【摘要】 目的:从代谢组学角度开展肿瘤共病抑郁的研究,将在复杂疾病发生发展机制以及药物治疗新靶点方面做出有益探索。本实验采用代谢组学方法检测荷瘤抑郁样模型小鼠血清小分子代谢物的变化及抗抑郁药氟西汀的影响,探讨代谢组学在肿瘤共病抑郁研究中的应用。方法:制备移植性荷瘤小鼠模型,氟西汀处理组对荷瘤小鼠连续28 d灌胃给药,观察各组行为学反应。采用液相色谱串联四级杆飞行时间质谱(LC-QToF/MS)获取荷瘤小鼠与正常小鼠的血清代谢轮廓,并用正交信号校正的偏最小二乘法(OPLS)进行多元统计分析,结合单维水平筛选结果,得到荷瘤小鼠区别于正常对照小鼠的特征性差异代谢物,并观察氟西汀对上述代谢物的影响。结果:行为学反应结果显示,与正常小鼠相比,荷瘤小鼠表现抑郁相关性行为改变,氟西汀对荷瘤引起的行为学变化有显著改善作用。代谢组学分析结果显示,荷瘤小鼠血清中乙酰肉碱和油酰胺的含量较正常小鼠显著降低,氟西汀处理后可增加荷瘤小鼠血清中的乙酰肉碱和油酰胺的含量。结论:基于代谢组学分析得到的特征性代谢产物的下调可能与荷瘤小鼠的抑郁样状态有关,氟西汀对这两种潜在生物标志物有明显的调节作用。代谢组学研究为疾病特异性生物标志物的筛选及药物药效的评价提供了新的思路与方法。更多还原

【Abstract】 Objective:To carry out a tumor comorbid depression research from the perspective of metabolomics will make a useful exploration for the mechanism of the occurrence and development of complex diseases and the new target of drug treatment.The purpose of this study was to investigate low-molecular metabolites in serums of tumor-bearing mice with depressive-like behaviors by metabolomics method,and evaluate the effect of antidepressant agent fluoxetine.Methods:The tumor-bearing mice model was established by tumor inoculation.Fluoxetine was orally administrated for a consecutive 28-day period after the inoculation.The depressive state of tumor-bearing mice was evaluated by behavioral responses.The metabolomic profiles were acquired based on liquid chromatography coupled to quadrupole time of flight mass spectrometer(LC-QToF/MS).The metabolites in serum of tumor-bearing mice characteristically different from control mice were obtained by orthogonal signal correction-partial least squares(OPLS) as multivariate statistical analysis followed by one-dimensional screening analysis.The effect of fluoxetine on the level of these characteristic metabolites was also observed.Results:The tumor-bearing mice exhibited depression-like behavior changes compared with that in the control group.The treatment of fluoxetine significantly improved behavioral responses caused by tumor burden.Compared with that in the controls,the serum concentrations of acetyl-L-carnitine and oleamide decreased significantly in the tumor-bearing group.While in the fluoxetine-treated group,the concentrations of these endogenous compounds increased.Conclusion:The down-regulation of characteristic metabolites derived from metabolomics analysis was associated with the depression-like state of the tumor-bearing mice.The abnormal changes of serum metabolites could be alleviated by the treatment of antidepressant agent fluoxetine.The metabolomics provides new insight and strategy for disease-specific biomarkers screening and drug efficacy evaluation.更多还原