Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
Proteome Sciences PLC, Coveham House, Surrey KT11 3EP, UK.
Biomolecules. 2023 Sep 30;13(10):1471. doi: 10.3390/biom13101471.
Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality globally. Although mild therapeutic hypothermia (TH) may improve outcomes in selected babies, the mechanism of action is not fully understood. A proteomics discovery study was carried out to analyse proteins in the plasma of newborns with HIE. Proteomic analysis of plasma from 22 newborns with moderate-severe HIE that had initially undergone TH, and relative controls including 10 newborns with mild HIE who did not warrant TH and also cord blood from 10 normal births (non-HIE) were carried out using the isobaric Tandem Mass Tag (TMT) 10plex labelling with tandem mass spectrometry. A total of 7818 unique peptides were identified in all TMT10plex samples, translating to 3457 peptides representing 405 proteins, after applying stringent filter criteria. Apart from the unique protein signature from normal cord blood, unsupervised analysis revealed several significantly regulated proteins in the TH-treated moderate-severe HIE group. GO annotation and functional clustering revealed various proteins associated with glucose metabolism: the enzymes fructose-bisphosphate aldolase A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase 1, phosphoglycerate kinase 1, and pyruvate kinase PKM were upregulated in newborns with favourable (sHIE+) outcomes compared to newborns with unfavourable (sHIE-) outcomes. Those with favourable outcomes had normal MR imaging or mild abnormalities not predictive of adverse outcomes. However, in comparison to mild HIE and the sHIE- groups, the sHIE+ group had the additional glucose metabolism-related enzymes upregulated, including triosephosphate isomerase, α-enolase, 6-phosphogluconate dehydrogenase, transaldolase, and mitochondrial glutathione reductase. In conclusion, our plasma proteomic study demonstrates that TH-treated newborns with favourable outcomes have an upregulation in glucose metabolism. These findings may open new avenues for more effective neuroprotective therapy.
缺氧缺血性脑病（HIE）是全球发病率和死亡率的重要原因。虽然轻度治疗性低体温（TH）可能改善某些婴儿的预后，但作用机制尚不完全清楚。本研究开展了一项蛋白质组学发现研究，以分析患有 HIE 的新生儿的血浆中的蛋白质。对 22 例初始接受 TH 治疗的中重度 HIE 新生儿的血浆进行了蛋白质组学分析，相对对照组包括 10 例轻度 HIE 新生儿（无需接受 TH），以及 10 例正常分娩（非 HIE）的脐血，使用同位素质谱标签（TMT）10 plex 标记和串联质谱进行分析。在应用严格的过滤标准后，在所有 TMT10plex 样本中鉴定出了 7818 个独特肽，转化为 3457 个肽，代表 405 个蛋白质。除了正常脐血的独特蛋白质特征外，无监督分析还揭示了 TH 治疗的中重度 HIE 组中几种明显受调控的蛋白质。GO 注释和功能聚类显示，各种与葡萄糖代谢相关的蛋白质：果糖二磷酸醛缩酶 A、甘油醛-3-磷酸脱氢酶、磷酸甘油酸变位酶 1、磷酸甘油酸激酶 1 和丙酮酸激酶 PKM 等酶在预后良好（sHIE+）的新生儿中上调，与预后不良（sHIE-）的新生儿相比。预后良好的新生儿的 MRI 正常或有轻度异常，但不会预测不良结局。然而，与轻度 HIE 和 sHIE-组相比，sHIE+组上调了更多与葡萄糖代谢相关的酶，包括磷酸丙糖异构酶、α-烯醇酶、6-磷酸葡萄糖酸脱氢酶、转醛醇酶和线粒体谷胱甘肽还原酶。总之，我们的血浆蛋白质组学研究表明，预后良好的接受 TH 治疗的新生儿有葡萄糖代谢上调。这些发现可能为更有效的神经保护治疗开辟新途径。
