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Metabolomics study on the effect of linezolid on the proliferation of MEG-01 megakaryocytes and the generation of platelet precursors
- ZHONGGUO YAOFANG Vol. 35, Issue 23, Pages: 2863-2869(2024)
- 作者机构：
1.陆军军医大学第一附属医院药剂科，重庆 400038
2.重庆医科大学附属儿童医院药剂科，重庆 401122
3.陆军军医大学组织学及胚胎学教研室，重庆 400038
- 作者简介：
- 基金信息：
DOI：10.6039/j.issn.1001-0408.2024.23.05
CLC： R978.1+9;R558+.2Published：15 December 2024，
Received：19 September 2024，
Revised：07 November 2024，
- 稿件说明：
移动端阅览
王宁,杨雅,熊丽蓉等.利奈唑胺影响MEG-01巨核细胞增殖及血小板前体生成的代谢组学研究 Δ[J].中国药房,2024,35(23):2863-2869.
WANG Ning,YANG Ya,XIONG Lirong,et al.Metabolomics study on the effect of linezolid on the proliferation of MEG-01 megakaryocytes and the generation of platelet precursors[J].ZHONGGUO YAOFANG,2024,35(23):2863-2869.
王宁,杨雅,熊丽蓉等.利奈唑胺影响MEG-01巨核细胞增殖及血小板前体生成的代谢组学研究 Δ[J].中国药房,2024,35(23):2863-2869. DOI： 10.6039/j.issn.1001-0408.2024.23.05.
WANG Ning,YANG Ya,XIONG Lirong,et al.Metabolomics study on the effect of linezolid on the proliferation of MEG-01 megakaryocytes and the generation of platelet precursors[J].ZHONGGUO YAOFANG,2024,35(23):2863-2869. DOI： 10.6039/j.issn.1001-0408.2024.23.05.
摘要
目的
2
研究利奈唑胺（LZD）对MEG-01巨核细胞代谢及细胞增殖和血小板前体生成的影响，为阐明LZD诱导的血小板减少症的发病机制提供参考。
方法
2
将MEG-01细胞接种于增殖培养基中，分为空白对照组（无处理）、溶剂对照组（4‰二甲基亚砜）和100、200、400、800 μg/mL LZD组，培养4 d后光镜下观察各组细胞增殖状态，进行细胞计数并检测细胞增殖活力。将细胞接种于分化培养基中，分为空白对照组（无处理）、溶剂对照组（4‰二甲基亚砜）和400 μg/mL LZD组，培养14 d后光镜下观察细胞的伪足生成情况，统计生成伪足的细胞比例及测量伪足相对长度，测定细胞中CD41、CD42b mRNA的表达水平。提取分化培养基中培养14 d的溶剂对照组和400 μg/mL LZD组细胞，运用液相色谱-串联质谱技术进行非靶向代谢组学和靶向能量代谢组学检测；在此基础上测量和观察添加丙酮酸（10 mmol/L）、LZD（400 μg/mL）+丙酮酸（10 mmol/L）培养14 d后细胞中丙酮酸相对含量及其对细胞增殖和伪足生成的影响。
结果
2
400 μg/mL LZD可显著抑制MEG-01细胞增殖和伪足的生成（
P
＜0.01）。400 μg/mL LZD处理后，MEG-01细胞的非靶向代谢组学分析结果显示，mTOR信号通路，丙氨酸、天冬氨酸和谷氨酸代谢以及癌症的中心碳代谢等与能量代谢相关的途径发生了显著变化；进一步的靶向能量代谢组学分析结果显示，400 μg/mL LZD处理后MEG-01细胞中三磷酸腺苷、鸟苷三磷酸、丙酮酸相对含量较溶剂对照组显著减少（
P
＜0.01），乳酸相对含量较溶剂对照组显著增加（
P
＜0.01）。与LZD组相比，LZD+丙酮酸组细胞中丙酮酸相对含量、细胞计数、生成伪足的细胞比例和伪足相对长度均显著升高/增加（
P
＜0.01）。
结论
2
LZD可能通过抑制线粒体能量代谢导致丙酮酸生成减少，进而抑制巨核细胞增殖和血小板前体生成，最终导致血小板减少症的发生。
Abstract
OBJECTIVE
2
To investigate the metabolic changes in MEG-01 megakaryocytes after treatment with linezolid （LZD） from metabolomic perspective and its impact on the the proliferation of cells and generation of platelet precursors.
METHODS
2
MEG-01 cells were seeded in proliferation medium and divided into blank control group （untreated）， solvent control group （4‰DMSO）， and 100， 200， 400， 800 μg/mL LZD groups. The proliferation status of cells in each group was observed under the microscope； cell proliferation and viability were assessed. Cells were also seeded in differentiation medium and divided into blank control group （untreated）， solvent control group （4‰DMSO）， and 400 μg/mL LZD group； after 14 days of culture， platelet precursor generation was observed under the microscope； immunofluorescence staining was performed to count the proportion of cells producing pseudopodia， the relative length of pseudopodia was measured， and the expression levels of CD41 and CD42b mRNA were assessed. Cells from the solvent control group and the 400 μg/mL LZD group， cultured in differentiation medium for 14 days， were extracted and subjected to non-targeted metabolomics and targeted energy metabolomics analysis using liquid chromatography-tandem mass spectrometry. The relative content of pyruvate in cells， after being cultured for 14 days with the addition of pyruvate （10 mmol/L） or LZD （400 μg/mL）+pyruvate （10 mmol/L）， was measured and observed， as well as its effects on cell proliferation and platelet precursor generation.
RESULTS
2
400 μg/mL LZD could significantly inhibit the proliferation of MEG-01 cells and the generation of platelet precursors （
P
＜0.01）. Non-targeted metabolomic analysis of MEG-01 cells after 400 μg/mL LZD treatment revealed significant changes in energy metabolism-related pathways such as mTOR signaling pathway， alanine， aspartate and glutamate metabolism， and central carbon metabolism in cancer. Targeted energy metabolomic analysis further showed that the relative contents of adenosine triphosphate， guanosine triphosphate， and pyruvate in MEG-01 cells were significantly reduced （
P
＜0.01）， while the relative contents of lactate were significantly increased （
P
＜0.01）. Compared with the LZD group， the relative content of pyruvate， cell count， the proportion of cells producing pseudopodia and the relative length of pseudopodia were significantly increased in the LZD+pyruvate group （
P
＜0.01）.
CONCLUSIONS
2
LZD may reduce pyruvate production by inhibiting mitochondrial energy metabolism， thereby suppressing megakaryocyte proliferation and platelet precursor production， ultimately leading to the occurrence of thrombocytopenia.
关键词
利奈唑胺血小板减少症血小板前体能量代谢丙酮酸
Keywords
thrombocytopeniaplatelet precursorenergy metabolismpyruvate
references
全国细菌耐药监测网. 2022年度中国细菌耐药监测报告[EB/OL].（2023-11-20）[2024-09-15]. https：//www.carss.cn/Report/Details?aId=917https://www.carss.cn/Report/Details?aId=917.
China National Bacterial Resistance Surveillance Network. 2022 annual report on bacterial resistance surveillance in China[EB/OL].（2023-11-20）[2024-09-15]. https：//www.carss.cn/Report/Details?aId=917https://www.carss.cn/Report/Details?aId=917.
王小文，赵松，宋阳，等.利奈唑胺在治疗难治性中枢神经系统革兰阳性球菌感染中的价值[J]. 中华医院感染学杂志，2010，20（20）：3207-3209.
WANG X W，ZHAO S，SONG Y，et al. Value of linezolid in treatment of Gram-positive refractory central nervous system infection caused by coccus[J]. Chin J Nosocomiol，2010，20（20）：3207-3209.
ZHANG L，YAN Y，LIAO R，et al. Effect of platelet parameters on linezolid-related thrombocytopenia in hospitalized patients[J]. Infect Drug Resist，2023，16：6145-6154.
王东晓，朱曼，郭代红，等. 930例糖肽类和噁唑烷酮类抗感染药物药品不良反应/事件报告分析[J]. 中国药物应用与监测，2017，14（1）：37-41.
WANG D X，ZHU M，GUO D H，et al.Analysis of 930 adverse drug reaction/event reports involving glycopeptide and oxazolidinone antibiotics[J].Chin J Drug Appl Monitor，2017，14（1）：37-41.
徐佳，黄琪，杨志玲. 我院区2016年利奈唑胺临床应用合理性评价[J]. 中国临床药理学与治疗学，2018，23（1）：110-115.
XU J，HUANG Q，YANG Z L. Evaluation of clinical rationality of linezolid in our hospital in 2016[J]. Chin J Clin Pharmacol Ther，2018，23（1）：110-115.
LI Y，XU W. Efficacy and safety of linezolid compared with other treatments for skin and soft tissue infections：a meta-analysis[J]. Biosci Rep，2018，38（1）：BSR20171125.
TSUJI Y，HOLFORD N H G，KASAI H，et al. Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients[J]. Br J Clin Pharmacol，2017，83（8）：1758-1772.
TAJIMA M，KATO Y，MATSUMOTO J，et al. Linezolid-induced thrombocytopenia is caused by suppression of platelet production via phosphorylation of myosin light chain 2[J]. Biol Pharm Bull，2016，39（11）：1846-1851.
黄柏铭，刘翠翠，赵晶晶，等. 血小板生成研究进展[J]. 中国细胞生物学学报，2022，44（1）：51-58.
HUANG B M，LIU C C，ZHAO J J，et al. Current pro- gress in thrombopoiesis[J]. Chin J Cell Biol，2022，44（1）：51-58.
赵志远，孟艳秋，甘慧，等. 血小板生成类药物研究进展[J]. 军事医学，2021，45（8）：626-631.
ZHAO Z Y，MENG Y Q，GAN H，et al. Research pro- gress in thrombopoietin drugs[J]. Mil Med Sci，2021，45（8）：626-631.
MARAY I，RODRÍGUEZ-FERRERAS A，ÁLVAREZ-ASTEINZA C，et al. Linezolid induced thrombocytopenia in critically ill patients：risk factors and development of a machine learning-based prediction model[J]. J Infect Chemother，2022，28（9）：1249-1254.
MILOSEVIC T V，PAYEN V L，SONVEAUX P，et al. Mitochondrial alterations （inhibition of mitochondrial protein expression，oxidative metabolism，and ultrastructure） induced by linezolid and tedizolid at clinically relevant concentrations in cultured human HL-60 promyelocytes and THP-1 monocytes[J]. Antimicrob Agents Chemother，2018，62（3）：e01599-e01517.
ALMEIDA L，DHILLON-LABROOY A，CASTRO C N，et al. Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis[J]. Immunity，2021，54（1）：68-83.
IMAI M，IZUMISAWA T，SAITO D，et al. Effects of antibacterial agents on cancerous cell proliferation[J]. Biol Pharm Bull，2023，46（5）：661-671.
JUNT T，SCHULZE H，CHEN Z，et al. Dynamic visuali- zation of thrombopoiesis within bone marrow[J]. Science，2007，317（5845）：1767-1770.
CAI Y，CHAI D，FALAGAS M E，et al. Immediate hematological toxicity of linezolid in healthy volunteers with different body weight：a phase Ⅰ clinical trial[J]. J Antibiot，2012，65（4）：175-178.
KAWASUJI H，TSUJI Y，OGAMI C，et al. Proposal of initial and maintenance dosing regimens with linezolid for renal impairment patients[J]. BMC Pharmacol Toxicol，2021，22（1）：13.
苟军强，李倩，尹东锋，等.利奈唑胺相关血液及代谢系统不良反应研究进展[J].解放军医学杂志，2024，49（8）：965-972.
GOU J Q，LI Q，YIN D F，et al.Research progress on adverse reactions of linezolid related to blood and metabolic systems[J].Med J Chin PLA，2024，49（8）：965-972.
BERNSTEIN W B，TROTTA R F，RECTOR J T，et al. Mechanisms for linezolid-induced anemia and thrombocytopenia[J]. Ann Pharmacother，2003，37（4）：517-520.
CHEN S L，SUN K F，XU B C，et al. Akt-mediated mitochondrial metabolism regulates proplatelet formation and platelet shedding post vasopressin exposure[J]. J Thromb Haemost，2023，21（2）：344-358.
FIDLER T P，CAMPBELL R A，FUNARI T，et al. Deletion of GLUT1 and GLUT3 reveals multiple roles for glucose metabolism in platelet and megakaryocyte function[J]. Cell Rep，2017，21（6）：1705.
SORIANO A，MIRÓ O，MENSA J. Mitochondrial toxicity associated with linezolid[J]. N Engl J Med，2005，353（21）：2305-2306.
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