CN108339111A - The medical usage of MG53 albumen - Google Patents
The medical usage of MG53 albumen Download PDFInfo
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- CN108339111A CN108339111A CN201810271994.9A CN201810271994A CN108339111A CN 108339111 A CN108339111 A CN 108339111A CN 201810271994 A CN201810271994 A CN 201810271994A CN 108339111 A CN108339111 A CN 108339111A
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- mouse
- ulcerative colitis
- albumen
- inflammatory bowel
- food
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Classifications
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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
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The present invention relates to a kind of medical usages of MG53 albumen, including recombined human secretion MG53 Lactococcus to be used to prepare the application of drug, pharmaceutical composition, food, health products and food additives of prevention and or treatment inflammation enteropathy etc..The present invention via in vivo and external related experiment confirm, recombined human MG53 albumen is to inflammatory bowel disease, including ulcerative colitis or Crohn disease, with excellent prevention and treatment and have no toxic side effect, can persistently and be effectively applied to prepare prevention and or treatment inflammation enteropathy drug, pharmaceutical composition, food, health products or food additives, these drugs, pharmaceutical composition, food, health products or food additives can be used for preventing and treating inflammatory bowel disease, have major application value.
Description
Technical field
The invention belongs to biomedicine fields, are related to recombined human MG53 albumen in prevention and or treatment inflammation enteropathy
Application.
Background technology
Inflammatory bowel disease (Inflammatory Bowel Disease, IBD) is a kind of autoimmunity of chronic recurrent
Property disease, and by active stage and paracmasis alternately with the characteristics of, be divided into ulcerative colitis (Ulcerative Colitis) and gram
Sick (Crohn's Disease) two types of sieve grace.Ulcerative colitis is a kind of chronic nonspecific colitis disease, with abdomen
It rushes down, abdominal pain and mucopurulent bloody stool are main clinical manifestation.Crohn disease be a kind of chronic granulomatous inflammation, with abdominal pain, diarrhea,
Fistula, anus lesion and different degrees of constitutional symptom are main clinical manifestation.Recently as life style increasingly westernization IBD
Illness rate in China in gradually increasing trend.The pathogenesis of IBD is not fully apparent from yet, cause IBD control rate be in compared with
Low-level causes IBD protracted courses repeatedly, influences patients ' life quality.
The main pathological change of inflammatory bowel disease is the extensive acute and chronic inflammation of intestinal mucosa with ulcer, erosion and bad
Extremely, this pathological change of intestinal mucosa causes barrier of intestinal epithelial cells monolayer to damage.Enterocyte and intercellular tight junction and
It is adhesively joined and together constitutes intestinal epithelial barrier, midgut epithelial cell is the basis for constituting intestinal epithelial barrier.Under pathologic condition,
The necrosis of enterocyte can cause cell permeability to increase so that enteric pathogenic bacteria, endotoxin and macromolecular substances pass through intestines
Road barrier enters in other histoorgans or the circulatory system, induces the generation of immunization inflammatory reaction, while enteron aisle is inflamed it
Afterwards, and the further necrosis of enterocyte can be caused to form vicious circle to amplify inflammatory reaction, eventually lead to IBD
Delay is repeatedly.The necrosis for repairing enterocyte is to prevent and treat the main direction of studying of IBD.
Intestinal epithelial cell membrane rupture is enterocyte necrosis and the main pathological basis that intestinal epithelial barrier destroys.Cell membrane
Repair one of the family member for the tripartite motif that albumen MG53 albumen is made of 477 amino acid, structure packet
It is Zinc finger domain, B-box and coiled-coiled structure respectively from N-terminal to C-terminal containing three structural domains, it is specific expressed in cardiac muscle
With Skeletal Muscle Cell.Previously the study found that after cell membrane is damaged, MG53 can assemble from cytoplasm to cell film transfer
In after birth breakage, after birth notch, repair cell film are closed.It gives in heart and brain kidney model of lung injury and in amyotrophia mouse model
The survival of cell can be promoted by film repair function by giving MG53, haved the function that treat disease, but had no on repairing intestines
Report in chrotoplast.On the other hand, the E3 ubiquitin ligase Ring finger structural domains in MG53 protein structures can play E3
Ubiquitinbond enzyme effect, the ubiquitination of induced insulin receptor 1 (IRS1), accelerates the decaying of IRS1, to which MG53 albumen also may be used
Important adjuster in decaying as albumen.
But due to the particularity of protein, administering mode is restricted, it is therefore necessary to which being made can be in enteron aisle part table
Up to activity, no antigen, method safe to use, convenient to take, convenient for mass producing MG53 albumen, and may be to colon
Damage plays more preferably therapeutic effect.
Invention content
In view of this, one of the objects of the present invention is to provide MG53 as the mark for diagnosing or treating ulcerative colitis
The application of object；The second object of the present invention is to provide a kind of recombined human MG53 albumen and is preparing prevention and or treatment inflammation
The drug of enteropathy or the application in health products；The third object of the present invention is that providing secretion people MG53 Protein reconstitution lactic acid bacterias exists
The drug for preparing prevention inflammatory bowel disease or the application in health products；The fourth object of the present invention is to provide recombined human MG53 eggs
Application in preparing the drug or health products of repairing enterocyte damage in vain.
In order to achieve the above objectives, the present invention provides the following technical solutions：
1, the present invention can detect MG53 contents less than normal mouse, knot in Ulcerative Colitis Model in blood circulation
MG53 contents are higher than normal mouse in intestines, and the above results prove that MG53 can be as the diagnosis biomarker of ulcerative colitis
Object；Targeting serum MG53 can be the potential medicine for treating Traumatic Colon in ulcerative colitis.Therefore
MG53 can be as the application for the marker for diagnosing or treating ulcerative colitis.
2, the present invention utilizes finds in MG53 knock-out mice Ulcerative Colitis Models, and MG53, which knocks out mouse, can be obviously promoted Portugal
The mouse colitis of glycan sodium sulphate induction aggravates mouse weight decline, diarrhea and phenomenon of occulting blood, colon lengths is promoted to shorten,
Reduce colitis mice survival rate.And it recombinates rhMG53 and especially treats ulcerative colitis and Crow in treatment inflammatory bowel disease
There is remarkable result in grace disease.Therefore recombined human MG53 albumen can prepare the drug of prevention and or treatment inflammation enteropathy, group
Close the application in object, health products, food or additive.
Preferably, the inflammatory bowel disease is ulcerative colitis.
Preferably, the inflammatory bowel disease is Crohn disease.
3, rhMG53 albumen and secreting active rhMG53 streptococcus lactis are recombinated respectively by intramuscular injection or oral medication
The mouse colitis (a kind of generally acknowledged ulcerative colitis experimental animal model) that can obviously inhibit dextran sulfate sodium to induce, changes
Kind mouse weight declines, diarrhea and phenomenon of occulting blood, inhibition colon lengths shorten, and improves colitis mice survival rate.The above results
Show that recombinate rhMG53 has good improvement result to colitis in mice, can be used for the prevention of ulcerative colitis.
In addition, recombination rhMG53 albumen and secreting active rhMG53 streptococcus lactis still reduce the induction of 2,4,6- trinitrobenzene sulfonic acid
Mouse colitis (a kind of generally acknowledged Crohn disease experimental animal model), alleviate weight loss phenomenon, increase survival rate, and press down
The shortening of colon lengths processed.The above results show to recombinate rhMG53 albumen and secreting active rhMG53 streptococcus lactis to small
Mouse Crohn disease has good improvement result.Therefore, secretion people MG53 Protein reconstitutions lactic acid bacteria is preparing prevention inflammatory bowel
Application in the drug of disease, composition, health products, food or additive.
Preferably, the inflammatory bowel disease is ulcerative colitis.
Preferably, the inflammatory bowel disease is Crohn disease.
It is furthermore preferred that the secretion people MG53 Protein reconstitution lactic acid bacterias contain the expression vector of expression MG53 genes.
It is furthermore preferred that the expression vector is connected into pNZ8148 carrier polyclone enzyme enzyme sites by MG53 genes.
4, application of the recombined human MG53 albumen in preparing the drug or health products of repairing enterocyte damage.
Above-mentioned recombination rhMG53 albumen can be mixed with pharmaceutically acceptable carrier, be used to prepare prevention ulcerative colitis
With the various preparations of the drug of Crohn disease.Can be sublingual by oral administration, it is transdermal, inject, instil, mucous membrane, spray, infusion, rectum or
Parenterai administration.
The beneficial effects of the present invention are：The invention discloses the medical usages of MG53 and its recombination MG53, are inflammatory
The diagnosing and treating of enteropathy provides new approach and drug, is of great significance to the monitoring of clinical inflammatory enteropathy and treatment.
Description of the drawings
In order to keep the purpose of the present invention, technical solution and advantageous effect clearer, the present invention provides following attached drawing and carries out
Explanation：
Fig. 1 is MG53 contents and the influence (A of positioning in Ulcerative Colitis Model mouse blood and colon：Ulcerative colitis
MG53 influences in scorching mice serum；B：The tissue of ulcerative colitis mouse Colon MG53 positions；C：Ulcerative colitis mouse
MG53 expression quantity in serum).
Fig. 2 is influence (A of the MG53 knock-out mices Ulcerative Colitis Model to weight, activity index and survival rate：Body
Weight；B：Disease activity index；C：Survival rate).
Fig. 3 is recombination rhMG53 albumen to Ulcerative Colitis Model, disease activity index, the influence (A of survival rate：Knot
Colitis model；B：Disease activity index；C：Survival rate).
Fig. 4 is the influence (A for recombinating rhMG53 albumen to Ulcerative Colitis Model mouse Colon length and pathological change：
Mouse Colon length；B：Pathological change).
The mouse colitis model weight and survival rate that Fig. 5 recombination rhMG53 albumen induces 2,4,6- trinitrobenzene sulfonic acid
Influence (A：Weight；B：Survival rate).
The secreting active rhMG53 streptococcus lactis of Fig. 6 is prepared and identification (A：Vector construction；B：PCR is detected；C：
Western blot detections).
Fig. 7 is influence of the secreting active rhMG53 streptococcus lactis to Ulcerative Colitis Model survival rate.
Fig. 8 is influence of the secreting active rhMG53 streptococcus lactis to Ulcerative Colitis Model weight survival rate.
Specific implementation mode
Below in conjunction with attached drawing, the preferred embodiment of the present invention is described in detail.
The preparation of embodiment 1, Ulcerative Colitis Model
It tests all animals and provides male C57BL/6 mouse by great Ping hospitals of army medical university of ground force Experimental Animal Center,
22~25g of weight, the surgical procedure in experimentation meet the regulation of army medical university of ground force experimental animal.It is randomly divided into normal
Group, model group, control group drink common aqua sterilisa, and model group all freely drinks 4% dextran sulfate sodium (DSS) 7 days, and observation is small
Mouse sign changes.Modeling each group mouse orbit blood sampling in the 8th day, room temperature 5000 leave the heart and collect supernatant serum in 10 minutes.Leave and take knot
Intestines extraction tissue samples albumen -80 spends to preserve to be fixed with 4% paraformaldehyde, traditional extraction tissue samples protein quantification, paraffin packet
It buries, be sliced, for detecting MG53 contents and positioning in tissue samples, serum MG53 detection method of content is shown in Publication No. CN
The Chinese patent of 103430023A, the results are shown in Figure 1.As shown in Figure 1, in Ulcerative Colitis Model group mouse blood circulation
MG53 contents are less than normal mouse, and MG53 contents are higher than normal mouse in colonic tissue, and MG53 is enriched in enterocyte.
Embodiment 2, MG53 knock out the preparation of Mouse Ulcerative Colitis Model
Taking the MG53 of Experimental Animal Center SPF grades of raising of great Ping hospitals of army medical university of ground force to knock out mouse, (mouse source is
Fiber crops build outstanding professor and give) 22~25g of weight, the surgical procedure in experimentation meets the rule of army medical university of ground force experimental animal
It is fixed.It is randomly divided into normal group, model group (4%DSS), MG53 knocks out mouse model group (4%DSS).In addition to Normal group,
Remaining 2 groups all freely drink 4% dextran sulfate sodium (DSS) 7 days, then change into and single steam water continuation and freely drink 7 days.It is observed continuously
Mouse weight, disease activity index, the influence of survival rate.
Ulcerative Colitis Model mouse disease activity index uses disease activity index (DAI) accurate quantification inflammatory bowel disease
Severity, standards of grading are：Body mass index (weight does not become 0, and it is 1 point to decline 1%-5%, and it is 2 points to decline 5%-10%,
It is 3 points to decline 10%-15%, and it more than 15% be 4 points to decline), stool scoring (be normally 0, be loosely 2 points, diarrhea 4
Point) and fecal blood scoring (normal 0 point, recessive bleeding is 2 points, and dominant bleeding is 4 points).
DAI scorings=(body mass index+stool scoring+fecal blood scoring)
MG53 knocks out Mouse Ulcerative Colitis Model mouse weight, disease activity index, result such as Fig. 2 institutes of survival rate
Show.As shown in Figure 2, model group mouse disease activity index since the 3rd day significantly increases, and weight loss, diarrhea occurs, and with
It experiment to continue gradually to aggravate, fecal occult blood occurs and have blood in stool, start within the 9th day death, 14 days death rates are 50%.MG53
Mouse Ulcerative Colitis Model mouse disease activity index since the 2nd day is knocked out significantly to increase, with model group it was found that
Disease activity index, weight, diarrhea, fecal occult blood and having blood in stool aggravate；And survival rate started death at the 6th day, and 10 days are dead
It is 90% to die rate.
The Ulcerative Colitis Model that embodiment 3, recombination rhMG53 protein protections DSS are induced
Take C57 22~25g of mouse weight of Experimental Animal Center SPF grades of raising of great Ping hospitals of army medical university of ground force, experiment
Surgical procedure in the process meets the regulation of army medical university of ground force experimental animal.It is randomly divided into normal group, model group (2.5%
DSS), rhMG53 treatment groups.In addition to Normal group, remaining 2 groups are all freely drunk 4% dextran sulfate sodium (DSS) 7 days,
The daily intramuscular injection 1mg/kg albumen of rhMG53 treatment groups (fiber crops build outstanding professor and give) then changes single water that steams into and continues freely to drink
7 days.Mouse weight, disease activity index, the influence of survival rate is observed continuously.
Ulcerative Colitis Model mouse colitis pathological score takes mouse Colon tissue (the 7th after the processing of time point DSS
It) paraffin embedding, slice are carried out, HE dyeing observes its pathology damage degree and scores, scoring is labeled as：Ulcer (0 point of inaction,
Be 1 point less than or equal to 3mm, be 2 points more than 3mm), inflammation (normal be 0 point, is slightly 1 point, and severe is 2 points), granulation tissue
(being not 0 point, promising 1 point), injured depth (normal is 0 point, and submucosa is 1 point, and muscle layer is 2 points, and placenta percreta is 3 points) and
Fibrosis (normal 0 point, slight is 1 point, and severe is 2 points).
The Ulcerative Colitis Model mouse results for recombinating the DSS inductions of rhMG53 protein protections are as shown in Figure 3.It drinks and contains
4%DSS induces C57BL/6 systems mouse, builds chmice acute IBD models, passes through mouse colitis disease activity index, colitis
The overall merits animal model modeling situation such as pathological score standard and survival rate.Compared to negative control group, acute IBD model mices
Weight loss, disease activity index increase (Fig. 3, A and B).RhMG53 (1mg/kg) is given in collaboration, finds and model control group phase
Than rhMG53 processing group mouse weights are not decreased obviously, stool forming, without apparent naked eyes bloody stool.Fig. 3 shows rhMG53 energy
Effectively reduce the acute IBD model mices Body weight disorders activity index and survival rate of DSS inductions.Show MG53 to ulcerative colitis
Scorching model mice has good protective effect.
The colon that Ulcerative Colitis Model mouse Colon length takes mouse Colon tissue to measure from ileocecus to anus is long
Degree, the results are shown in Figure 4.The results show that colon shortens (Fig. 4, A), colonic tissue pathology mucous membrane normal configuration is destroyed, crypts knot
Structure disorder (Fig. 4, B), model group colitis pathological score are apparently higher than control group (Fig. 4, B)；The exedens knot of 4%DSS inductions
Colitis model group survival rate is less than control group.Show successfully inducing mouse acute colitis model.Blank control group is compared, colon
DAI is significantly raised on day 3 for scorching modeling group mouse, shows weight loss, watery stool, the acute middle heavy colitis table of naked eyes bloody stool
It is existing.The above results show that rhMG53 processing group can significantly inhibit the shortening of model mice colon lengths.From Fig. 4 it can also be seen that
DSS model group mouse Colon lesion tissues mainly involve mucous layer and submucosa, and inflammatory cell type is mainly that monokaryon macrophage is thin
Born of the same parents and neutrophil leucocyte.The local mucous membrane layer holostrome necrosis of inflammation critical regions, forms ulcer.RhMG53 (1mg/kg) is significantly reduced
Model mice colonic tissue mononuclear macrophage and neutrophil infiltration, mitigate mucous layer necrosis and crypts disappears.
Embodiment 4, the effect of anti-Crohn disease
BALB/c mouse, male, 6~8 week old, 22~25g of weight, be randomly divided into normal group, model group, rhMG53
(1mg/kg) group.In addition to Normal group, other group of mouse peritoneal injects the anesthesia of 0.5% yellow Jackets, and flexible tubes are small
Heart is inserted into colon (proximal ends 3.5cm anus), and 2%2,4,6- of injection trinitrobenzene sulfonic acid, 100 μ L, mouse vertically overturns 1
Minute.From first day, rhMG53 (1mg/kg) was given in intramuscular injection respectively, normal group and 2,4,6- trinitrobenzene sulfonic acid models
Equivalent solvent 0.5%CMC-Na is given in group injection, continuous 7 days.Mouse weight is weighed daily, and observes diarrhea and situation of having blood in stool.
The results are shown in Figure 5.
If Fig. 5 is shown, 2,4,6- trinitrobenzene sulfonic acid model group mouse weight since the 2nd day significantly reduces, and abdomen occurs
It rushes down, fecal occult blood and situation of having blood in stool, and as experiment continues gradually to aggravate.Mouse can be effectively relieved in rhMG53 (1mg/kg)
Weight loss shows that rhMG53 has good protective effect to Crohn disease model mice.2 pairs of Crohn disease model mices of value
The influence of survival rate.
Fig. 5 also shows, after modeling 7 days, the survival rate only 50% of 2,4,6- trinitrobenzene sulfonic acid model group mouse, and
RhMG53 (1mg/kg) significantly improves the survival rate of colitis mice.
Embodiment 5, the Lactococcus lactis engineering bacteria for establishing excretion people MG53
Experimental strain and plasmid：Food grade lactic acid coccus NZ9000 and secretion expression carrier pNZ8148 is purchased from BioVector
Plasmid vector bacterium cell gene collection.People TRIM72 genes (MG53 protein coding genes), signal peptide and acidophilus breast bar
Bacterium total order is listed in NCBI gene pools and checks in, and primer and the synthesis of people's TRIM72 genes Shanghai Sangon Biotech Company provide, TRIM72 genes
Upstream increases SPusp45 signal peptide sequences, and it is specific as shown in SEQ ID NO.1 that downstream increases His gene orders.Plasmid is small to propose examination
Agent box is Tiangeng Products；Tricine and Nisin is Sigma Products；Coomassie brilliant blue kit is green skies company
Product；MG53 antibody fiber crops build outstanding professor and give.
The connection of secretion expression carrier pNZ8148 and MG53 genes：In connection site such as Fig. 6 shown in A.
1) recombination connection
PNZ8148 plasmid linearization carriers are handled with NcoI-KpnI：
Recombining reaction system：
50 DEG C of water-bath 25min of the soft mixings of total volume 10ul.
2) it converts
10 μ l of connection product are taken to be added 50 μ l competent cells (Tiangeng company), ice bath 30min, 42 DEG C of 90sec, ice immediately
Bathe 2min.Sterile LB culture mediums 37 DEG C of 150 μ l shaken cultivations 1 hour are added.Paving is cultivated in the LB tablets containing chloramphenicol.
3) bacterium colony screening experiment
A. picking stays overnight single bacterium colony in tablet
B. bacterium colony PCR is carried out with TRIM72 primers
C. electroresis appraisal positive colony
D. 4 positive bacterias are randomly choosed to be stayed overnight with 37 DEG C of shaking table cultures of 4ml single tubes
TRIM72-seqF：5’-caccgttctctgcccctg-3’(SEQ ID NO.2)
TRIM72-seqR：5’-ctgtgtcttgaggcgtgc-3’(SEQ ID NO.3)
4) extraction plasmid send survey
Bacterium solution extraction plasmid (Tiangeng company plasmid extraction kit) will be stayed overnight in 3.2.5, and send sequencing, as a result such as SEQ
Shown in ID NO.4.Correct plasmid is obtained, is named as Pnz8148-SPusp45-TRIM72, -80 DEG C save backup.
The preparation of lactic acid bacteria NZ9000 competence and electricity turn：
1) 4ml G/L-SGM17B culture mediums press the inoculum concentration of l%, and 4 μ l Lactococcus NZ9000 of access, 30 DEG C stand training
Support 12h；
2) bacterium solution for obtaining the 1st step is all added in the fresh G/L-SGM17B culture mediums of 80ml, culture to OD600=
0.3-0.35；
3) 4 DEG C, 5000g centrifuges 20min, abandons supernatant；
4) use the glycerine of 80ml0.5M sucrose/10% that precipitation is resuspended, 4 DEG C, 6000g centrifuges 20min, abandons supernatant；
5) 40ml 0.5M sucrose/10% glycerine/0.5mM EDTA is used to be resuspended precipitation, after the pre- 15min of ice, 4 DEG C, 6000g from
Heart 20min, abandons supernatant：
6) use the glycerine of 20ml0.5M sucrose/10% that precipitation is resuspended, 4 DEG C, 6000g centrifuges 20min, abandons supernatant；
7) it uses 80ml 0.5M sucrose/l0% glycerine that precipitation is resuspended, is distributed into 40 μ l/ pipes, -80 DEG C of preservations.
Recon electricity turns：
1) electric revolving cup is placed in and is pre-chilled on ice, and ultraviolet-sterilization in superclean bench.
2) (40 μ l/ pipes) competence is taken-managed from -80 DEG C of refrigerators, is placed in and is thawed on ice.Matter is taken out from -20 DEG C of refrigerators
Grain is placed in thaw on ice.
3) Pnz8148 connection MG53 products are added in 40ul competence, after flicking, by mixture as 10min in ice.
4) mixture of the 3rd step is transferred in the electric revolving cup of precooling, it is ensured that mixture, and must not in the bottom of electric revolving cup
There is bubble.
5) condensed water for removing electric revolving cup outer wall, electric revolving cup is put into electric shock instrument.
6) voltage of electric shock instrument is set as 2000V, the electric shock time is set as 4ms.
7) electric shock is primary.
Recon is recovered and PCR identifications：
1) after shocking by electricity, electric revolving cup is quickly taken out from electric shock tank.
2) GM17MC that lml ice baths are added regenerates liquid culture medium.
3) after gently using liquid-transfering gun mixing, ice bath 5min then moves to 1.5mlEP pipes, 30 DEG C of stationary culture 1-1.5h.
4) 10 μ l are taken, 100 μ l, 900 μ l are coated on BCP tablets, and 30 DEG C, anaerobism stands l-2d.
5) it is fallen in 3mlGM17 fluid nutrient mediums from the single bacterium for choosing flavescence on BCP tablets, 30 DEG C of stationary cultures are stayed overnight；
6) preparation of bacterium solution template DNA:Take 200 μ l bacterium solutions in the sterile EP centrifuge tubes of 1.5ml, 12,000 leave the heart, abandon
Culture medium is removed, and the sterile ultra-pure waters of 100 μ l is added, thalline is resuspended.Then above-mentioned EP pipes are placed in -80 DEG C of placement 15min, boiling water
15min is heated in bath, thalline is made fully to crack, and 12000 leave heart 3min, and supernatant is template DNA；
7) take 1 μ l bacterium solutions DNA as template, using MG53 as each 0.3 μ l of upstream and downstream primer, primer sequence draws for upstream
Object：5’-caccgttctctgcccctg-3’(SEQ ID NO.2)；Downstream primer：5’-ctgtgtcttgaggcgtgc-3’
(SEQ ID NO.3), molecular weight：250bp.10 × PCR buffer solutions, 2 μ l, dNTP solution, 2 μ l and 0.2 μ l of Taq DNA polymerase
Enter cycle after being denaturalized 5min, circulating temperature and time are 94 DEG C, and it is 20 μ l that 30s, which adds water to total volume,；Through 94 DEG C 55 DEG C 74 DEG C,
25 cycles, then re-extend 10min for 72 DEG C；Product is detected through 1.0% agarose gel electrophoresis, as a result as shown in B in Fig. 6.
Destination protein is expressed：
1) it chooses PCR in 7 and is accredited as positive recon, by 5% inoculum concentration, the glycerol stock of 150 μ l is inoculated into 3ml
In GM17 fluid nutrient mediums, 30 DEG C of stationary culture 48h；
2) 2ml bacterium solutions 12000rpm is taken, 4 DEG C, centrifuges 5min；
3) the centrifugation supernatant of 2ml is taken, 200 μ l 150% (w/v) trichloroacetic acids (TCA) are added, after 4 DEG C are protected from light standing 12h,
12000rpm, centrifuges 10min by 4 DEG C, and the acetone that precipitation lml is pre-chilled is resuspended；12000rpm, centrifuges 10min by 4 DEG C, and precipitation is used
The acetone of 1ml precoolings is resuspended；12000rpm, centrifuges 10min by 4 DEG C, carefully draws supernatant with the liquid-transfering gun of 1ml, retains precipitation,
After natural air drying, the ddH of 100 μ l is added2O and 20 μ l loading loading buffer (6 ×), boiling water boiling 10min,
12000rpm, room temperature, centrifuge 10min after it is spare；
4) 500 μ l ddH of thalline2O is resuspended, 12000rpm, room temperature, and supernatant, 200 μ l pH of thalline are abandoned after centrifuging 5min
(8.0) phosphate buffer (PBS) is resuspended, and 5 μ l lysozymes (50mg/ml) are added, and 20 μ l SDS are added in 37 DEG C of water-bath 1.5h
Solution (20%) boils 10min in boiling water, and 50 μ l loading loading buffer (6 ×), boiling water boiling 10min are added,
12000rpm, room temperature, centrifuge 10min after it is spare.
5) equivalent total protein will be taken after electrophoresis, to be gone on nitrocellulose filter in 10%SDS polyacrylamide gels.Room
Temperature is lower to close nonspecific binding site with 5% skimmed milk power, then by film and the MG53 antibody (dilution 1 of antibody:800)4
DEG C be incubated overnight.TBST washes film 3 times, and goat-anti rabbit secondary antibody (dilution 1 is added:10000) it is incubated at room temperature 1h.TBST washes film 3 times
Afterwards, using the Odys-sey infrared imaging system imaging system scanning analysis of LI-COR companies of the U.S..As a result, it has been found that NZ9000-
There are the expression of MG53 in TRIM72 bacterium solutions, and the expression (Fig. 6, C) in NZ9000-VC without MG53.
Embodiment 6, excretion people MG53 Lactococcus protection DSS induction Ulcerative Colitis Model and TNBS induction
The influence of anti-Crohn disease
Take C57 22~25g of mouse weight of Experimental Animal Center SPF grades of raising of great Ping hospitals of army medical university of ground force, experiment
Surgical procedure in the process meets the regulation of army medical university of ground force experimental animal.It is randomly divided into normal group, model group (4%DSS),
The Lactococcus lactis treatment group of excretion people MG53, Lactococcus lactis control group.Except Normal group and Lactococcus lactis control group
Outside, 4% dextran sulfate sodium (DSS) is all freely drunk 7 days for remaining 2 groups, the Lactococcus lactis treatment group of excretion people MG53 is daily
Gavage.Single water that steams then is changed into continue freely to drink 7 days.The influence of mouse survival rate is observed continuously, the results are shown in Figure 7.Knot
Fruit shows that the Lactococcus lactis of excretion people MG53 can improve Crohn disease model mice survival rate.
Embodiment 7, excretion people MG53 Lactococcus lactis protection TNBS induction anti-Crohn disease influence
Take C57 22~25g of mouse weight of Experimental Animal Center SPF grades of raising of great Ping hospitals of army medical university of ground force, experiment
Surgical procedure in the process meets the regulation of army medical university of ground force experimental animal.It is randomly divided into normal group, model group (TNBS), outside
Secrete the Lactococcus lactis treatment group of people MG53, Lactococcus lactis control group.As shown in figure 8,2,4,6- trinitrobenzene sulfonic acid models
Group mouse weight since the 2nd day significantly reduces, and diarrhea, fecal occult blood occurs and situation of having blood in stool, and as experiment continues
Gradually aggravate.Mouse weight mitigation can be effectively relieved in the Lactococcus lactis treatment group of excretion people MG53, improve Crohn disease model
The influence of mouse survival rate.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Sequence table
<110>Third affiliated hospital of army medical university of ground force of the Chinese People's Liberation Army（Aseptic sursery research institute）
<120>The medical usage of MG53 albumen
<160> 4
<170> SIPOSequenceListing 1.0
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gcgcccggcc tcctgcacca ggagctgtcc tgcccgctgt gcctgcagct gttcgacgcg 120
cccgtgacag ccgagtgcgg ccacagtttc tgccgcgcct gcctaggccg cgtggccggg 180
gagccggcgg cggatggcac cgttctctgc ccctgctgcc aggcccccac gcggccgcag 240
gcactcagca ccaacctgca gctggcgcgc ctggtggagg ggctggccca ggtgccgcag 300
ggccactgcg aggagcacct ggacccgctg agcatctact gcgagcagga ccgcgcgctg 360
gtgtgcggag tgtgcgcctc actcggctcg caccgcggtc atcgcctcct gcctgccgcc 420
gaggcccacg cacgcctcaa gacacagctg ccacagcaga aactgcagct gcaggaggca 480
tgcatgcgca aggagaagag tgtggctgtg ctggagcatc agctggtgga ggtggaggag 540
acagtgcgtc agttccgggg ggccgtgggg gagcagctgg gcaagatgcg ggtgttcctg 600
gctgcactgg agggctcctt ggaccgcgag gcagagcgtg tacggggtga ggcaggggtc 660
gccttgcgcc gggagctggg gagcctgaac tcttacctgg agcagctgcg gcagatggag 720
aaggtcctgg aggaggtggc ggacaagccg cagactgagt tcctcatgaa atactgcctg 780
gtgaccagca ggctgcagaa gatcctggca gagtctcccc cacccgcccg tctggacatc 840
cagctgccaa ttatctcaga tgacttcaaa ttccaggtgt ggaggaagat gttccgggct 900
ctgatgccag cgctggagga gctgaccttt gacccgagct ctgcgcaccc gagcctggtg 960
gtgtcttcct ctggccgccg cgtggagtgc tcggagcaga aggcgccgcc ggccggggag 1020
gacccgcgcc agttcgacaa ggcggtggcg gtggtggcgc accagcagct ctccgagggc 1080
gagcactact gggaggtgga tgttggcgac aagccgcgct gggcgctggg cgtgatcgcg 1140
gccgaggccc cccgccgcgg gcgcctgcac gcggtgccct cgcagggcct gtggctgctg 1200
gggctgcgcg agggcaagat cctggaggca cacgtggagg ccaaggagcc gcgcgctctg 1260
cgcagccccg agaggcggcc cacgcgcatt ggcctttacc tgagcttcgg cgacggcgtc 1320
ctctccttct acgatgccag cgacgccgac gcgctcgtgc cgctttttgc cttccacgag 1380
cgcctgccca ggcccgtgta ccccttcttc gacgtgtgct ggcacgacaa gggcaagaat 1440
gcccagccgc tgctgctcgt gggtcccgaa ggcgccgagg cccaccacca ccatcaccac 1500
tgaggtacc 1509
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caccgttctc tgcccctg 18
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<213>Artificial sequence (Artificial Sequence)
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ctgtgtcttg aggcgtgc 18
<210> 4
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<212> DNA
<213>Artificial sequence (Artificial Sequence)
<400> 4
agatctagtc ttataactat actgacaata gaaacattaa caaatctaaa acagtcttaa 60
ttctatcttg agaaagtatt ggtaataata ttattgtcga taacgcgagc ataataaacg 120
gctctgatta aattctgaag tttgttagat acaatgattt cgttcgaagg aactacaaaa 180
taaattataa ggaggcactc acctaggatg aaaaaaaaga ttatctcagc tattttaatg 240
tctacagtga tactttcggc tgcgcccggc ctcctgcacc aggagctgtc ctgcccgctg 300
tgcctgcagc tgttcgacgc gcccgtgaca gccgagtgcg gccacagttt ctgccgcgcc 360
tgcctaggcc gcgtggccgg ggagccggcg gcggatggca ccgttctctg cccctgctgc 420
caggccccca cgcggccgca ggcactcagc accaacctgc agctggcgcg cctggtggag 480
gggctggccc aggtgccgca gggccactgc gaggagcacc tggacccgct gagcatctac 540
tgcgagcagg accgcgcgct ggtgtgcgga gtgtgcgcct cactcggctc gcaccgcggt 600
catcgcctcc tgcctgccgc cgaggcccac gcacgcctca agacacagct gccacagcag 660
aaactgcagc tgcaggaggc atgcatgcgc aaggagaaga gtgtggctgt gctggagcat 720
cagctggtgg aggtggagga gacagtgcgt cagttccggg gggccgtggg ggagcagctg 780
ggcaagatgc gggtgttcct ggctgcactg gagggctcct tggaccgcga ggcagagcgt 840
gtacggggtg aggcaggggt cgccttgcgc cgggagctgg ggagcctgaa ctcttacctg 900
gagcagctgc ggcagatgga gaaggtcctg gaggaggtgg cggacaagcc gcagactgag 960
ttcctcatga aatactgcct ggtgaccagc aggctgcaga agatcctggc agagtctccc 1020
ccacccgccc gtctggacat ccagctgcca attatctcag atgacttcaa attccaggtg 1080
tggaggaaga tgttccgggc tctgatgcca gcgctggagg agctgacctt tgacccgagc 1140
tctgcgcacc cgagcctggt ggtgtcttcc tctggccgcc gcgtggagtg ctcggagcag 1200
aaggcgccgc cggccgggga ggacccgcgc cagttcgaca aggcggtggc ggtggtggcg 1260
caccagcagc tctccgaggg cgagcactac tgggaggtgg atgttggcga caagccgcgc 1320
tgggcgctgg gcgtgatcgc ggccgaggcc ccccgccgcg ggcgcctgca cgcggtgccc 1380
tcgcagggcc tgtggctgct ggggctgcgc gagggcaaga tcctggaggc acacgtggag 1440
gccaaggagc cgcgcgctct gcgcagcccc gagaggcggc ccacgcgcat tggcctttac 1500
ctgagcttcg gcgacggcgt cctctccttc tacgatgcca gcgacgccga cgcgctcgtg 1560
ccgctttttg ccttccacga gcgcctgccc aggcccgtgt accccttctt cgacgtgtgc 1620
tggcacgaca agggcaagaa tgcccagccg ctgctgctcg tgggtcccga aggcgccgag 1680
gcccaccacc accatcacca ctgaggtacc actagttcta gagagctcaa gctttctttg 1740
aaccaaaatt agaaaaccaa ggcttgaaac gttcaattga aatggcaatt aaacaaatta 1800
cagcacgtgt tgctttgatt gatagccaaa aagcagcagt tgataaagca attactgata 1860
ttgctgaaaa attgtaattt ataaataaaa atcacctttt agaggtggtt tttttattta 1920
taaattattc gtttgatttc gctttcgata gaacaatcaa atcgtttctg agacgtttta 1980
gcgtttattt cgtttagtta tcggcataat cgttaaaaca ggcgttatcg tagcgtaaaa 2040
gcccttgagc gtagcgtggc tttgcagcga agatgttgtc tgttagatta tgaaagccga 2100
tgactgaatg aaataataag cgcagcgtcc ttctatttcg gttggaggag gctcaaggga 2160
gtttgaggga atgaaattcc ctcatgggtt tgattttaaa aattgcttgc aattttgccg 2220
agcggtagcg ctggaaaatt tttgaaaaaa atttggaatt tggaaaaaaa tggggggaaa 2280
ggaagcgaat tttgcttccg tactacgacc ccccattaag tgccgagtgc caatttttgt 2340
gccaaaaacg ctctatccca actggctcaa gggtttgagg ggtttttcaa tcgccaacga 2400
atcgccaacg ttttcgccaa cgttttttat aaatctatat ttaagtagct ttatttttgt 2460
ttttatgatt acaaagtgat acactaattt tataaaatta tttgattgga gttttttaaa 2520
tggtgatttc agaatcgaaa aaaagagtta tgatttctct gacaaaagag caagataaaa 2580
aattaacaga tatggcgaaa caaaaagatt tttcaaaatc tgcggttgcg gcgttagcta 2640
tagaagaata tgcaagaaag gaatcagaac aaaaaaaata agcgaaagct cgcgttttta 2700
gaaggatacg agttttcgct acttgttttt gataaggtaa ttatatcatg gctattaaaa 2760
atactaaagc tagaaatttt ggatttttat tatatcctga ctcaattcct aatgattgga 2820
aagaaaaatt agagagtttg ggcgtatcta tggctgtcag tcctttacac gatatggacg 2880
aaaaaaaaga taaagataca tggaatagta gtgatgttat acgaaatgga aagcactata 2940
aaaaaccaca ctatcacgtt atatatattg cacgaaatcc tgtaacaata gaaagcgtta 3000
ggaacaagat taagcgaaaa ttggggaata gttcagttgc tcatgttgag atacttgatt 3060
atatcaaagg ttcatatgaa tatttgactc atgaatcaaa ggacgctatt gctaagaata 3120
aacatatata cgacaaaaaa gatattttga acattaatga ttttgatatt gaccgctata 3180
taacacttga tgaaagccaa aaaagagaat tgaagaattt acttttagat atagtggatg 3240
actataattt ggtaaataca aaagatttaa tggcttttat tcgccttagg ggagcggagt 3300
ttggaatttt aaatacgaat gatgtaaaag atattgtttc aacaaactct agcgccttta 3360
gattatggtt tgagggcaat tatcagtgtg gatatagagc aagttatgca aaggttcttg 3420
atgctgaaac gggggaaata aaatgacaaa caaagaaaaa gagttatttg ctgaaaatga 3480
ggaattaaaa aaagaaatta aggacttaaa agagcgtatt gaaagataca gagaaatgga 3540
agttgaatta agtacaacaa tagatttatt gagaggaggg attattgaat aaataaaagc 3600
ccccctgacg aaagtcgacg gcaatagtta cccttattat caagataaga aagaaaagga 3660
tttttcgcta cgctcaaatc ctttaaaaaa acacaaaaga ccacattttt taatgtggtc 3720
ttttattctt caactaaagc acccattagt tcaacaaacg aaaattggat aaagtgggat 3780
atttttaaaa tatatattta tgttacagta atattgactt ttaaaaaagg attgattcta 3840
atgaagaaag cagacaagta agcctcctaa attcacttta gataaaaatt taggaggcat 3900
atcaaatgaa ctttaataaa attgatttag acaattggaa gagaaaagag atatttaatc 3960
attatttgaa ccaacaaacg acttttagta taaccacaga aattgatatt agtgttttat 4020
accgaaacat aaaacaagaa ggatataaat tttaccctgc atttattttc ttagtgacaa 4080
gggtgataaa ctcaaataca gcttttagaa ctggttacaa tagcgacgga gagttaggtt 4140
attgggataa gttagagcca ctttatacaa tttttgatgg tgtatctaaa acattctctg 4200
gtatttggac tcctgtaaag aatgacttca aagagtttta tgatttatac ctttctgatg 4260
tagagaaata taatggttcg gggaaattgt ttcccaaaac acctatacct gaaaatgctt 4320
tttctctttc tattattcct tggacttcat ttactgggtt taacttaaat atcaataata 4380
atagtaatta ccttctaccc attattacag caggaaaatt cattaataaa ggtaattcaa 4440
tatatttacc gctatcttta caggtacatc attctgtttg tgatggttat catgctggat 4500
tgtttatgaa ctctattcag gaattgtcag ataggcctaa tgactggctt ttataatatg 4560
agataatgcc gactgtactt tttacagtcg gttttctaat gtcactaacc tgccccgtta 4620
gttgaagaag gtttttatat tacagctcc 4649
Claims (10)
- Applications of the 1.MG53 as the marker for diagnosing or treating ulcerative colitis.
- 2. recombined human MG53 albumen prepare the drug of prevention and or treatment inflammation enteropathy, composition, health products, food or Application in additive.
- 3. application according to claim 1, it is characterised in that：The inflammatory bowel disease is ulcerative colitis.
- 4. application according to claim 1, it is characterised in that：The inflammatory bowel disease is Crohn disease.
- 5. secrete people MG53 Protein reconstitutions lactic acid bacteria prepare the prevention drug of inflammatory bowel disease, composition, health products, food or Application in additive.
- 6. application according to claim 4, it is characterised in that：The inflammatory bowel disease is ulcerative colitis.
- 7. application according to claim 5, it is characterised in that：The inflammatory bowel disease is Crohn disease.
- 8. application according to any one of claim 4 to 6, it is characterised in that：The secretion people MG53 Protein reconstitution lactic acid Bacterium contains the expression vector of expression MG53 genes.
- 9. application according to claim 7, it is characterised in that：The expression vector is connected into pNZ8148 by MG53 genes and carries At body polyclone enzyme enzyme site.
- 10. recombined human MG53 albumen repairs drug, composition, health products, food or the addition of enterocyte damage preparing Application in agent.
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| CN201810271994.9A CN108339111B (en) | 2018-03-29 | 2018-03-29 | Medical application of MG53 protein |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810271994.9A CN108339111B (en) | 2018-03-29 | 2018-03-29 | Medical application of MG53 protein |
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| CN108339111B CN108339111B (en) | 2022-06-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4058044A4 (en) * | 2019-11-11 | 2023-05-17 | Ohio State Innovation Foundation | Treatment for inflammatory bowel disease and radiation-induced intestinal injury |
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| CN108339111B (en) | 2022-06-03 |
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