CN112697895B - Application of palmitoyl carnitine as detection target in preparation of ICP (inductively coupled plasma) auxiliary diagnostic kit - Google Patents
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Abstract
The invention discloses application of palmitoyl carnitine as a detection target in preparation of an ICP (inductively coupled plasma) auxiliary diagnostic kit. Application of palmitoyl carnitine as a detection target in preparation of serum/plasma auxiliary diagnostic reagent for intrahepatic cholestasis of pregnancy. The application of the reagent for quantitatively detecting palmitoyl carnitine in preparing the serum/plasma auxiliary diagnostic reagent for intrahepatic cholestasis of pregnancy. According to the invention, the palmitoyl carnitine is a lipid metabolism molecule with high specificity and sensitivity highly related to the ICP pathogenesis, and the multi-factor Logistic regression analysis result shows that the palmitoyl carnitine and the ICP pathogenesis have a significant correlation, the ROC is shown in the figure, the AUC is 0.896, and laboratory support can be provided for ICP screening and diagnosis treatment.
Description
Technical Field
The invention belongs to the fields of metabonomics and reproductive medicine, and relates to application of palmitoyl carnitine serving as a detection target point in preparation of an ICP (inductively coupled plasma) auxiliary diagnostic kit.
Background
Intrahepatic Cholestasis of Pregnancy (ICP) is a complication that seriously compromises maternal and infant health during pregnancy, is a pregnancy-related syndrome characterized by skin itch, elevated serum liver enzymes and total bile acids, has a morbidity up to 12.0%, can cause poor pregnancy fatality such as intrauterine fetal distress, spontaneous preterm birth, stillbirth and the like, and increases morbidity and mortality of perinatal infants. The greatest risk of ICP to pregnancy is the occurrence of unpredictable intrauterine fetal death, and studies have shown that perinatal mortality is about 6-10 times that of normal pregnancies. If ICP can be found early and intervention is carried out, mother-infant complications caused by the disease can be effectively reduced, and disease pain and economic pressure of the disease on the mother and the infant and families of the mother and the infant can be reduced. However, clinical monitoring of ICP to date is limited and can only be based on total bile acid screening, with low sensitivity and specificity. Therefore, the research on sensitive molecular events occurring in the ICP disease and the screening of susceptibility biomarkers (refractory biomarkers) can provide effective means for diagnosis and implementation intervention of the ICP disease, and have great scientific significance for promoting the health of human mothers and infants.
Metabolomics (metablomics) is an emerging omics technology that studies metabolites, called phenotypical-closest omics, to be considered as a comprehensive interpretation of genomic, proteomic performance results. In recent years, metabonomics is successfully applied to early prediction of various diseases, becomes a highly concerned omics platform for screening of sensitive prediction markers of transformed medical diseases, and the metabonomics is used for diagnosis of related diseases in gestation period and research of pathogenesis, and becomes a hot emerging field. Metabolomics can reveal the mechanism of ICP from a completely new perspective and look for sensitive molecular diagnostic markers.
However, at present, no stable metabolic molecular marker for ICP auxiliary diagnosis is reported, and if metabolic substances with specific or abnormal expression of ICP are screened out as molecular markers and corresponding auxiliary diagnosis kits are developed, the diagnosis status of ICP in China is greatly improved.
Disclosure of Invention
The primary object of the present invention is to solve the above technical problems and provide a pregnancy serum/plasma metabolism molecular marker related to ICP auxiliary diagnosis.
The second purpose of the invention is to provide the application of UPLC-Q active MS based on the pregnancy serum/plasma metabolism molecular marker for ICP auxiliary diagnosis.
It is a third object of the present invention to provide a kit for ICP-assisted diagnosis.
The purpose of the invention is realized by the following technical scheme:
application of palmitoyl carnitine as a detection target in preparation of serum/plasma auxiliary diagnostic reagent for intrahepatic cholestasis of pregnancy.
The application of the reagent for quantitatively detecting palmitoyl carnitine in preparing the serum/plasma auxiliary diagnostic reagent for intrahepatic cholestasis of pregnancy.
A serum/plasma auxiliary diagnosis kit for intrahepatic cholestasis of pregnancy comprises a palmitoyl carnitine standard substance and a carbon-13 labeled palmitoyl carnitine stable isotope internal standard substance.
As a preferred embodiment of the present invention, the diagnostic kit comprises a palmitoyl carnitine standard, a carbon-13 labeled palmitoyl carnitine stable isotope internal standard, a chromatographic column (100 mm. times.2.1 mm, particle size 1.9um Thermo Scientific, Germany) matched with Hypersil GOLD C18, reagent A (for protein precipitation, containing 100% methanol), reagent B (for mobile phase, containing 0.1% formic acid in water), reagent C (for mobile phase, containing 0.1% formic acid in acetonitrile), and reagent D (for reconstitution, ultra pure water).
The invention is characterized in that the palmitoyl carnitine can be used as a serum/plasma metabolic molecular marker related to ICP auxiliary diagnosis.
Specifically, palmitoyl carnitine is obtained by screening as a serum/plasma metabolic molecular marker by the following method: (1) establishing a unified specimen library and a database: tissue specimens and blood samples meeting the standard are collected by a Standard Operating Procedure (SOP), and complete demographic data and clinical data are collected by the system. (2) Analysis of placental tissue metabonomics of ICP patients: selecting ICP case and healthy female control matched with ICP case age, detecting the content of each metabolite in ICP case and placental tissue of control group by UPLC-Q active MS method, analyzing the metabolite commonality and characteristic between ICP case and healthy female control, and screening differential expression metabolite. (3) Detection of palmitoyl carnitine metabolism molecular marker in serum/plasma of ICP patient: the sample size is enlarged, and the content of metabolic molecule palmitoyl carnitine in ICP cases and control serum/plasma is also detected by using an UPLC-Q active MS method.
The invention has the beneficial effects that:
the serum/plasma metabolism molecule marker palmitoyl carnitine provided by the invention as a marker for ICP diagnosis has the advantages that:
the invention collects blood and tissue samples meeting the standard by a Standard Operation Program (SOP), systematically collects complete demographic data, clinical data and the like (the data can be used for judging the disease progress, the influence of factors such as patient age and the like on the pathogenesis), and adopts a UPLC-Q active MS-based metabonomics method, through researching the change of metabolites in ICP cases of primiparity and single pregnancy and healthy pregnant woman control tissues/serum matched with the age of the ICP cases, the palmitoyl carnitine is found to be a high-specificity and high-sensitivity lipid metabolism molecule highly related to the pathogenesis of the ICP, and the multi-factor Logistic regression analysis result shows that the palmitoyl carnitine is obviously related to the pathogenesis of the ICP, the ROC of which is shown in the attached figure and the AUC of which is 0.896, thereby providing laboratory support for the ICP screening and diagnosis treatment.
The method adopts a metabonomics research method to obtain the metabolite palmitoyl carnitine which is specifically and abnormally expressed in the placenta tissues of a patient at the initial stage, and simultaneously adopts an UPLC-Q active MS method to verify in the serum of an ICP large sample; the application of the method and the strategy accelerates and ensures the application of the diagnosis kit of the serum/plasma metabolism molecular marker palmitoyl carnitine, and provides a method and a reference on the strategy for the development of other disease biomarkers.
According to the invention, by controlling the influence factors of age and the like on the disease development, the application prospect of the serum/plasma metabolism molecular marker palmitoyl carnitine in ICP diagnosis is researched, the influence of abnormally expressed palmitoyl carnitine on ICP development is explained, and the diagnostic value of the palmitoyl carnitine on ICP is disclosed. Therefore, the invention obtains the serum/plasma metabolism molecular marker specific to the ICP pathogenesis; through the research and application of the serum/plasma metabolism molecular marker palmitoyl carnitine and the diagnosis kit, the diagnosis of ICP is more convenient and feasible, a foundation is laid for clinicians to quickly and accurately diagnose ICP and take treatment measures, and help is provided for finding a novel small molecular drug target with potential treatment value.
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FIG. 1 diagnostic value of serum palmitoyl carnitine on ICP
Detailed Description
Example 1 Collection and data collation of study specimens
The inventor collects a large number of peripheral blood samples and placenta tissue samples of ICP patients and healthy control pregnant women from the subsidiary Wuxi Fuju health care institute of Nanjing medical university in 2017 to 2018 and 10 months (the samples for research are collected at the same period, and the sampling, subpackaging and storing conditions are uniform), and selects 100 samples meeting the following standards from the samples through the arrangement of sample data as experimental samples for metabonomic detection and verification based on the UPLC-Q active MS method:
(1) inclusion into case groups: ICP diagnostic criteria refer to the ICP patient clinical guidelines (first edition), with specific criteria as follows: 1) skin itch in the middle and late gestation, or with various degrees of jaundice; 2) laboratory examination: increase of serum Total Bile Acid (TBA) (>40 μmol/L), or slight to moderate increase of transaminase (ALT and AST), and optionally increase of bilirubin; 3) pregnancy is the only cause of cutaneous pruritus and biochemical abnormalities; 4) the patients have good general conditions and no obvious symptoms of vomiting, poor appetite, weakness and other diseases; 5) the symptoms, physical signs and serum biochemical indexes quickly return to normal after delivery. 50 ICP patients with complete clinical data were collected.
(2) Inclusion in normal control group: no pregnancy complication and complication exists, the caesarean section delivery indications comprise hip position, pelvis abnormality, social factors and the like, and 50 normal pregnant women with complete clinical data are collected.
(3) Two sets of exclusion criteria: 1) (iii) other liver and gall diseases; 2) there are other pregnancy complications such as hypertensive disorders of pregnancy or blood, urine or biochemical abnormalities that cannot be explained by ICP; 3) systemic diseases such as diabetes, hypertension, mental and neurological diseases, etc.; 4) suffering from a genetic or immune disease; 5) those who have a history of blood transfusion, transplantation or immunotherapy; 6) patients with history of oral contraceptives.
The study adopts 100 samples meeting the standard in total, and the system collects the conditions of demographic data, clinical data and the like of the samples.
Example 2ICP patient differential Metabolic profiling
The 4 ICP cases and 4 healthy controls meeting the conditions are subjected to metabonomic detection to obtain related results. The specific experimental method is as follows:
1.1 instruments
UPLC Ultimate 3000system (dionex) hplc; q-active triple quadrupole tandem mass spectrometer; TraceFinder 3.1(Thermo Fisher Scientific); simca P13.0 (Umetrics, Sweden); XW-80A vortex mixer (Shanghai Qingpu Shanghai West apparatus works); electronic balance (MettlerAE type 240); KQ3200B model ultrasonic cleaner (kunshan ultrasonic instrument ltd).
1.2 reagents
500 metabolite standards (. gtoreq.98.0%, Sigma-Aldrich, St.Louis, MO, USA); methanol and acetonitrile (more than or equal to 99.9 percent, Merck, German); formic acid (. gtoreq.98.0%, Sigma-Aldrich, St.Louis, MO, USA); n-hexane (chromatographic grade, not less than 98.0%, Aladdin reagent (Shanghai) Co., Ltd.); chloroform (not less than 99.9%, Alfa-Esa (China) chemical Co., Ltd.); ultra pure water (PURELAB Ultra water purifier, ELGA corporation, uk); liquid nitrogen (greater than or equal to 99.9 percent, applied physical research institute of Nanjing university).
1.3 preparation of Standard solutions and Standard library establishment
Accurately weighing appropriate amount of each metabolite standard, dissolving with methanol, n-hexane or chloroform to obtain standard stock solution with concentration of 1mg/mL, and diluting the stock solution to obtain 100 μ g/mL standard working solution. Mixing all dissolved single standard stock solutions into a mixed standard stock solution with the concentration of 1 mu g/mL, diluting the mixed standard stock solution to obtain a mixed standard working solution with the concentration of 100ng/mL, and storing the mixed standard working solution in a refrigerator with the temperature of-20 ℃. And collecting retention time according to the methods 1.4 and 1.5 to establish a standard substance library.
1.3 pretreatment of tissues
50mg of tissue was taken, 150. mu.L of water was added, 10. mu.L of internal standard A was added, 10. mu.L of internal standard B was added, 10. mu.L of internal standard C was added, 40. mu.L of methanol was added, vortex 30s was performed, protein was precipitated, centrifugation was performed in a refrigerated centrifuge at 16000g for 15min at 4 ℃, the supernatant was transferred to a 1.5ml inlet EP tube, and the supernatant was concentrated to dryness in a centrifugal concentration desiccator (Labconco, USA) at room temperature and reconstituted with 10. mu.L of ultrapure water for analysis.
1.4 ultra performance liquid chromatography tandem mass spectrometry
1.4.1 chromatographic conditions: hypersil GOLD C18 column (100 mm. times.2.1 mm, particle size 1.9 μm Thermo Scientific, Germany), mobile phase A acetonitrile (containing 0.1% formic acid) and mobile phase B ultrapure water (containing 0.1% formic acid), flow rate 0.40ml/min, using gradient elution, mobile phase gradient see Table 1.1, column temperature: 40 ℃, sample introduction: 5 μ L.
Table 1.1 mobile phase gradient
1.4.2 Mass Spectrometry conditions: the heating electrospray ionization mode (HESI) was used, positive ion mode spray voltage: 3.5 kV; negative ion mode spray voltage: 2.5 kV; capillary temperature in two modes: 250 ℃, heater temperature: 425 ℃, sheath gas flow: 50AU, auxiliary gas flow: 13AU, reverse air flow: 0 AU; lens voltage: 60V. Adopting a full-scanning mode, wherein the scanning range is as follows: 70to 1050 m/z; resolution ratio: 70000.
1.5 substance identification
Metabolites were characterized and relatively quantified by comparison to their exact molecular weight and retention time using TraceFinder 3.1(Thermo Fisher Scientific) software.
1.6 data analysis
Orthogonal partial least squares-discriminant analysis (OPLS-DA) was performed using Simca P13.0 (Umetrics, Sweden).
1.7 Metabonomics analysis results
Selecting data with at least half of data in each group as non-null values to perform significance difference analysis, and screening metabolites with expression difference fold more than 1.5 fold (up-down regulation) and P value (t test) less than 0.05 as differential expression metabolites. We initially screened 178 metabolites in 4 cases of ICP and 4 healthy controls using UPLC-Q active MS, 11 of which were significantly different and expression of palmitoyl carnitine was significantly elevated.
Example 3 verification of expression of molecular markers of ICP serum/plasma palmitoyl carnitine metabolism based on UPLC-Q active MS method
According to the detection method of UPLC-Q active MS in example 2, the inventor detects palmitoyl carnitine by using pregnancy serum samples of 50 ICP patients and 50 healthy control groups of an independent population, and draws a ROC curve according to the palmitoyl carnitine serum samples. Demographic characteristics, differences in the distribution between the groups of subjects between TBA (μmol/L) levels and the mean expression level of the metabolic molecular marker palmitoyl carnitine (log of mass spectrum peak area) in serum/plasma samples were compared using the student t-test. The statistical analysis is completed by using SPSS16.0 statistical analysis software. The statistical significance level P value was set to 0.05 and all statistical tests were two-sided. The results are shown in Table 1. According to the validation experiment of palmitoyl carnitine in serum, the inventors detected a significant difference (P <0.01) in the expression of the metabolic molecular marker palmitoyl carnitine in the serum of the "ICP case" group (50 cases) and the "healthy female control" group (50 cases). The result of multi-factor Logistic regression analysis shows that the palmitoyl carnitine is obviously associated with the pathogenesis of ICP, the ROC is shown in the figure, and the AUC is 0.896. The palmitoyl carnitine is a metabolic molecular marker highly related to the ICP pathogenesis, and can be used for preparing an ICP auxiliary diagnosis kit.
EXAMPLE 4 preparation of Carnitine palmitoyl detection and diagnosis kit for ICP diseases
Firstly, screening a metabolic molecular marker palmitoyl carnitine related to ICP diseases in placenta tissues by a UPLC-Q active MS-based metabonomics technology, and taking the palmitoyl carnitine as a molecular index for diagnosing the ICP diseases. The content of the metabolic molecular marker palmitoyl carnitine in the plasma is verified by an UPLC-Q active MS method, and is found to be remarkably increased in an ICP group. The kit comprises a reagent and a consumable for detecting the palmitoyl carnitine, wherein a standard palmitoyl carnitine substance is adopted for qualitative and quantitative determination, and a stable isotope internal standard substance of the palmitoyl carnitine labeled by carbon 13 is adopted for auxiliary quantitative and auxiliary qualitative determination. Other examples are a reversed phase column (Hypersil GOLD C18 column, 100 mm. times.2.1 mm, particle size 1.9 μm), a reagent for precipitating plasma proteins (100% methanol), a reagent for mobile phase (water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid), and a reagent for extracting palmitoyl carnitine (100% ultrapure water) for UPLC chromatographic separation. The value of the kit is that the content of the palmitoyl carnitine in the serum can be detected only by 100 mul of plasma in pregnancy, the ICP disease can be diagnosed through the content, and dynamic monitoring and observation of the treatment effect are easy to carry out.
The specific kit comprises the following components:
palmitoyl carnitine standard substance
Carbon 13-labeled palmitoyl carnitine
Chromatographic column (Thermo 100mm X2.1 mm, particle size 1.9 μm, Hypersil GOLD C18 chromatographic column)
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).
TABLE 1 comparison of ICP patients with the results of normal control palmitoyl carnitine detection
**P<0.01。
Claims (3)
1. Application of palmitoyl carnitine as a detection target in preparation of serum/plasma auxiliary diagnostic reagent for intrahepatic cholestasis of pregnancy.
2. The application of the reagent for quantitatively detecting palmitoyl carnitine in preparing the serum/plasma auxiliary diagnostic reagent for intrahepatic cholestasis of pregnancy.
3. A serum/plasma auxiliary diagnosis kit for intrahepatic cholestasis of pregnancy is characterized by comprising a palmitoyl carnitine standard substance and a carbon-13 labeled palmitoyl carnitine stable isotope internal standard substance.
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