CN107714717A - Application of the polyinosinic acid in the medicine for treating or preventing colitis is prepared - Google Patents
Application of the polyinosinic acid in the medicine for treating or preventing colitis is prepared Download PDFInfo
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- CN107714717A CN107714717A CN201710943160.3A CN201710943160A CN107714717A CN 107714717 A CN107714717 A CN 107714717A CN 201710943160 A CN201710943160 A CN 201710943160A CN 107714717 A CN107714717 A CN 107714717A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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Abstract
The invention discloses application of the polyinosinic acid in the medicine for treating or preventing colitis is prepared, experimental result is shown, the colitis intestinal permeability of DSS inductions is can obviously reduce through polyinosinic acid intervention, mouse Colon mucosa injury degree after intervention substantially mitigates, it is rotten to the corn without obvious congestion and edema and large area, show that polyinosinic acid has good application prospect in terms of colitis is treated and prevented.
Description
Technical field
The present invention relates to colitis field is treated or prevented, treatment or prevention are being prepared more particularly, to polyinosinic acid
Application in the medicine of colitis.
Background technology
Ulcerative colitis (ulcerative colitis, UC) belongs to clinical common inflammatory bowel disease
(inflammatory bowel disease,IBD).Its cause of disease is not still fully aware of, it is considered that with genetic predisposition, immune
Inflammation, gut flora and psychologic factors etc. are relevant.UC mainly invades colon, and pathological manifestations are Injured colonic mucosa, congested
Oedema, erosion, deep layer ulcer are formed, and body of gland is destroyed arrangement disorder, mucous membrane and the visible big amount lymphocyte of submucosa, it is thermophilic in
Property granulocyte infiltration, intestinal permeability increase.Clinical manifestation is stomachache, diarrhoea, mucus pus and blood stool etc., its incidence of disease western countries
It is higher by about 24.3/10 ten thousand, and in recent years, with the raising of living standards of the people and the pollution of environment, the UC incidences of disease and illness
Rate, in the trend that rises appreciably, has a strong impact on minimal invasive treatment and work, carrys out great burden to society, economy-zone in China.Research is aobvious
Show, the key of UC pathogenesis is that immune system is reacted for the abnormal immune of gut flora and food antigens, is caused substantial amounts of
Inflammatory factor is in inflammation damnification caused by enteron aisle localized clusters.Ulcerative colitis still lacks specific treatment means, existing water
The main purpose of poplar acid supplement, glucocorticoid and immunodepressant class drug therapy is to reach clinical remission and avoid complication
Generation, long-term use can bring serious adverse reaction and offer limited effectiveness to patient, therefore find the new treatment means of UC
Become the focus studied both at home and abroad and difficult point.Polyinosinic acid (Poly (I:C it is)) artificial synthesized nucleotides dimer, energy
The generation of efficient inducing interferon, suppress the viral duplication infected, phagocyte activity can also be strengthened in addition and improve machine
Body immunity function, there is antiviral, antitumor, enhancing lymphocyte immunologic function and suppress nucleic acid metabolism.But it is directed to
Poly(I:C) whether can activate body inherent immunity as immunostimulant to react, enteron aisle when strengthening ulcerative colitis
Immune tolerance function, still need further to be studied so as to regulate and control the not normal inflammatory reaction of enteron aisle.
The content of the invention
Polyinosinic acid and exedens knot are to determine to solve the defects of above-mentioned prior art and deficiency, the purpose of the present invention
A kind of interactively between enteritis, there is provided application of polyinosinic acid in the medicine for treating or preventing colitis is prepared.
The technical solution used in the present invention is：
The present invention studies polyinosinic acid and exedens knot using the mouse for inducing acute ulcer colitis as experimental subjects
Correlation between enteritis.
The present invention provides a kind of application of polyinosinic acid in the medicine for treating or preventing colitis is prepared.
Preferably, the colitis is ulcerative colitis.
The beneficial effects of the invention are as follows：
The mouse Colon mucosa injury for inducing acute ulcer colitis is heavier, it is seen that obvious congestion and edema, extensively big face
Long-pending erosion, deep layer ulcer are formed, and body of gland is destroyed arrangement disorder, mucous membrane and the visible big amount lymphocyte of submucosa, it is thermophilic in
Property granulocyte infiltration, through polyinosinic acid injection treatment after mouse mucosa injury degree substantially mitigate, colonic mucosa is complete, portion
Divide visible mild hyperaemia oedema and a small amount of inflammatory cell infiltration, enteritis activity index (DAI) scoring is less than model group, tested
Show that polyinosinic acid has certain preventive and therapeutic action to the colitis of induction.Model group intestinal permeability is higher than dry simultaneously
Pre- group and control group, show that polyinosinic acid intervention can be by reducing colitis intestinal permeability, so as to improve the colon of mouse
Inflammation shape.
Brief description of the drawings
Fig. 1 is the processing procedure figure of intervention group mouse；
Fig. 2 is the changes of weight figure of normal group, model group and intervention group mouse；
Fig. 3 is that normal group, model group and intervention group stool in mice are occulted blood experimental result；
Fig. 4 is the DAI appraisal results of normal group, model group and intervention group mouse；
Fig. 5 is the enteron aisle depth map of normal group, model group and intervention group mouse；
Fig. 6 is the HE coloration results figure (40 ×) of normal group, model group and intervention group mouse；
Fig. 7 is the HE coloration results figure (200 ×) of normal group, model group and intervention group mouse；
Fig. 8 is the intestinal permeability result of normal group, model group and intervention group mouse.
Embodiment
Clearly and completely retouched below with reference to the design of embodiment and accompanying drawing to the present invention and caused technique effect
State, to be completely understood by the purpose of the present invention, feature and effect.Obviously, described embodiment is the part of the present invention
Embodiment, rather than whole embodiments, based on embodiments of the invention, those skilled in the art is not paying creative work
On the premise of the other embodiment that is obtained, belong to the scope of protection of the invention.
Embodiment
Experimental animal and packet
From female, 6-8 week old, C57BL/6 healthy mices 36, Guangdong Medical Lab Animal Center is purchased from.At random
It is divided into three groups, every group 12, is divided into normal group, model group and intervention group, the processing mode of every group of experimental animal is as shown in table 1.
After experiment, the animal 6 after every group of processing is served only for gavage, and LPMC extractions and HE dyes are used for after FITC-Dextran detection permeabilities
Color, 6 are served only for RNA extractions, Protein Extraction, and this experiment uses dextran sulfate sodium (Dextran sulfate sodium
Salt, DSS) (160110) to mouse carry out modeling.
The experimental animal of table 1 is grouped and processing
The preparation of IBD models
Model group and intervention group mouse drinking concentration 5%DSS solution induce acute ulcer colitis, and normal group mouse is just
Often drinking-water.- 3 before DSS raisings, 0,3 day, intraperitoneal injection Poly (I:C) 25ug/.Intervention group induces acute in reference DSS
- the 3 of ulcerative colitis, 0,3 day, intraperitoneal injection Poly (I:C), injection volume is 25ug/, and processing procedure is as shown in Figure 1.
Experimental result
Mouse weight changes
Respectively to the measured body weight of three groups of mouse, its changes of weight is as shown in Fig. 2 normal group mouse stool and urine is normal, body
Again increase, hair is glossy, diet, activity, the state of mind are normal.Compared to the mouse of normal group, model group mouse then exists
Modeling starts mucus loose stools occur 3 days or so, and symptom gradually aggravates, and symptom is even more serious within 5 days or so, it is seen that pus and blood stool, disappears
Symptom, the intervention group mouse such as thin, weight loss, hair are matt, diet significantly reduces, chilly, lazy move occurred at 5 days or so
Mucus loose stools, become thin, the symptom such as weight loss, hair are matt, diet significantly reduces, chilly, lazy move；Pus and blood stool, body weight subtract
Gently, diet significantly reduces, chilly, the result such as lazy move show that obvious colitis occurs in model group, shows that IBD models are successfully built
It is vertical.
Stool in mice is occulted blood experiment：
Occult blood experimental grade criterion：Negative (-)：Do not show blue-green after 3 minutes；Weakly positive (+)：Show in 30~60 seconds
Blueness；Positive (++)：Show blue-green immediately；Strong positive (+++)：Show navy blue immediately.
Fecal occult blood experiment is carried out to three groups of mouse, as a result as shown in figure 3, experimental result display model group shows dark blue immediately
Color shows as strong positive, and intervention group shows that blue-green shows as weakly positive after 30 seconds.As a result show, compared with normal group, mould
Type group stool in mice is occulted blood seriously, and intervention group mouse is passing through Poly (I:C) fecal occult blood symptom is clearly better after Results.
Mouse DAI scores：
The standards of grading of colitis injury severity score:With reference to this experiment, colitis disease activity index (DAI) scoring ginseng
The standard for examining Suthceland LR is carried out, and specific standards of grading are：Shaped particles shape class just, is occulted blood and tests negative scoring 0；Pine
The scattered half graininess class for being not adhere to anus just, negative scoring 1 of such as occulting blood, is occulted blood and tests score positive 2；It is adhered to the liquid of anus
State class just, is occulted blood and tests score positive 3, the visible bloody stool scoring 4 of naked eyes.
Three groups of mouse colitis injury severity scores are assessed, in the DAI that the 1st, 3,5,7 day calculates 3 groups of mouse, knot
Fruit is as shown in Figure 4.The disease activity index scoring (disease activity index, DAI) of model group is significantly higher than control
Group (P<0.01), Poly (I:C) intervention group is substantially less than model and shines group (P<0.01), as a result show, with Body weight loss mould
Type group mouse starts lazy move, loose stools, mucous bloody stool occur in the 3rd~5 day after modeling, and the DAI of intervention group reduces compared with model group,
Intervention group body weight changes compared with model group indifference, and the symptom shape of intervention group mouse, which improves, to be become apparent from, the results showed that Poly (I:C) energy
It is obviously improved the colitis damage of mouse.
Mouse intestinal length change：
In 8d, cervical dislocation puts to death three groups of mouse, rounds a section colon, form is substantially carried out to the colon of three groups of mouse
Observation is learned, as a result as shown in Figure 5.Referring to Fig. 5, experimental result display model group colon shortens, it is seen that obvious congestion and edema, has greatly
Area is rotten to the corn, and intervention group colon oedema is lighter compared with model group, and rotten to the corn area is small, shows Poly (I:C) have obvious
Treat curative effect.
HE coloration results：
Three groups of mouse Colon segmental colonic tissues are taken, PBS is rinsed well, and 24 hours are fixed with formic acid solution.
Dehydration with it is transparent
Dehydration is progressively carried out from low-concentration ethanol to high concentration ethanol.Sample is first placed in the of short duration guarantor of 70% ethanol
Deposit, can both be dehydrated, while also play the role of to continue fixation to sample.When starting film-making, after sample is stayed overnight in 80% ethanol, according to
Secondary immersion volume fraction is 95% ethanol I, II each 2h, 100% ethanol I, II each 1.5h.Dimethylbenzene I, II is transparent twice, respectively
40min/ times.Detect by an unaided eye transparency in clearing process, avoids transparent deficiency or excessive.
Embedding and section
The 30min of paraffin I, the 1h of paraffin II, the 1.5h of paraffin III, (58 DEG C~60 DEG C of embedding wax fusing point, cuts for conventional waxdip embedding
5um thickness wax disk(-sc)s, the interior exhibition piece of 42 DEG C of water-baths, conventional roasting piece.
Dyeing
Dye in haematine ﹣ Yihong (HE)：Baked wax disk(-sc) is dewaxed each 10min through dimethylbenzene I, II, absolute ethyl alcohol, 95%
Progressively rehydration is to 70% ethanol for ethanol, and every grade of 2min, after entering distilled water 3min, brazilwood extract dyeing 15min, 1% hydrochloride alcohol divides
Change 30s, flowing water rinses 20min, eosin stains 2min, crosses water, 95% ethanol 2min, 100% ethanol 2min, and dimethylbenzene I, II is each
5min, neutral gum mounting.
Histological score standard:1. inflammation:Nothing:0 point, slightly:1 point, moderate:2 degree, severe:3 points；2. goblet cell:Not
See disappearance:0 point, disappear:1 point；3. injured depth:Nothing:0 point, submucosa:1 point, muscle layer:2 points, placenta percreta:3 points；4. burst
Ulcer:Nothing:It is 0 point, rotten to the corn:1 point, ulcer:2 points；5. crypt abscess:Nothing:0 point, have:1 point.
Referring to Fig. 6 and Fig. 7, control group mice colonic mucosa is completely continuous, body of gland marshalling, no oedema, ulcer and gruel
Rotten formation.And model group (DSS groups) mouse Colon mucosa injury is heavier, it is seen that obvious congestion and edema, extensive large area erosion,
Deep layer ulcer is formed, and body of gland is destroyed arrangement disorder, mucous membrane and the visible big amount lymphocyte of submucosa, neutrophil cell leaching
Profit.Mucosa injury degree substantially mitigates under intervention group mouse mirror, and colonic mucosa is complete, partially visible mild hyperaemia oedema and a small amount of
Inflammatory cell infiltration, show Poly (I:C) there is obvious treatment curative effect.
Intestinal permeability
Intestinal permeability：According to 0.6mg/g amount (i.e. the mouse dosage of 100g body weight be 60mg FITC-Dextran it is (different
Thiocyanic acid fluorescein-glucose)) gavage FITC-Dextran is carried out to enteritis mouse, gavage takes peripheral blood after 4 hours, uses
FITC-Dextran contents in spectrophotometer (490nm) detection serum.
Intestinal permeability experiment, as a result as shown in figure 8, result is shown, the enteron aisle of model group mouse are carried out to three groups of mouse
Permeability is apparently higher than control group and Poly (I:C) intervention group, intervention group contrast with model group, and intestinal permeability has significance difference
Different p<0.05, show to use Poly (I:C the colitis intestinal permeability that can obviously reduce DSS inductions) is intervened.
Claims (2)
1. application of the polyinosinic acid in the medicine for treating or preventing colitis is prepared.
2. the application of polyinosinic acid according to claim 1, it is characterised in that the colitis is ulcerative colitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710943160.3A CN107714717A (en) | 2017-10-11 | 2017-10-11 | Application of the polyinosinic acid in the medicine for treating or preventing colitis is prepared |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710943160.3A CN107714717A (en) | 2017-10-11 | 2017-10-11 | Application of the polyinosinic acid in the medicine for treating or preventing colitis is prepared |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101474165A (en) * | 2009-01-20 | 2009-07-08 | 南京农业大学 | Polynucleotide microcapsule for treating diseases of livestock and poultry and preparation method thereof |
| CN102307586A (en) * | 2008-12-22 | 2012-01-04 | 都柏林伊丽莎白女皇神学院院长、研究员及专家协会 | Compounds and methods for the treatment of autoimmune and inflammatory disease |
| WO2016161372A1 (en) * | 2015-04-01 | 2016-10-06 | President And Fellows Of Harvard College | Immunoconjugates for programming or reprogramming of cells |
| CN107429232A (en) * | 2015-01-26 | 2017-12-01 | 菲特治疗公司 | The cell and its use and production method that immune regulative improves |
-
2017
- 2017-10-11 CN CN201710943160.3A patent/CN107714717A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307586A (en) * | 2008-12-22 | 2012-01-04 | 都柏林伊丽莎白女皇神学院院长、研究员及专家协会 | Compounds and methods for the treatment of autoimmune and inflammatory disease |
| CN101474165A (en) * | 2009-01-20 | 2009-07-08 | 南京农业大学 | Polynucleotide microcapsule for treating diseases of livestock and poultry and preparation method thereof |
| CN107429232A (en) * | 2015-01-26 | 2017-12-01 | 菲特治疗公司 | The cell and its use and production method that immune regulative improves |
| WO2016161372A1 (en) * | 2015-04-01 | 2016-10-06 | President And Fellows Of Harvard College | Immunoconjugates for programming or reprogramming of cells |
Non-Patent Citations (3)
| Title |
|---|
| 赵红伟等: "Poly I:C对结肠炎小鼠肠黏膜通透性的影响", 《国际消化病杂志》 * |
| 赵红伟等: "Poly I:C对肠炎小鼠肠道黏膜IL-17的影响", 《中国煤炭工业医学杂志》 * |
| 赵红伟等: "Poly IC对急性期溃疡性结肠炎小鼠免疫机制的影响", 《安徽卫生职业技术学院学报》 * |
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Application publication date: 20180223 |
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