【摘要】：目的通過代謝組學(xué)技術(shù)研究D-半乳糖(D-Gal)致衰老大鼠尿液代謝譜的動(dòng)態(tài)變化,并探究差異代謝物和行為學(xué)指標(biāo)的相關(guān)性。方法大鼠連續(xù)sc給予D-Gal 100 mg·kg-110周,并分別在第0,14,28,42,56和70天收集每只實(shí)驗(yàn)鼠的尿液,采用代謝組學(xué)技術(shù)對(duì)實(shí)驗(yàn)大鼠6次尿液樣本進(jìn)行核磁共振(NMR)數(shù)據(jù)采集并結(jié)合多元統(tǒng)計(jì)進(jìn)行分析。第70天開始采用Morris水迷宮檢測實(shí)驗(yàn)大鼠的學(xué)習(xí)記憶能力。行為學(xué)實(shí)驗(yàn)結(jié)束后,處死并制備腦切片,HE染色觀察海馬病理改變。結(jié)果對(duì)第0,14,28,42,56和70天模型組和正常對(duì)照組大鼠的尿液進(jìn)行主成分分析發(fā)現(xiàn),造模2~4周時(shí),兩組的代謝譜無差異;造模6~8周,兩組大鼠逐漸不同;造模10周時(shí),兩組完全不同。采用正交校正的偏最小二乘判別分析尋找兩組之間的差異物,在第10周發(fā)現(xiàn),乳酸、丙氨酸、α-酮戊二酸和膽堿等12個(gè)峰面積具有顯著性差異的潛在生物標(biāo)志物。將差異代謝物和穿越平臺(tái)次數(shù)、潛伏期以及目標(biāo)象限停留時(shí)間進(jìn)行關(guān)聯(lián)分析。結(jié)果表明,模型組中含量顯著性升高的差異代謝物膽堿、乳酸和二甲基甘氨酸與穿越平臺(tái)次數(shù)具有顯著性負(fù)相關(guān)(r=-0.90,-0.50和-0.52;n=10),甲酸與目標(biāo)象限停留時(shí)間呈顯著性負(fù)相關(guān)(r=-0.51,n=10);膽堿和甲酸與潛伏期呈顯著性正相關(guān)(r=0.72和0.53;n=10);而模型組含量顯著性降低的差異代謝物肌酸和牛磺酸與穿越平臺(tái)次數(shù)具有顯著性正相關(guān)(r=0.89和0.71;n=10),而丙氨酸與目標(biāo)象限停留時(shí)間呈顯著性正相關(guān)(r=0.74;n=10);牛磺酸、丙氨酸和肌酸與潛伏期呈顯著性負(fù)相關(guān)(r=-0.66,-0.50和-0.85;n=10);進(jìn)一步驗(yàn)證了差異代謝物與行為學(xué)指標(biāo)的相關(guān)性。結(jié)論D-Gal誘導(dǎo)的衰老大鼠尿液代謝譜變化和其學(xué)習(xí)記憶能力損傷有一定的相關(guān)性,基于1H-NMR代謝組學(xué)的尿液代謝譜變化規(guī)律,可作為D-Gal致衰老大鼠模型成功與否的評(píng)價(jià)指標(biāo)之一。
[Abstract]:Objective to study the dynamic changes of urine metabolic spectrum in aging rats induced by D-galactose (D-Gal) and to explore the correlation between different metabolites and behavioral indexes. Methods SD rats were given D-Gal 100mg kg-110 for a continuous week. Urine samples of each rat were collected on day 0, 14, 28, 42, 56 and 70, respectively. Six urine samples of experimental rats were collected by (NMR) and analyzed with multivariate statistics. The learning and memory abilities of experimental rats were measured by Morris water maze on day 70. At the end of behavioral experiment, he staining was used to observe the pathological changes of hippocampus. Results the urine of rats in the model group and the normal control group were analyzed by principal component analysis on the day 0 and 70. The results showed that there was no difference in metabolic spectrum between the two groups at 4 weeks of model making, the rats of the two groups were gradually different at 68 weeks of model making, and the two groups were completely different at 10 weeks of model making. Orthogonal corrected partial least squares discriminant analysis was used to find the difference between the two groups. In the 10th week, 12 potential biomarkers with significant differences in peak areas such as lactic acid, alanine, 偽 -ketoglutaric acid and choline were found. The differential metabolites were correlated with the times of crossing the platform, the latency and the target quadrant residence time. The results showed that the content of choline in the model group was significantly higher than that in the control group. Lactic acid and dimethyl glycine were negatively correlated with the times of crossing the platform (r = -0.90), formic acid was negatively correlated with the residence time of target quadrant (r = 0.51), choline and formic acid were positively correlated with latency (r 0.72 and 0.53 n ~ (10), while in the model group, they were positively correlated with the residence time of the target quadrant (r = 0.51), while those in the model group were positively correlated with the latency (r 0.72 and 0.53 n ~ (10). Significant positive correlation was found between creatine and taurine, which were significantly decreased (r = 0.89 and 0.71 n ~ (10), while alanine was positively correlated with the target quadrant residence time (r ~ (0.74) n ~ (10), taurine, and taurine were significantly correlated with the number of times of crossing the platform (r ~ (0.89) and (0.71) n ~ (10). There was a significant negative correlation between alanine and creatine (r ~ (-0.666) -0.50 and -0.85 n ~ (10), which further verified the correlation between different metabolites and behavioral indexes. Conclusion the changes of urine metabolic spectrum induced by D-Gal are related to the impairment of learning and memory ability in aged rats. The changes of urine metabolic spectrum based on 1H-NMR metabolomics can be used as an index to evaluate the success of aging rat model induced by D-Gal.
【作者單位】： 山西大學(xué)中醫(yī)藥現(xiàn)代研究中心;山西大學(xué)化學(xué)化工學(xué)院;山西大學(xué);山西省兒童醫(yī)院婦幼保健院;中國醫(yī)學(xué)科學(xué)院藥物研究所;Department
【基金】：The project supported by Applied Basic Research Project of Shanxi Province(201601D021164) Innovation Project of Higher Education Institutions In Shanxi Province(2016120) Construction of Science and Technology Basic Condition Platform of Shanxi Province(2014091022) and Program of Science and Technology of Shanxi Province(20140313008-14)~~
【分類號(hào)】：R-332

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