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WO2019201216A1 - Combinaison d'acide dodécanoïque et de prostaglandine e2 en tant que marqueur de diagnostic accessoire de macrosomie et son application - Google Patents

Combinaison d'acide dodécanoïque et de prostaglandine e2 en tant que marqueur de diagnostic accessoire de macrosomie et son application Download PDF

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Publication number
WO2019201216A1
WO2019201216A1 PCT/CN2019/082754 CN2019082754W WO2019201216A1 WO 2019201216 A1 WO2019201216 A1 WO 2019201216A1 CN 2019082754 W CN2019082754 W CN 2019082754W WO 2019201216 A1 WO2019201216 A1 WO 2019201216A1
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Prior art keywords
prostaglandin
serum
reagent
small molecule
dodecanoic acid
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Ceased
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PCT/CN2019/082754
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English (en)
Chinese (zh)
Inventor
陈敏健
赵子平
韦筱淇
曹易之
庄婷钰
黄艳倩
戴礼瑞
张逸
王擎
张鹏鹏
张静
裴雨洋
胡艳辉
孙蓉丽
陆春城
吴炜
夏彦恺
王心如
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Nanjing Medical University
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Nanjing Medical University
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Anticipated expiration legal-status Critical
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    • 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
    • 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
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/88—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving prostaglandins or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2560/00—Chemical aspects of mass spectrometric analysis of biological material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour

Definitions

  • the invention belongs to the field of analytical chemistry and clinical medicine, and relates to the combination of dodecanoic acid and prostaglandin E2 as a macroscopic auxiliary diagnostic marker and application thereof, and particularly based on UPLC-Q exactive MS detection of metabolic small molecule markers related to macrosogenesis. Combination of objects and their applications.
  • Macrosomia is a newborn that points to a weight of 4 kg or more within 1 hour of birth. The occurrence of huge children is harmful to both mother and baby. A huge child is one of the important factors in dystocia, and it also increases the risk of heart malformation. Now the study finds that the chances of a large child growing up with obesity are greater, and it will become a susceptible population of diabetes, hypertension and other diseases.
  • the early diagnosis of giant children is generally based on some of the mother's susceptible medical characteristics such as diabetes, obesity and expired pregnancy.
  • the early diagnosis of giant children needs to rely on B-ultrasound detection.
  • the B-ultrasound detection time is longer, the inspection price is higher, and some pregnant women are more concerned about the radiation of the B-ultrasound examination. All of these have made the diagnosis of the giant child difficult and brought a serious financial burden to the family, so it is urgent to find a new method of diagnosis.
  • Metabolomics/Metabonomics is a new discipline developed in the late 1990s by examining the changes in its metabolites or their changes over time after a genetic system has been genetically altered or stimulated or disturbed.
  • the metabolome is the downstream product and final product of the genome. It is a collection of small molecular compounds involved in the metabolism of the organism and maintaining the normal function and growth of the organism. It is mainly an endogenous small molecule with a relative molecular mass of less than 1000. These endogenous metabolic small molecules involve sugar metabolism, energy metabolism, lipid metabolism, amino acid metabolism, nucleic acid metabolism, and coenzyme metabolism.
  • the organism in its normal state is a complete system in which the metabolites in biological fluids, cells and tissues are in a stable equilibrium.
  • the pathological changes occurred in the body due to genetic or acquired causes, and this balance was broken, and metabolites and metabolic processes also changed accordingly.
  • Metabolomics analysis of changes in metabolic small molecules in the disease process can help people find relevant biomarkers to aid in the diagnosis of diseases, and also help people understand the disease through the metabolic pathways involved in small molecules themselves. Pathogenesis and provide specific targets for drug development.
  • metabolomics has made many significant research results in the early diagnosis of diseases in human diseases, such as cardiovascular disease, diabetes and cancer.
  • Related papers published in the academic journals Nature, Nature medicine, Journal of hepatology and Cancer research show the great potential and value of small metabolic molecules in the diagnosis of human diseases.
  • LC-MS liquid chromatography-mass spectrometry
  • GC-MS gas chromatography-mass spectrometry
  • NMR nuclear magnetic resonance
  • UPLC-Q exactive MSS is used for metabolomics analysis of small molecules of metabolism. If a stable small molecule of specific serum metabolism related to macrosomia is detected as a biomarker, UPLC- of the metabolic small molecule marker of the corresponding disease is developed.
  • Q exactive MS detection method is not only an international leader in this field, but also can create eye-catching economic benefits. It will also be a powerful boost to improve the maternal and child health level in China.
  • the object of the present invention is to provide a relevant combination of serum metabolic small molecule markers for the diagnosis of a large number of children during the diagnosis.
  • Another object of the present invention is to provide a method for detecting the above small molecule markers based on the UPLC-Q exactive MS method.
  • Still another object of the present invention is to provide a kit for detecting and diagnosing chromatographic mass spectrometry for the above-described serum metabolic small molecule marker.
  • a small molecule marker of serum metabolism during pregnancy associated with a giant child which is a serum metabolism of the small molecule dodecanoic acid and prostaglandin E2.
  • kits for early diagnosis or monitoring of a large child comprising a reagent for detecting a small molecule marker of dopanoic acid and/or prostaglandin E2 during pregnancy.
  • the kit comprises a reagent for detecting a small molecule marker dodecanoic acid and/or prostaglandin E2 during pregnancy by UPLC-Q exactive MS method.
  • the kit comprising the following reagents:
  • the kit further comprising:
  • Reagent A used for precipitation of protein, containing 100% methanol
  • Reagent B water for mobile phase containing 0.1% formic acid
  • Reagent C acetonitrile containing 0.1% formic acid for mobile phase
  • Reagent D For reconstitution, ultrapure water.
  • a method for detecting a small-molecular marker of serum metabolism in pregnancy associated with a giant child characterized in that the method uses UPLC-Q exactive MS method to detect a small molecule marker dodecanoic acid and/or prostaglandin E2 during pregnancy. content.
  • the liquid chromatography column is a Hypersil GOLD C18 column with a column temperature of 40 ° C;
  • the mobile phase A is water containing 0.1% formic acid
  • the mobile phase B is acetonitrile containing 0.1% formic acid
  • the flow rate is 400 ⁇ L/min
  • Instrument gradient 0-3min 1% B, 3-10min 1% to 99% B, 10-13min 99% B, 13-13.1min 99% to 1% B, 13.1-17min 1% B;
  • Injection method volume 10 ⁇ l;
  • HESI Heating electrospray ionization mode
  • Positive ion mode spray voltage positive mode, injection voltage is 3.5kV, negative mode, injection voltage is 2.5kV; for two modes, capillary temperature is 300 ° C, heater temperature is 425 ° C, sheath gas flow is 50 AU, The auxiliary air flow is 13 AU, the backflush gas flow is 0 AU, the full scan analysis (70 to 1,050 m/z), and the resolution is set to 70,000.
  • the inventors collected standard-compliant pregnant blood samples by standard operating procedure (SOP), systematically collected complete population basic information and clinical data, and analyzed by UPLC-Q exactive MS based metabolomics method.
  • SOP standard operating procedure
  • the experimental methods of research mainly include the following parts:
  • the gestational age is less than or equal to 41 weeks;
  • Group A healthy control group (15 people, 2.5kg ⁇ baby birth weight ⁇ 4kg):
  • the gestational age is less than or equal to 41 weeks;
  • Group B large group (15 people, baby birth weight ⁇ 4kg):
  • the gestational age is less than or equal to 41 weeks;
  • Fresh pregnant blood was centrifuged at 3000 rpm for 5 min in a centrifuge, and 100 ⁇ l of the supernatant was dispensed into a clean 1.5 ml EP tube.
  • Analytical instrument UPLC Ultimate 3000 system (Dionex) high performance liquid chromatography; Q-Exactive high resolution mass spectrometer.
  • the liquid chromatography column was a Hypersil GOLD C18 column (100 mm x 2.1 mm, particle size 1.9 ⁇ m, Thermo Scientific, Germany) with a column temperature of 40 °C.
  • the mobile phases used were (A) water containing 0.1% formic acid (Reagent B) and (B) Acetonitrile containing 0.1% formic acid (Reagent C).
  • Instrument gradient 0-3min 1% B, 3-10min 1% to 99% B, 10-13min 99% B, 13-13.1min 99% to 1% B, 13.1-17min 1% B (B refers to mobile phase B, the amount of mobile phase A in each gradient is 100% of the corresponding amount of mobile phase B, the same below).
  • Injection method volume 10 ⁇ l;
  • HESI Heating electrospray ionization
  • Positive ion mode spray voltage positive mode, injection voltage is 3.5kV, negative mode, injection voltage is 2.5kV; for both modes, capillary temperature is 300°C, heater temperature is 425°C, sheath gas flow is 50AU, auxiliary gas The flow rate is 13 AU, the backflush gas flow is 0 AU, the full scan analysis (70 to 1,050 m/z), and the resolution is set to 70,000.
  • Biomarker Screening Multiple linear regression was used to screen robust birth weight-related metabolite combinations, and multivariate logistic regression was used to identify key metabolite combinations.
  • the inventors have also prepared a diagnostic kit that can be used for dynamic monitoring of giant children, which comprises determining the stable and detectable dodecanoic acid in the serum of a subject during pregnancy. And prostaglandin E2 stable isotope internal standard and standard for dodecanoic acid and prostaglandin E2.
  • the diagnostic kit also includes a set of reagents and equipment for small molecule extraction and chromatographic separation of serum metabolism.
  • the present inventors used UPLC-Q exactive MS to compare metabolic small molecules in the serum of normal controls and large mothers during pregnancy, and found that there are serum metabolic small molecule markers in the serum during pregnancy that can be used to evaluate whether the mother has a large child and has diagnostic value.
  • the combination of the substance and the application of the UPLC-Q exactive MS for detecting the small molecule marker of serum metabolism has developed a huge diagnostic and monitoring kit for clinical application.
  • the superiority of the present invention for using serum metabolic small molecules during pregnancy as a marker for juvenile evaluation is as follows:
  • Serum metabolism Small molecule is a novel biomarker, which is strongly associated with disease outcomes. It is not only stable, minimally invasive, easy to detect, but also quantitatively accurate, which will greatly improve the sensitivity and specificity of large-scale diagnosis. The successful development of small molecule biomarkers will open up a new situation for the prevention and treatment of adverse birth outcomes, and provide reference for the development of biomarkers for other diseases.
  • the serum metabolic small molecule marker provided by the invention can be used as a diagnostic marker for giant children, and can detect a giant child in a small invasive manner at an early stage, thereby providing a basis for further deep examination by a clinician, and quickly and accurately grasping the disease of the patient. State and severity of illness, timely and more personalized prevention and treatment programs to support, delay and prevent disease progression.
  • the present invention verifies the maternal serum samples of the giant and healthy control populations, and proves that the combination of the dodecanoic acid and prostaglandin E2 in the serum during pregnancy has higher sensitivity and specificity in detecting large children, and can be used as a marker. Use.
  • the invention adopts a strict and multi-stage verification and evaluation system, and initially selects a plurality of serum metabolic small molecules through preliminary experiments, and uses UPLC-Q exactive MS to perform independent population verification, thereby ensuring the serum metabolic biomarkers and diagnostic methods. Reliability.
  • Figure 1 shows the birth weight of the first phase population and the control.
  • the top and bottom of the box diagram represent the seventy-fifth and twenty-fifth percentiles, respectively.
  • the upper to the lower of the box diagram represent the maximum to the minimum, (-) is the median, and (+) is the average.
  • Figure 2 shows the birth weight of the second-stage population and the control, as shown in Figure 1.
  • the ROC curve between the normal control group and the giant group was prepared using information on the combination of serum metabolic small molecules during pregnancy.
  • Example 1 Study object selection and grouping basis
  • the gestational age is less than or equal to 41 weeks;
  • Group A healthy control group (15 people, 2.5kg ⁇ baby birth weight ⁇ 4kg):
  • the gestational age is less than or equal to 41 weeks;
  • Group B large group (15 people, baby birth weight ⁇ 4kg):
  • the gestational age is less than or equal to 41 weeks;
  • Fresh pregnant blood was centrifuged at 3000 rpm for 5 min in a centrifuge, and 100 ⁇ l of the supernatant was dispensed into a clean 1.5 ml EP tube.
  • Analytical instrument UPLC Ultimate 3000 system (Dionex) high performance liquid chromatography; Q-Exactive high resolution mass spectrometer.
  • the liquid chromatography column was a Hypersil GOLD C18 column (100 mm x 2.1 mm, particle size 1.9 ⁇ m, Thermo Scientific, Germany) with a column temperature of 40 °C.
  • the mobile phases used were (A) water containing 0.1% formic acid (Reagent B) and (B) Acetonitrile containing 0.1% formic acid (Reagent C).
  • the instrument gradient was: 0-3 min 1% B, 3-10 min 1% to 99% B, 10-13 min 99% B, 13-13.1 min 99% to 1% B, 13.1-17 min 1% B.
  • Injection method volume 10 ⁇ l;
  • HESI Heating electrospray ionization mode
  • Positive ion mode spray voltage positive mode, injection voltage is 3.5kV, negative mode, injection voltage is 2.5kV; for two modes, capillary temperature is 300 ° C, heater temperature is 425 ° C, sheath gas flow is 50 AU, The auxiliary air flow is 13 AU, the backflush gas flow is 0 AU, the full scan analysis (70 to 1,050 m/z), and the resolution is set to 70,000.
  • Biomarker Screening Multiple linear regression was used to screen robust birth weight-related metabolite combinations, and multivariate logistic regression was used to identify key metabolite combinations.
  • the present inventors measured the ROC curve and evaluated the sensitivity of the test by detecting dodecanoic acid and prostaglandin E2 in serum samples of 15 independent and 15 controls of the independent population. Specificity, and then to assess the detection of the level of these two small molecules in the serum for the auxiliary diagnosis of giant children.
  • Figure 5 shows that the sensitivity of the combination of dodecanoic acid and prostaglandin E2 is 80.00%, the specificity is 86.67%, and the area under the ROC curve is 0.8267, which has a high diagnostic value.
  • dodecanoic acid and prostaglandin E2 has a better effect in assisting the diagnosis of giant children.
  • the UPLC-Q exactive MS method was used to determine the high-abundance metabolic small molecules in the serum of normal and large children. Then, in the UPLC-Q exactive MS-based metabolomics technique, metabolic small molecules associated with giants are screened as indicators for detecting whether they are large children and the degree of diagnosis. Finally, the number of corresponding small serum metabolism molecules selected was controlled to two, which is the optimized reduction based on the pre-experiment.
  • the kit includes a batch of reagents and consumables for detecting small molecules of serum metabolism during pregnancy, wherein the qualitative and quantitative metabolism of small molecules are based on the standard of dodecanoic acid and prostaglandin E2, and the auxiliary quantitative and auxiliary qualitative use of carbon 13 labeled twelve A stable isotope internal standard for alkanoic acid, carbon-13-labeled prostaglandin E2.
  • the specific kits are composed as follows:
  • Reagent A (containing 100% methanol)
  • Reagent B water containing 0.1% formic acid
  • Reagent C acetonitrile containing 0.1% formic acid
  • Reagent D (100% ultrapure water).

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Abstract

L'invention concerne une combinaison d'acide dodécanoïque et de prostaglandine E2 agissant en tant que marqueur de diagnostic accessoire de la macrosomie et une application de celle-ci, concernant les domaines de la chimie analytique et de la médecine clinique, le marqueur étant l'acide dodécanoïque métabolique de faible poids moléculaire et la prostaglandine E2 métabolique du sérum pendant la grossesse. Le marqueur adopte le procédé MS UPLC-Q exactif pour la détection, présente une meilleure sensibilité et une meilleure spécificité, et peut être utilisé pour le diagnostic ou la surveillance précoce de la macrosomie, ayant ainsi une meilleure valeur promotionnelle dans des applications cliniques.
PCT/CN2019/082754 2018-04-16 2019-04-15 Combinaison d'acide dodécanoïque et de prostaglandine e2 en tant que marqueur de diagnostic accessoire de macrosomie et son application Ceased WO2019201216A1 (fr)

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CN201810339674 2018-04-16
CN201810609595.9 2018-06-13
CN201810609595.9A CN108872424A (zh) 2018-04-16 2018-06-13 十二烷酸和前列腺素e2组合作为巨大儿辅助诊断标志物及其应用

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Publication number Priority date Publication date Assignee Title
CN108872424A (zh) * 2018-04-16 2018-11-23 南京医科大学 十二烷酸和前列腺素e2组合作为巨大儿辅助诊断标志物及其应用
CN114200121B (zh) * 2021-12-15 2025-01-14 广州市番禺区中心医院(广州市番禺区人民医院、广州市番禺区心血管疾病研究所) 一种前列腺炎相关标志物及试剂盒

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WO2016020495A1 (fr) * 2014-08-08 2016-02-11 Nestec S.A. Myo-inositol et un ou plusieurs probiotiques et son utilisation
WO2016020489A1 (fr) * 2014-08-08 2016-02-11 Nestec S.A. Vitamine b2 pour diabète gestationnel
WO2016050758A1 (fr) * 2014-09-30 2016-04-07 Nestec S.A. Composition nutritionnelle destinée à être utilisée pour traiter ou prévenir des états liés à la grossesse
CN106556655A (zh) * 2016-10-10 2017-04-05 南京医科大学 血清中与特发性男性不育相关的中链脂肪酸标志物及其检测方法和应用
CN107576747A (zh) * 2017-09-11 2018-01-12 南京医科大学 癸酸和前列腺素e2组合作为巨大儿辅助诊断标志物及其应用
CN108872424A (zh) * 2018-04-16 2018-11-23 南京医科大学 十二烷酸和前列腺素e2组合作为巨大儿辅助诊断标志物及其应用

Patent Citations (7)

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Publication number Priority date Publication date Assignee Title
WO2016020495A1 (fr) * 2014-08-08 2016-02-11 Nestec S.A. Myo-inositol et un ou plusieurs probiotiques et son utilisation
WO2016020489A1 (fr) * 2014-08-08 2016-02-11 Nestec S.A. Vitamine b2 pour diabète gestationnel
WO2016050758A1 (fr) * 2014-09-30 2016-04-07 Nestec S.A. Composition nutritionnelle destinée à être utilisée pour traiter ou prévenir des états liés à la grossesse
CN105181869A (zh) * 2015-09-21 2015-12-23 南京医科大学 一种巨大儿辅助诊断标志物及其应用
CN106556655A (zh) * 2016-10-10 2017-04-05 南京医科大学 血清中与特发性男性不育相关的中链脂肪酸标志物及其检测方法和应用
CN107576747A (zh) * 2017-09-11 2018-01-12 南京医科大学 癸酸和前列腺素e2组合作为巨大儿辅助诊断标志物及其应用
CN108872424A (zh) * 2018-04-16 2018-11-23 南京医科大学 十二烷酸和前列腺素e2组合作为巨大儿辅助诊断标志物及其应用

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