CN108210886A - Applications of the Metrnl in ulcerative colitis is prevented - Google Patents
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- CN108210886A CN108210886A CN201611128539.0A CN201611128539A CN108210886A CN 108210886 A CN108210886 A CN 108210886A CN 201611128539 A CN201611128539 A CN 201611128539A CN 108210886 A CN108210886 A CN 108210886A
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Abstract
The present invention relates to applications of the Metrnl in ulcerative colitis is prevented.The present invention is using Metrnl enteric epithelium specific knockdown mouse and compares wild-type mice accordingly, prepares the Ulcerative Colitis Model of DSS inductions, as a result shows：Metrnl enteric epithelium specific knockdown colitis in mice severity is significantly higher than control wild-type mice, Metrnl enteric epithelium specific knockdown mouse mucosal erosion degree is significantly higher than control wild-type mice, shows the effective drug that Metrnl albumen can be new as prevention ulcerative colitis.The present invention provides a kind of new method, and since Metrnl albumen is a kind of endogenous protein of human body in itself for prevention ulcerative colitis, the possible side effect very little to human body, therefore the safety as potential drug is very high.
Description
Technical field
The present invention relates to molecular biology and biomedicine field, specifically, being related to Metrnl is preventing exedens knot
Application in enteritis.
Background technology
Inflammatory bowel disease (Inflammatory Bowel Disease, IBD) is also known as enteritis, is the inflammation of one group of recurrent exerbation
Disease property intestines problem.Inflammatory bowel disease mainly includes Crohn disease (Crohn ' s disease, CD) and ulcerative colitis
(ulcerative colitis, UC) two classes.In developed country, the incidence of IBD has reached 1/1000.In China, last decade
Between total case of inflammatory bowel disease be about 350,000.It is worth noting that, the disease number of patients is increasing year by year, with preceding 10 years phases
Than, the total case load of inflammatory bowel disease increases about more than 24 times, wherein, cd patient quantity increases even more than 15 times.It bursts
Ulcer colitis lesion is predominantly located at the mucous layer of colon, and based on ulcer, involves rectum and lower distal colon more, but can be near
End extension, so that throughout entire colon, important symptom has diarrhea, pus and blood stool, abdominal pain and tenesmus, and the disease course of disease is long, sick
Feelings weight differs, normal recurrent exerbation, related with the morbidity of colon cancer, clinically often appears as recurrent exerbation and cures difficulty
Greatly, one of modern difficult treatment is classified as by the World Health Organization.The drug for treating ulcerative colitis includes salicylazosulfapyridine, kidney
The broad spectrum antiphlogistics drugs and immunosupress, immunomodulator etc. such as upper gland cortin there is no treatment ulcerative colitis at present
Specific medicament.
Metrnl albumen is made of altogether 311 amino acid, and the number of registration in NCBI is NM_001004431.1, annotates and is
Neuroglia cell of human breaks up regulatory factor meteorin sample molecules.Metrnl albumen is in people, mouse, ox, chicken, African melon
It identifies and in toad and zebra fish.
Chinese patent literature CN200980137344.4 discloses the therapeutical uses of Metrnl, is used to prepare treatment nerve
Disease, illness or the drug of damage of system, and point out that Metrnl is secretory growth factor, neuronal migration, regeneration can be promoted
And differentiation, available for treating general the nervous system disease, particularly it is related to brain, brain stem or spinal cord and/or outer for treating
The disease of all neurotrosises.Chinese patent ZL201310525184.9, disclose Metrnl albumen prepare hypoglycemic drug or
Application in health food.Chinese patent ZL201310525181.5, disclose Metrnl albumen prepare blood lipid-lowering medicine or
Application in health food.
However, the application about Metrnl albumen in ulcerative colitis is prevented, has not been reported.
Invention content
First purpose of the present invention is that the new use of Metrnl albumen or gene is provided for deficiency of the prior art
On the way.
Second object of the present invention is to provide a kind of method for the potential substance for screening prevention ulcerative colitis.
To realize above-mentioned first purpose, the technical solution adopted by the present invention is that：
The application of Metrnl albumen or gene or their synergist in the drug for preparing prevention ulcerative colitis.
The application of Metrnl albumen or gene or their synergist in the drug for preparing treatment ulcerative colitis.
Further, the drug improves ulcerative colitis mucosal erosion degree.
Further, the synergist is selected from agonist, upper adjustment or stabilizer etc..
Further, the amino acid sequence of the Metrnl albumen is as shown in SEQ ID NO.1.
Further, the drug also may include conventional pharmaceutical carrier or pharmaceutically acceptable auxiliary material, with pharmaceutical composition
The form of object is prepared into various dosage forms.Such as conventional solid pharmaceutical preparation drug such as tablet, pulvis or capsule can be prepared into
Deng；During for injecting, parenteral solution can be prepared into.In various preparations, the weight content of active constituent for 0.01%~
99.9%.
To realize above-mentioned second purpose, the technical solution adopted by the present invention is that：
A kind of method for the potential substance for screening prevention ulcerative colitis, includes the following steps：
A) candidate substances are contacted with the system of albumen containing Metrnl or gene；
B) influence of the observation candidate substances for Metrnl albumen or gene expression and activity, wherein, if the candidate
Matter can promote Metrnl gene expressions or improve Metrnl protein actives, then the candidate substances are prevention ulcerative colitis
Potential substance.
The invention has the advantages that：
The present invention is using Metrnl enteric epithelium specific knockdown mouse and compares wild-type mice accordingly, prepares DSS and lures
The Ulcerative Colitis Model led, as a result shows：Metrnl enteric epithelium specific knockdown colitis in mice severity
It is significantly higher than control wild-type mice, it is wild that Metrnl enteric epithelium specific knockdown mouse mucosal erosion degree is significantly higher than control
Raw type mouse shows the more effective drug that Metrnl albumen can be new as prevention ulcerative colitis.The present invention bursts for prevention
Ulcer colitis provides a kind of new method, and since Metrnl albumen is a kind of endogenous protein of human body in itself, right
The possible side effect very little of human body, therefore the safety as potential drug is very high.
Description of the drawings
Attached drawing 1 induces the comparison of lower two groups of the weight of animals variation for DSS.
Attached drawing 2 induces the comparison of lower two groups of animals ulcerative colitis global index comprehensive score for DSS.
Intestinal Tract Morphology picture when attached drawing 3 is two groups of animal not modelings.
Attached drawing 4 is two groups of animal DSS modelings, 5 days rear intestinal morphology pictures.
The comparison of two groups of animal mucosal erosion degree after attached drawing 5 induces 5 days for DSS.
Attached drawing 6 is people, rat, mouse Metrnl amino acid sequence overall length comparison charts.
Specific embodiment
The invention will be further elucidated with reference to specific embodiments.It should be understood that these embodiments are merely to illustrate this hair
It is bright rather than limit the scope of the invention.In addition, it should also be understood that, after the content of the invention recorded has been read, art technology
Personnel can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Fixed range.
Metrnl albumen and gene
People, rat, mouse Metrnl amino acid sequence overall length comparison charts are shown in Fig. 6.It can refer to document：CNS Neurosci
Ther.2014Apr；20(4):344-354.
Herein, Metrnl albumen used can be naturally occurring, for example it can be moved by isolating and purifying from lactation
Object.In addition, the Metrnl albumen can also be prepared manually, for example it is prepared according to conventional gene engineering technology.
Any suitable Metrnl albumen may be applicable to the present invention.The Metrnl albumen includes Metrnl albumen or its life of overall length
Object active fragment.It preferably, can be essentially identical with the amino acid sequence shown in SEQ ID NO.1.
The amino acid sequence of Metrnl albumen formed by the substitution of one or more amino acid residues, missing or addition
Row are also included in the present invention.Metrnl albumen or its bioactive fragment include the alternative sequence of a part of conserved amino acid,
The sequence that the amino acid substitutes has no effect on its activity or to remain its amount of activated.Appropriate amino acid of replacing is in the art
Known technology, the technology can easily be carried out and ensure not change the bioactivity of known molecular.These skills
Art recognizes those skilled in the art, in general, a kind of polypeptide nonessential amino acid area change single amino acids not
Bioactivity can be changed.
The bioactive fragment of any Metrnl albumen can be applied in the present invention.Herein, Metrnl eggs
The meaning of white bioactive fragment refers to a kind of polypeptide, still can keep all or part of work(of the Metrnl albumen of overall length
Energy.Under normal conditions, the bioactive fragment at least keeps 50%, 60% to 99% or 100% overall length Metrnl
The activity of albumen.
The present invention can also use the Metrnl albumen of all or part of amino acid through modifying or improveing, for example, can be with
The Metrnl albumen modified or improved to promote the effect of half-life period, validity, metabolism and/or albumen.The warp
Cross the conjugate that the Metrnl albumen modified or improved can be a kind of Metrnl albumen or the ammonia that it can be substituted or artificial
Base acid.It is described by modification or improvement Metrnl albumen or gene can have with natural Metrnl albumen or gene it is certain not
It is same, but blood vessel can be also expanded, and other adverse reactions or toxicity will not be brought.That is, any do not influence Metrnl
The version of the bioactivity of albumen or perhaps the biological function of gene can be used in the present invention.
Metrnl synergist and application thereof
" the Metrnl synergist " includes agonist, upper adjustment, stabilizer etc., refers to any improve Metrnl
Activity, improve Metrnl stability, raise Metrnl expression, increase Metrnl effective acting times substance, these
Substance is used equally for the present invention.They can be compound, chemical small molecule, biomolecule etc..The biomolecule can be with
Nucleic acid level (including DNA, RNA), protein level or viral product of up-regulation Metrnl expression etc..
Embodiment
First, method
1. animal：Wild-type mice is compareed using Metrnl enteric epithelium specific knockdown mouse and accordingly, every group 9~12
Example mouse, the breeding method of these mouse refer to patent applied for (application number 201610458874.0) and deliver document (Acta
Pharmacol Sin.2016Aug 22.doi:10.1038/aps.2016.70.[Epub ahead ofprint])。
2. dextran sulfate sodium (dextran sulfate sodium, DSS) is administered：Using the DSS (molecular weight of MP companies
36000-50000), 3% concentration is configured, is administered using free drinking way, prepares the Ulcerative Colitis Model of DSS inductions.
3. global index detects：Measured body weight is measured for 10 o'clock of every morning, and (the weight that scored changes of weight
It is 0 point to increase and change within 1%, and it is 1 point to change in 1%-5%, and it is 2 points to change in 5%-10%, is changed in 10%-
15% is 3 points, and it is 4 points to change more than 15%)；Stool in mice and archorrhagia situation are observed, using classification marking (not diarrhea
It is 0, it is 2 that loose stools, which does not account for anus, and it is 4 that loose stools, which accounts for anus,；Not bleeding is 0, and moderate bleeding is 2, severe bleeding 4).
4. morphologic detection：Histotomy is dyed using HE, Microscopic observation, each lesion degree according to it is light, in, weight three tier structure
Marking, III level to be most heavy ,-be without apparent lesion, the higher lesion that scores is heavier.Mucosal erosion：Necrosis involves mucous membrane shallow-layer for I
Grade, it is II grades to involve holostrome, if it is III level to have the mucous membrane shallow-layer necrosis more than at two.
2nd, result
1st, before to DSS, two groups of mouse weight mean values are all 27.2g.Under DSS inductions, mouse weight is decreased obviously；With it is right
It is compared according to wild-type mice, more obvious (Fig. 1, the * P of weight loss of Metrnl enteric epithelium specific knockdown mouse<0.05).
2nd, under DSS inductions, global index comprehensive score is carried out according to weight, excrement and archorrhagia situation, is observed
Metrnl enteric epithelium specific knockdown colitis in mice severity is significantly higher than control wild-type mice (Fig. 2, * P<
0.05)。
3rd, morphologic detection is shown, in the case where not giving DSS inductions, two groups of animal intestinal tract morphologic detections are not found
Apparent abnormal (Fig. 3)；After giving DSS and inducing 5 days, Metrnl enteric epithelium specific knockdown mouse mucosal erosion degree is notable
Higher than control wild-type mice (Fig. 4, Fig. 5, * P<0.05).
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, under the premise of the method for the present invention is not departed from, can also make several improvement and supplement, these are improved and supplement also should be regarded as
Protection scope of the present invention.
SEQUENCE LISTING
<110>Upper sea wind strength biological medicine Science and Technology Ltd.
<120>Applications of the Metrnl in ulcerative colitis is prevented
<130> /
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 127
<212> PRT
<213> mouse
<400> 1
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
100 105 110
Lys Ala Glu Glu Met Gly Ile Asn Pro Cys Glu Ile Asn Met Glu
115 120 125
Claims (7)
- The application of 1.Metrnl albumen or gene or their synergist in the drug for preparing prevention ulcerative colitis.
- The application of 2.Metrnl albumen or gene or their synergist in the drug for preparing treatment ulcerative colitis.
- 3. application according to claim 2, which is characterized in that the drug improves ulcerative colitis mucosal erosion journey Degree.
- 4. according to the application described in claim 1-3, which is characterized in that the synergist is selected from agonist, upper adjustment or steady Determine agent.
- 5. according to the application described in claim 1-3, which is characterized in that the amino acid sequence of the Metrnl albumen such as SEQ ID Shown in NO.1.
- 6. according to the application described in claim 1-2, which is characterized in that the drug also may include conventional pharmaceutical carrier.
- A kind of 7. method for the potential substance for screening prevention ulcerative colitis, which is characterized in that include the following steps：A) candidate substances are contacted with the system of albumen containing Metrnl or gene；B) influence of the observation candidate substances for Metrnl albumen or gene expression and activity, wherein, if the candidate substances energy Enough promote Metrnl gene expressions or improve Metrnl protein actives, then the candidate substances are to prevent diving for ulcerative colitis In substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611128539.0A CN108210886B (en) | 2016-12-09 | 2016-12-09 | Application of Metrnl in preventing and treating ulcerative colitis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611128539.0A CN108210886B (en) | 2016-12-09 | 2016-12-09 | Application of Metrnl in preventing and treating ulcerative colitis |
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| CN108210886A true CN108210886A (en) | 2018-06-29 |
| CN108210886B CN108210886B (en) | 2020-09-08 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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|---|---|---|---|---|
| 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 |
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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 |
|---|
| ZHI-YONG LI ET AL.: "" Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides"", 《ACTA PHARMACOLOGICA SINICA》 * |
| ZHI-YONG LI ET AL.: ""巨噬细胞极化对溃疡性结肠炎病情发展的影响"", 《诊断学理论与实践》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| CN108210886B (en) | 2020-09-08 |
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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. |