目的 研究京制牛黄解毒片对口腔黏膜炎大鼠的治疗作用及对血清代谢物的影响，探讨代谢途径和可能的机制。方法 建立大鼠口腔黏膜炎模型，通过口腔黏膜炎面积和病理组织学评估京制牛黄解毒片对口腔黏膜炎大鼠的治疗作用；采用超高效液相色谱-四级杆飞行时间质谱联用（UHPLC-QTOF/MS）技术对血清进行代谢组学研究，筛选潜在生物标志物并富集代谢通路；采用脂多糖诱导的小鼠骨髓巨噬细胞炎症模型进行验证。结果 京制牛黄解毒片可明显降低大鼠口腔黏膜炎面积，改善口腔黏膜炎大鼠黏膜组织病理变化。代谢组学分析共筛选到41个与口腔黏膜炎风险相关的生物标志物。将潜在生物标志物进行通路预测分析，影响较强的有脂类代谢通路和鞘脂信号通路。进一步采用脂多糖诱导的小鼠骨髓巨噬细胞进行验证，京制牛黄解毒片可以显著抑制细胞上清中炎症因子肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6、IL-1β的分泌，减少TNF-α表达，减少细胞活性氧（ROS）的生成，抑制细胞核因子-κB（NF-κB）核转位（P＜0.05、0.01）。京制牛黄解毒片可显著增加p-蛋白激酶B1（Akt）/Akt蛋白表达，抑制鞘氨醇-1-磷酸受体（S1PR3）蛋白的表达（P＜0.05、0.01）。结论 京制牛黄解毒片能够有效改善口腔黏膜炎模型大鼠的黏膜损伤，其作用机制可能通过影响鞘脂代谢和炎症信号等相关通路发挥作用。

Objective To explore the therapeutic effect of Jingzhi Niuhuang Jiedu Tablets on oral mucositis injury and its mechanism. Methods Establish a rat model of oral mucositis, and evaluate the therapeutic effect of Jingzhi Niuhuang Jiedu Tablets on rats with oral mucositis through assessment of the area of oral mucositis and pathological histology, conduct metabolomics research on serum using ultra-high performance liquid chromatography - quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) technology to screen potential biomarkers and enrich metabolic pathways, verify the results using a mouse model of bone marrow macrophage inflammation induced by lipopolysaccharide. Results Jingzhi Niuhuang Jiedu Tablets can significantly reduce the area of oral mucosal inflammation in rats and improve the pathological changes of the mucosal tissues in rats with oral mucosal inflammation. Metabolomics analysis identified 41 biomarkers related to the risk of oral mucosal inflammation. The potential biomarkers were subjected to pathway prediction analysis, and the pathways with stronger effects were lipid metabolism pathway and sphingolipid signaling pathway. Further verification was conducted using mouse bone marrow macrophages induced by LPS. The Jingzhi Niuhuang Jiedu Tablets group could significantly inhibit the secretion of inflammatory factors such as TNF-α, IL-6, and IL-1β in the cell supernatant, reduce the expression of TNF-α, reduce the generation of ROS in cells, and inhibit the nuclear translocation of NF-κB (P < 0.05, 0.01). Jingzhi Niuhuang Jiedu Tablets group could significantly increase the expression of p- Akt/Akt protein and inhibit the expression of S1PR3 protein (P < 0.05, 0.01). Conclusion Jingzhi Niuhuang Jiedu Tablets can effectively improve mucosal damage and may exert its effects by regulating sphingolipid metabolism and inflammatory signaling pathways.

北京市科技计划项目（Z241100009024041）