MiRNA marker for diagnosing and treating colorectal cancer and application of miRNA marker in preparation of medicine for preventing and treating colorectal cancer

Abstract

The invention discloses a miRNA marker for diagnosing and treating colorectal cancer and application of the miRNA marker in preparation of medicines for preventing and treating colorectal cancer, and belongs to the technical field of biological medicines. The miRNA is selected from one or more of the following components: hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p, hsa-miR-365b-3p, hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p, and hsa-miR-514b-5p, and the miRNA is selected from one or more of the following components: a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, a, the invention also provides application of the miRNA as a colorectal cancer detection or treatment target. The novel miRNA has the beneficial effects that the novel miRNA can be used as a colorectal cancer detection or treatment target, and whether a subject suffers from the colorectal cancer or is at the risk of colorectal cancer can be diagnosed by measuring the expression level of the miRNA. The diagnosis efficiency of the colorectal cancer is improved, and a new treatment target is provided for treating the colorectal cancer. The invention provides the application of liquiritin in preparation of medicines for preventing and treating colorectal cancer by regulating the expression quantity of miRNA or miR-23b, provides a new medical application of liquiritin, has better application prospect and medical value, and provides a new research direction for treatment of colorectal cancer.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a miRNA biomarker for diagnosing and treating colorectal cancer and its application in the preparation of drugs for preventing and treating colorectal cancer. Background Art

[0002] Colorectal cancer (CRC) is one of the most common digestive tract malignancies in humans. Due to reasons such as changes in dietary structure and population aging, the incidence and mortality of CRC are increasing year by year globally. According to the data of the World Health Organization (WHO) in 2022, the number of new cases of colorectal cancer was 1.926 million, and the number of death cases was 0.904 million. The incidence and mortality ranked third and second among all malignancies respectively. Currently, colorectal cancer has become a major disease endangering people's physical health, seriously increasing the economic and life burdens of patients, and the prevention and treatment situation is very severe.

[0003] Epigenetic modification refers to heritable changes in gene expression without causing permanent changes in the DNA sequence, and plays a central role in the pathogenesis of various cancers including colorectal cancer. The study of epigenetics has clarified the connection between certain colorectal cancer-specific gene expression patterns and the absence of gene alterations. Given the emerging role of epigenetic markers or regulators in colorectal cancer, they can be used as clinically relevant disease biomarkers for predicting, diagnosing, treating, and prognostic response. Epigenetic biomarkers in blood (serum or plasma) may have diagnostic or predictive value for colorectal cancer. Epigenetic biomarkers in tissues predict early lesions and invasion risk, and guide treatment plans and monitoring strategies. Epigenetic biomarkers in feces also have potential diagnostic applications, and NDRG4 methylation is used for screening adenomas and early colorectal cancer. It has been found that approximately 98% of the non-protein-coding genome is involved in the regulation of gene expression. These transcriptional mediators are usually referred to as non-coding RNA (ncRNA), which can be spliced post-transcriptionally but not translated into proteins, and can exert biological functions in a tissue-specific manner.

[0004] As a kind of non-coding RNA, microRNAs (miRNAs) have been reported to play important roles in post-transcriptional epigenetic mechanisms. They can regulate downstream target genes and thus participate in the occurrence and development of tumors as well as other biological functions. At present, abnormal expressions of various miRNAs have been found to be closely related to the progression of colorectal cancer. For example, miR-32 is highly expressed in colorectal cancer cells and promotes the proliferation of colorectal cancer cells by targeting BMP5 protein. Studies have shown that miR-23b often abnormally expresses in various tumors such as gastric cancer, CRC, and thyroid follicular carcinoma. Interfering with the expression level of miR-23b can significantly inhibit tumor growth. Therefore, further studying the expression levels and biological functions of miRNAs can provide new strategies for the early diagnosis, effective prevention, and treatment of colorectal cancer.

[0005] Traditional Chinese medicine has a long history of clinical application in preventing and treating cancer. A large number of studies have shown that traditional Chinese medicine has unique advantages in improving symptoms, prolonging survival time, regulating immune function, and improving quality of life. Licorice is a perennial herb of the genus Glycyrrhiza in the legume family. Chewing its peeled root can feel sweetness, so it is called "licorice". There are 20 species of Glycyrrhiza plants in the world, and 12 species in China. Among them, 3 species of licorice medicinal plants recognized by the national pharmacopoeia are Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Batal., and Glycyrrhiza glabra L. Usually, the licorice we refer to is Glycyrrhiza uralensis Fisch. In traditional medicine, the roots and rhizomes of various licorices are usually used to treat various problems such as asthma, hoarseness, cough, oral ulcers, liver diseases, heartburn, arterial diseases, palpitations, angina pectoris, pain, urinary tract stones, fever, neuralgia (nerve pain), skin and eye diseases, etc.

[0006] Licorice contains many important compounds, including triterpenes, saponins, flavonoids, coumarins, and other phenols, etc. At present, more than 300 kinds of flavonoids and their derivatives have been found in Glycyrrhiza plants, and liquiritin belongs to one of them. Some studies have shown that liquiritin can inhibit the proliferation of bladder cancer cell T24 by increasing the expressions of p21 and PTEN, and has the ability to induce apoptosis. However, the application of liquiritin in preventing and treating colorectal cancer has not been reported yet. Summary of the Invention

[0007] The technical problem to be solved by the present invention is how to propose a new microRNA as a detection or treatment target for colorectal cancer.

[0008] The present invention realizes the solution to the above technical problem through the following technical means:

[0009] The first aspect of the present invention provides the use of miRNA as a target for colorectal cancer detection or treatment, wherein the miRNA is selected from one or more of hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p, hsa-miR-365b-3p, hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p, hsa-miR-514b-5p;

[0010] The nucleotide sequences of hsa-miR-4488 to hsa-miR-514b-5p are shown in SEQ ID No.1 to 10.

[0011] The second aspect of the present invention provides the use of a reagent for measuring the expression level of the above miRNA in the preparation of a colorectal cancer diagnostic reagent. If the expression levels of hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p and / or hsa-miR-365b-3p are up-regulated, or the expression levels of hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p and / or hsa-miR-514b-5p are down-regulated, compared with the expression levels of the corresponding miRNA in the control sample, it indicates that the subject has colorectal cancer or is at risk of developing colorectal cancer.

[0012] The third aspect of the present invention provides a colorectal cancer detection kit, which contains a reagent capable of detecting the expression level of the above miRNA.

[0013] The fourth aspect of the present invention provides the application of liquiritin in the preparation of a drug for regulating the expression level of the above miRNA.

[0014] The fifth aspect of the present invention provides the application of liquiritin in the preparation of a drug for preventing and treating colorectal cancer by regulating the expression level of the above miRNA.

[0015] The sixth aspect of the present invention provides a drug for preventing and treating colorectal cancer by regulating the expression level of the above miRNA, and its active ingredient includes liquiritin.

[0016] Preferably, it further contains a pharmaceutically acceptable carrier.

[0017] Preferably, the pharmaceutically acceptable carrier is selected from one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants.

[0018] Preferably, it is formulated into a pharmaceutically acceptable dosage form.

[0019] Preferably, the dosage form is tablets, pills, ointments, capsules, oral liquids or granules.

[0020] The beneficial effects of the present invention are as follows:

[0021] 1. The present invention provides a novel miRNA, which can be used as a detection or treatment target for colorectal cancer, and can diagnose whether a subject has colorectal cancer or is at risk of developing colorectal cancer by measuring the expression level of this miRNA. It improves the diagnostic efficiency of colorectal cancer and provides a new treatment target for the treatment of colorectal cancer.

[0022] 2. The present invention also provides the application of liquiritin in the preparation of drugs for preventing and treating colorectal cancer by regulating the expression level of the above miRNA or miR-23b, providing a new medical use of liquiritin, having good application prospects and medical value, and providing a new research direction for the treatment of colorectal cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the sequencing flow chart for screening significantly different miRNAs in Example 1 of the present invention;

[0024] Figure 2 It is the graph showing the effect of liquiritin on the viability of SW480 cells detected by MTT in Example 1 of the present invention;

[0025] Figure 3 It is the correlation heat map of samples in group K and group M in Example 1 of the present invention; (Both the X-axis and Y-axis represent each sample, the color represents the correlation coefficient, the darker the color, the higher the correlation, and the lighter the color, the lower the correlation);

[0026] Figure 4 It is the statistical chart of the number of differential miRNAs and the related clustering heat map in Example 1 of the present invention, where A is the statistical chart of the number of differential genes after treatment with liquiritin, B is the statistical chart of the number of differential genes further screened by the screening conditions, and C is the expression level clustering heat map;

[0027] Figure 5 It is the GO analysis graph of the target genes of differential miRNAs in Example 1 of the present invention;

[0028] Figure 6 It is the KEGG analysis graph of the target genes of differential miRNAs in Example 1 of the present invention;

[0029] Figure 7 It is the expression level graph of miR-23b in colorectal cancer tissues of clinical patients in Example 1 of the present invention;

[0030] Figure 8 It is a figure showing the expression level (A) of miR-23b in SW480 cells intervened with different concentrations of liquiritin in Example 1 of the present invention and the results of in situ hybridization assay (B). Detailed implementation manners

[0031] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0032] The test materials and reagents used in the following embodiments can be obtained from commercial channels without special instructions.

[0033] For those not specifying specific techniques or conditions in the embodiments, they can all be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications.

[0034] Example 1:

[0035] 1. Screening of liquiritin concentration

[0036] Take human colorectal cancer cells SW480 in the logarithmic growth phase, adjust the cell density to 1.5×10 4 cells / mL, inoculate into a 96-well plate, 100 μL per well. After culturing for 24 h, wait for the cells to adhere, and then add equal amounts of liquiritin with different mass concentrations (25, 50, 100, 200, 400 μM), and set three replicates for each. After culturing for 24 h and 48 h respectively, add 20 μL of MTT (5 mg / mL) to each well, gently shake evenly, and culture in an incubator at 37 °C and 5% CO 2 for 4 h. Discard the supernatant, and add 150 μL of DMSO to each well. Gently shake the 96-well plate on a shaker for 8 min, and measure the absorbance of each well at 490 nm with an enzyme-labeled instrument.

[0037] 2. Collection of cell samples

[0038] ① Inoculate colorectal cancer SW480 cells that have grown to 80% in the logarithmic growth phase into a six-well plate, with a density of 1.8×10 5 / mL, 2 mL per well, and culture in an incubator at 37 °C and 5% CO 2 for 24 h to allow them to adhere fully.

[0039] ② Pour out the culture medium, and wash away the remaining culture medium and non-adherent cells with PBS. Divide the cells into two groups, the control group (colorectal cancer group) and the treatment group (liquiritin drug treatment groups at concentrations of 50, 100, and 200 μM), add culture medium and culture medium containing liquiritin respectively, and continue to culture for 48 h. Each group has three replicates, which are labeled as K1, K2, K3 and M1, M2, M3 respectively.

[0040] 3. Screen for significantly differentially expressed miRNAs

[0041] Extract RNA from 6 samples for sequencing. HiSeq2000 deep sequencing technology (BGI Shenzhen, Wuhan, China). Construct a small RNA library and a cDNA library. Use high-throughput sequencing technology to sequence miRNAs. Briefly, obtain the original sequencing data using an Illumina HiSeq2000 sequencer (BGI), and then map it to small RNA databases, including siRNA, miRBase, RFAM, siRNA, snoRNA, and other databases for classification and annotation. The entire sequencing process is as Figure 1 shown.

[0042] 4. Bioinformatics analysis

[0043] Use a variety of bioinformatics software (TargetScan, miRanda, and RNAhybrid) to predict the targets of differentially expressed miRNAs. After appropriate statistical analysis with a p-value less than 0.05, further perform KEGG and GO enrichment analysis on the common regions obtained from the three software.

[0044] 5. Confirmation of miRNAs expression

[0045] ① Use qRT-PCR to verify the differentially expressed miRNAs. Measure the concentration and purity of total RNA with a microplate reader. After adjusting the RNA concentration, synthesize cDNA. Finally, use qRT-PCR to verify the gene expression of the differentially expressed genes.

[0046] ② Fix and permeabilize the treated SW480 cells, hybridize the miR-23b with a labeled probe complementary to miR-23b under appropriate conditions, then wash away the unbound probes, and finally take pictures under a fluorescence microscope.

[0047] ③Tumor specimens of surgical patients were collected by surgeons from the Clinical Research Center of Wanbei General Hospital in Anhui Province, and pathological diagnosis was performed by the Pathology Department of the hospital. The samples were collected with the consent of the patient's family members or the direct consent of the patient. We clearly stated to them that the samples obtained would only be used for research and any personal data would be kept confidential. The entire research design was initially submitted to the hospital's ethics committee and sample collection was carried out. Only after obtaining approval of the research design and procedures did further research begin and was promoted. This approval fully followed the guidelines (No. 010) approved by the General Clinical Research Center of Wanbei Coal-Electricity Group General Hospital in Anhui Province on the basis of ensuring compliance with the ethical code of the World Medical Association. Subsequently, qRT-PCR detection of miR-23b was performed on the collected samples.

[0048] Research Results

[0049] 1. Screening of liquiritin concentration

[0050] The results were as Figure 2 shown. After SW480 cells were treated with liquiritin at concentrations of 25, 50, 100, 200, and 400 μM for 24 h and 48 h, the cells were inhibited to varying degrees. At 24 h, compared with the blank control group, the cell viability decreased at 200 and 400 μM, and there were significant differences (P < 0.01). At 48 h, compared with the blank control group, the cell viability decreased at 50, 100, 200, and 400 μM, and there were significant differences (P < 0.05). It is suggested that liquiritin can inhibit the proliferation of SW480 cells in a dose-dependent manner. Considering the effect of liquiritin on SW480 cells and the influence on cell viability, different concentrations of liquiritin (50, 100, 200 μM) were finally selected to treat SW480 cells for 48 h for subsequent experiments.

[0051] 2. Sequencing quality control and sample repeatability analysis

[0052] To explore the mechanism of liquiritin against colorectal cancer, in this study, SW480 cells before and after liquiritin treatment were sequenced. After excluding unqualified sequences, the Total Mapping of group K was 98.95%, 98.96% and 98.23% respectively, while that of group M was 98.34%, 98.3% and 98.38% respectively. In addition, the number of Reads (Mapped reads) that could be aligned to the genome was obtained by matching with the human genetic composition. It was found that there were 45759311 (97.22%), 34078523 (96.98%) and 42310973 (97.38%) reads in group K that could be aligned to the genome, and 46854608 (97.67%), 51990159 (97.79%) and 51361531 (97.70%) alignable reads were obtained from group M respectively. These results indicate that the sequencing data quality is good and suitable for further bioinformatics analysis.

[0053]

[0054] The correlation heatmaps of samples in group K and group M are shown as Figure 3 shown. It can be seen from the figure that the correlation values within group K (among K1, K2, and K3) and within group M (among M1, M2, and M3) are generally very high, basically between 0.98 and 1.0. This indicates that the data consistency between biological replicates or technical replicates within the same group is very high. It shows that the experiment has good repeatability and the sequencing data quality is relatively high.

[0055] 3. Screening of differentially expressed miRNAs

[0056] According to the gene expression levels of each sample, the detected significantly differentially expressed genes were statistically plotted (as Figure 4As shown in the figure, by comparing the differences in the expression levels of miRNAs between the two groups, it was found that after liquiritin treatment, the expression levels of 213 miRNAs in SW480 cells changed significantly, among which the expression levels of 131 miRNAs increased and the expression levels of 82 miRNAs decreased. Through the screening conditions of |log2(foldchange)|≥2, p-value<0.05 and Q<0.01, the differentially expressed miRNAs were further screened, and a total of 75 significantly different miRNAs were identified, 50 were up-regulated and 25 were down-regulated; among them, the top five up-regulated ones were: hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p, hsa-miR-365b-3p; the top five down-regulated ones were: hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p, hsa-miR-514b-5p.

[0057] 4. GO and KEGG functional enrichment analysis of significantly different miRNAs

[0058] (1) GO analysis of target genes of significantly different miRNAs

[0059] GO functional enrichment analysis of the target genes of the identified differentially expressed miRNAs found that there were 30 GO terms involved in biological processes (BP); 35 GO terms related to cellular components (CC); and 41 GO terms related to molecular functions (MF). Taking the GO classification as the abscissa and the percentage of target genes as the ordinate, a GO enrichment bar chart was drawn, which could intuitively show the percentage of the number of target genes annotated to the same GO. For example Figure 5As shown in the figure, the target genes in the BP ontology mainly regulate the G1 / S transition of the mitotic cell cycle, the transforming growth factor receptor signaling pathway, peptidyl-serine phosphorylation, the circadian regulation of gene expression, the activin receptor signaling pathway, phosphatidylinositol dephosphorylation, synaptic vesicle endocytosis, the regulation of cyclin-dependent protein serine / threonine kinase activity, protein ubiquitination, intracellular signal transduction, and transcriptional regulation. In the CC module, the transcription elongation factor complex, cyclin-dependent protein kinase holoenzyme complex, nuclear body, Golgi membrane, and centrosome-enriched target genes are the most numerous. In the MF module, it mainly involves phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity, protein serine / threonine kinase activity, translation factor activity, RNA binding, protein O-acetylglucosaminyltransferase activity, chromatin DNA binding, protein serine / threonine kinase activator activity, transforming growth factor binding, GTPase activity, etc., revealing the possible regulatory sites of liquiritin on SW480 cells.

[0060] (2) KEGG enrichment analysis of significantly differentially expressed miRNA target genes

[0061] Subsequently, hypergeometric tests were applied to perform KEGG enrichment analysis on significantly differentially expressed miRNAs (the results are as Figure 6 shown). It was found that compared with the whole genome background, the target genes of differentially expressed miRNAs were enriched in 86 pathways. The top 20 pathways with the highest significance included cell senescence, the p53 signaling pathway, etc., which are related to various cancers including colorectal cancer.

[0062] 5. Detection of miRNA expression levels in colorectal cancer patient tissues by qRT-PCR

[0063] To further verify the expression levels of differentially expressed miRNAs between colorectal cancer patients and adjacent tissues at the gene level, the qRT-PCR method was used to detect the expression levels of miRNAs in colorectal cancer patients and adjacent tissues. The results are as Figure 7 shown. Compared with adjacent tissues (control group), the expression level of miR-23b in colorectal cancer tissues was significantly upregulated (P < 0.01). The results showed that the change in the expression level of miR-23b was consistent with the high-throughput sequencing results.

[0064] 6. Verification of the expression levels of key miRNAs in vitro cells

[0065] To further verify the effect of liquiritin on the expression levels of miRNAs in colorectal cancer SW480 cells, the qRT-PCR technique was used to detect the expression levels of miR-23b in SW480 cells (control group) and SW480 cells treated with different concentrations (50, 100, 200 μM) of liquiritin. The results are asFigure 8 As shown in Figure A, liquiritin was able to significantly inhibit the expression level of miR-23b in SW480 cells, which was consistent with the results of high-throughput sequencing. In addition, the results of in situ hybridization assays showed that ( Figure 8 Figure B), miR-23b (green) in the liquiritin-treated group was significantly lower than that in the control group. Liquiritin was able to significantly inhibit the expression level of miR-23b in SW480 cells, which was consistent with the results of high-throughput sequencing.

[0066] Research conclusions

[0067] In this study, high-throughput sequencing and bioinformatics analysis were used to study the effects of liquiritin on the miRNA expression profiles in SW480 cells. Correlation analysis was performed on the differential miRNA data. The results showed that the similarity of the expression patterns between samples was relatively high, indicating that the detection experiment was relatively reliable and the sample selection was relatively reasonable, laying a theoretical foundation for subsequent differential miRNA analysis. Then, differential analysis was performed on the gene expression levels between groups in miRNA sequencing, and differential genes were screened using P value, Q value, and |log2FC|. The screening conditions were set as P < 0.05, Q < 0.01, and |log2FC| ≥ 2. A total of 75 differentially expressed miRNAs were identified between the control group and the drug-administered group. Among them, the expression levels of 50 miRNAs increased in the drug-administered group, and the expression levels of 25 miRNAs decreased. The top five up-regulated miRNAs were: hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p, hsa-miR-365b-3p; the top five down-regulated miRNAs were: hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p, hsa-miR-514b-5p (the sequences are shown in Table 1).

[0068] Finally, based on clinical samples and in vitro experiments, techniques such as qRT-PCR were used to analyze and verify the differential miRNAs.

[0069] The research results provide data reference for liquiritin to intervene in miRNAs involved in the development of colorectal cancer, and also provide important experimental basis for subsequent research.

[0070] Table 1

[0071]

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of miRNA as a target for colorectal cancer detection or treatment, characterized in that: The miRNA is selected from one or more of hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p, hsa-miR-365b-3p, hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p, and hsa-miR-514b-5p; The nucleotide sequences of hsa-miR-4488 to hsa-miR-514b-5p are shown in SEQ ID No.1 to 10.

2. Use of a reagent for measuring the expression level of miRNA according to claim 1 in the preparation of a colorectal cancer diagnostic reagent, characterized in that: If hsa-miR-4488, hsa-miR-4525, hsa-miR-3130-3p, hsa-miR-6805-5p and / or hsa-miR-365b-3p are upregulated, or hsa-miR-3529-3p, hsa-miR-1255b-5p, hsa-miR-23b-3p, hsa-miR-652-5p and / or hsa-miR-514b-5p are downregulated compared to the corresponding miRNA expression levels in the control sample, it indicates that the subject has colorectal cancer or is at risk of developing colorectal cancer.

3. A colorectal cancer detection kit, characterized in that: The kit contains a reagent capable of detecting the expression level of the miRNA according to claim 1.

4. Use of liquiritin in the preparation of a drug for regulating the expression of the miRNA described in claim 1.

5. Use of liquiritin in preparing a drug for preventing and treating colorectal cancer by regulating the expression of the miRNA described in claim 1.

6. A drug for preventing and treating colorectal cancer by regulating the expression of the miRNA according to claim 1, characterized in that: Its active ingredients include liquiritin.

7. The drug according to claim 6, characterized in that It also contains a pharmaceutically acceptable carrier.

8. The drug according to claim 7, characterized in that The pharmaceutically acceptable carrier is selected from one or more of a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant, an adsorption carrier and a lubricant.

9. The drug according to claim 6, characterized in that Prepared into pharmaceutically acceptable dosage forms.

10. The drug according to claim 9, characterized in that The dosage form is tablet, pill, paste, capsule, oral liquid or granule.

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