School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
Education Ministry Key Laboratory of Medical Electrophysiology, Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou 646000, China.
Int J Mol Sci. 2022 Jul 20;23(14):7978. doi: 10.3390/ijms23147978.
Radiation-induced thrombocytopenia is a common and life-threatening side effect of ionizing radiation (IR) therapy. However, the underlying pathological mechanisms remain unclear. In the present study, irradiation was demonstrated to significantly reduce platelet levels, inhibit megakaryocyte differentiation, and promote the apoptosis of bone marrow (BM) cells. A metabolomics approach and a UHPLC-QTOF MS system were subsequently employed for the comprehensive analysis of serum metabolic profiles of normal and irradiated mice. A total of 66 metabolites were significantly altered, of which 56 were up-regulated and 10 were down-regulated in irradiated mice compared to normal mice on day 11 after irradiation. Pathway analysis revealed that disorders in glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, sphingolipid metabolism, inositol phosphate metabolism, and tryptophan metabolism were involved in radiation-induced thrombocytopenia. In addition, three important differential metabolites, namely L-tryptophan, LysoPC (17:0), and D-sphinganine, which were up-regulated in irradiated mice, significantly induced the apoptosis of K562 cells. L-tryptophan inhibited megakaryocyte differentiation of K562 cells. Finally, serum metabolomics was performed on day 30 (i.e., when the platelet levels in irradiated mice recovered to normal levels). The contents of L-tryptophan, LysoPC (17:0), and D-sphinganine in normal and irradiated mice did not significantly differ on day 30 after irradiation. In conclusion, radiation can cause metabolic disorders, which are highly correlated with the apoptosis of hematopoietic cells and inhibition of megakaryocyte differentiation, ultimately resulting in thrombocytopenia. Further, the metabolites, L-tryptophan, LysoPC (17:0), and D-sphinganine can serve as biomarkers for radiation-induced thrombocytopenia.
辐射诱导性血小板减少症是电离辐射（IR）治疗的一种常见且危及生命的副作用。然而，其潜在的病理机制尚不清楚。在本研究中，照射显著降低了血小板水平，抑制了巨核细胞分化，并促进了骨髓（BM）细胞的凋亡。随后，采用代谢组学方法和 UHPLC-QTOF MS 系统对正常和照射小鼠的血清代谢谱进行了全面分析。在照射后 11 天，与正常小鼠相比，照射小鼠的血清中有 66 种代谢物显著改变，其中 56 种上调，10 种下调。通路分析表明，甘油磷脂代谢、烟酸和烟酰胺代谢、鞘脂代谢、肌醇磷酸代谢和色氨酸代谢紊乱与辐射诱导性血小板减少症有关。此外，在照射小鼠中上调的三个重要差异代谢物，即 L-色氨酸、LysoPC（17:0）和 D-鞘氨醇，显著诱导了 K562 细胞的凋亡。L-色氨酸抑制了 K562 细胞的巨核细胞分化。最后，在照射后第 30 天（即照射小鼠的血小板水平恢复正常时）进行了血清代谢组学分析。在照射后第 30 天，正常和照射小鼠的 L-色氨酸、LysoPC（17:0）和 D-鞘氨醇含量无显著差异。总之，辐射会导致代谢紊乱，这与造血细胞凋亡和巨核细胞分化抑制高度相关，最终导致血小板减少症。此外，代谢物 L-色氨酸、LysoPC（17:0）和 D-鞘氨醇可以作为辐射诱导性血小板减少症的生物标志物。
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