利用靶向极性代谢组学HILIC-MS/MS鉴定重组人促红细胞生成素给药候选血液生物标志物

IF 2.7 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS
Olivier Salamin, Lejla Ramic, Raul Nicoli, Serge Rudaz, Davy Guillarme, Tiia Kuuranne
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引用次数: 0

摘要

通过提高血红蛋白浓度和红细胞质量来增加氧运输是血液兴奋剂的一个关键目标,通常通过重组人促红细胞生成素(rHuEPO)给药或输血来实现。虽然运动员生物护照(ABP)为检测此类操作提供了有效的间接工具,但其敏感性和特异性可能有限,特别是在涉及微量剂量或混淆生理因素的情况下。为了解决这些局限性,鉴定新的生物标记物来补充现有的ABP标记物是必不可少的。本研究提出了一种靶向代谢组学方法,通过分析血浆和血清中的极性代谢物,从两个给药研究中发现rHuEPO给药的候选生物标志物:一个涉及单次CERA注射,另一个使用多剂量的epoetin delta。亲水相互作用色谱与串联质谱联用使一组极性内源性代谢物的选择性和敏感性检测成为可能。在数据归一化和严格的质量控制之后,应用广义最小二乘模型来证明代谢物信号的时间变化。在两项研究中,反应最灵敏、最一致的标志物是次黄嘌呤和肌苷,它们在rHuEPO治疗后显著增加。值得注意的是,这些代谢物的相对增加与网织红细胞百分比的最大值一致,反映了最大的红细胞生成活性。作为嘌呤代谢的中间体,它们的增加可能与红细胞生成过程中嘌呤周转的增加有关。这些发现表明,次黄嘌呤和肌苷是补充现有ABP参数的有希望的候选生物标志物。然而,需要进一步验证以确认其在ABP框架内的可靠性和适用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of Candidate Blood Biomarkers of Recombinant Human Erythropoietin Administration Using Targeted Polar Metabolomics by HILIC-MS/MS.

Increasing oxygen transport through elevated hemoglobin concentration and red blood cell mass is a key objective of blood doping, commonly achieved via recombinant human erythropoietin (rHuEPO) administration or blood transfusions. While the Athlete Biological Passport (ABP) offers an effective indirect tool for detecting such manipulations, its sensitivity and specificity may be limited, particularly in cases involving microdoses or confounding physiological factors. To address these limitations, the identification of novel biomarkers that complement current ABP markers is essential. This study presents a targeted metabolomics approach to discover candidate biomarkers of rHuEPO administration by analyzing polar metabolites in plasma and serum from two administration studies: one involving a single CERA injection, and the other using multiple doses of epoetin delta. Hydrophilic interaction chromatography hyphenated with tandem mass spectrometry enabled the selective and sensitive detection of a panel of polar endogenous metabolites. Following data normalization and stringent quality control, generalized least squares models were applied to evidence temporal changes in metabolite signals. Among the most responsive and concordant markers across both studies were hypoxanthine and inosine, which showed significant and marked increases following rHuEPO administration. Notably, the relative increase of these metabolites coincided with the maximum in reticulocyte percentages, reflecting maximal erythropoietic activity. As intermediates in purine metabolism, their increases are likely tied to augmented purine turnover during red blood cell production. These findings suggest that hypoxanthine and inosine are promising candidate biomarkers to complement existing ABP parameters. However, further validation is required to confirm their reliability and applicability within the ABP framework.

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来源期刊
Drug Testing and Analysis
Drug Testing and Analysis BIOCHEMICAL RESEARCH METHODS-CHEMISTRY, ANALYTICAL
CiteScore
5.90
自引率
24.10%
发文量
191
审稿时长
2.3 months
期刊介绍: As the incidence of drugs escalates in 21st century living, their detection and analysis have become increasingly important. Sport, the workplace, crime investigation, homeland security, the pharmaceutical industry and the environment are just some of the high profile arenas in which analytical testing has provided an important investigative tool for uncovering the presence of extraneous substances. In addition to the usual publishing fare of primary research articles, case reports and letters, Drug Testing and Analysis offers a unique combination of; ‘How to’ material such as ‘Tutorials’ and ‘Reviews’, Speculative pieces (‘Commentaries’ and ‘Perspectives'', providing a broader scientific and social context to the aspects of analytical testing), ‘Annual banned substance reviews’ (delivering a critical evaluation of the methods used in the characterization of established and newly outlawed compounds). Rather than focus on the application of a single technique, Drug Testing and Analysis employs a unique multidisciplinary approach to the field of controversial compound determination. Papers discussing chromatography, mass spectrometry, immunological approaches, 1D/2D gel electrophoresis, to name just a few select methods, are welcomed where their application is related to any of the six key topics listed below.
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