哌甲酯干预儿童多动症患者尿液的代谢组学研究
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摘要
目的基于代谢组学方法研究哌甲酯干预儿童多动症患者尿液内源性代谢物的变化,并探索哌甲酯的作用机制。方法采用气相色谱-质谱联用技术(GC-MS)检测37例儿童多动症患者哌甲酯干预前(病例0周组)、干预6周(病例6周组)、干预12周(病例12周组)和同期40例健康者(对照组)尿液内源性代谢物,经正交偏最小二乘法(OPLS)分析,寻找显著差异的变量,鉴定潜在生物标志物。结果对照组、病例0周组、病例12周组的尿液代谢谱发生了明显变化,病例0周组与对照组的代谢谱能够区分,同时病例12周组样本远离病例0周组,靠近对照组;利用商业化的代谢物谱库(如Wiley和NIST质谱库)及本实验室建立的标准品代谢物谱库鉴定了24种相关代谢标志物,哌甲酯干预后,这些代谢物的水平逆转到正常水平。结论本研究表明哌甲酯治疗儿童多动症具有良好的疗效,其作用机制可能与丙酮酸代谢、色氨酸代谢、苯丙氨酸代谢、甘氨酸,丝氨酸和苏氨酸代谢等代谢异常有关,代谢组学从机体整体代谢角度揭示了哌甲酯治疗儿童多动症的作用机制。
Objective To study the effect of methylphenidate on urinary endogenous metabolites in children with ADHD,and to explore the mechanism of methylphenidate. Methods The metabolites of urine in 37 children with ADHD treated with methylphenidate before intervention( case 0 week group),intervention for 6 weeks( 6 weeks group),intervention 12 weeks( 12 weeks group,and 40 healthy subjects( control group) were measured by gas chromatography-mass spectrometry( GC-MS),and analyzed by orthogonal partial least squares( OPLS) to find the significant differences biomarkers. Results The urine metabolic profile of the control group,the 0 week group and the 12 week group showed obvious changes. The metabolic profile of the 0 week group and the control group was differentiated,and the 12 week group was away from the 0 week group,and closed to the control group. 24 significant differences metabolites were identified using commercially available metabolite libraries( such as the Wiley and NIST mass pools) and the standard metabolite library established in our laboratory. The levels of these metabolites were reversed to normal level due to methylphenidate intervention.Conclusion This study shows that methylphenidate has a good curative effect on children with ADHD. Its mechanism is related to the metabolic abnormalities of pyruvate metabolism,tryptophan metabolism,phenylalanine metabolism,glycine,serine and threonine metabolism. The possible mechanism of methylphenidate in the treatment of children with ADHD was revealed from the overall metabolic point of the body. Metabolomics reveals possible therapeutic mechanism of methylphenidate for children with ADHD from overall metabolism of the body.
Objective To study the effect of methylphenidate on urinary endogenous metabolites in children with ADHD,and to explore the mechanism of methylphenidate. Methods The metabolites of urine in 37 children with ADHD treated with methylphenidate before intervention( case 0 week group),intervention for 6 weeks( 6 weeks group),intervention 12 weeks( 12 weeks group,and 40 healthy subjects( control group) were measured by gas chromatography-mass spectrometry( GC-MS),and analyzed by orthogonal partial least squares( OPLS) to find the significant differences biomarkers. Results The urine metabolic profile of the control group,the 0 week group and the 12 week group showed obvious changes. The metabolic profile of the 0 week group and the control group was differentiated,and the 12 week group was away from the 0 week group,and closed to the control group. 24 significant differences metabolites were identified using commercially available metabolite libraries( such as the Wiley and NIST mass pools) and the standard metabolite library established in our laboratory. The levels of these metabolites were reversed to normal level due to methylphenidate intervention.Conclusion This study shows that methylphenidate has a good curative effect on children with ADHD. Its mechanism is related to the metabolic abnormalities of pyruvate metabolism,tryptophan metabolism,phenylalanine metabolism,glycine,serine and threonine metabolism. The possible mechanism of methylphenidate in the treatment of children with ADHD was revealed from the overall metabolic point of the body. Metabolomics reveals possible therapeutic mechanism of methylphenidate for children with ADHD from overall metabolism of the body.
引文
1罗沽兰.奥氮平与哌醋甲酯治疗儿童多动症的疗效对比分析[J].吉林医学,2015,36(17):3827-3828
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4 郭田友,郭兰婷.伴品行障碍多动症儿童的临床观察[J].中国心理卫生杂志,2003,57(7):431-452
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6 占雪梅,周云芳,邹晓华.托莫西汀与利他林治疗儿童多动症的临床对照研究[J].中国药业,2009,18(11):72-73
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9 杨雯晴,蒋海强,李运伦,等.卡托普利干预自发性高血压大鼠血清代谢组学研究[J].中国药理学通报,2016,32(7):998-1003
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11 Wang XJ,Yang B,Zhang AH,et al.Potential drug targets on insomnia and intervention effects of Jujuboside A through metabolic pathway analysis as revealed by UPLC/ESI-SYNAPT-HDMS coupled with pattern recognition approach[J].J Proteom,2012,75(4):1411-1427
12 俞建峰,刘文明,蒋建红,等.乳酸代谢及乳酸清除率对重症中暑患者预后的评估价值[J].实用临床医药杂志,2015,19(23):44-47
13 王静.乳酸在运动型中枢疲劳中的作用及机制研究[D].北京:中国人民解放军军事医学科学院,2005,5:41
14 王凤阳,刘艳庭,张海峰,等.递增负荷运动下血乳酸丙酮酸的动态变化规律及乳酸阈机制探讨[J].中国组织工程研究与临床康复,2007,11(6):3193-3196
15 魏源,王革,王翔.试论乳酸代谢与运动训练的关系[J].湖南工程学院学报,2012,12(4):76-80
16 张风华.洪昭毅.注意缺陷多动障碍的神经生物学研究进展[J].中国行为医学科学,2001,10(6):629-631
17 李腾,彭靖,吕尚军,等.甘氨酸对烧伤大鼠心肌细胞能量代谢的影响[J].重庆医学,2012,41(33):3476-3477
18 Kopple JD.Phenylalanine and tyrosine metabolism in chronic kidney failure[J].J Nutr,2007,137(Suppl 1):1586-1590
19 Rath T,Roth E,Keidl R.Phenylalanine:total amino acid ratio in 45burn patients[J].Scand J Plast Reconstr Surg Hand Surg,1987,21(3):297-300
20 Liu Y,Zhang L,Wei S,et al.Song,endogenous L-carnosinelevel in diabetes rat cardiac muscle[J].Evid.Based Complement.Alternat.Med.2016,2016:1-7
21 Shui SF,Shen SJ,Huang RQ,et al.Metabonomic analysis of biochemical changes in the plasma and urine of carrageenan-induced rats after treatment with Yi-Guan-Jian decoction[J].J Chromatography B,2016,1033-1034:80-90
22 魏涌.医学生物化学[M].北京:世界图书出版公司,1998:208-216
23伏洁,周士新,刘光陵,等.儿童多动症遗传因素的研究进展[J].中国全科医学,2006,9(9):758-761
2 苏林雁,李雪荣.儿童注意缺陷多动障碍治疗进展[J].中华儿科杂志,1999,37(3):582
3 郭艳,施新宇.儿童多动症患儿家庭环境及其父母养育方式的探讨[J].实用医技杂志,2005,12(24):3702-3703
4 郭田友,郭兰婷.伴品行障碍多动症儿童的临床观察[J].中国心理卫生杂志,2003,57(7):431-452
5 纪平,陈盛菊.儿童多动症135例临床治疗分析[J].现代中西医结合杂志,2009,18(26):3171-3172
6 占雪梅,周云芳,邹晓华.托莫西汀与利他林治疗儿童多动症的临床对照研究[J].中国药业,2009,18(11):72-73
7 Rochfort S.Metabolomics reviewed:a new"omics"platform technology for systems biology and implications for natural products research[J].J Nat Prod,2005,68(12):1813-1820
8 Nicholson JK,Holmes E,Kinross JM,et al.Metabolic phenotyping in clinical and surgical environments[J].Nature,2012,491(7424):384-392
9 杨雯晴,蒋海强,李运伦,等.卡托普利干预自发性高血压大鼠血清代谢组学研究[J].中国药理学通报,2016,32(7):998-1003
10 中华医学会精神科分会.中国精神障碍分类与诊断标准[M].3版.济南:山东科学技术出版社,2001:151
11 Wang XJ,Yang B,Zhang AH,et al.Potential drug targets on insomnia and intervention effects of Jujuboside A through metabolic pathway analysis as revealed by UPLC/ESI-SYNAPT-HDMS coupled with pattern recognition approach[J].J Proteom,2012,75(4):1411-1427
12 俞建峰,刘文明,蒋建红,等.乳酸代谢及乳酸清除率对重症中暑患者预后的评估价值[J].实用临床医药杂志,2015,19(23):44-47
13 王静.乳酸在运动型中枢疲劳中的作用及机制研究[D].北京:中国人民解放军军事医学科学院,2005,5:41
14 王凤阳,刘艳庭,张海峰,等.递增负荷运动下血乳酸丙酮酸的动态变化规律及乳酸阈机制探讨[J].中国组织工程研究与临床康复,2007,11(6):3193-3196
15 魏源,王革,王翔.试论乳酸代谢与运动训练的关系[J].湖南工程学院学报,2012,12(4):76-80
16 张风华.洪昭毅.注意缺陷多动障碍的神经生物学研究进展[J].中国行为医学科学,2001,10(6):629-631
17 李腾,彭靖,吕尚军,等.甘氨酸对烧伤大鼠心肌细胞能量代谢的影响[J].重庆医学,2012,41(33):3476-3477
18 Kopple JD.Phenylalanine and tyrosine metabolism in chronic kidney failure[J].J Nutr,2007,137(Suppl 1):1586-1590
19 Rath T,Roth E,Keidl R.Phenylalanine:total amino acid ratio in 45burn patients[J].Scand J Plast Reconstr Surg Hand Surg,1987,21(3):297-300
20 Liu Y,Zhang L,Wei S,et al.Song,endogenous L-carnosinelevel in diabetes rat cardiac muscle[J].Evid.Based Complement.Alternat.Med.2016,2016:1-7
21 Shui SF,Shen SJ,Huang RQ,et al.Metabonomic analysis of biochemical changes in the plasma and urine of carrageenan-induced rats after treatment with Yi-Guan-Jian decoction[J].J Chromatography B,2016,1033-1034:80-90
22 魏涌.医学生物化学[M].北京:世界图书出版公司,1998:208-216
23伏洁,周士新,刘光陵,等.儿童多动症遗传因素的研究进展[J].中国全科医学,2006,9(9):758-761