CN116893237A - Metabolic marker related to neonatal pneumonia and myocardial damage and application thereof - Google Patents
Metabolic marker related to neonatal pneumonia and myocardial damage and application thereof Download PDFInfo
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- 230000002503 metabolic effect Effects 0.000 title claims abstract description 26
- 206010053584 Neonatal pneumonia Diseases 0.000 title claims abstract description 24
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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Abstract
The invention belongs to the technical field of biology, and relates to a metabolic marker related to neonatal pneumonia and myocardial damage and application thereof. The metabolic markers are one or more of 21 metabolic markers shown in ID NO. 1-21. The 21 differential metabolites show significant differences in the pneumonia and metabolism acidosis group, wherein AUC values of 4-Heptyloxyphenol, benzylsuccinate, 2-4-Dimethylphenol, phenylpropylmethylamine, S-Allyl-L-cysteine, farnesol, phe-Phe, PC (14:0/14:1 (9Z)) and Bilirubiin are all above 0.9, and the 21 differential metabolites have high diagnosis efficacy and can be used as diagnosis markers of neonatal pneumonia and myocardial damage.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a metabolic marker related to neonatal pneumonia and myocardial damage and application thereof.
Background
Pneumonia is a common medical condition and is the leading cause of death in children in developing countries. The neonate has the characteristics of imperfect immune function development, difficult movement and the like, and causes serious threat to the life health of the neonate, so that the rapid diagnosis of symptoms and the timely treatment are particularly important. Clinically, X-ray, CT examination and Lung Ultrasound (LUS) are generally used as main diagnosis means, but because of the complicated cause and various symptoms of pneumonia infection, no suitable method is available for identifying patients with complications or with higher nursing level, and it is still a great challenge to accurately identify high-risk pneumonia.
Metabonomics is a research method for searching the relative relation between metabolites and physiological and pathological changes by carrying out qualitative and quantitative analysis on all the metabolites in organisms, and the research object is mainly small molecular metabolites of substrates and products of various metabolic pathways. By analyzing the pathways perturbed by small molecule changes, it helps to reveal the mechanism of action in the occurrence of the disease. The LC-MS has higher sensitivity and resolution, and has high analysis speed and multiple detection substance types, and most of organic compounds can be analyzed by high performance liquid chromatography, so that the advantages are obvious. In addition, the LC-MS samples do not need additional derivatization treatment during collection, and the application range is relatively wider.
Some previous studies have shown that metabonomics techniques can be used for diagnosis of pneumonia, diagnosis of the etiology of pneumonia, and judgment of the severity of pneumonia, but there are currently less studies on the use of metabonomics methods to judge the concurrent myocardial damage to pneumonia.
Disclosure of Invention
The invention aims to provide a metabonomics method for judging the complicated myocardial damage of neonatal pneumonia, which is used for carrying out metabonomics data analysis on a sample, searching for differential metabolites and verifying the accuracy of the screened differential metabolites.
The invention is realized by the following technical scheme:
the invention provides metabolic markers associated with neonatal pneumonia and myocardial damage, wherein the metabolic markers are one or more of 21 metabolic markers shown in the following ID NO: 1-21:
1)2,4-Dimethylphenol
2)Phenylpropylmethylamine
3)S-Allyl-L-cysteine
4)cis-4-Octenedioic acid
5)Methyleugenol
6)D-Tyrosine
7)Ferulate
8)O-Acetylcarnitine
9)Benzylsuccinate
10)4-Heptyloxyphenol
11)Phlorisovalerophenone
12)2-Aminophenoxazin-3-one
13)Farnesol
14)Oleic acid
15)Sphingosine
16)Mesterolone
17)Phe-Phe
18)LysoPC(22:2(13Z,16Z))
19)Bilirubin
20)PC(14:0/14:1(9Z))
21)Ramifenazone。
in the above technical scheme, further, the metabolic marker is applied to the preparation of products for diagnosing the neonatal pneumonia and myocardial damage.
In the above technical solution, further, the product comprises a reagent for detecting the content of the metabolic marker in the subject sample.
In the above technical solution, further, the detecting includes detecting by liquid chromatography-tandem mass spectrometry.
In the above technical solution, further, the product is used for diagnosing whether neonatal pneumonia and myocardial damage occur or not by detecting the content level of the metabolic marker.
In the above technical solution, further, the product is used for distinguishing neonatal pneumonia from neonatal pneumonia complicated with myocardial damage.
In the above technical scheme, further, the product comprises a kit, a detection chip and test paper.
The invention provides a screening method of the metabolic markers, which comprises the following steps:
s1, collecting samples, wherein a serum sample of neonatal pneumonia complicated with myocardial damage is selected as an experimental group, and a serum sample of neonatal pneumonia (without complications) is selected as a control group;
s2, sample pretreatment;
s3, collecting neonatal pneumonia and myocardial damage serum sample data complicated with the pneumonia based on LC-MS;
s4, preprocessing data, and screening out metabolites with significant differences through statistical analysis;
s5, verifying the accuracy of the poor foreign matter based on an AUC value (namely the area under the curve) in the ROC subject working characteristic curve;
in the step S4, based on software One-MAP/PTO software, the collected LC-MS original data is converted into mzML format, and an excel format file containing the retention time of the compound and the mass-to-charge ratio information is obtained after peak matching;
in step S4, the processed data matrix is imported into One-MAP statistical software for qualitative and statistical analysis, and the qualitative result is checked based on an HMDB library. Screening out metabolites with significant differences through comprehensive univariate and multivariate analysis;
in step S5, the screened differential metabolites were characterized for subject operation (ROC) using MedCalc software, and the reliability of the screened differential was verified using "AUC values".
Compared with the prior art, the invention has the beneficial effects that: according to the invention, through metabonomics research, metabolic spectrum differences of a pneumonia-associated myocardial damage group relative to a pneumonia control group serum sample are analyzed, differential metabolites among groups are screened by combining univariate and multivariate statistical analysis, and the differential metabolites are verified, 21 differential metabolites are screened out to show significant differences in the pneumonia-associated myocardial damage group, wherein AUC values of 4-Heptyloxyphenol, benzylsuccinate, 2-4-Dimethylphenol, phenylpropylmethylamine, S-all-L-cysteine, farnesol, phe-Phe, PC (14:0/14:1 (9Z)) and Bilirubiin 9 substances are above 0.9, so that the method has higher prediction accuracy, and provides a new research thought and method for judging neonatal pneumonia-associated myocardial damage.
Drawings
FIG. 1 is a sample metabolic profile analysis: (A) is a PCA plot of QC in positive ion mode; (B) is a PCA plot of QC in negative mode ion;
FIG. 2 is a metabolic profile analysis of the pneumonic and myocardial damage group and pneumonic group in positive ion mode: (A) is a PLS-DA score map; (B) is a volcanic plot; (C) is a displacement check chart; wherein, (PN) represents the pneumonia group and (PN & MD) represents the pneumonia-associated myocardial damage group.
FIG. 3 is a metabolic profile analysis of the pneumonia-associated myocardial damage group and pneumonia group in negative ion mode: (A) is a PLS-DA score map; (B) is a volcanic plot; (C) is a displacement check chart; wherein, (PN) represents the pneumonia group and (PN & MD) represents the pneumonia-associated myocardial damage group.
Fig. 4 is a ROC validation graph of the differential metabolites of the pneumonia and the myocardial damage group and the pneumonia group.
Detailed Description
The invention is further illustrated below in connection with specific examples, but is not limited in any way.
Example 1
1. The method for analyzing the neonatal pneumonia complicated with myocardial damage based on non-targeted metabonomics comprises the following steps:
s1, sample collection
Serum samples of 10 cases of neonatal pneumonia complicated with myocardial damage were collected as an experimental group, and 20 cases of neonatal pneumonia (no complications) serum samples were collected as a control group. Blood samples were collected from Changzhou urban women and child healthcare institute (approval number: 2019017), serum was prepared by a standardized procedure, and neonatal parents signed informed consent.
S2, pretreatment of serum samples
On ice, 50ul of serum samples were removed in a 1.5ml EP tube; 200ul of cold methanol (containing mixed standard) is added respectively, vortex 1500r is oscillated for 4min, and the mixture is left to stand for 10min at low temperature; centrifuging at 14000g for 15min at 4deg.C; 200ul of supernatant was aspirated into the new EP tube; preparation of QC samples is the same as above; and (3) centrifuging and concentrating the sample at low temperature, and then placing the sample in a refrigerator at-40 ℃ for standby.
S3, collecting metabolic characteristic information of neonatal pneumonia and pneumonia complicated with myocardial damage serum samples based on LC-MS.
Before on-machine analysis, the samples were lyophilized again with 100ul of 20% methanol/water solution until completely dissolved, and after shaking centrifugation, the supernatant was taken for positive and negative ion pattern analysis. And carrying QC samples at each sample injection analysis treatment.
Liquid chromatography conditions: in positive ion mode, the following 15min gradient was used on a BEH C8 column (1.7 um,2.1 x 100 mm) at a flow rate of 0.35 mL/min: 0-1min,5% solvent B (mobile phase A:0.1% formic acid/water; mobile phase B:0.1% methanol/acetonitrile); 1.1-11min,5% -100% of solvent B;11.1-13min,100% solvent B;13.1-15min,5% solvent B; the column temperature was set at 50 ℃. In negative ion mode, on HSS T3 column (1.8 um,2.1 x 100 mm), the rest conditions are the same as in positive ion mode.
Mass spectrometry conditions: in positive ion mode, spray voltage +3.8kV, capillary temperature 320 ℃, and no target scan was performed on all samples from 70 to 1050m/z at 70000 resolution. The sheath gas flow rate is 35, the extracted mass spectrum characteristics are divided into a plurality of target lists, and the target lists are imported into an MS2 method for target MS/MS analysis; the resolution of the MS/MS fragment acquisition was 17500. In negative ion mode, the spraying voltage is-3.0 kV, and the rest conditions are the same as those in positive ion mode.
S4, data pretreatment and differential metabolite screening
And converting the collected LC-MS original data into mzML format based on software One-MAP/PTO, and performing peak matching to obtain an excel format file containing the retention time and mass-to-charge ratio information of the compound.
Importing the processed data matrix into One-MAP statistical software for qualitative determination, and checking qualitative results based on an HMDB library; screening out differential metabolites by combining univariate volcanic diagrams (FC >1.5, p < 0.05) with multivariate partial least squares discriminant analysis (VIP >1, p < 0.05)
S5.ROC analysis
The screened differential metabolites were plotted against the subject's working characteristics (ROC) using the MedCalc software, and the area under the ROC curve, i.e., AUC value, was calculated, with a larger AUC value indicating a higher accuracy of classification of the differential metabolites in the two groups.
2. Results
Sample metabolic profile analysis: the PCA plot in positive and negative ion mode shows the QC sample distribution set (fig. 1A, 1B), illustrating that data quality can be used for analysis.
Pneumonitis-complicated myocardial damage group and pneumonitis group metabolic profile analysis: PLS-DA modeling was performed based on metabonomics data from the pneumonia and pneumonia-associated myocardial damage group, with good separation in positive ion mode (FIG. 2A) and also with a tendency to separate in negative ion mode (FIG. 3A). The univariate volcanic diagrams in the positive and negative ion modes intuitively identify metabolites with large variation range and statistical significance (fig. 2B and 3B). Substitution test in positive and negative ion mode (FIGS. 2C, 3C) R 2 Greater than Q 2 The establishment model is proved to be good and stable.
Poor foreign matter ROC analysis: ROC analysis was performed on 21 significantly altered metabolites with AUC values greater than 0.75 for all 9 substances, farnesol, 4-Heptyloxyphenol, phe-Phe, PC (14:0/14:1 (9Z)), and others, above 0.9.
The research of the invention discovers that 21 differential metabolites have obvious changes in a pneumonia-complicated myocardial damage group, and the results of judging the accuracy of the classification of the substances by taking the substances as detection variables show that 21 differential metabolites 2,4-Dimethylphenol, phenylpropylmethylamine, S-all-L-cysteine, cis-4-Octenedioic acid, methyleugenol, D-Tyrosine, ferulate, O-Acetylcarnitine, benzylsuccinate, 4-Heptyloxyphenol, phlorisovalerophenone,
AUC values of 2-Aminofenoxazin-3-one, farnesol, oleic acid, sphingosine, mesterolone, phe-Phe, lysoPC (22:2 (13Z, 16Z)), bilirubicin, PC (14:0/14:1 (9Z)), and Ramifenazone are all above 0.75, wherein AUC values of 4-Heptyloxyphenol, benzylsuccinate, 2-4-Dimethylphenol, phenylpropylmethylamine, S-Allyl-L-cysteine, farnesol, phe-Phe, PC (14:0/14:1 (9Z)), and Bilirubicin 9 substances are above 0.9, and the prediction accuracy is high.
Claims (7)
1. A metabolic marker associated with neonatal pneumonia and myocardial damage, wherein the metabolic marker is one or more of 21 metabolic markers as shown in ID NOs 1-21:
1)2,4-Dimethylphenol
2)Phenylpropylmethylamine
3)S-Allyl-L-cysteine
4)cis-4-Octenedioic acid
5)Methyleugenol
6)D-Tyrosine
7)Ferulate
8)O-Acetylcarnitine
9)Benzylsuccinate
10)4-Heptyloxyphenol
11)Phlorisovalerophenone
12)2-Aminophenoxazin-3-one
13)Farnesol
14)Oleic acid
15)Sphingosine
16)Mesterolone
17)Phe-Phe
18)LysoPC(22:2(13Z,16Z))
19)Bilirubin
20)PC(14:0/14:1(9Z))
21)Ramifenazone。
2. use of the metabolic marker of claim 1 in the manufacture of a product for diagnosing neonatal pneumonia and myocardial damage.
3. The use according to claim 2, wherein the product comprises reagents for detecting the level of the metabolic marker in a sample from the subject.
4. The use according to claim 3, wherein the detection comprises detection by liquid chromatography-tandem mass spectrometry.
5. The use according to claim 2, wherein the product is used for diagnosing the occurrence of neonatal pneumonia and myocardial damage by detecting the level of the metabolic marker.
6. Use according to claim 2, wherein the product is for distinguishing neonatal pneumonia from neonatal pneumonia and from myocardial damage.
7. The use according to claim 2, wherein the product comprises a kit, a detection chip, a test paper.
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