CN111505099B - Diagnostic markers for NASH and uses thereof - Google Patents
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- CN111505099B CN111505099B CN202010319098.2A CN202010319098A CN111505099B CN 111505099 B CN111505099 B CN 111505099B CN 202010319098 A CN202010319098 A CN 202010319098A CN 111505099 B CN111505099 B CN 111505099B
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Abstract
The invention relates to the technical field of clinical examination and diagnosis, in particular to a diagnosis marker of NASH and application thereof, and the method comprises the following steps: NASH liver fibrosis model was established 20 weeks after C57/BL6 mice induced by CDAA diet, and the results showed that Sphingosine phosphate-related metabolite abnormality was first found in the CDAA model group mice, except for common bile acid and lipid metabolite disorders, in which Sphingosine, sphingosine 1-phosphate content was significantly increased. The invention also comprises the application of the reagent for detecting the diagnosis marker in preparing the NASH diagnosis kit. The composition has extremely high clinical application value for treating patients with NASH.
Description
Technical Field
The invention relates to the technical field of clinical examination and diagnosis, in particular to a diagnosis 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, a major cause of cirrhosis, fibrosis and liver failure. The disease is progressive, starting from steatosis or nonalcoholic fatty liver disease (NAFLD), progressing to inflamed fatty liver (NASH), and eventually leading to cirrhosis and fibrosis. The disease is often asymptomatic before severe liver function damage occurs.
NAFLD is about 20-23% diseased in the U.S. population, possibly up to 33% diseased in NASH in the U.S. population, about 2-3%. Some NASH patients will progress to advanced disease: about 15-50% of NASH patients develop severe fibrosis, and about 7-16% of patients develop cirrhosis. Liver-specific mortality in NASH cirrhosis patients is approximately 10% per decade.
Currently, there is no specific therapy for NASH.
Aiming at the defects of the prior art, the invention searches a plurality of NASH diagnosis markers by adopting mass spectrometry metabonomics technology, and determines the correlation between the expression quantity of each diagnosis marker and the severity of NASH. Diagnostic markers related to NASH of the invention and their use have not been reported at present.
Disclosure of Invention
A first object of the present invention is to provide NASH disease diagnostic markers that address the deficiencies of the prior art.
A second object of the present invention is to provide the use of a diagnostic marker as described above, in view of the deficiencies of the prior art.
A third object of the present invention is to provide a NASH diagnostic kit and its use, which address the deficiencies of the prior art.
In order to achieve the first object, the invention adopts the following technical scheme:
NASH disease diagnostic markers selected from Sphinganine1-phosphate or a combination of Sphinganine1-phos phase and Sphinganine.
Preferably, the marker further comprises a combination of Sphinganine1-phosphate with any one or more of the following markers, wherein the markers negatively correlated with NASH severity are: phosphoric Acid, L-Carnitine, L-Palmit oylcarnitine, L-Lactic Acid, taurine, lysoPE (0:0/22:2 (13Z, 16Z)), eicosapentanoic Acid, 1-aroidonoyl-sn-glycero-3-phospholanine, 1-olyl-sn-glycero-3-phosp hoethanolamine, L-methonine, malic Acid, 1-pentadecanoyl-glycero-3-p-phosphohale, lysoPE (0:0/20:3 (11Z, 14Z, 17Z)), lysoPE (0:0/24:6 (6Z, 9Z,12Z,15Z,18Z, 21Z)), 1-Heptadecanoylglyceropho sphoethanol amine, ent-7 alpha-hydrokaur-16-en-19-oic Acid, dihomogamma-acrylic-3-p-phospho-6, 2-glycero-3-p-phospho-clamp, lysoPE (0:0/20:3 (11Z, 14Z, 17Z)), lysoPE (0:0/24:6 (6Z, 9Z, 15Z, 18Z), 1-Heptadecanoylglyceropho sphoethanol amine, ent-7 alpha-hydrokaur-16-en-19-oic Acid, dihomogamma-3-phosp hoethanolamine, 2-acrylic Acid, 2-2:2 (52:20:3);
positively correlated with NASH severity is: sphingosine, oleamide, creatine, sphingosine 1-phosphate, DEHYDROASCORBIC ACID, cholic ACID, aspartame, sphinganine, taurourso deoxycholic ACID, 3,5-Tetradecadiencarnitine, stearoylcarnitine, 3a,7a-Dihydroxycholanoic ACID, platelet-activating factor, lysoPC (15:0), L-Carnitine, lysoPE (0:0/16:0), sulfolithocho lylglycine, 1-hexadecanoyl-sn-glycero-3-phosphoethanolamine, D-Gluconic ACID, sphingani ne1-phosphate, D-PANTOTHENIC ACID.
In order to achieve the second purpose, the invention adopts the following technical scheme:
the application of the diagnostic marker as a therapeutic target in preparing medicaments for treating NASH.
In order to achieve the third object, the present invention adopts the following technical scheme:
a NASH diagnostic kit comprising reagents for detecting a diagnostic marker as described above.
The application of the kit in preparing medicaments for detecting or diagnosing NASH.
The invention has the advantages that:
1. a plurality of NASH diagnosis markers are found for the first time, the correlation between the NASH diagnosis markers and the severity of NASH is found, the medical application of the NASH diagnosis markers is pointed out, and the NASH diagnosis markers have the advantages of being faster and more accurate. Meanwhile, a new way is provided for the treatment of patients such as NASH, and the application prospect is wide.
2. The mass spectrometry metabonomics method is adopted, experimental parameters are optimized, various diagnostic markers can be detected at one time, and the efficiency is high.
3. The combination of a plurality of diagnosis markers can synergistically act, so that the diagnosis accuracy is improved, and good news is brought to the treatment of the patients.
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FIG. 1 shows serum biochemical results of two groups of mice.
FIG. 2 is a graph showing serum oxidative stress index results from two groups of mice.
Fig. 3 is a graph of HE staining of liver tissue of two groups of mice, a: control group mice liver tissue HE staining pattern; b: model group mice liver tissue HE staining pattern.
Fig. 4 is a graph of staining of liver tissue of two groups of mice with sirius red, a: a staining chart of the liver tissue of the mice in the control group; b: model group mice liver tissue staining pattern of sirius scarlet.
FIG. 5 is a transmission electron microscope image of liver tissue of two groups of mice.
Detailed Description
The invention is further described below in conjunction with the detailed description. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications of the present invention may be made by those skilled in the art after reading the description of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Example 1
1. Experimental materials
1.1 animals: SPF-class C57BL/6 mice, 10, male, weighing about 16-20g, were purchased from the center of laboratory animals in the Central Hospital, attached to Shanghai university of Chinese medicine. The mice are bred in SPF clean class animal houses, the temperature is 22-24 ℃, and the mice are bred in laboratory with relative humidity of 40-60 percent, and the mice are naturally illuminated and are free to drink water.
1.2 reagents
GPT/ALT (Nanjing build), GOT/AST (Nanjing build), TG (Nanjing build), paraffin (Shanghai drug group), red staining solution of sirius (abcam), mayer hematoxylin staining solution (Biyun day), hematoxylin aqueous solution (Biyun day), eosin staining solution (Biyun day), myeloperoxidase (MPO) test box (Nanjing build), reactive Oxygen Species (ROS) test box (Nanjing build), malondialdehyde (MDA) test box (Nanjing build), PBS (Shanghai drug group), xylene (Shanghai drug group), SDS-PAGE (Biyun day), BCA protein quantification kit (Biyun day), primary antibody, secondary antibody dilution solution (Biyun day), glutaraldehyde (Shanghai drug group), absolute ethyl alcohol (Shanghai drug group), PVDF membrane (Millipore), 10×TBST (Shanghai), beta-actin (Cell Signaling Technology). The common feed is provided by a central hospital animal center of the attached Putuo of Shanghai traditional Chinese medicine university; CDAA feed was purchased from south-access terlofei feed technologies limited; the primary and secondary antibodies were purchased from Abcam corporation.
1.3 modeling and grouping:
10 male healthy C57BL/6 mice at the age of 8 weeks are randomly divided into 2 groups, namely a control group and a model group, after 1 week of pre-adaptation by cage feeding, and 5 mice are respectively arranged in each group. Starting from week 2, the control group was given: normal feed and equal volume distilled water are irrigated into the stomach; model group: CDAA diet + equal volume distilled water lavage. Ending the experiment at the end of week 20, and inducing the NASH liver fibrosis model.
1.4 general Condition records and liver index observations
Eating, motility, hair, weight. After the modeling is completed, the mice are placed in a metabolism cage, the mice are fasted without water control, the final body mass is weighed after 12 hours, the livers are taken, and the liver wet weight of the mice is accurately weighed. The liver index was calculated using the following formula: liver index (%) =liver mass (g)/body mass (g) ×100%.
2. Experimental method
2.1 liver tissue observation is carried out on the 20 th weekend, the experiment is ended, mice are placed in a metabolism cage, no water is forbidden for 12h after fasted, after jugular vein blood collection, all the mice are killed by adopting a heart puncture method, the liver is rapidly taken out, and part of liver tissue is fixed by 4% paraformaldehyde solution and used for preparing paraffin sections; 1mm is taken 3 Cutting left and right liver tissue, fixing in 2.5% glutaraldehyde fixing solution, and storing in refrigerator at 4deg.C for preparing transmission electron microscope sampleThe residual liver tissue is rapidly stored in a refrigerator at the temperature of minus 80 ℃ for liver tissue homogenate preparation; pathology examination: conventional paraffin embedding and slicing are used for HE staining and immunohistochemical staining, and hepatic steatosis, inflammation and fibrosis degree are observed under a light microscope. After the serum is stationary for 2 hours at normal temperature, the serum is centrifuged (3000 r.min) -1 10 min), taking upper serum, and performing biochemical detection on one part and using the other part for metabonomics analysis.
2.2 biomarker study
100 μl of serum sample was added with 400 μl of methanol and 4 μl of 2-phenylalanine (2 mg/mL), shaken for 2min, centrifuged at 15000r/min in a centrifuge at 4deg.C for 10min, 200 μl of supernatant was aspirated, and transferred into a sample vial for detection. Biomarkers were identified by accurate molecular weight in combination with a database of HMDB, mz/closed et al using high resolution mass spectrometry.
The instrument method is as follows: chromatographic column ACQUITYUPLC HSST3, (100 mm. Times.2.1 mm,1.8 μm); the flow rate is 0.3ml/min; column temperature is 40 ℃; mobile phase a, pure water (0.1% formic acid), and B, acetonitrile (0.1% formic acid).
Gradient elution was as follows: 0 to 2min 95 percent of A,2 to 12min 95 to 5 percent of A,12 to 15min 5 percent of A,15 to 17min 5 to 95 percent of A.
2.3 data analysis
LC/MS test data were extracted and pre-processed using SIEVE software (Thermo corporation) and normalized in Excel2010 before Principal Component Analysis (PCA) using SMICA-P software, orthogonal partial least squares-discriminant analysis (OPLS-DA) was performed on model and normal group mouse serum samples. Two-sample t-test was performed using SPSS22.0 statistical software, with the measured data expressed as x+ -s and the difference p <0.05 statistically significant.
3 results of experiments
Referring to FIGS. 1-5, in addition to the common bile acid and lipid metabolite disorders in the NASH model, we first discovered sphingosine phosphate related metabolite abnormalities. Wherein the content of Sphingosine, sphingosine 1-phosphate is significantly increased, which may be related to NASH inflammation.
TABLE 1
Note that: the FOLD change number is obtained from the NASH group/normal person.
Vip value >1 is an indicator of screening for a marker of significance.
Conclusion 4
We established a NASH liver fibrosis model 20 weeks after induction of C57/BL6 mice with CDAA diet. The results show that the HE staining and the sirius red staining show typical pathological manifestations of the NASH liver fibrosis, and the model group mice are also verified to show typical liver cell steatosis and mitochondrial deformation by using a transmission electron microscope for observation. Further analyzing the metabolic spectrum changes of the two groups of mice by mass spectrometry to identify the biomarker. The metabolic differences in serum and liver tissue samples of the two groups of mice are found to occur in sphingolipid metabolism, and through further quantitative analysis and research, the content of SG, S1P and DHS1P in the mice in the CDAA model group is found to be obviously increased. S1P is an important bioactive sphingolipid metabolite, and there is increasing evidence that S1P signaling is involved in the development of fibrosis, and has become a hotspot for the study of the mechanism of fibrosis in recent years. Recent studies have shown that the S1P-mediated SphK1/S1P/S1PR signaling pathway is involved in the development of liver injury and liver fibrosis. In the experiments, SG, S1P and DHS1P were all measured in CDAA rats. These serum indicators may be new biomarkers for assessing NASH severity.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and additions to the present invention may be made by those skilled in the art without departing from the principles of the present invention and such modifications and additions are to be considered as well as within the scope of the present invention.
Claims (5)
- Nash disease diagnostic marker, characterized in that the marker is selected from Sphinganine1-phosphate or a combination of Sphinganine1-phosphate and Sphinganine.
- 2. The marker of claim 1, further comprising a combination of sphingane 1-ph ospate with any one or more of the following markers, wherein the markers negatively correlated with NASH severity are: phosphoricacid, L-Carnitine, L-Palmitoylcarnitine, L-LacticAcid, taurine, lysoPE (0:0/22:2 (13Z, 16Z)), eicosapentomoicacid, 1-arachidoonyl-sn-glycero-3-phospholanolamine, 1-ole-yl-sn-glycero-3-phosphoethanolamine, L-methionine, malicAcid, 1-pentadecanoyl-glycero-3-phosphate, lysoPE (0:0/20:3 (11Z, 14Z, 17Z)), lysoPE (0:0/24:6 (6Z, 9Z,12Z,15Z,18Z, 21Z)), 1-Heptadecanoylglycerophosphoethanolamine, ent-7 alpha-hydroxykur-16-en-19-oil-housing, dih omo-gamma-linnicid, 2-Acyl-sn-glycero-3-phosphocholine, oleicacid, PC (18:1 (9Z), L-0 (38:3 (11Z, 14Z, 17Z)), lysoPE (0:0/24:6 (6Z, 9Z,12Z,15Z, 18Z), 1-Heptadecanoylglycerophosphoethanolamine, ent-7 alpha-hydroxykur-16-en-19-oil-container, dih omo-gamma-linnicid, 2-yl-sn-glycero-3-phosphocholine, oleicacid, PC (18:1 (9Z)), lysoPE (37:20:3 (37Z) and (37:1/9Z).Markers positively correlated with NASH severity are: sphingosine, oleamide, creatine, sphingosin e1-phosphate, DEHYDROASCORBICACID, cholicacid, aspartame, sphinganine, tauro ursodeoxycholicacid, 3,5-Tetradecadiencarnitine, stearoylcarnitine, 3a,7a-Dihydroxycholanoi cacid, platelet-activatingfactor, lysoPC (15:0), L-Carnitine, lysoPE (0:0/16:0), sulfolithoc holylglycine, 1-hexadecanoyl-sn-glyco-3-phosphoethanolamine, D-glucericid, sphingan ine1-phosphate, D-PANTOTHENICACID.
- 3. Use of a diagnostic marker according to any one of claims 1 or 2 as a therapeutic target in the manufacture of a medicament for the treatment of NASH.
- 4. A NASH diagnostic kit comprising reagents for detecting a diagnostic marker according to any one of claims 1 to 2.
- 5. The use of the kit of claim 4 in the preparation of NASH medicaments.
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| CN112522383A (en) * | 2020-12-01 | 2021-03-19 | 南京师范大学常州创新发展研究院 | Preparation method of miRNA marker of non-alcoholic steatohepatitis |
| CN112626197A (en) * | 2020-12-23 | 2021-04-09 | 南京师范大学常州创新发展研究院 | Preparation method of lncRNA marker of non-alcoholic steatohepatitis |
| CN113295793B (en) * | 2021-05-20 | 2022-11-04 | 复旦大学附属中山医院 | Biomarker for predicting early diabetes and diabetes occurrence, detection method and application thereof |
| CN114236021B (en) * | 2021-10-12 | 2024-07-23 | 凯莱谱科技股份有限公司 | Model for evaluating liver fibrosis degree based on bile acid construction |
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| CN101932238A (en) * | 2007-11-30 | 2010-12-29 | 加利福尼亚大学董事会 | Methods of treating non-alcoholic steatohepatitis (nash) using cysteamine products |
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