺、吴茱萸黄碱、橙皮苷和人参皂苷Re)同时参与调节SPEM细胞的线粒体ATP合成电子转运、氧化还原膜转运体活性以及核糖体功能，可能是SQQT调控SPEM细胞病理演变的潜在物质基础。结论 中药复方SQQT通过多种成分对应多个靶点的整体调控作用，实现抑制胃黏膜SPEM细胞异常增殖和分化。Abstract: Objective This study aimed to investigate the therapeutic impact of SQQT on the pathological phenotype of spasmolytic polypeptide-expressing metaplasia (SPEM) cells in the gastric mucosa, and to explore the potential mechanisms underlying its intervention in the pathological evolution of SPEM cells.Methods Retrospective analysis was conducted to assess SQQT's effect on gastric precancerous lesions and SPEM cell distribution. In a murine model, the effect of SQQT on SPEM cytopathic phenotype was evaluated. A "component-target" network map was constructed using chromatography, single-cell RNA data, and network pharmacology analysis, followed by topological analysis.Results ① SQQT effectively alleviated gastric mucosal atrophy, intestinal metaplasia, and dysplasia in patients with precancerous gastric lesions, and reduced SPEM cell formation at the gastric mucosal base; ②Notably, SQQT significantly reduced the count of SPEM cells in the gastric mucosa of mice induced by the tamoxifen compound method, effectively targeting and suppressing the abnormal expression of key marker proteins such as Ki67 and CD44v9. ③ This study identified a total of 27 components and 118 targets from the compound that are intimately associated with the pathological transition of proliferating SPEM cells. Topological analysis revealed that SQQT primarily regulates cellular processes including energy metabolism, ribosomal function, cell communication, and apoptotic signaling pathways, thereby exerting a profound impact on SPEM cell proliferation and differentiation. Intriguingly, six specific chemical constituents—Citric acid, Root bark phenol, Demethylated ruthenic amide, Wu Zhu Yu Huang alkaloid, Hesperidin, and Ginsenoside Re—were implicated in regulating critical biological functions such as mitochondrial ATP synthesis electron transport, redox membrane transporter activity, and ribosome function in SPEM cells, potentially constituting the material basis for compound regulation of SPEM cell pathology.Conclusion The traditional Chinese medicine compound SQQT effectively suppresses abnormal proliferation and differentiation of SPEM cells in the gastric mucosa by harnessing the synergistic effects of multiple components targeting diverse biological pathways.
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表 1 实验分组和药物干预信息表
组别 剂量和浓度 干预方式 空白对照组 蒸馏水0.1 mL/10 g/d 灌胃 SPEM模型组 蒸馏水0.1 mL/10 g/d 灌胃 复方高剂量组 1.84 g/mL/d 灌胃 复方中剂量组 0.92 g/mL/d 灌胃 复方低剂量组 0.46 g/mL/d 灌胃 
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表 2 小鼠胃组织病理学评分
病理改变 分数 1 2 3 4 黏膜炎症
(H&E)黏膜及黏膜下层有斑块浸润的混合白细胞，显著存在粒细胞浸润则额外计分0.5。 多灶性联合白细胞浸润未扩展至黏膜下层 淋巴滤泡中白细胞数量显著增加，延伸至肌层 全黏膜层炎症 黏膜化生
(AB-PAS)胃体罕见小病灶 影响范围＜1/3腺体细胞的中等病灶 影响范围在1/3~2/3腺体细胞的大病灶 影响范围>2/3腺体细胞的大病灶
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表 3 不同部位胃黏膜病理组织学疗效等级分析
例(%) 病变 叶酸组 中药辨证方组 OR 95%CI P 例数 有效 例数 有效 炎症 胃体 32 12(37.5) 68 21(30.9) 1.343 0.556~3.242 0.637 胃窦 97 28(28.9) 190 60(31.6) 0.879 0.515~1.502 0.512 总体 129 40(31.0) 259 81(31.3) 0.984 0.623~1.553 0.944 萎缩 胃体 26 15(57.7) 38 27(71.1) 0.556 0.195~1.583 0.166 胃窦 82 38(46.3) 167 93(44.3) 0.687 0.404~1.168 0.271 总体 108 53(49.1) 205 120(58.5) 0.658 0.401~1.056 0.083 肠化 胃体 20 10(50.0) 29 17(58.6) 0.706 0.224~2.221 0.891 胃窦 75 37(49.3) 153 74(48.4) 1.039 0.598~1.807 0.552 总体 95 47(49.5) 182 91(50.0) 0.966 0.587~1.590 0.892 异型增生 胃体 10 7(70.0) 18 14(77.8) 0.667 0.116~3.838 0.821 胃窦 60 41(68.3) 126 84(66.7) 1.079 0.559~2.084 0.650 总体 70 48(68.6) 144 98(68.1) 1.018 0.550~1.883 0.956
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