CN111505099A - Diagnostic marker for NASH and application thereof - Google Patents
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Abstract
The invention relates to the technical field of clinical examination and diagnosis, in particular to a diagnostic marker of NASH and application thereof, a method comprises the steps of establishing a NASH hepatic fibrosis model after inducing C57/B L6 mice for 20 weeks through CDAA diet, and results show that Sphingosine phosphate-related metabolite abnormality is found for the first time in CDAA model group mice except common bile acid and lipid metabolite disorders, wherein the Sphingosine, Sphingosine1-phosphate and Sphingosine1-phosphate content are obviously increased.
Description
Technical Field
The invention relates to the technical field of clinical examination and diagnosis, in particular to a diagnostic marker of NASH and application thereof.
Background
Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease in the United states NASH is a fatty inflammation of the liver that is the primary cause of cirrhosis, fibrosis and liver failure.
NAF L D has a prevalence of about 20-23%, possibly up to 33%, NASH in the US population of about 2-3% some NASH patients will progress to advanced disease, about 15-50% of NASH patients develop severe fibrosis and about 7-16% develop cirrhosis.
Currently, there is no specific therapy for NASH.
Aiming at the defects of the prior art, the invention finds a plurality of NASH diagnostic markers by adopting a mass spectrometric metabonomics technology and determines the correlation between the expression quantity of each diagnostic marker and the severity of NASH. The diagnostic marker for NASH of the present invention and its use have not been reported at present.
Disclosure of Invention
The first purpose of the present invention is to provide a diagnostic marker for NASH disease, which addresses the deficiencies of the prior art.
A second object of the present invention is to address the deficiencies of the prior art by providing the use of a diagnostic marker as described above.
The third purpose of the present invention is to provide a promoter and inhibitor related to NASH, which is aimed at the defects of the prior art.
The fourth purpose of the invention is to provide a NASH diagnosis kit and the application thereof aiming at the defects of the prior art.
It is a fifth object of the present invention to address the deficiencies of the prior art by providing a method for detecting a diagnostic marker for NASH.
In order to achieve the first purpose, the invention adopts the technical scheme that:
a diagnostic marker for NASH disease, the marker being selected from sphingosine1-phosphate or a combination of sphingosine1-phosphate and sphingosine.
Preferably, the marker also includes combination of Sphingane 1-phosphate with any one or more of Sphingane, Sphingane 1-phosphate, Phosphoric Acid, L-Carnitine, Oleamide, Creatine, L-Palmitoylcarnitine, L0-L active Acid, Taurine, DEHYDRAOASCORBIC Acid, L ysoPE (0:0/22:2(13Z,16Z)), cholic Acid, Eicosapancanolic Acid, Aspartame, 1-arachidonoyl-n-glycero-3-phosphoethanolamide, Taylosylamine, Taylosylurea, 1-xylosyl-3-phospholactone, 1-oxyphyllotonic-3-phospholactone, 1-oxyphyllotoxin-3-phospholactone, 1-3-phospholactone, 2-15-phenoxy-diol, 2-phenoxy-3-2-7, 12-D-phenoxy-3, 2-7-phenoxy-3-2-D (1-11-phenoxy-11, 23-11-D-phenoxy-11, 1-11-phenoxy-11-2-D-11-phenoxy-11-7-D-11-D-a-11-2-D-11-2-D-a-2-D-2-D11-D-11-D-11-D (2-D, 2-D-11-D-11-D-2-11-D-11-D-11-2-D-11-D-2-D-.
Preferably, the NASH severity is negatively correlated with the levels of Phosphoric Acid, L-Carnitine, L-Palmitoylcarnitine, L-L active Acid, Taurine, L ysoPE (0:0/22:2(13Z,16Z)), Eicosapentanoic Acid, 1-arachidonoyl-sn-glycero-3-phosphoethanolamine, 1-oleoyl-sn-glycero-3-phosphoethanolamine, L-methine, Malic Acid, 1-pendeodecanoyl-3-p-phosphoester, L-oleope (0:0/20:3(11Z,14Z,17Z)), GlycoPE (0:0/24:6, 6-Z-12, 15: 11-7-15-7-15-7-15-7-15-7-11-7-15-7-11-7-15-7-11-7-one of phospholine;
the NASH severity is positively correlated with the levels of Sphingosine, Oleamide, Creatine, Sphingosine1-phosphate, DEHYDROASCORBIC ACID, cholic ACID, Aspartame, Sphinganine, Tauroursodeoxycholic ACID, 3, 5-Tetradecadienoic carbonitine, Stearoylcarnitine, 3a,7 a-dihydroxycyanoic ACID, Platlet-activating factor, L ysPC (15:0), L-Carnitine, L ysPE (0:0/16:0), Sulfolithocholesylnic ACID, 1-cyclohexanedicarbonyl-sn-glycero-3-phosphate, HED-glucinic ACID, Sphingolide 1-amide, and Aconitid.
In order to achieve the second object, the invention adopts the technical scheme that:
the diagnostic marker is used as a therapeutic target for preparing the medicine for treating NASH.
In order to achieve the third object, the invention adopts the technical scheme that:
an inhibitor which is a substance for reducing the expression level of a marker selected from the group consisting of Sphingosine, Oleamide, Creatine, Sphingosine1-phosphate, DEHYDROASCORBIC ACID, cholic ACID, Aspartame, Sphinganine, Tauroursodeoxycholic ACID, 3, 5-Tetradecadiencarbonitine, Stearoylcarnitine, 3a,7 a-dihydrochycholic ACID, Plateactivating factor, L ysPC (15:0), L-Carnitine, L ysophoPE (0:0/16:0), sulfolactocholic ACID, 1-heptadecadienyl-n-glycerol-3-phosphate, D-gluconolactic ACID, Sphingogenic ACID, and PAnantid.
A promoter which is a substance for increasing the expression level of a marker selected from the group consisting of phorotrical, L-Carnitine, L-Palmitoylcarnitine, L-L1 active Acid, Taurine, L ysopro (0:0/22:2(13Z,16Z)), Eicosapentanoic Acid, 1-arachidonoyl-sn-glycerino-3-phosphoethanolamine, 1-arachidonyl-sn-glycerino-3-phosphoethanolamine, 1-oleoyl-sn-glycerino-3-phosphoethanolamine, L-methionine, Malic Acid, 1-pendeoyl-glycerino-3-p-phosphoester, L-osylpe (0:0/20:3(11Z,14Z,17Z)), alginic Acid (0:0/24:6, 12Z-11, 11-15Z, 11-15-7-15-7-11-15Z-11-15-11-15-11-15-7-15-11Z-11-16Z), and 15-11-16Z).
Preferably, the inhibitor and the promoter are both selected from small molecule compounds or biological macromolecules, wherein the biological macromolecules are small interfering RNA, dsRNA, shRNA, micro RNA and antisense nucleic acid which take marker proteins or transcripts thereof as target sequences and can inhibit the expression of the marker proteins or gene transcription; or a construct capable of expressing or forming said small interfering RNA, dsRNA, microRNA, antisense nucleic acid.
In order to achieve the fourth object, the invention adopts the technical scheme that:
a NASH diagnostic kit comprising reagents for detecting the diagnostic marker as described above.
The kit is applied to the preparation of the NASH detection or diagnosis medicine.
In order to achieve the fifth object, the invention adopts the technical scheme that:
a method for detecting a NASH diagnostic marker adopts a mass spectrometric metabonomics technology, wherein the operation conditions comprise a chromatographic column of ACQUITY UP L C HSST3, (100mm x 2.1mm, 1.8 mu m), a flow rate of 0.3ml/min, a column temperature of 40 ℃, mobile phases of pure water (0.1% formic acid) and acetonitrile (0.1% formic acid), and gradient elution of 95% A in 0-2 min, 95% -5% A in 2-12 min, 12-15 min, 5% A and 5% -95% A in 15-17 min.
By the method, various diagnostic markers can be detected at one time, and good news is brought to treatment of NASH patients.
The invention has the advantages that:
1. the method finds a plurality of NASH diagnostic markers for the first time, finds the correlation between the NASH diagnostic markers and the severity of the NASH one by one, and points out the medical application of the NASH diagnostic markers, thereby having the advantages of rapidness and accuracy. Meanwhile, a new way is provided for treating patients of NASH and the like, and the application prospect is wide.
2. The method adopts a mass spectrum metabonomics method, optimizes experimental parameters, can detect various diagnostic markers at one time, and has high efficiency.
3. The combination of a plurality of diagnosis markers can realize synergistic effect, the diagnosis accuracy is improved, and good news is brought to the treatment of patients of the type.
Drawings
FIG. 1 shows the biochemical results of two groups of mice sera.
FIG. 2 shows the results of the serum oxidative stress index of two groups of mice.
FIG. 3 is a graph showing HE staining of liver tissues of two groups of mice.
FIG. 4 is a graph of sirius red staining of liver tissues of two groups of mice.
Figure 5 is a transmission electron microscopy image of liver tissue from two groups of mice.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
Example 1
1. Experimental Material
1.1 animals, 10 SPF grade C57B L/6 mice, male, with weight of 16-20g, purchased from the laboratory animal center of the subsidiary Putuo center Hospital of Shanghai medical university, were bred in the SPF clean-grade animal room at 22-24 deg.C and relative humidity of 40-60%, and were bred under natural light with free drinking water.
1.2 reagents
GPT/A L T (Nanjing institute of technology), GOT/AST (Nanjing institute of technology), TG (Nanjing institute of technology), paraffin (Shanghai group of drugs), azure red staining solution (Abcam), Mayer hematoxylin staining solution (Biyunshi), hematoxylin water solution (Biyunshi), eosin staining solution (Biyunshi), MPO (Biyunshi institute of technology), ROS (reactive oxygen species) assaying kit (Nanjing institute of technology), malondialdehyde (MDA institute of technology), PBS (Shanghai group of drugs), xylene (Shanghai group of drugs), SDS-Milan kit (Biyunshi PAGE), BCA protein quantification kit (Biyunshi), MAb, Biyao dilution (Biyunshi), glutaraldehyde (Shanghai group of drugs), absolute ethyl alcohol (Shanghai group of drugs), PVDF (PVDF-Milli group of drugs), PVDF-protein quantification kit (Bilipony group of drugs), TBST 10, SAE (Biyunshi group of drugs), Biyao protein research center (Abnay research center), technology company, technology.
1.3 modeling and grouping:
10 male healthy C57B L/6 mice aged 8 weeks are fed in cages for pre-adaptation for 1 week and then randomly divided into 2 groups, namely a control group and a model group, wherein 5 mice in each group are fed in cages, the control group is fed with common feed and distilled water with the same volume for intragastric administration from the 2 nd week, the model group is fed with CDAA diet and distilled water with the same volume for intragastric administration, the experiment is ended at the end of the 20 th week, and the NASH hepatic fibrosis model is induced.
1.4 general case recording and liver index observations
After the model building is finished, the mouse is placed in a metabolism cage, the food is not forbidden to be fed, the final body mass is measured after 12h, the liver is taken, the wet weight of the liver of the mouse is accurately measured, and the liver index is calculated by the following formula that the liver index (%) -liver mass (g)/body mass (g) is × 100%.
2. Experimental methods
2.1 liver tissue Observation at the end of 20 weeks, the experiment was completed, the mice were placed in a metabolism cage, fasting was not prohibited for 12h, and after jugular vein blood collection, all mice were sacrificed by cardiac punctureQuickly taking out the liver, and fixing part of liver tissues by 4% paraformaldehyde solution for preparing paraffin sections; take 1mm3Fixing the cut pieces of the left and right liver tissues in 2.5% glutaraldehyde fixing solution, storing in a refrigerator at 4 ℃ for transmission electron microscope sample preparation, and rapidly storing the rest liver tissues in a refrigerator at-80 ℃ for liver tissue homogenate preparation; and (3) pathological examination: embedding in paraffin, slicing, HE staining, immunohistochemical staining, and observing hepatic steatosis, inflammation and fibrosis degree under light microscope. Standing serum at room temperature for 2 hr, and centrifuging (3000r min)-110min), taking the upper serum, and performing biochemical detection on one part and metabonomics analysis on the other part.
2.2 biomarker Studies
The apparatus comprises a chromatographic column of ACQUITYUP L C HSST3, (100mm x 2.1mm, 1.8 μm), a flow rate of 0.3ml/min, a column temperature of 40 ℃, and mobile phases A, pure water (0.1% formic acid) and B, acetonitrile (0.1% formic acid).
The gradient elution was as follows: 95% of A in 0-2 min, 95% -5% of A in 2-12 min, 12-15 min, 5% of A, and 5% -95% of A in 15-17 min.
2.3 data analysis
L C/MS detection data are extracted and preprocessed by using SIEVE software (Thermo company), after the data are normalized in Excel2010, SMICA-P software is used for carrying out Principal Component Analysis (PCA), orthogonal partial least squares-discriminant analysis (OP L S-DA) is carried out on mouse serum samples of a model group and a normal group, SPSS22.0 statistical software is used for carrying out two-sample t test, the metering data are expressed by x +/-S, and P <0.05 is different and has statistical significance.
3 results of the experiment
Referring to FIGS. 1-5, we first discovered sphingosine phosphate-related metabolite abnormalities in addition to the common bile acid and lipid metabolite disorders in the NASH model. Wherein the content of Sphingosine, Sphingosine1-phosphate and Sphingosine1-phosphate is increased remarkably, which is probably related to NASH inflammation.
TABLE 1
Note that FO L D change values were obtained from NASH groups/normal.
Vip value > 1 is an index for screening significant markers.
4 conclusion
The results show that typical NASH hepatic fibrosis pathological manifestations appear in HE staining and sirius red staining, and typical liver cell steatosis and mitochondrial deformation appear in model group mice through transmission electron microscope observation, mass spectrometry is further adopted to analyze metabolic spectrum changes of the two groups of mice, biomarkers are identified, metabolic differences in serum and liver tissue samples of the two groups of mice appear in sphingolipid metabolism, and through further quantitative analysis research, SG, S1P and DHS1P are found to be obviously increased in the CDAA model group mice, S1P is an important bioactive sphingolipid metabolite, more and more evidence shows that S1P signal conduction participates in the development of fibrosis in recent years, so that the recent research becomes a hotspot of S1P-mediated SphK 4/S1 355/S1 465/S1 signal transduction, and the possibility of liver fibrosis damage detection of rats in the biological liver fibrosis damage detection of the serum, the biological damage evaluation of the SASH 1, the liver fibrosis detection of the rat P, the liver fibrosis damage detection of the rat, the liver fibrosis detection of the rat, the rat fibrosis detection of the rat fibrosis damage of the rat, the rat fibrosis damage of the rat fibrosis, the liver.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and additions can be made without departing from the principle of the present invention, and these should also be considered as the protection scope of the present invention.
Claims (10)
- A diagnostic marker for NASH disease, characterized in that the marker is selected from sphingosine1-phosphate or a combination of sphingosine1-phosphate and sphingosine.
- 2. The diagnostic marker according to claim 1, wherein the marker further comprises a combination of Sphingane 1-phosphate with any one or more of Sphingane, Sphingane 1-phosphate, Phosphoric Acid, L-Carnitine, Oleamide, Creatine, L-Palmitoylcarnitine, L0-L active Acid, Taurine, DEHYDRAOASCORBIC Acid, L ysophoPE (0:0/22:2(13Z,16Z)), cholic Acid, Eicosaphenohanoic Acid, Asparatome, 1-arachidonoyl-sn-glycero-3-phosphoethanolate, Taurophosphoethanolamine, Tauroquinone, 1-acetominolactone, 1-acetocyanohydrin-sp-3-phospholactone, 1-acetocyanodiol, 2-12-5-15-phospholactone, 12-5-15-phenoxy-3-12-diol, 1-5-2-phenoxy-7-diol, 12-2-phenoxy-3-2-lactone (1-5-15-2-phenoxy-3-7-2-5-2-phenoxy-7-12-11-23-2-carboxylactone (1-3-11-2-D), or 1-2-4-2-1-4-2-4-2-D-1-2-4-2-1-4-D-4-1-2-one-2-one-2-D-2-D-.
- 3. The marker according to claim 2, wherein the NASH severity is negatively correlated with the levels of Phosphoric Acid, L-Carnitine, L-Palmitoylcarnitine, L-L1 active Acid, Taurine, L ysoPE (0:0/22:2(13Z,16Z)), Eicosapentanoic Acid, 1-arachidonoyl-sn-glycero-3-phoshanol amine, 1-oleoyl-sn-glycero-3-phos-ophosphoethanoamine, L-methionine, lic Acid, 1-pentanedioyl-glycero-3-p-phosphate, L ysophoPE (0:0/20:3(11Z,14Z L, 17Z (17Z) 8-glycero-3-p-phospho), 1-7-15-7 (15: 11-11: 11Z), 15-7-6319, 15: 11-7-60-11-7-epoxyacetic Acid), 1-7-11-7-epoxyethane amide, 15-11-7-11-7-11Z, 11-7-4-11-7-6-4-11-one, 15, respectively;the NASH severity is positively correlated with the levels of Sphingosine, Oleamide, Creatine, Sphingosine1-phosphate, DEHYDROASCORBIC ACID, cholic ACID, Aspartame, Sphinganine, Tauroursodeoxycholic ACID, 3, 5-Tetradecadienoic carbonitine, Stearoylcarnitine, 3a,7 a-dihydroxyoxoethanoic ACID, Platlet-activating factor, L ysPC (15:0), L-Carnitine, L ysPE (0:0/16:0), Sulfolicholylcholine, 1-cyclohexanedicarbonyl-sn-glycero-3-phosethanolate, HED-gluconolactic ACID, Sphingogenic ACID 1-amide, and OTID.
- 4. Use of a diagnostic marker according to any of claims 1 or 2 as a therapeutic target in the manufacture of a medicament for the treatment of NASH.
- 5. An inhibitor is a substance which reduces the expression level of Sphingosine, Oleamide, Creatine, Sphingosine1-phosphate, DEHYDROASCORBIC ACID, cholic ACID, Aspartame, Sphinganine, Tauroursodeoxycholic ACID, 3, 5-Tetradecadiencarbonitine, Stearoylcarnitine, 3a,7 a-dihydroxycholeanic ACID, platinum-activating factor, L ysophoPC (15:0), L-Carnitine, L ysophoPE (0:0/16:0), sulfochlorocholecycline, 1-heptadecadienyl-serine-3-phosphoethanolamine, D-glycosylD, dsRNA, RNA sequences capable of forming a small interfering RNA, RNA sequences capable of inhibiting transcription of small molecules, RNA-RNA, RNA-RNA, RNA.
- 6. A promoter characterized in that the promoter is a substance which increases the expression level of a marker selected from the group consisting of Phosphoric Acid, L-Carnitine, L-Palmitoylcarnitine, L-L active Acid, Taurine, L ysophope (0:0/22:2(13Z,16Z)), Eicosapentanoic Acid, 1-arachidonoyl-sn-glycero-3-phosphoethanolamine, 1-oleoyl-sn-glycero-3-phosphoethanolamine, L-methylenone, malicic Acid, 1-pentadeoyl-glycero-3-phosphoester, L ysophope (0:0/20:3(11Z,14Z,17Z L) (PE 0: 6, 6: 6-glycero-3-p-phospholine), 1-8511-11-15-7-11-7-15-7-15-11-15-11-7-11-15-7-11-7-11Z), 1-15-11Z).
- 7. The promoter according to claim 6, wherein the promoter is selected from a small molecule compound or a biological macromolecule which is a small interfering RNA, dsRNA, shRNA, microRNA, antisense nucleic acid targeting a marker protein or a transcript thereof and capable of inhibiting expression of the marker protein or transcription of a gene; or a construct capable of expressing or forming said small interfering RNA, dsRNA, microRNA, antisense nucleic acid.
- 8. A NASH diagnostic kit comprising a reagent for detecting the diagnostic marker of any one of claims 1 to 2.
- 9. Use of the kit of claim 8 for the preparation of a medicament for the detection or diagnosis of NASH.
- 10. A method for detecting the diagnostic marker of any of claims 1-2, wherein the method employs mass spectrometric metabonomics technology, wherein the operating conditions are that the chromatographic column is ACQUITY UP L CHSST3, (100mm x 2.1mm, 1.8 μm), the flow rate is 0.3ml/min, the column temperature is 40 ℃, the mobile phase is pure water (0.1% formic acid) and acetonitrile (0.1% formic acid), the gradient elution is 0-2 min 95% A, 2-12 min 95% -5% A, 12-15 min, 5% A, 15-17 min 5% -95% A.
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