CN108872424A - Dodecanoic acid and prostaglandin E2 combination are used as macrosomia's auxiliary diagnosis marker and its application - Google Patents
Dodecanoic acid and prostaglandin E2 combination are used as macrosomia's auxiliary diagnosis marker and its application Download PDFInfo
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- macrosomia
- prostaglandin
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- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 206010025394 Macrosomia Diseases 0.000 title claims abstract description 60
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 title claims abstract description 34
- 229960002986 dinoprostone Drugs 0.000 title claims abstract description 34
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 239000003550 marker Substances 0.000 title claims abstract description 29
- 238000003745 diagnosis Methods 0.000 title abstract description 19
- 150000003384 small molecules Chemical class 0.000 claims abstract description 53
- 210000002966 serum Anatomy 0.000 claims abstract description 52
- 230000035935 pregnancy Effects 0.000 claims abstract description 35
- 230000002503 metabolic effect Effects 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000012544 monitoring process Methods 0.000 claims abstract description 8
- 238000013399 early diagnosis Methods 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 35
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000012071 phase Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000001514 detection method Methods 0.000 claims description 17
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 15
- 235000019253 formic acid Nutrition 0.000 claims description 15
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000007791 liquid phase Substances 0.000 claims description 9
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 8
- 239000010931 gold Substances 0.000 claims description 8
- 229910052737 gold Inorganic materials 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 claims description 8
- 238000004949 mass spectrometry Methods 0.000 claims description 5
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 4
- 238000000132 electrospray ionisation Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
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- 238000007664 blowing Methods 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 2
- 238000009007 Diagnostic Kit Methods 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
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- 238000002705 metabolomic analysis Methods 0.000 description 1
- 230000001431 metabolomic effect Effects 0.000 description 1
- 239000003147 molecular marker Substances 0.000 description 1
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- 238000010202 multivariate logistic regression analysis Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
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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
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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- 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
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- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
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- G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
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Abstract
The invention belongs to analytical chemistry and clinical medicine domains, disclose dodecanoic acid and prostaglandin E2 combination as macrosomia's auxiliary diagnosis marker and its application, which is pregnancy period blood serum metabolic small molecule dodecanoic acid and prostaglandin E2.The marker is detected using UPLC-Q exactive MS method, is had preferable sensitivity and specificity, be can be used in the early diagnosis or monitoring of macrosomia, has preferable clinical application promotional value.
Description
Invention field
The invention belongs to analytical chemistry and clinical medicine domains, are related to dodecanoic acid and prostaglandin E2 combination as huge
Youngster's auxiliary diagnosis marker and its application particularly detect generation relevant to macrosomia's generation based on UPLC-Q exactive MS
Thank the combination of small molecule marker and its application.
Background technique
1 hour inner body is more than or equal to the newborn of 4kg again after macrosomia (Macrosomia) refers to birth.The hair of macrosomia
Life is all harmful to mother and baby.One of an important factor for macrosomia is difficult labour, it can also be such that the risk for suffering from heart malformations increases.Now
The study found that macrosomia grows up, the probability of future trouble obesity is larger, will be susceptible to suffer from people as a variety of diseases such as diabetes, hypertension
Group.
Some susceptible medical features that the early diagnosis of macrosomia is generally basede on mother at present such as suffer from diabetes, obesity
And prolonged pregnancy.However the crowd for not having features described above, the early diagnosis of macrosomia need to rely on B ultrasound detection.However B
Super detection time is longer, checks that price is higher, and some pregnant woman also more worry the radiation of ultrasound diagnosis.These all give huge
Youngster's diagnosis brings difficulty and brings serious financial burden to family, thus needs to find the side of new macrosomia's diagnosis
Method.
Metabolism group (Metabolomics/Metabonomics) is grow up phase late 1990s one new
Set up schools section, it be by investigate biosystem be genetically changed it is stimulated or disturbance after, the variation of metabolite or its with
The variation of time, to study a science of biosystem.So-called metabolism group (Metabolome) is the downstream product of genome
It is also final product, is some participation organism metabolism, the small molecule for maintaining organism normal function and growth and development
The set of object is closed, mainly endogenous small molecule of the relative molecular mass less than 1000, these endogenous metabolism small molecules are related to
Glycometabolism, energetic supersession, lipid metaboli, amino acid metabolism, nucleic acid metabolism, coenzyme metabolism etc..
Organism under normal condition is a complete system, and the metabolin in biological fluid, cell and tissue is in
One stable equilibrium state.Pathological change will have occurred due to heredity or the day after tomorrow in body, this balance is just broken, generation
It thanks product and metabolic process and also produces corresponding variation.Metabolism small molecule is understood in lysis by metabonomic analysis
Variation, people can be helped, which to find related biomarker (biomarker), can also be helped with the diagnosis of aided disease
Help others the metabolic pathway that is related to by small-molecule substance itself understand the pathogenesis of disease and provided specifically for medicament research and development
The target of property.In recent years, metabolism group achieves many tools in the research of mankind's various diseases in the early diagnosis of disease
Significant research achievement, such as cardiovascular disease, diabetes and cancer, correlative theses are published in academic journal
《Nature》,《Nature medicine》,《Journal of hepatology》With《Cancer research》On, show
Metabolism small molecule huge potentiality and value in diagnosing human disease.
The common technology of metabolism group research at present includes liquid chromatograph mass spectrography (LC-MS), chromatography of gases-mass spectrum connection
With (GC-MS) and nuclear magnetic resonance technique (NMR).Nuclear magnetic resonance technique feature is to component to be measured without destruction, Sample pretreatment letter
It is single, but sensitivity is lower；Gas chromatography-mass spectrography has preferable sensitivity and reproducibility, but generally to use derivatization
Method carries out pre-treatment to sample, so that experimental procedure becomes complicated.And LC-MS has sample process simple, high sensitivity is faced
The practical feature of bed.UPLC-Q exactive MS is the combination of high resolution mass spectrum of new generation Yu ultra high efficiency liquid phase, is had
Compared to the stronger sensitivity of traditional LC-MS, specificity and stability.So being metabolized using UPLC-Q exactive MSS
The metabonomic analysis of small molecule, if stable specific serum metabolism small molecule relevant to macrosomia's morbidity can be found as life
Object marker, and the UPLC-Q exactive MS detection method of the metabolism small molecule mark of corresponding disease is researched and developed, not only at this
Field is in first place in the world, can also create the economic benefit to attract people's attention, also will be to China's baby's health level is improved
Primary strong promotion.
Summary of the invention
The purpose of the present invention is provide relevant pregnancy period blood serum metabolic small molecule marker combination for macrosomia's auxiliary diagnosis.
Another object of the present invention, which is to provide, detects above-mentioned small molecule marker based on UPLC-Q exactive MS method
Method.
A further object of the present invention is to provide chromatographic mass spectrometry detection for above-mentioned blood serum metabolic small molecule marker and examine
Disconnected kit.
The purpose of the present invention is what is realized by following technical measures：
Pregnancy period blood serum metabolic small molecule marker relevant to macrosomia, the marker are blood serum metabolic small molecule dodecane
Acid and prostaglandin E2.
Application of the pregnancy period blood serum metabolic small molecule marker in preparation macrosomia early diagnosis or monitoring reagent.
A kind of kit early diagnosed or monitor macrosomia, the kit contain detection pregnancy period blood serum metabolic small molecule mark
The reagent of will object dodecanoic acid and/or prostaglandin E2.
The kit, the kit contain small using UPLC-Q exactive MS method detection pregnancy period blood serum metabolic
The reagent of molecular marker dodecanoic acid and/or prostaglandin E2.
The kit, the kit contain following reagent：
Dodecanoic acid and/or prostaglandin E2 standard items；
The dodecanoic acid stable isotope internal standard compound that carbon 13 marks；
The prostaglandin E2 stable isotope internal standard compound that carbon 13 marks.
The kit, the kit also contain：
Hypersil GOLD C18 chromatographic column；
Reagent A：Protein precipitation is used, and 100% methanol is contained；
Reagent B：Mobile phase is used, the water containing 0.1% formic acid；
Reagent C：Mobile phase is used, the acetonitrile containing 0.1% formic acid；
Reagent D：It redissolves and uses, ultrapure water.
A method of detecting above-mentioned pregnancy period blood serum metabolic small molecule marker relevant to macrosomia, it is characterised in that should
Method is using UPLC-Q exactive MS method detection pregnancy period blood serum metabolic small molecule marker dodecanoic acid and/or prostate
The content of plain E2.
The method, in this method：
One, liquid-phase condition：
Liquid-phase chromatographic column is Hypersil GOLD C18 chromatographic column, and column temperature is 40 DEG C；
Mobile phase A is the water containing 0.1% formic acid, and Mobile phase B is the acetonitrile containing 0.1% formic acid, and flow velocity is 400 μ L/min；
Instrument gradient is：0-3min 1%B, 3-10min 1% arrives 99%B, 10-13min 99%B, 13-13.1min
99% arrives 1%B, 13.1-17min 1%B；
Input mode：10 μ l of volume；
Two, Mass Spectrometry Conditions
1. heating electrospray ionisation mode (HESI) is analyzed；
2. positive ion mode spray voltage：Holotype, injection electric 3.5kV, negative mode, injection electric 2.5kV；It is right
In both of which, capillary temperature is 300 DEG C, and heter temperature is 425 DEG C, and sheath throughput is 50AU, and secondary air amount is
13AU, blowback throughput are 0AU, and full scan analyzes (70 to 1,050m/z), and resolution ratio is set as 70,000.
The present invention is described in detail as follows：
The present inventor acquires standard compliant pregnancy period blood sample with S.O.P. (SOP), and system is collected complete
Crowd's basic information and clinical data, and use the metabolism group method based on UPLC-Q exactive MS and analyzed.
The experimental method specifically studied mainly includes following components：
One, research object selection and group basis
First stage screening stage
It is included in pregnant and lying-in women totally 97 people at random.
1. the age is between 23 to 36 years old；
2. pregnant week is less than or equal to 41 weeks；
3. case containing macrosomia (birth weight >=4kg, 16 people).
Second stage Qualify Phase
It is included in case and control pregnant and lying-in women totally 30 people.
A group：Healthy control group (15 people, 2.5kg≤birth weight<4kg)：
1. the age is between 23 to 36 years old；
2. pregnant week is less than or equal to 41 weeks；
3. without whole body major disease.
B group：Macrosomia's group (15 people, birth weight >=4kg)：
1. the age is between 23 to 36 years old；
2. pregnant week is less than or equal to 41 weeks；
3. without whole body major disease.
Two, UPLC-Q exactive MS metabonomic analysis and macrosomia diagnose with the screening of metabolism small molecule and verifying
1. Sample pretreatment
1.1. fresh pregnancy period blood is centrifuged 5min in centrifuge 3000rpm, and 100 μ l of supernatant is taken to dispense to clean 1.5ml EP
Guan Zhong.
1.2.50 μ l serum adds 50 μ l of water to add 300 μ l methanol (reagent A) protein precipitations again.
1.3. supernatant is drawn, is dried in vacuo with being dried with nitrogen to use again.
1.4. dried object (reagent D) is reconstructed.
2. instrument detects
2.1. analysis instrument：UPLC Ultimate 3000system (Dionex) high performance liquid chromatograph；Q-
Exactive high-resolution mass spectrometer.
2.2. liquid-phase condition：
Liquid-phase chromatographic column be Hypersil GOLD C18 chromatographic column (100mm × 2.1mm, 1.9 μm of partial size, Thermo
Scientific, Germany), column temperature is 40 DEG C.
Water (reagent B) and (B) of the mobile phase used for (A) containing 0.1% formic acid contain the acetonitrile (reagent C) of 0.1% formic acid.
Instrument gradient is：0-3min 1%B, 3-10min 1% arrives 99%B, 10-13min 99%B, 13-13.1min
99% arrives 1%B, and (B refers to Mobile phase B to 13.1-17min 1%B, the amount of the amount of mobile phase A and corresponding Mobile phase B in each gradient
Totally 100%, similarly hereinafter).
Input mode：10 μ l of volume；
2.3. Mass Spectrometry Conditions
Heating electrospray ionisation mode (HESI) is analyzed；
Positive ion mode spray voltage：Holotype, injection electric 3.5kV, negative mode, injection electric 2.5kV；For
Both of which, capillary temperature be 300 DEG C, heter temperature be 425 DEG C, sheath throughput be 50AU, secondary air amount 13AU,
Blowback throughput is 0AU, and full scan analyzes (70 to 1,050m/z), and resolution ratio is set as 70,000.
3. substance is qualitative
Metabolism small molecule is qualitative to compare Chromatographic information (retention time) using with standard items dodecanoic acid and prostaglandin E2
With Information in Mass Spectra (accurate molecular weight, isotope distribution and MS/MS fragment information), and in real time compare sample in Isotopic Internal Standard mark
The Chromatographic information of quasi- product (the prostaglandin E2 stable isotope internal standard compound of dodecanoic acid, the label of carbon 13 that carbon 13 marks) (retains
Time).
4. data are analyzed：
Biomarker screening is screened steady metabolin related with birth weight using multiple linear regression and is combined, then
Using Multivariate Logistic Regression confirmation key metabolites combination.
5. healthy control group, macrosomia organize the difference and diagnostic significance for being metabolized small molecule in serum sample.
Corrected pregnant latter stage BMI and pregnant week, multiple linear regression analysis find dodecanoic acid and the forefront of pregnancy period serum
Parathyrine E2 is combined to be positively correlated with the birth weight of filial generation.Corrected pregnant latter stage BMI and pregnant week, Multivariate Logistic Regression point
Analysis discovery pregnancy period serum dodecanoic acid and prostaglandin E2 combination increase the risk for significantly improving that filial generation is macrosomia.Using only
Vertical crowd diagnoses macrosomia, sensitivity 80.00%, specificity 80.00%, ROC song using above-mentioned metabolism small molecule combinatorial
Area is 0.8978 under line, diagnostic value with higher.
Three, diagnostic reagent box preparation method
According to above-mentioned a series of experiments as a result, the present inventor is also prepared for a kind of diagnosis that can be used for macrosomia's dynamic monitoring
Kit, the diagnostic kit include to be stabilized in measurement subject's pregnancy period serum and detectable dodecanoic acid and forefront
The standard items of parathyrine E2 stable isotope internal standard and dodecanoic acid and prostaglandin E2.Diagnostic kit further includes a set of serum generation
Thank small molecule extraction and used in chromatograph reagent and equipment.
Beneficial effects of the present invention：
The present inventor compares in normal control and mother's macrosomia pregnancy period serum by using UPLC-Q exactive MS
Metabolism small molecule, it was found that existing in pregnancy period serum can be used for assessing whether mother pregnant macrosomia, with diagnostic value
The UPLC-Q exactive MS's of the combination of blood serum metabolic small molecule marker and the blood serum metabolic small molecule marker detection
Using developing can be convenient for macrosomia's diagnosis of clinical application, monitoring reagent box.
The present invention is advantageous in that using the marker that pregnancy period blood serum metabolic small molecule is evaluated as macrosomia：
(1) blood serum metabolic small molecule is a kind of new biomarkers, is associated with disease outcome by force, not only stable, micro-
It creates, be easy to detect, and is quantitative accurate, the sensibility and specificity of macrosomia's diagnosis, the micromolecular biology mark will be greatly improved
The successful exploitation of will object will start completely new situation for the prevention and treatment of bad birth outcomes, mention for the development of other diseases biomarker
For using for reference.
(2) blood serum metabolic small molecule marker provided by the invention can be used for the diagnosis marker of macrosomia, can be in early stage
Macrosomia is detected by invasive manner, to provide foundation for the further testing in depth testing of clinician, is suffered from quick and precisely to grasp
The morbid state and coincident with severity degree of condition of person take the control prece of more personalized to provide support in time, delay and prevent disease
Disease progression.
(3) present invention is verified using mother's pregnancy period serum sample of macrosomia and normal healthy controls crowd, it was demonstrated that pregnant
Dodecanoic acid and prostaglandin E2 combination have higher sensitivity and specificity in detection macrosomia in phase serum, can be used as mark
Will object uses.
(4) present invention uses tight, multistage verifying and appraisement system, and initial stage screens a variety of serum generations by preliminary experiment
Thank to small molecule, carry out independent crowd's verifying using UPLC-Q exactive MS, ensure that the blood serum metabolism biological marker and
The reliability of diagnostic method.
(5) UPLC-Q exactive MS technology sample process is simple, and instrument is analyzed rapidly and accurately, clinic with higher
Diagnose practical value.
Detailed description of the invention
The case of Fig. 1 first stage crowd and the birth weight of control.
The the 75th and the 25th percentile, the upper end to lower end of box figure are respectively represented at the top and bottom of box figure
Representative is up to minimum value, and (-) is median, and (+) is average.
The case of Fig. 2 second stage crowd and the birth weight of control, caption refer to Fig. 1.
Fig. 3 screening stage, corrected pregnant latter stage BMI and pregnant week, multiple linear regression and Multivariate Logistic Regression point
Unanimously the combination of discovery pregnancy period serum dodecanoic acid and prostaglandin E2 significantly improves the risk that filial generation is macrosomia for analysis.
Fig. 4 is metabolized small molecule combinatorial detection level fluctuation (mean ± standard deviation).
Fig. 5 Qualify Phase, the Normal group made of the information of pregnancy period blood serum metabolic small molecule combinatorial and macrosomia
ROC curve between group.
Specific embodiment
The present invention will be further explained by examples below.
The selection of 1 research object of embodiment and group basis
The present inventor is from the satisfactory macrosomia's infant of the attached Nanjing healthcare hospital for women & children collection of Nanjing Medical University and just
Normal mother's children pregnancy period blood sample (macrosomia and control birth weight difference are shown in Fig. 1, Fig. 2).It weighs to newborn after birth,
Weight is equal to or more than 4kg person in 1 hour after being such as born, that is, is diagnosed as " macrosomia ".First stage incorporates conform at random
The 97 pregnant and lying-in women's samples asked, wherein 15 are macrosomia；Second stage is included in 30 pregnant and lying-in women's samples, wherein 15 controls 15
Example macrosomia, the screening experiment object as macrosomia's pregnancy period plasma metabolism small molecule biomarker.Specific sample group
Standard is as follows：
First stage screening stage
It is included in pregnant and lying-in women totally 97 people at random.
4. the age is between 23 to 36 years old；
5. pregnant week is less than or equal to 41 weeks；
6. case containing macrosomia (birth weight >=4kg, 16 people).
Second stage Qualify Phase
It is included in case and control pregnant and lying-in women totally 30 people.
A group：Healthy control group (15 people, 2.5kg≤birth weight<4kg)：
4. the age is between 23 to 36 years old；
5. pregnant week is less than or equal to 41 weeks；
6. without whole body major disease.
B group：Macrosomia's group (15 people, birth weight >=4kg)：
4. the age is between 23 to 36 years old；
5. pregnant week is less than or equal to 41 weeks；
6. without whole body major disease.
The screening of embodiment 2UPLC-MS metabolism group macrosomia's biomarker
1. Sample pretreatment
1.1. fresh pregnancy period blood is centrifuged 5min in centrifuge 3000rpm, and 100 μ l of supernatant is taken to dispense to clean 1.5ml EP
Guan Zhong.
1.2.50 μ l serum adds 50 μ l of water to add 300 μ l methanol (reagent A) protein precipitations again.
1.3. supernatant is drawn, is dried in vacuo with being dried with nitrogen to use again.
1.4. dried object (reagent D) is reconstructed.
2. instrument detects
2.1. analysis instrument：UPLC Ultimate 3000system (Dionex) high performance liquid chromatograph；Q-
Exactive high-resolution mass spectrometer.
2.2. liquid-phase condition：
Liquid-phase chromatographic column be Hypersil GOLD C18 chromatographic column (100mm × 2.1mm, 1.9 μm of partial size, Thermo
Scientific, Germany), column temperature is 40 DEG C.
Water (reagent B) and (B) of the mobile phase used for (A) containing 0.1% formic acid contain the acetonitrile (reagent C) of 0.1% formic acid.
Instrument gradient is：0-3min 1%B, 3-10min 1% arrives 99%B, 10-13min 99%B, 13-13.1min
99% arrives 1%B, 13.1-17min 1%B.
Input mode：10 μ l of volume；
2.3. Mass Spectrometry Conditions
1. heating electrospray ionisation mode (HESI) is analyzed；
2. positive ion mode spray voltage：Holotype, injection electric 3.5kV, negative mode, injection electric 2.5kV；It is right
In both of which, capillary temperature is 300 DEG C, and heter temperature is 425 DEG C, and sheath throughput is 50AU, and secondary air amount is
13AU, blowback throughput are 0AU, and full scan analyzes (70 to 1,050m/z), and resolution ratio is set as 70,000.
3. substance is qualitative
Metabolism small molecule is qualitative to compare Chromatographic information (retention time) using with standard items dodecanoic acid and prostaglandin E2
With Information in Mass Spectra (accurate molecular weight, isotope distribution and MS/MS fragment information), and in real time compare sample in Isotopic Internal Standard mark
The Chromatographic information of quasi- product (the prostaglandin E2 stable isotope internal standard compound of dodecanoic acid, the label of carbon 13 that carbon 13 marks) (retains
Time).
4. data are analyzed：
Biomarker screening is screened steady metabolin related with birth weight using multiple linear regression and is combined, then
Using Multivariate Logistic Regression confirmation key metabolites combination.
5. healthy control group, macrosomia organize the difference and diagnostic significance for being metabolized small molecule in serum sample.
Corrected pregnant latter stage BMI and pregnant week, multiple linear regression analysis find the product dodecanoic acid of pregnancy period serum with before
Column parathyrine E2 is combined to be positively correlated with the birth weight of filial generation.Corrected pregnant latter stage BMI and pregnant week, Multivariate Logistic Regression
Analysis finds that pregnancy period serum dodecanoic acid and prostaglandin E2 combination increase the risk (figure for significantly improving that filial generation is macrosomia
3)。
The stability analysis of 3 blood serum metabolic small molecule of embodiment
Using embodiment 2 method to the stability of mother's pregnancy period serum dodecanoic acid and prostaglandin E2 combined horizontal into
Row evaluation (interval time is 2 weeks).The results show that dodecanoic acid and prostaglandin E2 combination measurement horizontal stable (figure in serum
4), have as diagnosis/monitoring marker characteristic.
Embodiment 4 is metabolized diagnosis of the small molecule combinatorial to macrosomia
According to above-mentioned UPLC-Q exactive MS metabolism group method, the present inventor by independent 15 case of crowd and
The pregnancy period blood serum sample detection dodecanoic acid and prostaglandin E2 of 15 controls, draw ROC curve with this and assess the sensitive of detection
Property and specificity, and then assess in detection serum this 2 metabolism small molecule levels to the auxiliary diagnosis effect of macrosomia.
Fig. 5 shows that the sensitivity for combining dodecanoic acid and prostaglandin E2 is 80.00%, specificity 86.67%, ROC
Area under the curve is 0.8267, diagnostic value with higher.
So combination dodecanoic acid and prostaglandin E2 have the effect of preferably auxiliary diagnosis macrosomia.
Embodiment 5 is used for the production of macrosomia's blood serum metabolic small molecule detection and diagnosis kit
Determine in normal and macrosomia's infant mother's pregnancy period serum have by the method for UPLC-Q exactive MS first
There is the metabolism small molecule compared with high abundance.Then, it is wherein being sieved by the metabonomic technology based on UPLC-Q exactive MS
Metabolism small molecule relevant to macrosomia is selected, as the index detected whether as macrosomia and diagnostic routine.It finally will screening
The quantity of correspondence blood serum metabolic small molecule out is controlled at 2, this is simplifying for the optimization made on the basis of preliminary experiment.
This kit includes a collection of detection of pregnancy period blood serum metabolic small molecule reagent and consumptive material, wherein metabolism small molecule is qualitative and quantitative
Using the standard items of dodecanoic acid and prostaglandin E2, assisted quantitative and the qualitative dodecanoic acid marked using carbon 13 of auxiliary, carbon
The stable isotope internal standard compound of the prostaglandin E2 of 13 labels.It is other that there are also the mating reverse chromatograms columns for being used for UPLC chromatographic isolation
(Hypersil GOLD C18 chromatographic column, 100mm × 2.1mm, 1.9 μm of partial size), the reagent (100% for precipitating haemocyanin
Methanol), for mobile phase reagent (water containing 0.1% formic acid and containing 0.1% formic acid acetonitrile), it is small for extracting metabolism
The reagent (100% ultrapure water) of molecule.The value of this kit is only 100 μ l pregnancy period serum of needs, can be detected serum generation
It thanks to the content of small molecule marker, then occurs to carry out early stage auxiliary diagnosis by content combine detection macrosomia, and be easy to carry out
Dynamic monitoring and observation therapeutic effect.
Specific kit forms are as follows：
Dodecanoic acid standard items
Prostaglandin E2 standard items
The dodecanoic acid stable isotope internal standard compound that carbon 13 marks
The prostaglandin E2 stable isotope internal standard compound that carbon 13 marks
Chromatographic column (Thermo 100mm × 2.1mm, 1.9 μm of partial size, Hypersil GOLD C18 chromatographic column)
Reagent A (contains 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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Claims (8)
1. pregnancy period blood serum metabolic small molecule marker relevant to macrosomia, it is characterised in that the marker is small point of blood serum metabolic
Sub- dodecanoic acid and prostaglandin E2.
2. pregnancy period blood serum metabolic small molecule marker described in claim 1 is in preparation macrosomia early diagnosis or monitoring reagent
Application.
3. the kit of a kind of early diagnosis or monitoring macrosomia, it is characterised in that the kit contains detection pregnancy period blood serum metabolic
The reagent of small molecule marker dodecanoic acid and/or prostaglandin E2.
4. kit according to claim 3, it is characterised in that the kit contains using UPLC-Q exactive MS
Method detects the reagent of pregnancy period blood serum metabolic small molecule marker dodecanoic acid and/or prostaglandin E2.
5. kit according to claim 4, it is characterised in that the kit contains following reagent：
Dodecanoic acid and/or prostaglandin E2 standard items；
The dodecanoic acid stable isotope internal standard compound that carbon 13 marks；
The prostaglandin E2 stable isotope internal standard compound that carbon 13 marks.
6. kit according to claim 5, it is characterised in that the kit also contains：
Hypersil GOLD C18 chromatographic column；
Reagent A：Protein precipitation is used, and 100% methanol is contained；
Reagent B：Mobile phase is used, the water containing 0.1% formic acid；
Reagent C：Mobile phase is used, the acetonitrile containing 0.1% formic acid；
Reagent D：It redissolves and uses, ultrapure water.
7. a kind of method for detecting pregnancy period blood serum metabolic small molecule marker relevant to macrosomia as described in claim 1,
It is characterized in that this method detects pregnancy period blood serum metabolic small molecule marker dodecane using UPLC-Q exactive MS method
The content of acid and/or prostaglandin E2.
8. according to the method described in claim 7, it is characterized in that in this method：
One, liquid-phase condition：
Liquid-phase chromatographic column is Hypersil GOLD C18 chromatographic column, and column temperature is 40 DEG C；
Mobile phase A is the water containing 0.1% formic acid, and Mobile phase B is the acetonitrile containing 0.1% formic acid, and flow velocity is 400 μ L/min；
Instrument gradient is：0-3min 1%B, 3-10min 1% arrives 99%B, 10-13min 99%B, 13-13.1min 99%
To 1%B, 13.1-17min 1%B；
Input mode：10 μ l of volume；
Two, Mass Spectrometry Conditions
1. heating electrospray ionisation mode (HESI) is analyzed；
2. positive ion mode spray voltage：Holotype, injection electric 3.5kV, negative mode, injection electric 2.5kV；For two
Kind of mode, capillary temperature are 300 DEG C, and heter temperature is 425 DEG C, and sheath throughput is 50AU, secondary air amount 13AU, instead
Air blowing flow is 0AU, and full scan analyzes (70 to 1,050m/z), and resolution ratio is set as 70,000.
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| CN114200121A (en) * | 2021-12-15 | 2022-03-18 | 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) | Prostatitis related marker and kit |
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| CN105181869A (en) * | 2015-09-21 | 2015-12-23 | 南京医科大学 | Fetal macrosomia auxiliary diagnostic marker and application thereof |
| WO2016020489A1 (en) * | 2014-08-08 | 2016-02-11 | Nestec S.A. | Vitamin b2 for gestational diabetes |
| WO2016020495A1 (en) * | 2014-08-08 | 2016-02-11 | Nestec S.A. | Myo-inositol and one or more probiotic and use thereof |
| CN106556655A (en) * | 2016-10-10 | 2017-04-05 | 南京医科大学 | Medium-chain fatty acid mark related to idiopathic male infertility in serum and its detection method and application |
| CN107576747A (en) * | 2017-09-11 | 2018-01-12 | 南京医科大学 | Capric acid and prostaglandin E2 combination are used as macrosomia's auxiliary diagnosis mark and its application |
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| CN108872424A (en) * | 2018-04-16 | 2018-11-23 | 南京医科大学 | Dodecanoic acid and prostaglandin E2 combination are used as macrosomia's auxiliary diagnosis marker and its application |
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| WO2016020489A1 (en) * | 2014-08-08 | 2016-02-11 | Nestec S.A. | Vitamin b2 for gestational diabetes |
| WO2016020495A1 (en) * | 2014-08-08 | 2016-02-11 | Nestec S.A. | Myo-inositol and one or more probiotic and use thereof |
| CN105181869A (en) * | 2015-09-21 | 2015-12-23 | 南京医科大学 | Fetal macrosomia auxiliary diagnostic marker and application thereof |
| CN106556655A (en) * | 2016-10-10 | 2017-04-05 | 南京医科大学 | Medium-chain fatty acid mark related to idiopathic male infertility in serum and its detection method and application |
| CN107576747A (en) * | 2017-09-11 | 2018-01-12 | 南京医科大学 | Capric acid and prostaglandin E2 combination are used as macrosomia's auxiliary diagnosis mark and its application |
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| WO2019201216A1 (en) * | 2018-04-16 | 2019-10-24 | 南京医科大学 | Combination of dodecanoic acid and prostaglandin e2 as auxiliary diagnostic marker of macrosomia and application thereof |
| CN114200121A (en) * | 2021-12-15 | 2022-03-18 | 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) | Prostatitis related marker and kit |
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