WO2024120401A1 - 急性主动脉夹层血浆生物标志物及其应用 - Google Patents

急性主动脉夹层血浆生物标志物及其应用 Download PDF

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WO2024120401A1
WO2024120401A1 PCT/CN2023/136534 CN2023136534W WO2024120401A1 WO 2024120401 A1 WO2024120401 A1 WO 2024120401A1 CN 2023136534 W CN2023136534 W CN 2023136534W WO 2024120401 A1 WO2024120401 A1 WO 2024120401A1
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glucoside
isopentenyladenine
aortic dissection
reagent
acute aortic
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French (fr)
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顾爱华
李庆国
徐诚
金经�
刘倩
李文祥
徐进
梁静佳
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南京医科大学
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G01N30/08—Preparation using an enricher
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86

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  • the invention belongs to the field of biomedicine and relates to plasma-specific metabolic markers of acute aortic dissection and applications thereof.
  • Acute aortic dissection is the most devastating aortic lesion, and its incidence is increasing worldwide. It is characterized by pulsating blood entering the media through a tear in the intima, causing the aortic wall to separate. Despite improvements in treatment strategies, the mortality and morbidity of AAD patients remain high. According to the 2011 inpatient records of the China Health Insurance Research Institute (CHIRA), the annual incidence of aortic dissection in China was estimated to be 2.8 cases per 100,000 people, and about 48.6% of aortic dissection patients died before hospital evaluation. Not only that, patients with aortic dissection in China tend to be younger than those in developed countries. There is growing evidence that aortic dissection has become more severe in China. In addition, AAD usually does not show clinical symptoms before an acute attack, and early diagnosis and screening of AAD is of great significance for the prevention and treatment of the disease.
  • CHIRA China Health Insurance Research Institute
  • the diagnostic methods used for AAD are mainly the use of imaging tools, among which chest CT is the main one.
  • this type of detection method has a certain lag and cannot provide timely predictions of the occurrence of the disease.
  • some invasive angiography will cause additional damage to the body.
  • vascular structure and metabolic disorders are closely related to the occurrence of AAD.
  • the metabolomics phenotype is very sensitive to small variations and will change rapidly in response to physiological and pathological stress. Therefore.
  • the analysis of low molecular weight blood metabolites can indeed provide a map of potential physiological systems, providing a new and rapid and reliable method for the early diagnosis of AAD.
  • the levels of smooth muscle myosin heavy chain (smMHC), human soluble elastin fragment (sELAF), calmodulin (calponin), and soluble ST2 are significantly higher than those in healthy people.
  • these differential molecules as proteins are not conducive to technology promotion, the detection cost is also high, and most of them have a limited half-life. Therefore, new biomarkers are needed for early detection and prevention of AAD.
  • the present invention establishes a convenient, low-traumatic, and low-cost AAD screening and diagnosis method through a group of differential metabolic markers in the peripheral serum of patients.
  • the purpose of the present invention is to provide a novel acute aortic dissection blood Plasma biomarkers.
  • Another object of the present invention is to provide the use of plasma biomarkers for acute aortic dissection.
  • Another object of the present invention is to provide the use of a reagent for detecting the biomarker.
  • isopentenyladenine-7-N-glucoside in the preparation of auxiliary diagnostic reagents for acute aortic dissection.
  • the structural formula of isopentenyladenine-7-N-glucoside is shown below:
  • the reagent for detecting Isopentenyladenine-7-N-glucoside is a reagent for quantitatively detecting Isopentenyladenine-7-N-glucoside.
  • the reagent for detecting Isopentenyladenine-7-N-glucoside is a reagent for quantitatively detecting Isopentenyladenine-7-N-glucoside by online solid phase extraction-liquid chromatography-tandem mass spectrometry.
  • An auxiliary diagnostic kit for acute aortic dissection comprising:
  • a reagent for quantitatively detecting Isopentenyladenine-7-N-glucoside comprising an Isopentenyladenine-7-N-glucoside standard.
  • the acute aortic dissection auxiliary diagnosis kit comprises:
  • the reagent for quantitatively detecting Isopentenyladenine-7-N-glucoside by online solid phase extraction-liquid chromatography-tandem mass spectrometry comprises:
  • Online solid phase extraction reagents include: HLB SPE column, specification is 5 ⁇ l, 20mm*3.9mm, mobile phase A: water, mobile phase B: methanol, mobile phase C: acetonitrile;
  • Liquid chromatography detection reagents include: Poroshell 120 EC-C 18 chromatographic column, specification is 2.7 ⁇ l, 2.1 mm*50 mm; mobile phase A: 10 mol/L ammonium acetate solution containing 0.1% formic acid, mobile phase B: acetonitrile containing 0.1% formic acid.
  • the present invention discovered a metabolic molecule, Isopentenyladenine-7-N-glucoside, which has significant differences between AAD patients and healthy people and can be used as a highly specific and sensitive biomarker for screening and diagnosing acute aortic dissection.
  • the application of this metabolic molecule can be used to prepare AAD auxiliary diagnostic reagents, providing a convenient, low-invasive, low-cost method for the screening and diagnosis of aortic dissection in the future, and can provide an effective reference for accurate diagnosis and timely treatment evaluation of clinical patients.
  • FIG. 1 ROC curve of plasma Isopentenyladenine-7-N-glucoside detection for risk assessment of acute aortic dissection.
  • Blood samples from patients were collected within 72 hours of onset, and blood samples from the control group were collected at the physical examination center. All anticoagulated blood samples were allowed to stand at room temperature for 30 minutes, then centrifuged at 1000g for 10 minutes to obtain plasma. The plasma samples were then quickly divided and stored at -80°C. Before testing, the samples were thawed on ice, then centrifuged at 3000r/min for 15 minutes at room temperature, and the upper plasma was tested.
  • Acetonitrile (CAN, Fisher Chemical, USA): Optimal MS grade;
  • Ammonia water (purity 28%-30%, Sigma-Aldrich, USA);
  • Plasma samples 100 ⁇ L were added with chloroform:methanol (400 ⁇ L, 2:1 (v/v)) and internal standard and rotated for 20 minutes. The samples were then centrifuged at 13,000 rpm for 20 minutes at 4°C to separate the aqueous and organic layers. The supernatant was then transferred to a new tube and dried in a SpeedVac. After drying, the lipid-containing organic layer was The machine phase was redissolved with chloroform:methanol (20 ⁇ L, 2:1 (v/v)) and isopropanol:acetonitrile:water (60 ⁇ L, 2:1:1 (v/v)). Transferred to a 2 ml injection bottle for machine testing. Take 3 ⁇ l of each sample of equal volume and mix them as quality control samples (QC). The quality control samples were randomly interspersed with multiple injections during the sample test to test the stability of the instrument and method.
  • QC quality control samples
  • the metabolites in each sample were analyzed using online solid phase extraction-liquid chromatography-tandem mass spectrometry (XLC/MS/MS) technology.
  • the online solid phase extraction system was connected to the liquid chromatography separation system by a ten-way valve, and the samples were enriched and analyzed online by valve switching.
  • an HLB SPE column (5 ⁇ l, 20mm*3.9mm, Waters Oasis) was used; mobile phase A was water, mobile phase B was methanol, and mobile phase C was acetonitrile.
  • the specific gradient elution conditions can be found in Table 1.
  • a Poroshell 120 EC-C 18 column (2.7 ⁇ l, 2.1mm*50mm) was used; mobile phase A was 10mol/L ammonium acetate solution (containing 0.1% formic acid), and mobile phase B was acetonitrile (containing 0.1% formic acid); flow rate was 0.4mL/min; column temperature was 40°C; injection volume was 50 ⁇ l.
  • the gradient elution conditions and the ten-way valve switching program can be found in Table 2.
  • an electrospray ion source (ESI) was used; the detection mode was positive ion mode; the scanning mode was dynamic multiple reflection detection mode (DMRM); the capillary voltage was 3500V, the nozzle voltage was 500V; the nitrogen temperature was 250°C, the drying temperature was 300°C; the ammonia flow rate was 12mL/min, the drying gas flow rate was 6mL/min; the nebulizing gas pressure was 241kPa; the cycle time was 400ms; the shortest residence time was 13.86ms, and the longest residence time was 198.9ms.
  • the relevant gradient elution program information is shown in Table 1, and the mass spectrometry related parameter information is shown in Table 2.
  • MassLynx v4.0 software was used for mass spectrometry system control and data acquisition, and the data were automatically processed by the QuanLynx application. SparkLink v3.0 software was used to control the tandem system.
  • the experiment detected the response values of Isopentenyladenine-7-N-glucoside in the plasma of patients with aortic dissection and the control group in the primary ESI + and ESI - ionization modes.
  • the metabolite profiles in the plasma of patients with acute aortic dissection were significantly different from those in the control group, among which Isopentenyladenine-7-N-glucoside was the most significant.
  • Isopentenyladenine-7-N-glucoside in the patient group was significantly increased relative to the control group (Table 3). This indicates that Isopentenyladenine-7-N-glucoside metabolic markers are associated with acute aortic dissection and can be used to predict acute aortic dissection.
  • Table 3 Mass spectrometry detection of the expression value and test P value of Isopentenyladenine-7-N-glucoside in the plasma of patients with aortic dissection and control subjects
  • Isopentenyladenine-7-N-glucoside in plasma can be used as a potential marker for the diagnosis of acute aortic dissection. It has excellent diagnostic effect, meets the requirements of convenience, low trauma and low cost, is suitable for early screening of acute aortic dissection, and is conducive to auxiliary diagnosis and treatment evaluation.

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Abstract

本发明公开了急性主动脉夹层血浆生物标志物及其应用。检测Isopentenyladenine-7-N-glucoside的试剂在制备急性主动脉夹层辅助诊断试剂盒中的应用。本发明发现了在AAD患者和健康人群间具有显著差异性的代谢分子Isopentenyladenine-7-N-glucoside，可作为用于筛选和诊断急性主动脉夹层的高特异性和敏感性的生物标志物。该代谢分子的应用，能够用于制备AAD辅助诊断试剂，为未来主动脉夹层筛选和诊断提供便捷、低创伤、低成本的方法，可以为临床病人的准确诊断和及时治疗评估提供有效的参考依据。

Description

急性主动脉夹层血浆生物标志物及其应用 技术领域
本发明属于生物医药领域，涉及急性主动脉夹层血浆特异性代谢标志物及其应用。
背景技术
急性主动脉夹层(AAD)是最具破坏性的主动脉病变，其发病率在世界范围内呈上升趋势。其特征是搏动的血液通过内膜的裂口进入中膜，使主动脉壁分离。尽管治疗策略有所改善，但AAD患者的死亡率和发病率仍然很高。根据中国健康保险研究院(CHIRA)2011年的住院患者记录，估计中国主动脉夹层的年发病率为每10万人2.8例，约48.6％的主动脉夹层患者在医院评估前死亡。不仅如此，中国的主动脉夹层患者往往比发达国家年轻。越来越多的证据表明，主动脉夹层在中国变得更加严重。此外，AAD通常在急性发作之前不会出现临床症状，AAD的早期诊断筛检对疾病的防治有重大意义。
目前用于AAD诊断检测的方法主要为影像学工具的使用，其中以胸部CT为主。但这一类检测手段存在一定滞后性，无法及时提供疾病发生的预测。且一部分侵入性式的造影术会对身体造成额外伤害。一般认为，血管结构和代谢紊乱与AAD的发生密切相关。代谢组学表型对微小变异非常敏感，会随着生理和病理应激的反应而迅速变化，因此。低分子量血液代谢物的分析确实可以提供潜在生理***图谱，为AAD的早期诊断提供快速可靠的新方法。
根据以往的研究报道，在AAD患者中，平滑肌肌球蛋白重链(smMHC)、人类可溶性弹性蛋白片段(sELAF)、钙调蛋白(calponin)、和可溶性ST2的水平显著高于健康人。然而，这些差异分子作为蛋白质并不利于技术推广，检测成本也较高，而且大多数都有有限的半衰期。因此,需要新的生物标记物进行AAD早期检测和预防。在此，本发明通过一组患者外周血清内差异代谢标志物，建立一种便捷、低创伤、低成本的AAD筛选诊断方法。
发明内容
本发明的目的是针对现有技术的上述不足，提供一种新的急性主动脉夹层血 浆生物标志物。
本发明的另一目的是提供急性主动脉夹层血浆生物标志物的应用。
本发明的又一目的是提供检测该生物标志物的试剂的应用。
本发明的目的可通过以下技术方案实现：
Isopentenyladenine-7-N-glucoside在制备急性主动脉夹层辅助诊断试剂中的应用。Isopentenyladenine-7-N-glucoside结构式如下所示:
检测Isopentenyladenine-7-N-glucoside的试剂在制备急性主动脉夹层辅助诊断试剂盒中的应用。
作为本发明的一种优选，所述的检测Isopentenyladenine-7-N-glucoside的试剂为定量检测Isopentenyladenine-7-N-glucoside的试剂。
作为本发明的进一步优选，所述的检测Isopentenyladenine-7-N-glucoside的试剂为利用在线固相萃取-液相色谱-串联质谱法定量检测Isopentenyladenine-7-N-glucoside的试剂。
一种急性主动脉夹层辅助诊断试剂盒，包含：
1)血浆样品处理试剂；
2)定量检测Isopentenyladenine-7-N-glucoside的试剂，其中包含Isopentenyladenine-7-N-glucoside标准品。
作为本发明的一种优选，所述的急性主动脉夹层辅助诊断试剂盒，包含：
1)血浆样品处理试剂；
2)在线固相萃取-液相色谱-串联质谱法定量检测Isopentenyladenine-7-N-glucoside的试剂，其中包含 Isopentenyladenine-7-N-glucoside标准品。
作为本发明的进一步优选，所述的在线固相萃取-液相色谱-串联质谱法定量检测Isopentenyladenine-7-N-glucoside的试剂包含：
a)在线固相萃取试剂包含：HLB SPE柱，规格为5μl，20mm*3.9mm，，流动相A：水，流动相B：甲醇，流动相C：乙腈；
b)液相色谱检测试剂包含：使用Poroshell 120 EC-C18色谱柱，规格为2.7μl，2.1mm*50mm；流动相A：含0.1％甲酸的10mol/L乙酸铵溶液，流动相B：含0.1％甲酸的乙腈。
有益效果：
本发明发现了在AAD患者和健康人群间具有显著差异性的代谢分子Isopentenyladenine-7-N-glucoside，可作为用于筛选和诊断急性主动脉夹层的高特异性和敏感性的生物标志物。该代谢分子的应用，能够用于制备AAD辅助诊断试剂，为未来主动脉夹层筛选和诊断提供便捷、低创伤、低成本的方法，可以为临床病人的准确诊断和及时治疗评估提供有效的参考依据。
附图说明
图1血浆Isopentenyladenine-7-N-glucoside检测对急性主动脉夹层风险评估结果ROC曲线。
具体实施方式
以下通过具体实例来说明本发明的技术方案，此仅为本发明的部分实例，不可以此作为本发明的限制原因，且其中的各项细节可在不违背本发明精神下做适当的修饰。
实施例1
一、实验材料与方法
1.1病理选择
本研究对象来自南京医科大学第二附属医院，自2017年1月至2019年4月期间招募，在获得书面知情同意书后，根据国际疾病分类第十版临床修改(ICD-10-CM)代码I71纳入确诊的急性主动脉夹层病例。排除同时患有马凡综合征、癌症和结 缔组织疾病患者。健康对照为同期体检、血常规检查的健康人群。将病例与对照组按年龄和性别进行配对后进行后续检测。此次研究已获得伦理委员会的批准，严格按照人体实验伦理学标准实施。
1.2样本采集
患者血样在发病72小时内收集全血样本，对照组血样于体检中心采集。所有经抗凝处理的血样在室温静置30分钟后，进行1000g离心10分钟，获得血浆。然后迅速将血浆样本分装并置于-80℃保存。检测前，样本在冰上解冻，然后在室温下3000r/min离心15min，取上层血浆检测。
1.3仪器与试剂
甲醇、氯仿(CNW Technologies)：纯度HPLC；
乙腈(CAN,美国Fisher Chemical)：Optimal MS级别；
醋酸铵(纯度≥98％，美国Sigma-Aldrich公司)；
氨水(纯度28％-30％，美国Sigma-Aldrich公司)；
Isopentenyladenine-7-N-glucoside(纯度99％，Sigma Aldrich Ltd)；
纯水(来自纯水仪)。
1260在线固相萃取***；
1260型液相色谱仪；
6470型三重四极杆质谱联用仪；
Heraeus Fresco17型离心机(Thermo Fisher Scientific)；
Forma 900 series型超低温冰箱(Thermo Fisher Scientific)；
YM-080S型超声仪；
DHG-9023A型烘箱；
LNG-T98型真空干燥仪。
电子天平(上海天平仪器厂)。
全温振荡器(常州菲普)。
1.4样本处理
取血浆样品(100μL)加入氯仿：甲醇(400μL，2:1(v/v))和内标并旋转混合，振动20分钟。然后在4℃下以13000rpm离心20分钟，以分离水和有机层。随后，将上清液转移到新试管中，并在SpeedVac中干燥。干燥后，含有脂质的有 机相用氯仿：甲醇(20μL，2:1(v/v))和异丙醇：乙腈：水(60μL，2:1:1(v/v))重新溶解。转移至2ml进样瓶上机检测。取等体积的样本各3μl，混合后作为质量控制样(QC)。质控样本随机穿插在样本检测中多次进样，检测仪器与方法的稳定性。
1.5检测分析
利用在线固相萃取-液相色谱-串联质谱(XLC/MS/MS)技术对每个样品中代谢物进行分析。用十通阀将在线固相萃取***与液相色谱分离***进行连接，通过阀切换方式进行样品在线富集和分析。对于在线固相萃取***，使用HLB SPE柱(5μl，20mm*3.9mm，Waters Oasis)；流动相A为水，流动相B为甲醇，流动相C为乙腈，具体的梯度洗脱条件可见表1。对于色谱***，使用Poroshell 120 EC-C18色谱柱(2.7μl，2.1mm*50mm)；流动相A为10mol/L乙酸铵溶液(含0.1％甲酸)，流动相B为乙腈(含0.1％甲酸)；流量0.4mL/min；柱温40℃；进样量50μl。梯度洗脱条件及十通阀切换程序可见表2。对于质谱***，使用电喷雾离子源(ESI)；检测方式为正离子模式；扫描模式为动态多反映检测模式(DMRM)；毛细管电压为3500V，喷嘴电压500V；氮气温度250℃，干燥气温300℃；氨气流量12mL/min，干燥气流量6mL/min；雾化气压力241kPa；循环时间400ms；最短驻留时间13.86ms，最长驻留时间198.9ms。相关梯度洗脱程序信息见表1，质谱相关参数信息见表2。
表1梯度洗脱程序具体参数
表2十通阀切换程序
使用MassLynx v4.0软件进行质谱***控制和数据采集，由QuanLynx应用程序自动处理数据。使用SparkLinkv3.0软件对串联***进行控制。
二、检测分析结果
试验检测了主动脉夹层患者和对照组血浆中Isopentenyladenine-7-N-glucoside在一级ESI+，ESI-电离模式下的响应值。急性主动脉夹层患者血浆中代谢物图谱与对照组相比有显著的差别，其中以Isopentenyladenine-7-N-glucoside差别最为显著。患者组中Isopentenyladenine-7-N-glucoside相对对照组显著升高(表3)。说明Isopentenyladenine-7-N-glucoside代谢标志物与急性主动脉夹层相关，可用于急性主动脉夹层预测。对血浆中Isopentenyladenine-7-N-glucoside的水平进行ROC曲线分析，结果显示AUC＝0.9184(图1)，表示其对急性主动脉夹层的预测具有显著的优势。
表3：质谱检测主动脉夹层患者和对照人群血浆中Isopentenyladenine-7-N-glucoside的表达值和检验P值
由以上结果可知，血浆中Isopentenyladenine-7-N-glucoside可作为急性主动脉夹层诊断的潜在标志物，其诊断的效果优异，符合便捷、低创伤、低成本的要求，适用于急性主动脉夹层的早期筛选，并有利于辅助诊断和治疗评价。

Claims (7)

  1. Isopentenyladenine-7-N-glucoside在制备急性主动脉夹层辅助诊断试剂中的应用。
  2. 检测Isopentenyladenine-7-N-glucoside的试剂在制备急性主动脉夹层辅助诊断试剂盒中的应用。
  3. 根据权利要求2所述的应用，其特征在于所述的检测Isopentenyladenine-7-N-glucoside的试剂为定量检测Isopentenyladenine-7-N-glucoside的试剂。
  4. 根据权利要求3所述的应用，其特征在于所述的检测Isopentenyladenine-7-N-glucoside的试剂为利用在线固相萃取-液相色谱-串联质谱法定量检测Isopentenyladenine-7-N-glucoside的试剂。
  5. 一种急性主动脉夹层辅助诊断试剂盒，其特征在于包含：
    1)血浆样品处理试剂；
    2)定量检测Isopentenyladenine-7-N-glucoside的试剂，其中包含Isopentenyladenine-7-N-glucoside标准品。
  6. 根据权利要求5所述的急性主动脉夹层辅助诊断试剂盒，其特征在于包含：
    1)血浆样品处理试剂；
    2)在线固相萃取-液相色谱-串联质谱法定量检测Isopentenyladenine-7-N-glucoside的试剂，其中包含Isopentenyladenine-7-N-glucoside标准品。
  7. 根据权利要求5所述的急性主动脉夹层辅助诊断试剂盒，其特征在于所述的在线固相萃取-液相色谱-串联质谱法定量检测Isopentenyladenine-7-N-glucoside的试剂包含：
    a)在线固相萃取试剂包含：HLB SPE柱，规格为5μl，20mm*3.9mm，，流动相A：水，流动相B：甲醇，流动相C：乙腈；
    b)液相色谱检测试剂包含：使用Poroshell 120 EC-C18色谱柱，规格为2.7μl，2.1mm*50mm；流动相A：含0.1％甲酸的10mol/L乙酸铵溶液，流动相B：含0.1％甲酸的乙腈。
PCT/CN2023/136534 2022-12-05 2023-12-05 急性主动脉夹层血浆生物标志物及其应用 WO2024120401A1 (zh)

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