CN108210886B - Application of Metrnl in preventing and treating ulcerative colitis - Google Patents
Application of Metrnl in preventing and treating ulcerative colitis Download PDFInfo
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Abstract
The invention relates to application of Metrnl in preventing and treating ulcerative colitis. The method adopts Metrnl intestinal epithelium specific knockout mice and corresponding control wild type mice to prepare DSS-induced ulcerative colitis models, and the results show that: the severity of ulcerative colitis of the Metrnl intestinal epithelium specific knockout mouse is obviously higher than that of a control wild type mouse, and the intestinal mucosa erosion degree of the Metrnl intestinal epithelium specific knockout mouse is obviously higher than that of the control wild type mouse, so that the Metrnl protein can be used as a new effective medicament for preventing and treating ulcerative colitis. The invention provides a new method for preventing and treating ulcerative colitis, and the Metrnl protein is an endogenous protein of a human body and has small possible side effect on the human body, so that the Metrnl protein has high safety as a potential medicament.
Description
Technical Field
The invention relates to the fields of molecular biology and biomedicine, in particular to application of Metrnl in preventing and treating ulcerative colitis.
Background
Inflammatory Bowel Disease (IBD), also known as enteritis, is a group of recurrent Inflammatory Bowel diseases. Inflammatory bowel disease mainly includes two types of Crohn's Disease (CD) and Ulcerative Colitis (UC). In developed countries, the incidence of IBD reaches 1/1000. In china, the total number of cases of inflammatory bowel disease is about 35 ten thousand in the last decade. It is noteworthy that the number of patients increases year by year, with a total number of cases of inflammatory bowel disease that is about more than 24-fold higher than in the first 10 years, with an even more than 15-fold increase in the number of patients with crohn's disease. The ulcerative colitis is mainly located in the mucosa layer of the colon, mainly ulcers mostly affect the rectum and the distal colon, but can be expanded towards the proximal end, so that the important symptoms of the ulcerative colitis are diarrhea, bloody purulent stool, abdominal pain and tenesmus, the disease course is long, the disease condition is not uniform, the ulcerative colitis often repeatedly attacks, the ulcerative colitis is related to the attack of colon cancer, the clinical symptoms are frequently repeated, the cure difficulty is high, and the ulcerative colitis is classified as one of the modern difficult diseases by the world health organization. The medicines for treating ulcerative colitis comprise broad-spectrum anti-inflammatory medicines such as sulfasalazine, adrenocortical hormone and the like, and immunosuppressive agents, immunomodulators and the like, and at present, no specific medicine for treating ulcerative colitis exists.
The Metrnl protein consists of 311 amino acids in total, and has the accession number NM — 001004431.1 in NCBI, annotated as a human glial cell differentiation regulator, meteorin-like molecule. Metrnl protein has been identified in humans, mice, cattle, chickens, xenopus laevis and zebrafish.
Chinese patent document CN200980137344.4 discloses the therapeutic use of Metrnl for preparing a medicament for treating diseases, disorders or damages of the nervous system, and indicates that Metrnl is a secreted growth factor that promotes nerve migration, regeneration and differentiation, and can be used for treating general nervous system diseases, in particular for treating diseases involving brain, brain stem or spinal cord and/or peripheral nerve injury. Chinese patent ZL201310525184.9 discloses application of Metrnl protein in preparation of hypoglycemic drugs or health-care food. Chinese patent ZL201310525181.5 discloses application of Metrnl protein in preparation of blood fat reducing medicines or health-care food.
However, the application of Metrnl protein in preventing and treating ulcerative colitis has not been reported.
Disclosure of Invention
The first purpose of the invention is to provide a new application of Metrnl protein or gene aiming at the defects in the prior art.
The second purpose of the invention is to provide a method for screening potential substances for preventing and treating ulcerative colitis.
In order to achieve the first purpose, the invention adopts the technical scheme that:
application of Metrnl protein or gene or synergist thereof in preparing medicines for preventing and treating ulcerative colitis.
Application of Metrnl protein or gene or synergist thereof in preparing medicines for treating ulcerative colitis.
Further, the medicine improves the degree of intestinal mucosal erosion of ulcerative colitis.
Further, the synergist is selected from an agonist, an up-regulator or a stabilizer and the like.
Furthermore, the amino acid sequence of the Metrnl protein is shown in SEQ ID NO. 1.
Furthermore, the medicine can also comprise a conventional medicinal carrier or a pharmaceutically acceptable auxiliary material, and is prepared into various dosage forms in the form of a medicinal composition. For example, it can be prepared into conventional solid preparation medicines such as tablets, powders or capsules; for injection, it can be prepared into injection. In various preparations, the weight content of the active ingredients is 0.01-99.9%.
In order to achieve the second object, the invention adopts the technical scheme that:
a method for screening potential substances for preventing and treating ulcerative colitis comprises the following steps:
a) contacting a candidate substance with a system comprising a Metrnl protein or gene;
b) and observing the influence of a candidate substance on Metrnl protein or gene expression and activity, wherein if the candidate substance can promote the Metrnl gene expression or improve the Metrnl protein activity, the candidate substance is a potential substance for preventing and treating ulcerative colitis.
The invention has the advantages that:
the method adopts Metrnl intestinal epithelium specific knockout mice and corresponding control wild type mice to prepare DSS-induced ulcerative colitis models, and the results show that: the severity of ulcerative colitis of the Metrnl intestinal epithelium specific knockout mouse is obviously higher than that of a control wild type mouse, and the intestinal mucosa erosion degree of the Metrnl intestinal epithelium specific knockout mouse is obviously higher than that of the control wild type mouse, so that the Metrnl protein can be used as a new and more effective medicament for preventing and treating ulcerative colitis. The invention provides a new method for preventing and treating ulcerative colitis, and the Metrnl protein is an endogenous protein of a human body and has small possible side effect on the human body, so that the Metrnl protein has high safety as a potential medicament.
Drawings
FIG. 1 is a comparison of the change in body weight of two groups of animals induced by DSS.
FIG. 2 is a comparison of overall index composite scores of two groups of animals induced by DSS.
Figure 3 is a picture of the intestinal morphology of two groups of animals without molding.
Figure 4 is a picture of intestinal morphology of two groups of animals after 5 days of DSS modeling.
FIG. 5 is a graph showing the comparison of the degree of intestinal mucosal erosion in two groups of animals after 5 days of DSS induction.
FIG. 6 is a full-length alignment chart of Metrnl amino acid sequences of human, rat and mouse.
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.
Metrnl protein and gene
The full-length alignment of the Metrnl amino acid sequence of human, rat and mouse is shown in FIG. 6. References may be made to: CNS neuroscither.2014apr; 20(4):344-354.
In this context, the Metrnl protein used may be naturally occurring, e.g. it may be isolated and purified from a mammal. Furthermore, the Metrnl protein may also be artificially prepared, e.g., according to conventional genetic engineering techniques. Any suitable Metrnl protein may be suitable for use in the present invention. The Metrnl protein includes a full-length Metrnl protein or a biologically active fragment thereof. Preferably, it may be substantially identical to the amino acid sequence shown in SEQ ID NO. 1.
The amino acid sequence of the Metrnl protein formed by substitution, deletion or addition of one or more amino acid residues is also included in the invention. The Metrnl protein or a biologically active fragment thereof comprises a part of a conservative amino acid substitution sequence, wherein the amino acid substitution sequence does not influence the activity of the Metrnl protein or keeps partial activity of the Metrnl protein. Appropriate substitutions of amino acids are well known in the art and can be readily made and ensure that the biological activity of the known molecule is not altered. These techniques allow one of skill in the art to recognize that, in general, changing a single amino acid in a non-essential amino acid region of a polypeptide does not alter biological activity.
Any biologically active fragment of Metrnl protein can be used in the present invention. In this context, a biologically active fragment of a Metrnl protein is understood to mean a polypeptide which still retains all or part of the function of the full-length Metrnl protein. Typically, the biologically active fragment retains at least 50%, 60% to 99%, or 100% of the activity of the full-length Metrnl protein.
The invention can also be used with modified or improved Metrnl proteins of all or part of the amino acids, e.g., Metrnl proteins that can be modified or improved to promote half-life, efficiency, metabolism, and/or potency of the protein. The modified or modified Metrnl protein may be a conjugate of the Metrnl protein, or it may be a substituted or artificial amino acid. The modified or improved Metrnl protein or gene may be different from the native Metrnl protein or gene in a certain point, but can also dilate blood vessels without causing other adverse reactions or toxicity. That is, any variant that does not affect the biological activity of the Metrnl protein or the biological function of the gene can be used in the present invention.
Metrnl synergist and application thereof
The 'Metrnl synergist' includes an agonist, an up-regulator, a stabilizer and the like, and means any substance which can improve the activity of Metrnl, improve the stability of Metrnl, up-regulate the expression of Metrnl and prolong the effective action time of Metrnl, and the substances can be used in the invention. They may be chemical compounds, small chemical molecules, biological molecules, etc. The biological molecules can be at the nucleic acid level (including DNA and RNA), at the protein level, or can be virus products for up-regulating Metrnl expression, and the like.
Examples
Method and device
1. Animals: metrnl enteroepithelium-specific knockout mice and corresponding control wild-type mice were used, 9-12 mice per group, and the methods for breeding these mice are described in the patent application (application No. 201610458874.0) and published literature (ActaPharmacol sin.2016Aug 22.doi:10.1038/aps.2016.70.[ Epub ahead of print ]).
2. Dextran Sulfate Sodium (DSS) administration: DSS (molecular weight 36000-50000) of MP company is adopted, 3% concentration is configured, and a free drinking mode is adopted for administration, so that a DSS-induced ulcerative colitis model is prepared.
3. And (3) overall index detection: body weight was measured at 10 am every day and the weight change was scored (weight gain and change within 1% was 0 points, change within 1% -5% was 1 points, change within 5% -10% was 2 points, change within 10% -15% was 3 points, change over 15% was 4 points); the mice were observed for fecal and anal bleeding and graded for score (0 for no diarrhea, 2 for loose stool, 4 for loose stool, 0 for no bleeding, 2 for moderate bleeding, 4 for severe bleeding).
4. And (3) morphological detection: tissue sections are stained by HE, observed under a mirror, the degree of each lesion is graded according to three grades of light, medium and heavy, grade III is the heaviest, no obvious lesion is formed, and the lesion is heavier when the grade is higher. Mucosal erosion: the necrosis affecting the superficial mucosa layer is grade I, the affecting whole mucosa layer is grade II, and if there are more than two superficial mucosa necroses, grade III.
Second, result in
1. Before administration of DSS, the mean body weight of both groups of mice was 27.2 g. Under the induction of DSS, the body weight of the mice decreased significantly; the decrease in body weight was more pronounced in Metrnl intestinal epithelium-specific knockout mice compared to control wild-type mice (figure 1,. P < 0.05).
2. Under the induction of DSS, overall index comprehensive scoring was performed based on body weight, stool and anal bleeding, and it was observed that the severity of ulcerative colitis in Metrnl enteroepithelium-specific knockout mice was significantly higher than that in control wild-type mice (figure 2,. sp < 0.05).
3. Morphological examination revealed that no significant abnormalities were found in intestinal morphological examination in both groups of animals without induction of DSS administration (fig. 3); after 5 days of induction with DSS, Metrnl intestinal epithelium-specific knockout mice had significantly higher degree of intestinal mucosal erosion than control wild-type mice (fig. 4, fig. 5,. sp < 0.05).
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
SEQUENCE LISTING
<110> Shanghai Fengjin biomedical science and technology Co., Ltd
Application of <120> Metrnl in preventing and treating ulcerative colitis
<130>/
<160>1
<170>PatentIn version 3.3
<210>1
<211>127
<212>PRT
<213>mouse
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Ser Ala Pro Cys Arg Pro Cys Ser Asp Thr Glu Val Leu Leu Ala Ile
1 5 10 15
Cys Thr Ser Asp Phe Val Val Arg Gly Phe Ile Glu Asp Val Thr His
20 25 30
Val Pro Glu Gln Gln Val Ser Val Ile Tyr Leu Arg Val Asn Arg Leu
35 40 45
His Arg Gln Lys Ser Arg Val Phe Gln Pro Ala Pro Glu Asp Ser Gly
50 55 60
His Trp Leu Gly His Val Thr Thr Leu Leu Gln Cys Gly Val Arg Pro
65 70 75 80
Gly His Gly Glu Phe Leu Phe Thr Gly His Val His Phe Gly Glu Ala
85 90 95
Gln Leu Gly Cys Ala Pro Arg Phe Ser Asp Phe Gln Arg Met Tyr Arg
100 105110
Lys Ala Glu Glu Met Gly Ile Asn Pro Cys Glu Ile Asn Met Glu
115 120 125
Claims (4)
- Application of Metrnl protein or gene in preparation of medicines for improving ulcerative colitis intestinal mucosa erosion degree.
- 2. The use of claim 1, wherein the Metrnl protein has an amino acid sequence shown in SEQ ID No. 1.
- 3. The use according to claim 1, wherein the medicament further comprises a conventional pharmaceutical carrier.
- 4. A method for screening potential substances for improving the degree of intestinal mucosal erosion of ulcerative colitis, which comprises the following steps:a) contacting a candidate substance with a system comprising a Metrnl protein or gene;b) and observing the influence of a candidate substance on Metrnl protein or gene expression and activity, wherein if the candidate substance can promote the Metrnl gene expression or improve the activity of the Metrnl protein, the candidate substance is a potential substance for improving the intestinal mucosal erosion degree of the ulcerative colitis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611128539.0A CN108210886B (en) | 2016-12-09 | 2016-12-09 | Application of Metrnl in preventing and treating ulcerative colitis |
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| CN201611128539.0A CN108210886B (en) | 2016-12-09 | 2016-12-09 | Application of Metrnl in preventing and treating ulcerative colitis |
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| CN108210886A CN108210886A (en) | 2018-06-29 |
| CN108210886B true CN108210886B (en) | 2020-09-08 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115364217A (en) * | 2021-05-18 | 2022-11-22 | 中国人民解放军海军军医大学 | Application of Metrnl protein or gene in maintaining intestinal barrier |
| WO2023138644A1 (en) * | 2022-01-21 | 2023-07-27 | 四川好医生攀西药业有限责任公司 | Polypeptide compound and use thereof in treatment of enteritis |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014116556A2 (en) * | 2013-01-25 | 2014-07-31 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for regulating thermogenesis and muscle inflammation using metrnl and metrn |
| CN104977415A (en) * | 2015-03-09 | 2015-10-14 | 中国人民解放军第二军医大学 | Applications and kit of METRNL protein as inflammatory bowel disease diagnostic serum marker |
| CN106018828A (en) * | 2016-06-19 | 2016-10-12 | 曹帅 | Reagent kit for detecting intestinal diseases |
-
2016
- 2016-12-09 CN CN201611128539.0A patent/CN108210886B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014116556A2 (en) * | 2013-01-25 | 2014-07-31 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for regulating thermogenesis and muscle inflammation using metrnl and metrn |
| CN104977415A (en) * | 2015-03-09 | 2015-10-14 | 中国人民解放军第二军医大学 | Applications and kit of METRNL protein as inflammatory bowel disease diagnostic serum marker |
| CN106018828A (en) * | 2016-06-19 | 2016-10-12 | 曹帅 | Reagent kit for detecting intestinal diseases |
Non-Patent Citations (2)
| Title |
|---|
| " Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides";Zhi-yong LI et al.;《Acta Pharmacologica Sinica》;20160815;第37卷;第1458页右栏第1段-第1464页左栏第2段 * |
| "巨噬细胞极化对溃疡性结肠炎病情发展的影响";Zhi-yong LI et al.;《诊断学理论与实践》;20151225;第14卷(第6期);第569页右栏第5段-第570页右栏第2段 * |
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Effective date of registration: 20220831 Address after: 200433 No. 800 Xiang Yin Road, Shanghai, Yangpu District Patentee after: PLA Naval Military Medical University Address before: Room 1A27, Building 3, No. 500, Songbin Road, Baoshan District, Shanghai, 200940 Patentee before: SHANGHAI FENGJING BIOMEDICAL TECHNOLOGY Co.,Ltd. |