CN116769899A - Application of has-miR-196 in plasma exosome in clinical diagnosis and evaluation of morphine/heroin dependence - Google Patents
Application of has-miR-196 in plasma exosome in clinical diagnosis and evaluation of morphine/heroin dependence Download PDFInfo
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Abstract
The invention discloses application of has-miR-196 in plasma exosomes in clinical diagnosis and evaluation of morphine/heroin dependence, and belongs to the technical field of molecular biology. According to the invention, through researching the change of microRNA expression in serum exosomes of morphine/heroin dependent patients, the hsa-miR-196a-5p and hsa-miR-196b-5p can be used as clinical morphine/heroin dependent biological detection markers, and are used as important auxiliary indexes for morphine/heroin dependent diagnosis, so that the method has important clinical application value and significance for clinical diagnosis and evaluation of morphine/heroin dependent.
Description
Technical Field
The invention relates to the technical field of molecular biology, in particular to application of has-miR-196 in plasma exosomes in clinical diagnosis and evaluation of morphine/heroin dependence.
Background
Morphine, one of the most common opioid addictions, the drug heroin, is also an opioid addictive substance, which is metabolized to morphine in the body after being ingested. Morphine/heroin not only has strong analgesic effect, but also can cause feelings of excitement, pleasure and the like after being absorbed in a large amount, and is the most common medicine/drug causing addiction. After a large amount of morphine/heroin is inhaled, the neurotransmitter of the midbrain-limbic system is disturbed, and then the neurotransmitter of brain areas such as prefrontal cortex, amygdala and the like is disturbed, and the irreversible abnormal remodeling is gradually formed in the nerve loop in the brain, so that a patient repeatedly drinks morphine/heroin and other opioids in an uncontrolled manner, and finally morphine/heroin dependence (dependency) is formed!
Because changes in neurotransmitters in the brain of morphine-addicted patients cannot be detected clinically, and there is no accepted means for assessing changes in the structure or functionality of the neural circuits in the brain after morphine addiction, it is still difficult to objectively predict the patient's response to treatment and dynamically track changes in efficacy clinically at present. Therefore, the exploration and verification of the molecular marker with diagnosis specificity for clinical diagnosis and evaluation of morphine/heroin dependence has important clinical application value and significance-!
Exosomes, spherical vesicles of about 30-100nm in diameter, have the effect of transporting functional proteins or nucleic acids to recipient cells and are considered to be an important component of intercellular communication. Recent evidence suggests that exosomes may be produced by a wide range of cell types in the central nervous system, involved in physiological and pathophysiological processes such as synaptic plasticity, signal transduction, neuroinflammation and degeneration in the central nervous system. However, the use of exosome screening for novel circulating biomarkers for diagnosing morphine/heroin dependence has not been reported.
microRNA (miRNA) is an endogenous RNA molecule widely expressed in organisms, the nucleic acid chain length of the microRNA is about 22-24 nt, the microRNA is a non-coding RNA molecule which is relatively clear in current research, the microRNA can be combined with a target gene nucleic acid sequence through recognition and targeting pairing to play a role in regulating and controlling transcription of the target gene, the microRNA is an important mechanism for regulating and controlling gene expression in organisms, and synthesis and abnormal expression of the microRNA are involved in formation and development of various diseases and are also used as potential molecular markers for predicting nervous system diseases.
In summary, specifically expressed exosome micrornas may be morph/heroin dependent biomarkers and therapeutic targets, requiring further research verification.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide the miRNA marker for clinical diagnosis and evaluation of morphine/heroin dependence, which has important significance for clinical diagnosis and evaluation of morphine/heroin dependence.
The first object of the invention is to provide application of a reagent for detecting a plasma exosome molecular marker has-miR-196 in preparing a morphine/heroin dependent clinical diagnosis and evaluation kit, wherein the markers has-miR-196 comprises hsa-miR-196a-5p and hsa-miR-196b-5p.
The base sequences of hsa-miR-196a-5p and hsa-miR-196b-5p are as follows:
>hsa-miR-196a-5p MIMAT0000226
UAGGUAGUUUCAUGUUGUUGGG
>hsa-miR-196b-5p MIMAT0001080
UAGGUAGUUUCCUGUUGUUGGG
preferably, the morphine/heroin dependent clinical diagnosis and assessment kit is a kit for quantitatively detecting the molecular marker has-miR-196 of the plasma exosome.
Preferably, the diagnosis and evaluation are to predict whether the subject is a morphine/heroin dependent patient based on the difference in the expression level of the markers between the subject and normal patient.
The second object of the invention is to provide a morphine/heroin dependent clinical diagnosis and assessment kit, which contains a detection reagent of a plasma exosome molecular marker has-miR-196; the markers has-miR-196 comprise hsa-miR-196a-5p and hsa-miR-196b-5p.
Preferably, the detection reagent is a reagent for quantitatively detecting a plasma exosome molecular marker has-miR-196.
Preferably, the detection reagent comprises a quantitative detection reagent for gene and/or protein levels.
Preferably, the kit is to detect exosomes isolated from plasma.
Preferably, the kit further comprises a plasma exosome extraction reagent.
According to the invention, through researching the change of microRNA expression in serum exosomes of patients with morphine/heroin dependence, microRNA with the most significant significance is screened out and applied to clinical diagnosis of clinical morphine/heroin dependence, so that an effective index of clinical prognosis prediction is found. Specifically, the invention discovers that hsa-miR-196a-5p and hsa-miR-196b-5p can be used as clinical morphine/heroin dependent biological detection markers and serve as important auxiliary indicators for morphine/heroin dependent diagnosis.
Drawings
FIG. 1 expression levels of hsa-miR-196a-5p and hsa-miR-196b-5p in plasma exosomes from different groups of patients. HC is a healthy subject; MH is morphine/heroin dependent patient. And (3) injection: because the sequences of hsa-miR-196a-5p and hsa-miR-196b-5p are only one base, the sequences cannot be distinguished, and the detection results of the expression quantity of the two are the same.
Detailed Description
The following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1
To assess exosomes hsa-miR-196a-5p and hsa-miR-196b-5p can be used for clinical morphine/heroin dependent biological detection markers. We tested in 16 morphine/heroin dependent patients and 7 healthy subjects by the following inventive protocol and performed relevant statistical analyses.
1. Group entry selection
The study included 7 age-matched healthy subjects (control group) and 16 morphine/heroin dependent patients. All patients were continuously admitted to the Guangzhou white cloud psychological hospital from 12 months 2020 to 12 months 2021.
The inclusion criteria for the patient were:
(1) age 18-65 years old;
(2) meets the diagnostic criteria for DSM-IV opioid (morphine-or heroin) -dependent;
(3) no clear history of neurological diseases and no family history of mental diseases exists in the past;
(4) voluntarily participate in the study, follow-up visit and observation are well conducted, and compliance is good;
the exclusion criteria were:
(1) acute opioid withdrawal phase, CIWA-Ar >9 minutes;
(2) with severe neurological or psychiatric disorders caused by diseases other than chronic morphine/heroin dependence: such as cerebral apoplexy, intracranial infection, brain tumor, schizophrenia, major depressive disorder, bi-directional disorder, etc.;
(3) once experiencing brain trauma or other brain tissue damage;
(4) any other psychotropic medication is being taken or is in the short term, or other drug or other substance dependence is present.
2. Collection of clinical specimens
A total of 10mL of blood was collected from the patient using EDTA blood collection tubes.
3. Extraction of plasma exosomes
Exosomes were isolated and plasma was centrifuged at 3000g for 15 min at 4 ℃ to remove apoptotic bodies.
Exosomes were isolated using Size Exclusion (SEC). The method is briefly summarized as follows: 1mL of the plasma sample after filtration with a 0.8 μm filter was diluted with 1.5-fold PBS, then purified by Exosujur exclusion column (Echobiotech, china), the sample was eluted with 0.01M PBS according to the specification, the target fraction 2mL was collected, and finally the sample was purified by a molecular weight cut-off of 100kDaThe collected exosome solution was concentrated to 200 μl by a ultrafiltration tube (Merck, germany).
4. Isolation and analysis of exosome RNA
According toMini kit (Qiagen, cat. No. 217004) instructions for isolation of plasma exosomes. The concentration and purity of RNA was assessed by the RNA Nano 6000 Assay Kit of Agilent Bioanalyzer 2100 System (Agilent Technologies, calif., USA).
5. Library construction
By usingMini kit (Qiagen, cat. No. 217004) isolated total exosome RNA, then passed through PrimeScript TM cDNA synthesis was performed by RT reagent Kit (Perfect Real Time) (TAKARA, RR 037A). The expression abundance of the target gene is increased by->The probe was subjected to real-time qPCR detection with a cDNA template volume of 2. Mu.L per PCR reaction.
Establishing a small RNA library, wherein the input amount of each sample is 1ng-500ng, adding an index sequence, and the library establishment kit is UMI kit: QIAseq miRNA Library Kit (Qiagen, frederick, MD), unique UMI sequences can be added to each small RNA. Library quality was assessed via Agilent Bioanalyzer 2100 and qPCR.
microRNA sequencing and analysis
Index-labeled samples were clustered in acBot Cluster Generation system by TruSeq PE Cluster Kitv 3-cBaot-HS (Illumina, san Diego, calif., USA) followed by double-ended sequencing on the Illumina Hiseq platform.
The original sequence obtained by sequencing contains a linker sequence or a low-quality sequence, in order to ensure the accuracy of information analysis, the quality control needs to be carried out on the original data to obtain a high-quality sequence (namely Clean Reads), and the quality control standard of the original sequence is as follows:
(1) For each sample, the sequence with low quality value is removed.
(2) Removing Reads with the content of unknown base N (N is an unrecognizable base) of more than or equal to 10%;
(3) Removing reads without 3' linker sequences;
(4) Cleaving the 3' linker sequence;
(5) Removing sequences shorter than 15 or longer than 35 nucleotides;
bowtie aligned clear Reads with Silva, gtRNAdb, rfam and Repbase databases, filtering out rRNA, tRNA, snRNA, snoRNA and other ncRNAs and repeats, respectively, and the remaining Reads were used for identification of known miRNAs and prediction of new miRNAs by alignment with miRbase and human genome (GRCh 38). And comparing to obtain the read quantity of each miRNA, and calculating the expression quantity TPM.
7. Statistical analysis
Differential expression analysis is carried out on microRNA expression TPM calculated by sequencing detection of 2 groups of samples, differential expression analysis among samples (groups) is carried out by using an edge method, a p value is calculated, and a q value is corrected and calculated by using an FDR method.
8. Results show that:
the expression levels of hsa-miR-196a-5P (sequence UAGGUAGUUUCAU GUUGUUGGG) and hsa-miR-196b-5P (sequence UAGGUAGUUUCCUGUUGUUGGG) in the plasma exosomes of morphine/heroin dependent patients were significantly reduced compared to the control group (healthy subjects), with significant differences (P < 0.05), see FIG. 1.
From this, the expression of hsa-miR-196a-5p and hsa-miR-196b-5p in the exosomes of the plasma samples of normal patients and morphine/heroin dependent patients has significant statistical difference, and can be used as biomarkers for clinical diagnosis and evaluation of morphine/heroin dependence.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (9)
1. Application of a reagent for detecting plasma exosome molecular marker has-miR-196 in preparing a morphine/heroin dependent clinical diagnosis and evaluation kit, wherein the markers has-miR-196 comprise hsa-miR-196a-5p and hsa-miR-196b-5p.
2. The use of claim 1, wherein the hsa-miR-196a-5p has the sequence: UAGGUAGUUUCAUGUUGUUGGG; the sequence of hsa-miR-196b-5p is as follows: UAGGUAGUUUCCUGUUGUUGGG.
3. The use according to claim 1, wherein the morphine/heroin dependent clinical diagnosis and assessment kit is a kit for quantitatively detecting the plasma exosome molecular marker has-miR-196.
4. The use of claim 1, wherein the diagnosis and assessment is to predict whether the subject is a morphine/heroin dependent patient based on the difference in marker expression levels between the subject and normal patient.
5. The morphine/heroin dependent clinical diagnosis and assessment kit is characterized by comprising a detection reagent of a plasma exosome molecular marker has-miR-196; the markers has-miR-196 comprise hsa-miR-196a-5p and hsa-miR-196b-5p.
6. The kit of claim 5, wherein the detection reagent is a reagent for quantitatively detecting the plasma exosome molecular marker has-miR-196.
7. The kit of claim 6, wherein the detection reagent comprises a quantitative detection reagent for gene and/or protein levels.
8. The kit according to claim 5, wherein the kit is for detecting an exosome isolated from plasma.
9. The kit of claim 5, further comprising a plasma exosome extraction reagent.
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| CN202210650356 | 2022-06-09 | ||
| CN2022106503564 | 2022-06-09 |
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