CN113599505A - Application of collagen in preparation of medicine for treating/preventing high myopia - Google Patents
Application of collagen in preparation of medicine for treating/preventing high myopia Download PDFInfo
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- CN113599505A CN113599505A CN202110826451.0A CN202110826451A CN113599505A CN 113599505 A CN113599505 A CN 113599505A CN 202110826451 A CN202110826451 A CN 202110826451A CN 113599505 A CN113599505 A CN 113599505A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6887—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids from muscle, cartilage or connective tissue
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/16—Ophthalmology
Abstract
The invention discloses an application of Collagen in preparing a medicament for treating/preventing high myopia, wherein the medicament targets Collagen alpha-1(XII) chain protein. The corneal protein difference of people with different myopia degrees of human eyes is explored from the biomechanical angle, corneal difference protein related to biomechanics in the people with high, medium and low myopia is found, the obvious difference of the expression level of Collagen alpha-1(XII) chain protein in the corneal stroma of the middle and high myopia people and the low myopia people is found, and an important theoretical basis is provided for the Collagen alpha-1(XII) chain protein serving as a drug target point for treating/preventing medium and high myopia.
Description
Technical Field
The invention relates to the technical field of biological medicines. More specifically, the invention relates to an application of collagen in preparing a medicament for treating/preventing high myopia.
Background
Myopia is a global high incidence disease, and high myopia is one of the main causes of low vision of young people in China. High myopia, also known as progressive myopia, is another eye disease completely different from simple myopia, and with the increase of age, the anterior-posterior axis of the eye is continuously lengthened, the posterior segment of the eyeball is enlarged, accompanied by degenerative change of fundus choroid retina, the vision is difficult to correct to normal after wearing glasses, and the vision gradually declines, so that serious disorder can occur.
At present, the mechanism of the occurrence and development of myopia is unknown, so that no effective means for preventing and treating the high myopia in the mechanism is available.
Disclosure of Invention
The invention aims to provide application of collagen serving as a target point in preparing a medicament for treating/preventing high myopia.
It is still another object of the present invention to provide a medicament for the treatment/prevention of moderate to high myopia.
It is still another object of the present invention to provide a pharmaceutical composition for the treatment/prevention of middle and high myopia.
Still another object of the present invention is to provide a use of collagen in preparing a detection reagent for high myopia.
To achieve the objects and other advantages in accordance with the present invention, there is provided a use of a Collagen for the preparation of a medicament for the treatment/prevention of middle-high myopia, the medicament targeting Collagen alpha-1(XII) chain protein.
Preferably, the Collagen is applied to the preparation of a medicament for treating/preventing high myopia, and the medicament targets Collagen alpha-1(XII) chain protein in corneal stroma.
Preferably, the Collagen is applied to the preparation of a medicament for treating/preventing high myopia, and the medicament can regulate the expression amount of Collagen alpha-1(XII) chain protein.
Preferably, the Collagen is applied to the preparation of a medicament for treating/preventing high myopia, and the medicament can improve the expression amount of Collagen alpha-1(XII) chain protein.
Preferably, the Collagen is applied to the preparation of a medicament for treating/preventing high myopia, and the medicament can improve the expression amount of Collagen alpha-1(XII) chain protein in corneal stroma.
The invention also provides a medicament for treating/preventing the middle-high myopia, which can improve the expression level of Collagen alpha-1(XII) chain protein.
The invention also provides a pharmaceutical composition for treating/preventing the middle-high myopia, which comprises a Collagen alpha-1(XII) chain protein promoter and a targeting agent, wherein the Collagen alpha-1(XII) chain protein promoter is loaded on the targeting agent, and the targeting agent targets the Collagen alpha-1(XII) chain protein.
The invention also provides an application of the Collagen in preparing a detection reagent for medium-high myopia, wherein the detection reagent takes Collagen alpha-1(XII) chain protein as a biomarker for medium-high myopia. .
The invention at least comprises the following beneficial effects:
the invention explores the corneal protein difference of people with different myopia degrees from the biomechanical angle, finds out the corneal difference protein related to the biomechanics in the high, medium and low myopia people, finds that the expression level of Collagen Collagen alpha-1(XII) chain protein in the corneal stroma of the medium and high myopia people and the low myopia people has obvious difference, and the relative expression quantity of the Collagen alpha-1(XII) chain protein of the low myopia people is obviously higher than that of the medium myopia people and the high myopia people; the results show that the Collagen alpha-1(XII) chain can be used as an important target for treating/preventing high myopia, the Collagen alpha-1(XII) chain can improve the corneal biomechanical characteristics of a myopia patient, adjust the content of the Collagen alpha-1(XII) chain, improve the refractive condition of the patient, improve the corneal biomechanical properties, and further achieve the effect of treating/preventing high myopia (slowing the myopia progression), and the discovery has important significance for the development of myopia medicines in the medical field; the invention provides an important reference basis for early diagnosis, prognosis judgment and early intervention treatment of the high myopia in the future, and has a larger practical clinical value.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a graph showing the difference in TMT analysis of the amount of Collagen alpha-1(XII) chain protein in three myopic groups in accordance with the present invention;
FIG. 2 is a graph showing the difference of PRM verified Collagen alpha-1(XII) chain protein content in three groups of myopic population.
Detailed Description
The present invention is further described in detail below with reference to the drawings and examples so that those skilled in the art can practice the invention with reference to the description.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.
< Experimental example 1>
Screening of differentially expressed proteins Using TMT labelling technology
(1) Protein extraction and peptide fragment enzymolysis: selecting 9 cases of patients with high, medium and low myopia from an eye hospital of Tianjin in 2019 to 2019 in 7 months with SMILE (approved by ethical committee of the eye hospital of Tianjin), collecting corneal stroma taken out of the SMLE surgery, extracting proteins in corneal stroma samples of each case by an SDT (4% (w/v) SDS, 100mM Tris/HCl pH7.6, 0.1M DTT) cracking method, then carrying out protein quantification by a BCA method, carrying out trypsin enzymolysis on proteins in each sample by a filtered protein quantification (FASP) method, and carrying out peptide fragment quantification (OD 2800).
(2) TMT marking: each sample was labeled with 100. mu.g of the peptide fragment according to the protocol of the Thermo TMT labeling kit.
(3) And (3) peptide fragment grading: the labeled peptides of each group (High myopia group, moderate myopia group, and low myopia group) were mixed in equal amounts and fractionated using a High pH Reversed-Phase Peptide Fractionation kit. Firstly, acetonitrile and 0.1% trifluoroacetic acid (TFA) are adopted for column balance, then a mixed labeled peptide fragment sample is loaded, pure water is added, then low-speed centrifugation is carried out for desalination treatment, finally high-pH acetonitrile solution with sequentially increased concentration is adopted for gradient elution of column-bound peptide fragments, each eluted peptide fragment sample is dried in vacuum, then 12 mu L of 0.1% FA is used for redissolving the freeze-dried sample, and OD280 is used for determining the concentration of the peptide fragment.
(4) Data acquisition: each peptide fragment fraction sample was separated using a nanoliter flow rate HPLC liquid phase system Eacy nLC. The buffer solution A was 0.1% formic acid aqueous solution, and the solution B was 0.1% formic acid acetonitrile aqueous solution (acetonitrile: 84%). The column was equilibrated with 95% solution A, and the sample was applied to a loading column (Thermo Scientific Acclaim PepMap100, 100. mu.m. by 2cm, NanoViperC18) by an autosampler and separated by an analytical column (Thermo Scientific EASY column, 10cm, ID 75. mu.m, 3. mu.m, C18-A2) at a flow rate of 300 nL/min.
After chromatographic separation, a sample is subjected to mass spectrometry by using a Q-active mass spectrometer, wherein the detection mode is that the scanning range of positive ions and parent ions is 300-1800m/z, the primary mass spectrum resolution is 70,000at 200m/z, the AGC (automatic gain control) target is 1e6, the Maximum IT is 50ms, and the Dynamic exclusion time (Dynamic exclusion) is 60.0 s. The mass-to-charge ratio of the polypeptide and the polypeptide fragments was collected as follows: 20 fragment patterns (MS2 scan) were collected after each full scan (full scan), MS2Activation Type was HCD, lsolation window was 2m/z, secondary prime resolution was 17500at 200m/z (TMT 6-plex) or 35,000at 200m/z (TMT 10-plex), Normalized color Energy was 30ev, and Underfill was 0.1%.
(5) Protein identification and quantitative analysis: the RAW data of mass spectrometry is RAW file, and the library checking identification and quantitative analysis are carried out by using Mascot2.2 and Proteome discovery 1.4. The relevant parameters and specifications are shown in table 1:
TABLE 1
(6) Screening differential proteins: adopting Persesus software to carry out one-factor variance analysis, and screening out the differential expression protein according to the screening standard that the difference multiple of the proteins among groups is more than 1.2 times and p is less than 0.05, specifically: screening a differential expression protein set 1 of a high myopia group and a low myopia group and a differential expression protein set 2 of a medium myopia group and a low myopia group according to the screening standard, and screening a union set of the differential expression protein set 1 and the differential expression protein set 2 to obtain a target differential expression protein; and performing bioinformatics analysis on the identified differential expression protein, and screening candidate differential expression protein with potential research prospect.
TMT test results show that (as shown in figure 1), the average expression value of Collagen alpha-1(XII) chain protein in the low myopia group is 1.12, the average expression value in the medium myopia group is 1.01, and the average expression value in the high myopia group is 0.89; the expression of Collagen alpha-1(XII) chain protein in the high myopia group and the medium myopia group is obviously different from that in the low myopia group, and the expression of Collagen alpha-1(XII) chain protein in the low myopia group is obviously higher than that in the medium myopia group and the high myopia group, so the Collagen alpha-1(XII) chain protein can be selected as a potential difference protein.
The expression difference of the candidate protein in the cornea of the myopic eye with different degrees is verified in a targeted mode by using a Parallel Reaction Monitoring (PRM) technology. All subjects had no other corneal disease and did not affect corneal stromal protein outcome analysis. The study was approved by ethics committee of the ophthalmic hospital Tianjin. Screening the proteins differentially expressed in the cornea stroma of high myopia population, moderate myopia population and low myopia population.
< example 2>
The PRM relative quantitative calculation is applied to verify the potential difference protein (Collagen alpha-1(XII) chain protein) screened as above
(1) Selecting 9 cases of high, medium and low myopia patients (approved by ethical committee of eye hospitals in Tianjin City) who carry out SMILE operation from eye hospitals in 2019 to 7 months in 2019, collecting corneal stroma taken out in the SMLE operation, and carrying out protein extraction and trypsin enzymolysis on the corneal stroma of each case to obtain peptide segments;
(2) selecting one random sample from each group, respectively taking a proper amount of peptide fragments after enzymolysis, mixing the peptide fragments into a Pool sample in an equal amount, removing 1 mu g of Pool mixed peptide fragments, and performing chromatographic separation by adopting an HPLC system, wherein the buffer solution A is 0.1% formic acid aqueous solution, the buffer solution B is 0.1% formic acid acetonitrile aqueous solution (acetonitrile is 84%), a chromatographic column is balanced by 95% A solution, and the sample is subjected to gradient separation by a chromatographic analysis column, and the liquid phase separation gradient is as follows: 0 min-2 min, linear gradient of B liquid from 5% to 10%, 2 min-45 min, linear gradient of B liquid from 10% to 30%; 45 min-55 min, linear gradient of B liquid from 30% to 100%; 55 min to 60min, maintaining the linear gradient of the B liquid at 100 percent;
(3) the Pool samples were separated by HPLC and analyzed by mass spectrometry using Q-exact HF mass spectrometer (Thermo Scientific). Analysis duration: 60min, detection mode: positive ion, parent ion scan range: 300-1800m/z, first-order mass spectral resolution: 60,000atm/z 200, AGC target: 3e6, primary Maximum IT: 50 ms. Peptide secondary mass spectrometry was acquired by triggering acquisition of 20 secondary mass spectra (MS2 scan) after each full scan (full scan), secondary mass resolution: 15,000at m/z200, AGC target: 1e5, secondary Maximum IT: 50MS, MS2Activation Type: HCD, Isolation window:1.6Th, Normalized fusion energy: 27. performing MS2 scanning on a candidate peptide fragment of the target protein by LC-MS/MS in a targeted shotgun scanning mode;
(4) and screening the identified target peptide fragments according to the result of qualitative protein analysis, reserving credible peptide fragments, and introducing the credible peptide fragments suitable for PRM analysis into mass spectrum analysis software Xcaliibur for PRM method setting. 10ug of mixed peptide fragment was injected each time and chromatographically separated using HPLC system. Buffer solution: the solution A was 0.1% formic acid aqueous solution, and the solution B was 0.1% formic acid acetonitrile aqueous solution (acetonitrile: 84%). The column was equilibrated with 95% of solution A. The sample was subjected to gradient separation by chromatography column at a flow rate of 5 ul/min. The liquid phase separation gradient is as follows, the linear gradient of the liquid B is from 5 percent to 10 percent in 0min to 2 min, the linear gradient of the liquid B is from 10 percent to 30 percent in 2 min to 45 min; 45 min-55 min, linear gradient of B liquid from 30% to 100%; 55 min to 60min, maintaining the linear gradient of the B liquid at 100 percent;
(5) the peptide fragments after HPLC separation were subjected to PRM mass spectrometry using a Q-exact HF mass spectrometer (Thermo Scientific). Analysis duration: 60min, detection mode: a positive ion. Primary mass spectrum scanning range: 300-1800m/z, mass spectral resolution: 60,000(m/z 200), AGC target: 3e6, Maximum IT: 200 ms. After each one-stage MS scan (full MS scan), 20 PRM scans (MS2 scans) were acquired according to the Inclusion list, Isolation window:1.6Th, mass spectral resolution: 30,000(m/z 200), AGC target: 3e6, Maximum IT: 120MS, MS2Activation Type: HCD, Normalizedcollision energy: 27;
(6) and (3) carrying out three times of repeated PRM detection on the Pool mixed sample, finally carrying out data analysis on a PRM original file by adopting software Skyline 3.7.0, and quantifying the target protein and the target peptide fragment.
The PRM verification result shows that: as shown in fig. 2, Collagen alpha-1(XII) chain protein expressed mean 2.32 in the low myopia group, 1.19 in the medium myopia group, 1.36 in the high myopia group, 0.514 in the medium myopia/low myopia group, 0.003 in p, 0.586 in the high myopia/low myopia group, 0.038 in p, 1.139 in the high myopia/medium myopia group, and 0.603 in p.
And comparing the PRM result with the TMT result, and showing that the PRM verification result is consistent with the relative quantitative result trend of the TMT. The expression of Collagen alpha-1(XII) chain protein in the high myopia group and the moderate myopia group was significantly less than that in the low myopia group.
The experiments prove that the Collagen alpha-1(XII) chain can be used as a target point to prepare the medicine for treating/preventing the middle-high myopia.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.
Claims (8)
1. The application of the Collagen in preparing the medicine for treating/preventing the middle-high myopia is characterized in that the medicine targets the Collagen alpha-1(XII) chain protein.
2. Use of Collagen according to claim 1 for the preparation of a medicament for the treatment/prevention of high myopia, wherein said medicament targets the Collagen alpha-1(XII) chain protein in the corneal stroma.
3. Use of the Collagen of claim 1 for the preparation of a medicament for the treatment/prevention of high myopia, wherein said medicament is capable of modulating the amount of Collagen alpha-1(XII) chain protein expressed.
4. The use of Collagen according to claim 1 for the preparation of a medicament for the treatment/prevention of high myopia, wherein said medicament is capable of increasing the amount of Collagen alpha-1(XII) chain protein expressed.
5. Use of Collagen according to claim 1 for the preparation of a medicament for the treatment/prevention of high myopia, wherein said medicament is capable of increasing the amount of Collagen alpha-1(XII) chain protein expressed in the corneal stroma.
6. A medicament for treating/preventing high myopia, which is characterized in that the medicament can increase the expression level of Collagen alpha-1(XII) chain protein.
7. The pharmaceutical composition for treating/preventing the middle-high myopia is characterized by comprising a Collagen alpha-1(XII) chain protein promoter and a targeting agent, wherein the Collagen alpha-1(XII) chain protein promoter is loaded on the targeting agent, and the targeting agent targets the Collagen alpha-1(XII) chain protein.
8. The application of Collagen in preparing a detection reagent for medium-high myopia is characterized in that the detection reagent takes Collagen alpha-1(XII) chain protein as a biomarker for medium-high myopia.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016178586A2 (en) * | 2015-05-01 | 2016-11-10 | Auckland Uniservices Limited | Collagen compositions and preparation and uses thereof |
| US20180055913A1 (en) * | 2014-07-29 | 2018-03-01 | Vanderbilt University | Recombinant collagen iv surrogates and uses thereof |
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2021
- 2021-07-21 CN CN202110826451.0A patent/CN113599505A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180055913A1 (en) * | 2014-07-29 | 2018-03-01 | Vanderbilt University | Recombinant collagen iv surrogates and uses thereof |
| WO2016178586A2 (en) * | 2015-05-01 | 2016-11-10 | Auckland Uniservices Limited | Collagen compositions and preparation and uses thereof |
Non-Patent Citations (4)
| Title |
|---|
| ALEX GENTLE等: "Collagen Gene Expression and the Altered Accumulation of Scleral Collagen during the Development of High Myopia", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 19 * |
| 王丽娜;张丰菊;李宏;朱廷准;刘佳;: "正常中国人非高度近视眼前极和后极部巩膜内层组织中Ⅰ型胶原蛋白的表达水平", 眼视光学杂志, no. 04 * |
| 赵桂秋等: "胶原在圆锥角膜中的表达", 青岛大学医学院学报, vol. 39, no. 1 * |
| 赵燕燕等: "巩膜胶原交联疗法治疗进行性近视的研究进展", 中华眼科杂志 * |
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