CN117250278A - Application of metabolite detection reagent in preparation of diagnosis kit for depression accompanied by sleep disorder - Google Patents
Application of metabolite detection reagent in preparation of diagnosis kit for depression accompanied by sleep disorder Download PDFInfo
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- nitrosoaniline
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Classifications
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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
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
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Abstract
The invention relates to the field of in-vitro diagnostic reagents, in particular to application of a metabolite detection reagent in preparing a diagnostic kit for depression accompanied by sleep disorder. The invention discovers for the first time that the content of cyclic serine and/or N, N-dimethyl-4-nitrosoaniline in blood of patients with sleep disorder depression is significantly higher than that of people without sleep disorder depression. Therefore, the reagent for detecting the cycloserine and/or the N, N-dimethyl-4-nitrosoaniline is used for preparing the diagnosis kit for the depression accompanied by the sleep disorder, and can realize effective diagnosis of the depression accompanied by the sleep disorder.
Description
Technical Field
The invention relates to the field of in-vitro diagnostic reagents, in particular to application of a metabolite detection reagent in preparing a diagnostic kit for depression accompanied by sleep disorder.
Background
Depression is a mental disorder which is relatively common in all ages at present, and is mainly characterized by obvious and continuous low emotion, and is accompanied by symptoms such as sleep disorder, anorexia, slow thinking, distraction, interest loss and the like, and the idea of suicide is generated when the illness is serious. In recent years, the incidence rate of the traditional Chinese medicine rises year by year, and WHO statistics show that depression is the fourth disease in the world. Meanwhile, the incidence rate of the traditional Chinese medicine composition has a trend of increasing year by year, and the data show that 28% and 26% of the total worldwide major depressive disorder and anxiety disorder increase in 2020. Currently, a method for diagnosing the depression generally comprises the steps that a clinician combines complaints and clinical manifestations of patients and grading scales related to the depression, judges whether the depression and the severity of the depression are caused according to scale scores and symptom syndromes of the patients, but confirms that the depression is relatively subjective according to subjective judgment and subjective scores of the doctor, so that misdiagnosis rate and missed diagnosis rate of the clinical depression reach nearly 80%. Sleep disorders are common symptoms of depression, 60% -80% of depressed patients may have insomnia symptoms, and the mechanism of association between sleep disorders and depression is not clear, and may include activation of inflammatory pathways, neuroplasticity, and disturbances in circadian rhythm, etc. Sleep disorders have become an important risk factor for depression, while sleep-concomitant disorders are an important indicator of the severity of a depressed patient. If a reliable marker accompanied with sleep disorder depression can be found, the diagnosis and treatment status of the depression can be greatly improved.
Metabonomics refers to the measurement of small molecular substances that are involved in metabolism, growth and various vital activities in the human body, downstream of genomic expression, and can directly represent changes in the body's environment. Research on serum metabolic markers is an important method for finding objective biomarkers for depression associated with sleep disorders. For example, the Chinese patent application No. CN 202210269957.01-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine detection reagent is used for diagnosing depression accompanied by sleep disorder by using 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine as a marker. However, in order to improve the accuracy of diagnosis and meet the demands of various complicated clinical practical situations, it is desired to further develop more diagnostic agents for depression accompanied by sleep disorder.
The structural formula of Cycloserine (Cycloserine) is:
cycloserine is a second-line antitubercular drug capable of inhibiting the growth of tubercle bacillus.
The N, N-Dimethyl-4-nitrosoaniline (N, N-Dimethyl-4-nitrosoaniline) has the structural formula:
n, N-dimethyl-4-nitrosoaniline is used in the prior art mainly for organic synthesis and as a dye intermediate.
The connection of cycloserine and two metabolites of N, N-dimethyl-4-nitrosoaniline with depression accompanied by sleep disorder is not reported at present.
Disclosure of Invention
Aiming at the problems of the prior art, the invention aims to provide an application of a metabolite detection reagent in preparing a diagnosis kit for depression accompanied by sleep disorder.
The use of a reagent for detecting cycloserine and/or N, N-dimethyl-4-nitrosoaniline in the preparation of a diagnostic kit for depression associated with sleep disorders.
Preferably, the reagent is a reagent for detecting the content of human plasma cycloserine and/or N, N-dimethyl-4-nitrosoaniline.
Preferably, the reagent is a liquid chromatography-mass spectrometry detection reagent.
Preferably, the liquid chromatography-mass spectrometry combined detection reagent comprises: l-2-phenylalanine, methanol, acetonitrile, formic acid, N-dimethyl-4-nitrosoaniline and cycloserine.
Preferably, the model for diagnosing depression associated with sleep disorders is:
logpit(P)＝-25.022+0.007*(Cycloserine)
and/or logpit (P) = -40.904+0.012 (N, N-Dimethyl-4-nitrosoaniline)
Wherein, log pi (P) represents risk index, cyclerine is the detection value of Cycloserine, and N, N-Dimethyl-4-nitrosoaniline is the detection value of N, N-Dimethyl-4-nitrosoaniline.
The invention also provides a diagnosis kit for depression accompanied by sleep disorder, which comprises reagents for detecting cycloserine and/or N, N-dimethyl-4-nitrosoaniline.
Preferably, the reagent is a reagent for detecting the content of cycloserine and/or N, N-dimethyl-4-nitrosoaniline in human plasma.
Preferably, the reagent is a liquid chromatography-mass spectrometry detection reagent.
Preferably, the liquid chromatography-mass spectrometry combined detection reagent comprises: l-2-phenylalanine, methanol, acetonitrile, formic acid, N-dimethyl-4-nitrosoaniline and cycloserine.
Preferably, the model for diagnosing depression associated with sleep disorders is:
logpit(P)＝-25.022+0.007*(Cycloserine)
and/or logpit (P) = -40.904+0.012 (N, N-Dimethyl-4-nitrosoaniline)
Wherein, log pi (P) represents risk index, cyclerine is the detection value of Cycloserine, and N, N-Dimethyl-4-nitrosoaniline is the detection value of N, N-Dimethyl-4-nitrosoaniline.
The invention provides a novel diagnosis marker for depression accompanied by sleep disorder and a novel diagnosis kit for depression accompanied by sleep disorder, which can realize effective diagnosis of depression accompanied by sleep disorder; and human plasma can be used as a detection sample, so that the damage to patients is low. The invention has good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a ROC curve of cycloserine as a diagnostic marker for sleep disorder depression;
FIG. 2 is a ROC curve of N, N-dimethyl-4-nitrosoaniline as a diagnostic marker for sleep disorder depression.
Detailed Description
In the following examples, reagents and materials not specifically described are commercially available.
EXAMPLE 1 relationship between cycloserine and N, N-dimethyl-4-nitrosoaniline in blood with sleep disorder depression
In this example, N-dimethyl-4-nitrosoaniline and cycloserine were analyzed by liquid chromatography-mass spectrometry (LC-MS) detection.
1. Experimental method
1. A subject
(1) Group of patients with sleep disorder depression: patients at mental health center of Huaxi hospital of university of Sichuan and first diagnosed with depression accompanied by sleep disorder by clinic are randomly selected as study subjects from 2022.10 months to 2022.12 months. The study was carried into 29 patients with sleep disorder depression, including 10 men, 19 women, 8 men 14-29 years old, and 14 women, with average age of 21 years old; 2 men and 4 women aged 30-45 years old; female aged 46-61 years 1 case. The case inclusion criteria were mainly: according to the diagnosis standard of the Chinese mental disorder classification and diagnosis standard (CCMD-3) on depression according to the mental disorder diagnosis and statistics handbook (DSM) on the identification of sleep disorder, clinically diagnosing the sleep disorder-complicated depression; new cases; the medical treatment is not used in 2 weeks before the present visit or the medical history is simpler; the disease time is within 2 years; the patient age is 18-60 years old; the exclusion criteria were mainly: patients suffering from a concurrent metabolic disease such as diabetes; past or present with neurological or psychiatric disorders; patients who have alcoholism or rely on illegal drug use in the past;
(2) Healthy controls: the healthy control group samples are all screened from the health physical examination center of Huaxi hospital of Sichuan university, the healthy control group is matched with the patient samples in age and sex, no metabolic disease history exists in the past, the indexes of each physical examination are basically normal, and no medical history exists in the recent physical examination. A total of 29 cases were included, 19 cases for females and 10 cases for males, except if the healthy control group currently had any neurological, I-axis or II-axis disease or systemic disease.
2. Method of
2.1 pretreatment of specimens
Blood samples from all subjects in this study were taken using a kit containing the chelating agent ethylenediamine tetraacetic acid (EDTA) (BDFranklin Lakes, NJ, USA) was collected by a 5ml vacuum tube, centrifuged at 4000r/min for 10min after collection, and the plasma was separated after centrifugation and placed in an EP tube for storage at-80 ℃.
2.2 liquid chromatography mass spectrometry (LC-MS) analysis
(1) Sample processing
Before liquid chromatography-mass spectrometry, taking out the sample stored at-80 ℃, thawing at normal temperature, and placing 150ul of the sample in an EP test tube of 1.5 ml; adding 450ul of protein precipitant methanol-acetonitrile (volume ratio V: V=2:1, containing L-2-phenylalanine, 2 ug/ml)), vortex oscillating for 1min, ultrasonic extracting with ice water bath for 10min, and standing at-40deg.C for 2 hr; at 13000rpm,4 ℃ under centrifugation for 10min, extracting 150ul supernatant with a syringe, filtering the organic phase through 0.22um holes, transferring to LC injection bottle, preserving at-80 ℃ until LC-MS analysis. Wherein, the quality control sample (QC) is prepared after mixing the extracting solutions of all samples in equal volume, and the extracts are all placed at a low temperature of-20 ℃ for precooling.
(2) Standard solution stock solution preparation
N, N-dimethyl-4-nitrosoaniline stock solution (1 mg/mL):
precisely weighing N, N-dimethyl-4-nitrosoaniline, adding 5mL of 0.1% formic acid water to prepare a stock solution with the concentration of 1mg/mL, subpackaging, and storing at-80 ℃.
Cycloserine stock (1 mg/mL):
accurately weighing cycloserine, adding 10mL of 0.1% formic acid water, preparing stock solution with concentration of 1mg/mL, subpackaging, and storing at-80deg.C.
(3) Chromatographic conditions
The experiment was performed with ACQUITYHSST3 (100 mm. Times.2.1 mm,1.8 um) for chromatographic separation at a column temperature of 45 ℃; adopting A-water (containing formic acid with the volume ratio of 0.1%) and B-acetonitrile as mobile phases, wherein the flow rate is 0.35ml/min; the sample loading per sample was 5ul. Elution was performed with 95% a,5% b mobile phase within 0-4 minutes; eluting with mobile phase 70% A and 30% B at 4-8 min; eluting with 50% of A,50% of B mobile phase in 8-10 min; eluting with 20% A,80% B mobile phase within 10-14 min; eluting with 100% B mobile phase within 14-15.1 min; elution was performed with 95% A,5% B mobile phase over 15.1-16 min.
(4) Mass spectrometry conditions
Electrospray ion source, positive ion scan mode, spray voltage 3,000v, sheath gas (nitrogen) 45arb, auxiliary gas (nitrogen) 16arb, ion transport tube temperature 225 ℃, vaporization temperature 450 ℃, collision gas (argon) 1.5mTorr.
Statistical analysis of 3 target metabolites
Statistical analysis of metabolites in this example 2 metabolites were included: n, N-dimethyl-4-nitrosoaniline (N, N-dimethyl-4-nitrosoaniline), cycloserine (cycloserine).
2. Experimental results
The original results for the target metabolites are shown in table 1.
TABLE 1 original results for target metabolites
Note that: in the table, "control X" refers to the xth healthy control sample, and "concomitant sleep disorder depression X" refers to the xth patient with sleep disorder depression.
The average value obtained by detecting the two target metabolites is shown in table 2, and the data in the table show that compared with the healthy control, the serum metabolites of the patients with sleep disorder and depression are obviously increased, and the target metabolites have the potential of being used as diagnostic markers.
TABLE 2 mean value of target metabolites
The SPSS Statistics was used to statistically analyze the sample data, and the target metabolite model was as follows:
logpit(P)＝-25.022+0.007*(Cycloserine)
logpit(P)＝-40.904+0.012*(N,N-Dimethyl-4-nitrosoaniline)
wherein, log pi (P) represents risk index, cyclerine is the detection value of Cycloserine, and N, N-Dimethyl-4-nitrosoaniline is the detection value of N, N-Dimethyl-4-nitrosoaniline.
Diagnosis of depression accompanied by sleep disorder was performed on the sample set using the above model, ROC curves of two target metabolites are shown in fig. 1 and 2, and performance of the model is shown in table 3.
Table 3 performance of the model
Therefore, when the N, N-dimethyl-4-nitrosoaniline or cycloserine is used alone to construct a model for diagnosing the depression accompanied by the sleep disorder, the AUC is higher than 0.9, and the specificity and the sensitivity are both higher than 0.9, so that the two target metabolites can be used alone as markers for diagnosing the depression accompanied by the sleep disorder, and simultaneously, the two target metabolites can be combined to diagnose the depression accompanied by the sleep disorder.
Example 3A diagnostic kit for depression associated with sleep disorders
The kit is used for detecting the content of cycloserine and/or N, N-dimethyl-4-nitrosoaniline in human plasma, and the detection method is a liquid chromatography-mass spectrometry technology.
The kit of this example comprises the following reagents, individually packaged: l-2-phenylalanine, methanol, acetonitrile, formic acid, N-dimethyl-4-nitrosoaniline and cycloserine.
The kit of this example was used as described in the section "2.3 liquid chromatography mass spectrometry (LC-MS) analysis" of example 1.
The kit can diagnose the risk of sleep disorder depression of the crowd to be tested by detecting the content of cycloserine and/or N, N-dimethyl-4-nitrosoaniline in human blood plasma: if the level of cyclic serine and/or N, N-dimethyl-4-nitrosoaniline is high (relative to healthy people), the risk of suffering from depression associated with sleep disorders is high, and if the level of cyclic serine and/or N, N-dimethyl-4-nitrosoaniline is low (relative to healthy people), the risk of suffering from depression associated with sleep disorders is low. Can be used for diagnosing the depression accompanied with the sleep disorder clinically, provides effective basis for patients to take relevant therapeutic measures or decisions, and has good clinical application prospect.
Claims (10)
1. The use of a reagent for detecting cycloserine and/or N, N-dimethyl-4-nitrosoaniline in the preparation of a diagnostic kit for depression associated with sleep disorders.
2. Use according to claim 1, characterized in that: the reagent is a reagent for detecting the content of human plasma cycloserine and/or N, N-dimethyl-4-nitrosoaniline.
3. Use according to claim 1, characterized in that: the reagent is a liquid chromatography-mass spectrometry combined detection reagent.
4. Use according to claim 4, characterized in that: the liquid chromatography-mass spectrometry detection reagent comprises: l-2-phenylalanine, methanol, acetonitrile, formic acid, N-dimethyl-4-nitrosoaniline and cycloserine.
5. Use according to claim 4, characterized in that: the models for diagnosing depression accompanied by sleep disorder are:
logpit(P)＝-25.022+0.007*(Cycloserine)
and/or logpit (P) = -40.904+0.012 (N, N-Dimethyl-4-nitrosoaniline)
Wherein, log pi (P) represents risk index, cyclerine is the detection value of Cycloserine, and N, N-Dimethyl-4-nitrosoaniline is the detection value of N, N-Dimethyl-4-nitrosoaniline.
6. A diagnostic kit for depression associated with sleep disorders, comprising reagents for detecting cycloserine and/or N, N-dimethyl-4-nitrosoaniline.
7. The kit of claim 6, wherein: the reagent is a reagent for detecting the content of cycloserine and/or N, N-dimethyl-4-nitrosoaniline in human plasma.
8. The kit of claim 6, wherein: the reagent is a liquid chromatography-mass spectrometry combined detection reagent.
9. The kit of claim 8, wherein:
the liquid chromatography-mass spectrometry detection reagent comprises: l-2-phenylalanine, methanol, acetonitrile, formic acid, N-dimethyl-4-nitrosoaniline and cycloserine.
10. The kit of claim 8, wherein: the models for diagnosing depression accompanied by sleep disorder are:
logpit(P)＝-25.022+0.007*(Cycloserine)
and/or logpit (P) = -40.904+0.012 (N, N-Dimethyl-4-nitrosoaniline)
Wherein, log pi (P) represents risk index, cyclerine is the detection value of Cycloserine, and N, N-Dimethyl-4-nitrosoaniline is the detection value of N, N-Dimethyl-4-nitrosoaniline.
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