CN114544826B - Application of reagent for detecting histidine in blood plasma in preparation of depression detection kit - Google Patents
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- 238000000034 method Methods 0.000 claims description 18
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- CWRILEGKIAOYKP-SSDOTTSWSA-M [(2r)-3-acetyloxy-2-hydroxypropyl] 2-aminoethyl phosphate Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCCN CWRILEGKIAOYKP-SSDOTTSWSA-M 0.000 claims description 10
- 235000003704 aspartic acid Nutrition 0.000 claims description 10
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 10
- 229960003104 ornithine Drugs 0.000 claims description 10
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 26
- 230000002503 metabolic effect Effects 0.000 description 9
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- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The application discloses an application of a reagent for detecting histidine in blood plasma in preparing a depression detection kit, and belongs to the field of depression detection. The use of the present application is based on the fact that there is a difference in histidine in plasma between depressed patients and normal persons, which is sufficient for accurate differentiation between depressed patients and normal persons. Further, the application also discloses application of the reagent for detecting 9 markers including histidine in preparation of a depression detection kit. The kit can realize quantifiable objective detection and has the advantages of sensitivity, rapidness and high reliability.
Description
Technical Field
The application belongs to the field of depression detection, and particularly relates to application of a reagent for detecting histidine in blood plasma in preparation of a depression detection kit.
Background
Depression is a major type of mood disorder, characterized by a significant and persistent depression in the mood. As one of the diseases with the highest disability rate in the world, the burden of depression patients on families, healthcare systems and society is enormous. It is estimated that up to 50% of 80 ten thousand suicide animals worldwide exist annually. Currently, the global depression patient population accumulates more than 3.5 hundred million people, and China has more than 5400 ten thousand people suffering from depression.
The depression has remarkable hereditary property, the hereditary rate reaches 30% -40%, and a plurality of hereditary factors are involved. It is also affected by a variety of non-genetic factors that increase the complexity of the pathogenesis of depression. The unclear pathogenesis causes that the diagnosis method for the disease is always remained on subjective observation levels such as a questionnaire scale, and lacks objective examination indexes, and meanwhile, the operation difficulty is high and the diagnosis period is long. Therefore, it is urgent to develop a sensitive, rapid, highly reliable diagnostic method or apparatus based on quantifiable objective indicators.
Histidine is an alpha-amino acid of the formula C 6 H 9 N 3 O 2 The molecular weight was 155. Within the nutritional category, histidine is considered an amino acid essential to humans, mainly children. After years of development, humans can initially synthesize it themselves, at which time it becomes a non-essential amino acid. Histidine can dilate blood vessel and lower blood pressure, and can be used for treating angina pectoris and cardiac insufficiency.
At present, no relation between histidine in blood and depression has been reported.
Disclosure of Invention
The application aims to solve the problems that: provides a new application of histidine as a marker of depression.
The technical scheme of the application is as follows:
the application of a reagent for detecting histidine in blood plasma in preparing a depression detection kit.
Further, the reagent is a reagent for a liquid chromatography-mass spectrometry method or a reagent for a liquid chromatography method.
Further, the kit comprises T 3 HSS chromatographic column, pure water dissolved 0.1% formic acid as mobile phase a and acetonitrile dissolved 0.1% formic acid as mobile phase B.
Further, the kit also comprises reagents for detecting ornithine, C10:1 acyl carnitine, lysophosphatidylethanolamine (22:5), tyrosine, lysophosphatidylcholine (16:1), lysophosphatidylcholine (22:0), phosphatidylethanolamine (36:4) and aspartic acid in plasma.
Further, when the concentration of ornithine, lysophosphatidylethanolamine (22:5), lysophosphatidylcholine (16:1), phosphatidylethanolamine (36:4) in the plasma of the subject is higher than that of normal human, and the concentration of histidine, C10:1 acyl carnitine, tyrosine, lysophosphatidylcholine (22:0) and aspartic acid is lower than that of normal human, it can be determined that the risk of depression is high.
A depression detection kit comprising a reagent for detecting histidine in plasma.
Further, the reagent is a reagent for a liquid chromatography-mass spectrometry method or a reagent for a liquid chromatography method.
Further, the kit comprises T 3 HSS chromatographic column, pure water dissolved 0.1% formic acid as mobile phase a and acetonitrile dissolved 0.1% formic acid as mobile phase B.
Further, the kit also comprises reagents for detecting ornithine, C10:1 acyl carnitine, lysophosphatidylethanolamine (22:5), tyrosine, lysophosphatidylcholine (16:1), lysophosphatidylcholine (22:0), phosphatidylethanolamine (36:4) and aspartic acid in plasma.
Further, the kit contains instructions for determining criteria for depression;
the criteria for determining depression are: a person at high risk of depression can be determined when the concentration of ornithine, lysophosphatidylethanolamine (22:5), lysophosphatidylcholine (16:1), phosphatidylethanolamine (36:4) in the plasma of the subject is higher than that of normal persons, and the concentration of histidine, C10:1 acyl carnitine, tyrosine, lysophosphatidylcholine (22:0) and aspartic acid is lower than that of normal persons.
The key point of the application is that it is determined that the human plasma histidine level is significantly correlated with depression, so that the risk of depression can be judged by detecting the human plasma histidine level, and as for the specific means for detecting histidine, various means disclosed in the prior art can be used, and the embodiment of the application adopts a liquid chromatography-mass spectrometry combined method for detection, but is not meant to be limited to the method.
The application provides a novel depression detection marker and a novel depression detection kit, which can realize quantitative objective detection of depression and have the advantages of sensitivity, rapidness and high reliability.
The combination of diagnostic markers is beneficial to improving the accuracy of diagnosis. Patent application CN111141863a discloses a polypeptide marker combination for depression diagnosis, the AUC of which is at most 0.949, the sensitivity is 93.3%, and the specificity is 83.3%. The further preferred kit of the application has the area under the curve AUC of ROC of up to 0.96, the sensitivity of 0.91 and the specificity of 0.93 by detecting 9 plasma metabolic markers, and the overall accuracy is higher than that of the existing depression diagnosis marker combination.
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 application as defined by the appended claims.
The above-described aspects of the present application 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 application is limited to the following examples only. All techniques implemented based on the above description of the application are within the scope of the application.
Drawings
Fig. 1: relative amounts of histidine in depressed and normal control plasma; CON, control; MDD, depression.
Fig. 2: relative amounts of 9 plasma metabolic markers in the depressed and normal control plasma; CON, control; MDD, depression; ornithine; histidine C is C10, 1 acyl carnitine; lysophosphatidylethanolamine (22:5); e, tyrosine; lysophosphatidylcholine (16:1); lysophosphatidylcholine (22:0); phosphatidylethanolamine (36:4); aspartic acid; * P <0.01, p <0.001.
Fig. 3: ROC curves for predicted depression with the combination of 9 plasma metabolic markers.
Detailed Description
Example 1A depression detection kit and method of use
1. Composition of the kit
Standard pure liquid containing 12mg/ml plasma metabolism marker, 1C 8 BEH column (1.7 μm, 2.1X100 mm) and 1T 3 HSS column (1.8 μm, 2.1X100 mm), pure water dissolved 0.1% formic acid, acetonitrile dissolved 0.1% formic acid. Wherein the plasma metabolic marker is histidine.
2. Application method
(a) Injecting the prepared plasma sample into a chromatographic column through an automatic sampler, and separating metabolites in positive and negative ionization modes respectively under the specific chromatographic conditions that: mobile phase A is 0.1% formic acid dissolved in pure water; mobile phase B was 0.1% formic acid dissolved in acetonitrile. For the positive mode, the gradient initially starts at 10% b, increases linearly to 40% b in 4 minutes after 1 minute, then increases to 100% b in 12 minutes and remains for 5 minutes, then returns to the initial ratio balance for about 3 minutes. In negative mode, the gradient starts at 100% a, increases linearly to 40% b after 1 minute, then increases to 100% b in 9 minutes, and remains for 4 minutes, then returns to the initial ratio equilibrium for about 4 minutes. The column temperature was 55 ℃.
(b) The isolated metabolites were imported into Shimadzu LC (30 AD) -MS (TQ 8050) to obtain dynamic Multiple Response Monitoring (MRM) data for validation, the main parameters of mass spectrometry were the same as positive and negative modes: the flow rate of the heating gas is 10L/min; the flow rate of the dry gas flow is 10L/min; the flow rate of the atomized air flow is 3L/min; the DL temperature was 250 ℃; the temperature of the heating block is 400 ℃; the interface heater temperature was 300 ℃.
(c) Based on the relative concentration of histidine, the subject is assessed for depression. Relative concentrations <0.0079 determine a high risk of depression.
The kit is designed based on the plasma metabolic marker provided by the application, and can be used for accurately diagnosing and accurately evaluating patients suffering from depression.
Example 2A depression detection kit and method of use thereof
1. Composition of the kit
Standard pure liquid containing 12mg/ml plasma metabolism marker, 1C 8 BEH column (1.7 μm, 2.1X100 mm) and 1T 3 HSS column (1.8 μm, 2.1X100 mm), pure water dissolved 0.1% formic acid, acetonitrile dissolved 0.1% formic acid. Wherein the plasma metabolic markers are 9 of ornithine, histidine, C10:1 acyl carnitine, lysophosphatidylethanolamine (22:5), tyrosine, lysophosphatidylcholine (16:1), lysophosphatidylcholine (22:0), phosphatidylethanolamine (36:4), aspartic acid and the like.
When the detection kit is designed, the standard substances can be packaged independently or can be prepared into a mixture for packaging.
2. Application method
(a) Injecting the prepared plasma sample into a chromatographic column through an automatic sampler, and separating metabolites in positive and negative ionization modes respectively under the specific chromatographic conditions that: mobile phase A is 0.1% formic acid dissolved in pure water; mobile phase B was 0.1% formic acid dissolved in acetonitrile. For the positive mode, the gradient initially starts at 10% b, increases linearly to 40% b in 4 minutes after 1 minute, then increases to 100% b in 12 minutes and remains for 5 minutes, then returns to the initial ratio balance for about 3 minutes. In negative mode, the gradient starts at 100% a, increases linearly to 40% b after 1 minute, then increases to 100% b in 9 minutes, and remains for 4 minutes, then returns to the initial ratio equilibrium for about 4 minutes. The column temperature was 55 ℃.
(b) The separated metabolites were imported into a liquid chromatograph-mass spectrometer Shimadzu LC (30 AD) -MS (TQ 8050) to acquire dynamic multi-reaction monitoring (MRM) data for validation, and the main parameters of the mass spectrum were the same as positive and negative modes: the flow rate of the heating gas is 10L/min; the flow rate of the dry gas flow is 10L/min; the flow rate of the atomized air flow is 3L/min; the DL temperature was 250 ℃; the temperature of the heating block is 400 ℃; the interface heater temperature was 300 ℃.
(c) Based on the relative concentrations of plasma metabolic markers in the plasma samples, the subject is assessed for depression. A person at high risk of depression can be determined when the concentration of ornithine, lysophosphatidylethanolamine (22:5), lysophosphatidylcholine (16:1), phosphatidylethanolamine (36:4) in the plasma of the subject is higher than that of normal persons, and the concentration of histidine, C10:1 acyl carnitine, tyrosine, lysophosphatidylcholine (22:0) and aspartic acid is lower than that of normal persons.
To demonstrate the effectiveness of histidine in assessing depression, the present application provides the following experimental examples.
Experimental example 1 comparison of plasma histidine concentration between depressed patients and Normal controls
50 cases of clinical depression and normal control were collected, each of which was prepared as 5ml plasma samples. 100 samples were taken from a first hospital affiliated with Chongqing university, subjects in the depression group excluded from past or present suffering from other neurological or psychiatric disorders, alcoholism or dependence on illicit drug use or pregnancy, and were diagnosed as depression by a first hospital affiliated with Chongqing university using the DSM-IV-TR standard, and a Hamiltonian depression scale was implemented to assess the severity of depression. Normal control subjects were excluded from any past or present neurological disease, I-axis or II-axis disease or systemic medical disease. The study protocol fully met the ethical criteria of human trials and was approved by the ethical committee of Chongqing medical university, subjects were known prior to the test and were given written consent.
The plasma sample is tested for the plasma histidine concentration by the kit and the method of the embodiment 1, and the result is shown in figure 1, wherein the plasma histidine concentration of the patient suffering from depression is obviously lower than that of the control (p<0.001 FDR of 0.0019, log 2 |FC|＝-0.2222。
Note that: FDR refers to the false discovery rate, FDR of 0.0019 indicates that the expected value of the ratio of the number of false rejections (rejecting true (original) hypotheses) to the number of all rejected original hypotheses is 0.0019.
The results of the experimental examples show that the plasma histidine of the patients with depression is obviously higher than that of the normal people, and the plasma histidine concentration can be used for distinguishing the patients with depression from the normal people.
Experimental example 2 evaluation of Performance of the kit of example 2
1. Method of
50 cases of clinical depression and normal control were collected, each of which was prepared as 5ml plasma samples. 100 samples were taken from a first hospital affiliated with Chongqing university, subjects in the depression group excluded from past or present suffering from other neurological or psychiatric disorders, alcoholism or dependence on illicit drug use or pregnancy, and were diagnosed as depression by a first hospital affiliated with Chongqing university using the DSM-IV-TR standard, and a Hamiltonian depression scale was implemented to assess the severity of depression. Normal control subjects were excluded from any past or present neurological disease, I-axis or II-axis disease or systemic medical disease. The study protocol fully met the ethical criteria of human trials and was approved by the ethical committee of Chongqing medical university, subjects were known prior to the test and were given written consent.
Plasma samples were assayed for ornithine, histidine, C10:1 acyl carnitine, lysophosphatidylethanolamine (22:5), tyrosine, lysophosphatidylcholine (16:1), lysophosphatidylcholine (22:0), phosphatidylethanolamine (36:4) and aspartic acid content by the kit and method of example 2, and depression was determined and analyzed for ROC according to the method of example 2.
2. Results
The levels of the 9 plasma metabolic markers are shown in figure 2, and a significant difference was seen between the control group and the depressed patients.
As shown in fig. 3, the results of ROC analysis revealed that by detecting the content of 9 plasma metabolic markers, depression can be predicted very accurately, wherein the area under the curve AUC of ROC is as high as 0.96, sensitivity is 0.91, and specificity is 0.93.
In conclusion, the kit provided by the application can be used for rapid auxiliary diagnosis of depression and has a good application prospect.
Claims (4)
1. The application of a reagent for detecting histidine in blood plasma in preparing a depression detection kit is characterized in that:
the reagent is a reagent for a liquid chromatography-mass spectrometry method or a reagent for a liquid chromatography method.
2. The use according to claim 1, characterized in that: the kit comprises T 3 HSS chromatographic column, pure water dissolved 0.1% formic acid as mobile phase a and acetonitrile dissolved 0.1% formic acid as mobile phase B.
3. Use according to claim 1 or 2, characterized in that: the kit also comprises reagents for detecting ornithine, C10:1 acyl carnitine, lysophosphatidylethanolamine (22:5), tyrosine, lysophosphatidylcholine (16:1), lysophosphatidylcholine (22:0), phosphatidylethanolamine (36:4) and aspartic acid in plasma.
4. A use according to claim 3, wherein: a person at high risk of depression can be determined when the concentration of ornithine, lysophosphatidylethanolamine (22:5), lysophosphatidylcholine (16:1), phosphatidylethanolamine (36:4) in the plasma of the subject is higher than that of normal persons, and the concentration of histidine, C10:1 acyl carnitine, tyrosine, lysophosphatidylcholine (22:0) and aspartic acid is lower than that of normal persons.
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