目的 探究复方阿胶浆对乳腺癌联合化疗诱导疲乏小鼠抑郁情绪的内源性代谢物及代谢途径的影响。方法 构建乳腺癌联合化疗诱导疲乏小鼠模型，给予复方阿胶浆或养正消积胶囊干预后，以小鼠体质量、摄食量、肿瘤体积、糖水偏好率、悬尾实验及强迫游泳实验不动时间、海马区组织病理形态、外周血中免疫细胞数量百分比、血清及脑组织中炎症因子水平为指标，观察复方阿胶浆对乳腺癌联合化疗诱导疲乏小鼠抑郁情绪的治疗作用；采用超高效液相色谱-四级杆飞行时间串联质谱法分析小鼠血清代谢物水平，筛选差异代谢物，考察复方阿胶浆对乳腺癌联合化疗诱导疲乏小鼠抑郁情绪治疗作用的潜在机制。结果 给予复方阿胶浆干预后，与模型组比较，小鼠糖水偏好率显著增加（P＜0.01），悬尾实验和强迫游泳实验不动时间显著降低（P＜0.01），脑组织海马区神经元细胞损伤得到改善，尼氏小体数量增加，外周血中CD45⁺、CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺细胞百分比显著增加（P＜0.05、0.01），血清及脑组织中炎症因子白细胞介素-6（interleukin-6，IL-6）、IL-1β、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）水平显著降低（P＜0.05、0.01）。代谢组学研究表征了乳腺癌联合化疗诱导疲乏小鼠抑郁情绪32个血清生物标记物，其中26个在给予复方阿胶浆治疗后回调，通路富集分析得到4条主要潜在代谢通路，分别为苯丙氨酸代谢途径、色氨酸代谢途径、精氨酸生物合成途径以及鞘脂代谢途径。结论 复方阿胶浆可能通过提高免疫功能、降低炎症因子水平进而调节氨基酸的合成与代谢、脂质代谢等途径发挥治疗乳腺癌联合化疗诱导疲乏小鼠抑郁情绪的作用。

Objective To investigate the effect of Fufang E’jiao Jiang (复方阿胶浆) on endogenous metabolites and metabolic pathways of depressive mood in fatigue mice induced with breast cancer combined with chemotherapy. Methods A model of fatigue associated with combination chemotherapy for breast cancer was established. After treatment with Fufang E’jiao Jiang or Yangzheng Xiaoji Capsules (养正消积胶囊), the following indicators were used to observe the therapeutic effect of Fufang E’jiao Jiang on depressive mood in mice with breast cancer-related fatigue following combination chemotherapy: body weight, food intake, tumor volume, sugar water preference rate, immobility time in the tail suspension test and forced swim test, histopathological morphology of the hippocampus, percentage of immune cells in peripheral blood, and levels of inflammatory factors in serum and brain tissue. Ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry was used to analyze metabolite levels in serum of mice, the differential metabolites were screened, and the potential mechanism of therapeutic effect of Fufang E’jiao Jiang on depressive mood in fatigue mice with breast cancer undergoing combination chemotherapy was investigated. Results After the administration of Fufang E’jiao Jiang intervention, compared with model group, the preference rate for sugar water in mice was significantly increased (P < 0.01), the immobility time in tail suspension and forced swimming experiments were significantly decreased (P < 0.01), neuronal cell damage in hippocampus of brain tissue was improved, and the number of Nissl bodies was increased, the percentage of CD45⁺, CD3⁺, CD4⁺, CD8⁺ and CD4⁺/CD8⁺ ratio in peripheral blood were significantly increased (P < 0.05, 0.01), the levels of inflammatory factors interleukin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α) in serum and brain tissue were significantly decreased (P < 0.05, 0.01). Metabolomics research characterized 32 serum biomarkers of depressive mood in mice induced by combined chemotherapy for breast cancer, of which 26 were reversed after treatment with Fufang E’jiao Jiang. Pathway enrichment analysis identified four major potential metabolic pathways, namely the phenylalanine metabolic pathway, tryptophan metabolic pathway, arginine biosynthesis pathway and sphingolipid metabolic pathway. Conclusion Fufang E’jiao Jiang may exert its therapeutic effects on depressive mood in fatigue mice with breast cancer combined with chemotherapy by enhancing immune function, reducing inflammatory factor levels, and regulating amino acid synthesis and metabolism, lipid metabolism and other pathways.

R285.5

东阿阿胶股份有限公司横向课题（22042240002）；国家中医药多学科创新团队项目（ZYYCXTD-D-202407）；黑龙江省重点研发计划（2022ZX02C04）