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ENGLISH ABSTRACT
基于纳升液相色谱串联四极杆飞行时间质谱的急性敌草快中毒患者的血浆蛋白质组学研究
张天祺
杨娜
王敏
罗雪梅
朱怀军
作者及单位信息
·
DOI： 10.3760/cma.j.issn.1671-0282.2025.03.010
Plasma proteomic study of patients with acute diquat poisoning based on nano-liquid chromatography tandem quadrupole time-of-flight mass spectrometry
Zhang Tianqi
Yang Na
Wang Min
Luo Xuemei
Zhu Huaijun
Authors Info & Affiliations
Zhang Tianqi
Pharmaceutical Department, Nanjing Drum Tower Hospital (the Affiliated Hospital of Nanjing University Medical School), Nanjing 210008, China
Yang Na
Pharmaceutical Department, Nanjing Drum Tower Hospital (the Affiliated Hospital of Nanjing University Medical School), Nanjing 210008, China
Wang Min
Pharmaceutical Department, Nanjing Drum Tower Hospital (the Affiliated Hospital of Nanjing University Medical School), Nanjing 210008, China
Luo Xuemei
Pharmaceutical Department, Nanjing Drum Tower Hospital (the Affiliated Hospital of Nanjing University Medical School), Nanjing 210008, China
Zhu Huaijun
Pharmaceutical Department, Nanjing Drum Tower Hospital (the Affiliated Hospital of Nanjing University Medical School), Nanjing 210008, China
·
DOI： 10.3760/cma.j.issn.1671-0282.2025.03.010
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摘要

目的应用蛋白质组学技术研究急性敌草快中毒患者的血浆蛋白表达特征，筛选急性敌草快中毒诊疗和预后相关的靶标和生物标志物。

方法本研究为病例对照研究。纳入人群为2022年8月至2023年12月在南京大学医学院附属鼓楼医院收治的敌草快中毒患者。选取同期对年龄与性别匹配后的健康志愿者作为对照组。收集两组人群的一般临床资料和血浆样本，应用基于纳升液相色谱串联四极杆飞行时间质谱的蛋白质组学技术对血浆蛋白进行定性与定量检测。采用Mann-Whitney U检验比较两组血浆蛋白表达差异。

结果本研究共纳入8例敌草快中毒患者与7例健康对照，共鉴定得到491个血浆蛋白。与对照组相比，中毒组有76个差异表达蛋白，包括35个上调蛋白和41个下调蛋白。GO分析表明，差异表达蛋白主要与氧转运蛋白活性、受体结合以及透明质酸结合内肽酶抑制剂活性等相关；KEGG通路富集分析发现其与补体和凝血级联反应，中性粒细胞外陷阱形成以及血小板活化有关。此外，脂联蛋白（adiponectin, ADIPOQ）的表达不仅在中毒患者中升高，在非幸存者中的表达高于幸存者（ P<0.01）。

结论急性敌草快中毒患者的多个血浆蛋白表达异常，可能参与敌草快中毒的病理过程。ADIPOQ对急性敌草快中毒的诊疗和预后具有潜在的应用价值。

敌草快;纳升液相色谱串联四极杆飞行时间质谱;蛋白质组学;预后;生物标志物
ABSTRACT

ObjectiveTo investigate the expression characteristics of plasma proteins in patients with acute diquat poisoning by proteomic technology, and to screen the targets and biomarkers related to the diagnosis, treatment and prognosis of acute diquat poisoning.

MethodsThis study was a retrospective case-control study. Patients with diquat poisoning admitted to Nanjing University Affiliated Drum Tower Hospital from August 2022 to December 2023 were enrolled. Healthy volunteers matched for age and gender during the same period were selected as the control group. The general clinical data and plasma samples were collected, and qualitative and quantitative analyses of plasma proteins were performed by proteomic technology based on nanoliter liquid chromatography tandem quadrupole time-of-flight mass spectrometry. Mann-Whitney U test was used to compare differences of plasma protein expression between the two groups.

ResultsA total of 8 diquat poisoning patients and 7 healthy individuals were included in this study, and 491 plasma proteins were identified. Compared with control group, 76 differentially expressed proteins were obtained from the poisoned group, including 35 up-regulated proteins and 41 down-regulated proteins. GO analysis showed that the differentially expressed proteins were mainly associated with oxygen transporter activity, receptor binding, and hyaluronic acid-binding endopeptidase inhibitor activity. KEGG pathway enrichment analysis revealed that differentially expressed proteins were associated with complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation. In addition, the expression of adiponectin (ADIPOQ) was not only increased in poisoned patients, but also significantly higher in non-survivors than in survivors ( P<0.01).

ConclusionsMultiple plasma proteins with abnormal expression may be involved in the pathological process of acute diquat poisoning. ADIPOQ may have potential application value in the diagnosis, treatment, and prognosis of acute diquat poisoning.

Diquat;Nanoliter liquid chromatography tandem quadrupole time-of-flight mass spectrometry;Proteomics;Prognosis;Biomarker
Zhu Huaijun, Email: mocdef.aabnisyylgjn_jhz
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引用本文

张天祺,杨娜,王敏,等. 基于纳升液相色谱串联四极杆飞行时间质谱的急性敌草快中毒患者的血浆蛋白质组学研究[J]. 中华急诊医学杂志,2025,34(03)：342-349.

DOI:10.3760/cma.j.issn.1671-0282.2025.03.010

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敌草快（diquat, DQ）是一种高效且环保的非选择性联吡啶类除草剂，广泛应用于农业生产活动中。同时，DQ也是临床中毒事件的常见元凶，毒性较强，致死率高达60% [ 1 ]。随着百草枯的禁售，DQ的使用频率迅速上升，因而DQ中毒人数也显著增加。与百草枯毒性有所不同，DQ毒性主要累及肾脏、肝脏以及胃肠等脏器，对肺部损伤较轻微 [ 2 ]。DQ进入体内后首先损伤消化道，患者出现腹部剧烈疼痛以及麻痹性肠梗阻；随后在肾脏浓缩沉积，产生肾脏毒性，临床表现为肌酐急速升高，伴随血尿、蛋白尿、少尿或无尿，常规利尿剂无效，甚至部分重症患者在24 h内进展为急性肾衰竭，最终死于多脏器衰竭 [ 3 ]。研究表明，DQ毒性可能与炎症反应、氧化应激等机制相关，但其具体机制未完全阐明，且临床救治方法没有明显突破，仍未发现特效解毒药物 [ 4 ]。基于DQ复杂的多脏器毒性，笔者认为进一步深入地研究DQ损伤脏器的毒性机制，寻找潜在的分子靶点对提高临床救治率有重要的临床价值。
基于质谱的蛋白质组学技术通过解析生物体内组织以及细胞中的蛋白质整体表达、修饰状态以及蛋白质互作情况，为挖掘疾病发生的内在机制、诊断或预后生物标志物和潜在的治疗靶点提供新的思路和信息 [ 5 ]。Chen等 [ 6 ]应用基于液质联用（liquid chromatography-mass spectrometry, LC-MS）的蛋白组学技术研究了DQ对人肾上皮细胞胞内蛋白质表达的影响。Zhang等 [ 7 ]联合蛋白质组、转录组等多组学技术在动物水平揭示了DQ中毒小鼠与健康小鼠的肾脏内在分子差异。目前，尚无文献报道急性DQ中毒患者体内的血浆蛋白质组研究。鉴于此，本研究通过基于纳升液相色谱串联四极杆飞行时间质谱（nano-liquid chromatography tandem quadrupole time-of flight mass spectrometry, nanoLC-QTOF-MS）的非靶向蛋白质组学技术，挖掘DQ中毒患者与健康人群之间的血浆蛋白表达的差异，从蛋白质角度揭示DQ毒性可能的内在分子机制，并为开发诊疗和预后相关的生物标志物提供新的思路。
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备注信息
A
朱怀军，Email: mocdef.aabnisyylgjn_jhz
B

张天祺：研究设计、数据处理与分析、论文撰写；杨娜：样本收集、实验操作；王敏：收集数据、统计分析；罗雪梅：病例收集、数据整理；朱怀军：论文指导与修改、统计分析

C
所有作者声明无利益冲突
D
江苏省研究型医院学会精益化用药-石药专项科研基金资助项目 (JY202124)
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