CN111265653A - Application of atrial natriuretic peptide in preparation of medicine for treating inflammatory bowel disease - Google Patents
Application of atrial natriuretic peptide in preparation of medicine for treating inflammatory bowel disease Download PDFInfo
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- CN111265653A CN111265653A CN202010083380.5A CN202010083380A CN111265653A CN 111265653 A CN111265653 A CN 111265653A CN 202010083380 A CN202010083380 A CN 202010083380A CN 111265653 A CN111265653 A CN 111265653A
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- inflammatory bowel
- natriuretic peptide
- bowel disease
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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
- A61K38/22—Hormones
- A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention relates to application of atrial natriuretic peptide in preparing a medicament for treating inflammatory bowel disease. The use of atrial natriuretic peptide in the manufacture of a medicament for the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease comprises ulcerative colitis, Crohn's disease, indeterminate colitis; the beneficial effects are that: has no adverse effect on normal cells and no toxic or side effect, and can effectively relieve colitis inflammation of colon and reduce secretion of colon tissue inflammatory cytokines.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to application of atrial natriuretic peptide in preparing an anti-inflammatory drug.
Background
Inflammatory Bowel Disease (IBD) mainly includes Ulcerative Colitis (UC) and Crohn's Disease (CD), and its breakthrough in treatment is not separate from the development of new drugs.
Major therapeutic agents for IBD include 5 aminosalicylic acid, glucocorticoids, immunosuppressive agents and biologics, which induce and maintain disease remission through immunomodulation. In recent years, drug development mainly focuses on biological agents and small molecule targeted drugs, but researches on hormone drugs are relatively lacking. Although glucocorticoid can induce and relieve rapidly and is low in price, due to the fact that physiological functions such as growth, development and metabolism are regulated at the same time, side effects are more after long-term use, gastrointestinal hemorrhage, osteoporosis, metabolic disorder and the like are easily caused, and the glucocorticoid cannot be used for maintaining and treating IBD.
However, the strong anti-inflammatory effect shown by the hormone drugs suggests that we can search for a new breakthrough from the aspect of endocrine-immune regulation and develop effective and cheap drugs. Use of murine chlamydia as disclosed in CN108815199A for the preparation of a medicament for the treatment of ulcerative colitis.
Atrial Natriuretic Peptide (ANP), also known as atrial natriuretic peptide (anna), is a peptide hormone originally extracted from atrial myocytes. At present, the research field of ANP is wider, and the ANP has the physiological functions of diuresis, natriuresis and vasodilation of vascular smooth muscle, can regulate water and salt balance and maintain blood pressure.
Disclosure of Invention
Aiming at the problems, the invention provides the application of atrial natriuretic peptide in preparing the medicaments for treating inflammatory bowel diseases, and mainly solves the blank of the application of atrial natriuretic peptide in anti-inflammatory medicaments, in particular medicaments for treating inflammatory bowel diseases in the prior art.
In order to solve the problems, the invention adopts the following technical scheme:
application of atrial natriuretic peptide in preparing anti-inflammatory drugs is provided.
Application of atrial natriuretic peptide in preparing medicines for treating inflammatory bowel disease.
One format, wherein the atrial natriuretic peptide amino acid sequence is: Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr.
In one form, the atrial natriuretic peptide has a chemical formula of C127H205N45O39S3。
One way, the inflammatory bowel disease includes ulcerative colitis, crohn's disease.
One way, the inflammatory bowel disease comprises indeterminate colitis.
The invention has the beneficial effects that:
has no adverse effect on normal cells and no toxic or side effect, and can effectively relieve colitis inflammation of colon and reduce secretion of colon tissue inflammatory cytokines.
Drawings
FIG. 1 is a graph showing the expression of ANP and its receptor in mouse intestinal tract and related lymphoid organs;
FIG. 2 is a graph of ANP alleviating intestinal inflammation in mice;
FIG. 3 is a graph showing that ANP reduces the expression of the mouse intestinal inflammatory factor and autophagy-related genes.
Detailed Description
EXAMPLE 1 therapeutic Effect on murine ulcerative colitis
Materials:
A. mice: the C57BL/6J mouse strain (purchased from Beijing Wittingle company) is raised to 20-22g under the SPF environment and is about 8 weeks old.
B. Human atrial natriuretic peptide ANP (available from Tocris biosciences, UK), amino acid sequence Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr, molecular weight 3080.46 Da; the purity was 95.8%.
The method and the result are as follows:
firstly, constructing a Dextran Sodium Sulfate (DSS) induced colitis mouse model and intervening ANP recombinant protein.
① grouping of experimental mice:
grouping of experimental mice: 24 male C57BL/6 mice were randomly divided into a control group, a DSS +2ugaNP group and a DSS +20ugaNP group, and 6 mice were adaptively bred for 7 days, observed for diet, activity, defecation and body weight.
② intervention in mice:
control group: drinking normal water freely for 7 days, and injecting 400ul PBS solution into the abdominal cavity on the 0 th, 1 th, 3 th, 5 th and 7 th days;
and (4) DSS group: mice freely drunk 2.5% DSS solution for 7 days, and were injected with 200ul PBS solution in the abdominal cavity on days 0, 1, 3, 5, and 7;
ANP intervention group: mice were free to drink 2.5% DSS solution for 7 days, and injected intraperitoneally with 200ul of PBS solution containing 2ug and 20ug of recombinant ANP on days 0, 1, 3, 5, and 7.
③ recording of general conditions in mice:
after the start of modeling, the weight, stool characteristics (normal, pasty stool or watery stool), bloody condition (no, occult blood or obvious bloody stool), activity condition (active or burnout) and the like of the mice were recorded every day.
④ mouse sacrifice and collection of specimens:
the mice are sacrificed on the 7 th day, the eyeballs are used for taking blood after the mice are anesthetized with pentobarbital sodium abdominal cavity, the abdominal cavity is opened along the abdominal midline, the complete straight colon is left from the part above the rectum to the ileocecal part, and the length of the colon is measured and recorded; while the spleen was removed and weighed. The colon feces are cleaned, and the distal colon tissue is taken and stored at-80 ℃ for RT-qPCR detection.
Second, real-time quantitative RT-qPCR
① extraction and concentration determination of total RNA
Clipping about 10mg of tissue, placing the clipped tissue in a 2ml EP tube, numbering, and adding 1ml of Trizol solution and 2 magnetic beads;
homogenizing in a grinding instrument at 65Hz for 2 times (120 sec); adding chloroform 200ul (1/5 volume trizol solution) into the homogenate lysate, covering a tube cover tightly, shaking vigorously for 15sec, and standing at room temperature for 5min after the solution is fully mixed until no phase separation phenomenon exists;
centrifuging: 4 ℃, 12000rpm, 15 min; the EP tube was carefully removed from the centrifuge and the homogenate was divided into three layers: colorless supernatant, a middle white layer and a lower organic phase with color;
another new 1.5ml EP tube was taken and numbered, 300ul of the supernatant was pipetted into the new EP tube, 300ul of an equal volume of isopropanol was added to the supernatant, the EP tube was gently inverted upside down to mix well, left at room temperature for 10min, centrifuged: 4 ℃, 12000rpm, 10 min; taking out the EP tube from the centrifuge, observing that RNA precipitates exist at the bottom of the test tube, and carefully discarding the supernatant to avoid discarding the RNA precipitates;
slowly add 1ml of pre-cooled 75% ethanol along the tube wall (note not to touch the pellet), invert the tube gently upside down, centrifuge: 4 ℃, 12000rpm, 5 min; carefully discarding the supernatant, inverting an EP tube on filter paper, drying and precipitating at room temperature for about 5min, adding appropriate amount of high-pressure double distilled water after drying and precipitating, and fully dissolving the precipitate, wherein the amount of added water is adjusted according to the amount of the precipitate;
and (5) after the RNA precipitate is completely dissolved, immediately separating by using a centrifuge.
② RNA concentration determination
The cuvette was cleaned, the spectrophotometer was turned on, and double distilled water was added to the cuvette and zeroed.
Adding 2ul of sample to be tested and 98ul of double distilled water into the cuvette, measuring and recording A260 and A280 numerical values,
to calculate the purity and concentration of RNA.
③ reverse transcription
Taking out a reagent required by reverse transcription, thawing at room temperature, performing vortex oscillation and uniform mixing, and performing instantaneous separation; preparing a reaction system: according to the following proportion of a reverse transcription reaction system, the dosage of each component required by a proper volume is calculated, and the components are respectively added into a 0.5ml EP tube and are instantaneously separated after being uniformly oscillated by a vortex instrument; reverse transcription: after preparing the reverse transcription reaction system, reverse transcription was carried out in a reverse transcription apparatus at 37 ℃ for 15min, 85 ℃ for 15 sec. Followed by PCR or storage at-20 ℃.
10ul reaction system: RNA-PrimerMix (5X)2ul + RNA test sample (1/concentration 1000) ul + DEPC water (10-2-VRNA) (ul).
④RT-qPCR
Taking out the reagent required by PCR, thawing at room temperature, performing vortex oscillation and mixing uniformly, and then performing instantaneous separation;
preparing a reaction system: preparing actually required dosage according to the number of samples to be detected and indexes to be detected and the following PCR reaction system proportion; instantly separating after the vortex instrument oscillates and is uniformly mixed;
sample adding: taking a 96-well PCR plate, designing a sample adding sequence and marking, firstly adding a mixture of 4ul of cDNA and water on one side wall, rotating the 96-well plate, adding a mixture of 6ul of SYBR Green and a primer on the other side wall, sealing the 96-well plate by using a sealing plate membrane after the sample adding is finished, and centrifuging;
amplification: putting the 96-well plate into a PCR instrument, opening a software system, and setting a program for amplification;
amplification conditions: pre-denaturing at 95 deg.C for 10min, performing amplification by repeating 40 cycles of denaturation at 95 deg.C for 30sec, annealing at 60 deg.C for 1min, extension at 72 deg.C for 30sec, and annealing;
analysis of results Using GAPDH or β -actin as an internal reference Gene
The method comprises the step of analyzing the expression condition of the target genes of each group relative to a control group.
10ul reaction system: 5ul SYBR Green dye +0.5ul, upper primer +0.5ul, lower primer +1ul, target gene +3ul dd H2O。
Primer sequences for RT-qPCR
Three, result in
(1) As shown in FIG. 1, three wild-type untreated 8-week-old male C57BL/6 mice were selected, and mRNA levels of the gene NPPA encoding ANP and its two major receptor NPR-A, NPR-C gene in the mice in the jejunum, ileum, colon and liver, spleen, kidney, appendix, small intestine PP node, mesenteric lymph node, thymus were examined by RT-qPCR and their mean and standard deviation were represented by bar graphs.
The higher the bar, the larger the relative expression of NPPA and NPR-A, NPR-C mRNA at the part, and the vertical axis value shows the ratio of the expression of NPPAmRNA at the part to the same mouse atrial NPPAmRNA.
(2) As in figure 2, the mice are grouped specifically as in the methods section. Measuring and calculating the ratio of the daily body weight of each mouse to the body weight of the mouse on day 0, and calculating the average value and standard deviation of each group; the results show that the average body weight of the mice in the original ANP group of each mouse is heavier than that in the DSS group, and has statistical significance, and the body weight of the mice under different dosage of ANP treatment has no statistical difference. The average spleen weight of the ANP group mice is lighter than that of the DSS group, and the average colon length of the ANP group mice is longer than that of the DSS group, and the ANP group mice and the DSS group have statistical significance; however, there were no statistical differences in spleen weight and colon length between the two groups at different doses of ANP.
ANP reduced intestinal inflammation in mice it reduced weight loss, spleen enlargement and colon shortening in DSS model mice, an effect that was dose independent.
(3) As shown in FIG. 3, mRNA levels of the inflammatory cytokines IL-1 β, TNF- α, IL-6, IFN- γ and autophagy-related genes ATG5 and ATG12 in the terminal colon tissues of the four groups of mice were measured by RT-qPCR, the height of the column indicates the average value of the ratio of the mRNA level to the β -actin, and the distance between the horizontal line above the column and the column indicates the standard deviation.
It will be apparent to those skilled in the art that various modifications may be made to the above embodiments without departing from the general spirit and concept of the invention. All falling within the scope of protection of the present invention. The protection scheme of the invention is subject to the appended claims.
Sequence listing
<110> affiliated cooperation hospital of college of Tongji medical college of Huazhong university of science and technology
Application of atrial natriuretic peptide in preparation of medicines for treating inflammatory bowel disease
<140>202010083380.5
<160>1
<170>SIPOSequenceListing 1.0
<210>1
<211>28
<212>PRT
<213> Artificial sequence
<400>1
Ser Leu Ala Ala Ser Ser Cys Pro Gly Gly Ala Met Ala Ala Ile Gly
1 5 10 15
Ala Gly Ser Gly Leu Gly Cys Ala Ser Pro Ala Thr
20 25
Claims (5)
1. Application of atrial natriuretic peptide in preparing medicines for treating inflammatory bowel disease.
2. The use of claim 1, wherein the atrial natriuretic peptide amino acid sequence is: Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-S er-Gly-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr.
3. The use of claim 1, wherein the atrial natriuretic peptide has the chemical formula C127H205N45O39S3。
4. The use of claim 1, wherein the inflammatory bowel disease comprises ulcerative colitis, Crohn's disease.
5. The use of claim 1, wherein the inflammatory bowel disease comprises indeterminate colitis.
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Cited By (2)
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| CN114288386A (en) * | 2022-01-25 | 2022-04-08 | 华中科技大学同济医学院附属协和医院 | Application of Del-1 as new biomarker for inflammatory bowel disease and therapeutic drug |
| CN114288388A (en) * | 2022-01-25 | 2022-04-08 | 华中科技大学同济医学院附属协和医院 | Application of omentum extract in preparation of medicine for treating inflammatory bowel disease |
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