目的 探讨小檗碱抑制APC^min/+小鼠结直肠腺瘤的作用机制。方法 随机取8只C57BL/6小鼠作为对照组，将APC^min/+小鼠随机分为模型组和小檗碱低、高（50、100 mg/kg）剂量组，每组8只，60%高脂饲料饲养，持续给药10周，观察结直肠肿瘤数量、最大肿瘤直径；苏木素-伊红（hematoxylin-eosin，HE）染色观察结直肠病理表现，免疫组化观察结直肠ki67、p53阳性率；高分辨非靶向代谢组学检测各组血清代谢物，运用正交偏最小二乘判别分析（orthogonal partial least squares discriminant analysis, OPLS-DA）筛选差异代谢物，对差异代谢物进行功能富集分析；RT-qPCR检测结直肠组织中鸟氨酸转氨甲酰酶（ornithine transcarbamylase，OTC）、精氨酸酶1/2（arginase 1/2，ARG1/2）、一氧化氮合酶2（nitric oxide synthase 2，NOS2）、精氨酸代琥珀酸裂解酶（argininosuccinate lyase，ASL）mRNA表达水平。结果 小檗碱可以显著减少APC^min/+小鼠结直肠肿瘤数量与最大肿瘤直径，改善肠道非典型增生和炎性浸润，抑制ki67和p53阳性表达率（P＜0.001）；代谢组学结果发现，与对照组比较，模型组小鼠有145个差异代谢物，与模型组比较，小檗碱组小鼠有51种差异代谢物，功能富集分析显示精氨酸生物合成途径代谢物DL-谷氨酸、L-瓜氨酸、N-乙酰-L-谷氨酸、N-α-乙酰-L-鸟氨酸在模型组小鼠血清中上调，小檗碱治疗后下调；RT-qPCR结果显示，与对照组比较，模型组小鼠肠道中OTC的mRNA表达水平下降（P＜0.001），ARG1、ARG2、NOS2的mRNA表达升高（P＜0.001）；与模型组比较，小檗碱低、高（50、100 mg/kg）剂量组可以恢复OTC mRNA表达（P＜0.001）、抑制ARG1、ARG2、NOS2的mRNA表达水平（P＜0.001）。结论 小檗碱对结直肠腺瘤的治疗作用可能与抑制血清精氨酸合成、调控精氨酸代谢关键基因表达有关。

Objective To explore the mechanisms by which berberine (BBR) inhibits colorectal adenoma (CRA) in APC^min/+ mice. Methods A total of eight C57BL/6 mice were randomly selected as the control group. APC^min/+ mice were randomly divided into the model group, low- and highdose (50, 100 mg/kg) BBR groups, with eight mice in each group. Mice were fed high-fat diet and administered treatment for 10 weeks. The number of colorectal tumors and the maximum tumor diameter were observed. Histopathological changes in the colorectal tissue were assessed using hematoxylin-eosin (HE) staining, and the expression rates of ki67 and p53 were evaluated via immunohistochemistry. Serum metabolites were detected using high-resolution untargeted metabolomics, and differential metabolites were identified using orthogonal partial least squares-discriminant analysis (OPLS-DA), followed by functional enrichment analysis. RT-qPCR was employed to assess the mRNA expression levels of ornithine transcarbamylase (OTC), arginase 1/2 (ARG1/2), nitric oxide synthase 2 (NOS2), and argininosuccinate lyase (ASL) in colorectal tissues. Results BBR significantly reduced both the number and size of colorectal tumors in APC^min/+ mice, improved atypical hyperplasia and inflammatory infiltration in the intestine, and suppressed the positive expression rates of ki67 and p53 (P < 0.01, 0.001). Metabolomics identified 145 differential metabolites between the model and control groups, and 51 differential metabolites between the model and BBR groups. KEGG analysis revealed that metabolites in the arginine biosynthesis pathway, DL-glutamate, L-citrulline, N-acetyl-L-glutamate, and N-α-acetyl-L-ornithine—were upregulated in the model group but downregulated following BBR treatment. RT-qPCR results indicated that compared to the control group, the expression level of OTC mRNA was decreased in the intestines of model group mice (P < 0.001), while the mRNA expressions of ARG1, ARG2and NOS2 were increased (P < 0.001). In comparison to the model group, the low- and high-dose BBR groups restored OTC mRNA expression (P< 0.001) and suppressed the mRNA expression levels of ARG1, ARG2 and NOS2 (P < 0.001).

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国家中医药管理局高水平中医药重点学科建设项目（zyyzdxk-2023187）;贵州省高等学校中西医结合防治疾病转化医学重点实验室（黔教技[2023]017号）;贵州中医药大学中西医结合防治消化系统疾病科技创新人才团队建设项目（贵中医TD合字[2023]001号）