基于质谱技术的早产儿视网膜病血代谢产物的初步研究

杨秋萍; 李思涛; 郝虎; 古霞; 石聪聪; 肖昕; 蔡尧

doi:10.7499/j.issn.1008-8830.2209142

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中国当代儿科杂志 ›› 2023, Vol. 25 ›› Issue (2) : 140-146. DOI: 10.7499/j.issn.1008-8830.2209142

论著·临床研究

基于质谱技术的早产儿视网膜病血代谢产物的初步研究

杨秋萍¹, 李思涛¹, 郝虎^1,2, 古霞¹, 石聪聪², 肖昕^1,2, 蔡尧¹

作者信息 +

Blood metabolites in preterm infants with retinopathy of prematurity based on tandem mass spectrometry: a preliminary study

YANG Qiu-Ping, LI Si-Tao, HAO Hu, GU Xia, SHI Cong-Cong, XIAO Xin, CAI Yao

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文章历史 +

摘要

目的应用液相色谱-串联质谱技术（liquid chromatography tandem mass spectrometry，LC-MS/MS）和代谢组学方法探讨早产儿视网膜病（retinopathy of prematurity，ROP）患儿出生血代谢产物差异，寻找ROP早期诊断的新的生物标记物。方法收集2013年1月—2016年12月中山大学附属第六医院住院的21例ROP患儿（ROP组）及同期21例非ROP患儿（非ROP组）干血片标本，利用LC-MS/MS进行代谢产物测定，运用正交偏最小二乘判别分析法（orthogonal partial least squares discriminant analysis，OPLS-DA）寻找差异物质和生物标记物。结果 ROP组和非ROP组患儿血代谢谱有明显差异，经模式识别分析、代谢物得分图（Score-plot，S-plot）、权重分析初步得出10个差异较大的氨基酸。进一步统计分析发现ROP组患儿血谷氨酸、亮氨酸、天冬氨酸、鸟氨酸和甘氨酸水平明显高于非ROP组，差异有统计学意义（P<0.05）。受试者工作特征曲线分析显示，谷氨酸及鸟氨酸对ROP诊断价值最高。结论 ROP患儿与非ROP患儿比较血代谢产物具有明显差异，谷氨酸及鸟氨酸是诊断ROP的代谢标志物。LC-MS/MS结合代谢组学分析方法在ROP早期识别与诊断中具有潜在的应用价值。

Abstract

Objective To study new biomarkers for the early diagnosis of retinopathy of prematurity (ROP) by analyzing the differences in blood metabolites based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and metabolomics. Methods Dried blood spots were collected from 21 infants with ROP (ROP group) and 21 infants without ROP (non-ROP group) who were hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2013 to December 2016. LC-MS/MS was used to measure the metabolites, and orthogonal partial least squares-discriminant analysis was used to search for differentially expressed metabolites and biomarkers. Results There was a significant difference in blood metabolic profiles between the ROP and non-ROP groups. The pattern recognition analysis, Score-plot, and weight analysis obtained 10 amino acids with a relatively large difference. Further statistical analysis showed that the ROP group had significant increases in blood levels of glutamic acid, leucine, aspartic acid, ornithine, and glycine compared with the non-ROP group (P<0.05). The receiver operating characteristic curve analysis showed that glutamic acid and ornithine had the highest value in diagnosing ROP. Conclusions Blood metabolites in preterm infants with ROP are different from those without ROP. Glutamic acid and ornithine are the metabolic markers for diagnosing ROP. LC-MS/MS combined with metabolomics analysis has a potential application value in the early identification and diagnosis of ROP.

导出引用

杨秋萍, 李思涛, 郝虎, 古霞, 石聪聪, 肖昕, 蔡尧. 基于质谱技术的早产儿视网膜病血代谢产物的初步研究[J]. 中国当代儿科杂志. 2023, 25(2): 140-146 https://doi.org/10.7499/j.issn.1008-8830.2209142

YANG Qiu-Ping, LI Si-Tao, HAO Hu, GU Xia, SHI Cong-Cong, XIAO Xin, CAI Yao. Blood metabolites in preterm infants with retinopathy of prematurity based on tandem mass spectrometry: a preliminary study[J]. Chinese Journal of Contemporary Pediatrics. 2023, 25(2): 140-146 https://doi.org/10.7499/j.issn.1008-8830.2209142

参考文献

1 中华医学会儿科学分会眼科学组. 早产儿视网膜病变治疗规范专家共识[J]. 中华眼底病杂志, 2022, 38(1): 10-13. DOI: 10.3760/cma.j.cn511434-20211119-00647.
2 李思涛, 黄小玲, 吴时光, 等. 极低出生体重早产儿尿代谢组学研究[J]. 中华儿科杂志, 2017, 55(6): 434-438. PMID: 28592011. DOI: 10.3760/cma.j.issn.0578-1310.2017.06.008.
3 Nivison-Smith L, Chua J, Tan SS, et al. Amino acid signatures in the developing mouse retina[J]. Int J Dev Neurosci, 2014, 33: 62-80. PMID: 24368173. DOI: 10.1016/j.ijdevneu.2013.12.005.
4 Cantelmo AR, Conradi LC, Brajic A, et al. Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy[J]. Cancer Cell, 2016, 30(6): 968-985. PMID: 27866851. PMCID: PMC5675554. DOI: 10.1016/j.ccell.2016.10.006.
5 蔡威, 汤庆娅, 王莹, 等. 中国新生儿营养支持临床应用指南[J]. 临床儿科杂志, 2013, 31(12): 1177-1182. DOI: 10.3969/j.issn.1000-3606.2013.12.020.
6 张德双, 王华, 陈娟. 早产儿视网膜病变的最新研究进展[J]. 中华妇幼临床医学杂志(电子版), 2012, 8(6): 783-786. DOI: 10.3877/cma.j.issn.1673-5250.2012.06.030.
7 Teoh ST, Leimanis-Laurens ML, Comstock SS, et al. Combined plasma and urinary metabolomics uncover metabolic perturbations associated with severe respiratory syncytial viral infection and future development of asthma in infant patients[J]. Metabolites, 2022, 12(2): 178. PMID: 35208252. PMCID: PMC8875115. DOI: 10.3390/metabo12020178.
8 Pieragostino D, Cicalini I, Di Michele S, et al. A case of suspected hyperphenylalaninemia at newborn screening by tandem mass spectrometry during total parenteral nutrition[J]. Metabolites, 2020, 10(2): 44. PMID: 31991569. PMCID: PMC7074497. DOI: 10.3390/metabo10020044.
9 Cicalini I, Tumini S, Guidone PI, et al. Serum steroid pro?ling by liquid chromatography-tandem mass spectrometry for the rapid confirmation and early treatment of congenital adrenal hyperplasia: a neonatal case report[J]. Metabolites, 2019, 9(12): 284. PMID: 31766536. PMCID: PMC6950672. DOI: 10.3390/metabo9120284.
10 李思涛, 郝虎, 刘梦娴, 等. 基于液相色谱-串联质谱联用技术的支气管肺发育不良患儿血代谢产物分析[J]. 中华围产医学杂志, 2019, 22(3): 173-179. DOI: 10.3760/cma.j.issn.1007-9408.2019.03.005.
11 Fu Z, Nilsson AK, Hellstrom A, et al. Retinopathy of prematurity: metabolic risk factors[J]. Elife, 2022, 11: e80550. PMID: 36420952. PMCID: PMC9691009. DOI: 10.7554/eLife.80550.
12 Zhou Y, Xu Y, Zhang X, et al. Plasma metabolites in treatment-requiring retinopathy of prematurity: potential biomarkers identified by metabolomics[J]. Exp Eye Res, 2020, 199: 108198. PMID: 32828955. DOI: 10.1016/j.exer.2020.108198.
13 Nilsson AK, Andersson MX, Sj?bom U, et al. Sphingolipidomics of serum in extremely preterm infants: association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2021, 1866(7): 158939. PMID: 33862236. PMCID: PMC8633973. DOI: 10.1016/j.bbalip.2021.158939.
14 Fu Z, L?fqvist CA, Liegl R, et al. Photoreceptor glucose metabolism determines normal retinal vascular growth[J]. EMBO Mol Med, 2018, 10(1): 76-90. PMID: 29180355. PMCID: PMC5760850. DOI: 10.15252/emmm.201707966.
15 Cakir B, Hellstr?m W, Tomita Y, et al. IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants[J]. JCI insight, 2020, 5(19): e140363. PMID: 33004691. PMCID: PMC7566718. DOI: 10.1172/jci.insight.140363.
16 Chi-Casta?eda D, Ortega A. Circadian regulation of glutamate transporters[J]. Front Endocrinol (Lausanne), 2018, 9: 340. PMID: 29977228 PMCID: PMC6021491 DOI: 10.3389/fendo.2018.00340.
17 杨曼, 谭薇. Müller细胞在糖尿病视网膜病变中的研究进展[J]. 国际眼科杂志, 2019, 19(11): 1874-1876. DOI: 10.3980/j.issn.1672-5123.2019.11.13.
18 雷祥, 栗占荣, 刘艳萍. 早产儿视网膜病变患儿血清谷氨酸水平变化的意义及其对预后的影响[J]. 中华实用儿科临床杂志, 2020, 35(1): 50-53. DOI: 10.3760/cma.j.issn.2095-428X.2020.01.013.
19 李志萍, 吴焕卿, 陈惠军. 早产儿视网膜病变患儿血清谷氨酸浓度变化及其相关关系[J]. 眼科新进展, 2014, 34(8): 782-784. DOI: 10.13389/j.cnki.rao.2014.0216.
20 Rhee SY, Jung ES, Park HM, et al. Plasma glutamine and glutamic acid are potential biomarkers for predicting diabetic retinopathy[J]. Metabolomics, 2018, 14(7): 89. PMID: 29950956. PMCID: PMC6013531. DOI: 10.1007/s11306-018-1383-3.
21 Ozcan Y, Huseyin G, Sonmez K. Evaluation of plasma amino acid levels in preterm infants and their potential correlation with retinopathy of prematurity[J]. J Ophthalmol, 2020, 2020: 8026547. PMID: 33489343. PMCID: PMC7801939. DOI: 10.1155/2020/8026547.
22 于菁, 王秋月. 富亮氨酸α-2糖蛋白-1与糖尿病血管并发症[J]. 国际内分泌代谢杂志, 2019, 39(6): 387-390. DOI: 10.3760/cma.j.issn.1673-4157.2019.06.006.
23 Mundo L, Tosi GM, Lazzi S, et al. LRG1 expression is elevated in the eyes of patients with neovascular age-related macular degeneration[J]. Int J Mol Sci, 2021, 22(16): 8879. PMID: 34445590. PMCID: PMC8396268. DOI: 10.3390/ijms22168879.
24 Low SWY, Connor TB, Kassem IS, et al. Small leucine-rich proteoglycans (SLRPs) in the retina[J]. Int J Mol Sci, 2021, 22(14): 7293. PMID: 34298915. PMCID: PMC8305803. DOI: 10.3390/ijms22147293.
25 Mikulski T, Dabrowski J, Hilgier W, et al. Effects of supplementation with branched chain amino acids and ornithine aspartate on plasma ammonia and central fatigue during exercise in healthy men[J]. Folia Neuropathol, 2015, 53(4): 377-386. PMID: 26785372. DOI: 10.5114/fn.2015.56552.
26 Hayasaka S, Kodama T, Ohira A. Retinal risks of high-dose ornithine supplements: a review[J]. Br J Nutr, 2011, 106(6): 801-811. PMID: 21767450. DOI: 10.1017/S0007114511003291.
27 Park SY, Kim J, Son JI, et al. Dietary glutamic acid and aspartic acid as biomarkers for predicting diabetic retinopathy[J]. Sci Rep, 2021, 11(1): 7244. PMID: 33790305. PMCID: PMC8012375. DOI: 10.1038/s41598-021-83165-5.
28 Guo D, Murdoch CE, Xu H, et al. Vascular endothelial growth factor signaling requires glycine to promote angiogenesis[J]. Sci Rep, 2017, 7(1): 14749. PMID: 29116138. PMCID: PMC5677092. DOI: 10.1038/s41598-017-15246-3.
29 Amelio I, Cutruzzolá F, Antonov A, et al. Serine and glycine metabolism in cancer[J]. Trends Biochem Sci, 2014, 39(4): 191-198. PMID: 24657017. PMCID: PMC3989988. DOI: 10.1016/j.tibs.2014.02.004.
30 Vandekeere S, Dubois C, Kalucka J, et al. Serine synthesis via PHGDH is essential for heme production in endothelial cells[J]. Cell Metab, 2018, 28(4): 573-587.e13. PMID: 30017355. DOI: 10.1016/j.cmet.2018.06.009.
31 Yang Y, Wu Z, Li S, et al. Targeted blood metabolomic study on retinopathy of prematurity[J]. Invest Ophthalmol Vis Sci, 2020, 61(2): 12. PMID: 32049343. PMCID: PMC7326483. DOI: 10.1167/iovs.61.2.12.