CN116535490B - Polypeptide ADSCP8 for reducing collagen content of scar dermis fibroblast and application thereof - Google Patents
Polypeptide ADSCP8 for reducing collagen content of scar dermis fibroblast and application thereof Download PDFInfo
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- CN116535490B CN116535490B CN202310718523.9A CN202310718523A CN116535490B CN 116535490 B CN116535490 B CN 116535490B CN 202310718523 A CN202310718523 A CN 202310718523A CN 116535490 B CN116535490 B CN 116535490B
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A61P17/00—Drugs for dermatological disorders
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- C12N15/76—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora for Actinomyces; for Streptomyces
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Abstract
The invention discloses a polypeptide ADSCP8 for reducing the collagen content of scar dermis fibroblast and application thereof. A polypeptide ADSCP8 has an amino acid sequence shown in SEQ ID NO. 1. The polypeptide ADSCP8 can inhibit the mRNA expression quantity of collagen genes COL1A1, COL1A2 and COL3A1 in human scar dermis fibroblast, and obviously reduce the protein expression quantity of a main myofibroblast marker ACTA2 in human scar dermis fibroblast. The polypeptide ADSCP8 can be used for preparing medicines or reagents for inhibiting the collagen content of scar dermis fibroblast and reducing the myofibroblast amount, and provides a new target point for inhibiting scar hyperplasia.
Description
Technical Field
The invention relates to the field of wound healing and scar, in particular to a polypeptide ADSCP8 for reducing the collagen content of scar dermis fibroblast and application thereof.
Background
Hypertrophic scars are a type of skin fibrotic disease and are mainly characterized by local excessive deposition of extracellular matrix such as collagen, and are a great challenge facing the surgical field of burn injuries and plastic surgery. It not only affects the beauty, but also causes symptoms such as itching, pain, contracture and the like, even disability, seriously reduces the life quality of the patient, and brings great pain to the body and the mind of the patient. The incidence rate of the hypertrophic scars of patients after skin injury and surgery is 39% -68%, and the incidence rate of burn patients is as high as 91%. At present, the method of local pressurization, laser intervention, drug injection, surgical excision and the like is mostly adopted to treat the hypertrophic scar, but all have limitations and adverse complications. Therefore, the method has important clinical significance by deeply researching the formation and regulation mechanism of the hypertrophic scar and searching an effective scar control means.
The polypeptide is a bioactive substance composed of 3-50 amino acid residues, and has the characteristics of small molecular weight, easy synthesis, high efficiency, low toxicity and the like. The number of polypeptide drugs currently marketed worldwide is 120 or more, and the polypeptide drugs cover various fields such as obesity, diabetes, anti-tumor and the like. In the skin-related field, there are afamelanolide (13 peptide) for improving sunlight tolerance of porphyrin patients, bacitracin (Bacitracin) for treating skin infection, gramicidin (cyclopeptide), and the like. There is currently no polypeptide drug for the treatment of hypertrophic scars.
Vimentin (Vimentin) is one of the proteins of the intermediate filament, and is an important component of the cytoskeleton of eukaryotes, which is critical to the integrity and cytoskeletal stability of the cells. Vimentin is expressed in a variety of mesenchymal cell types: fibroblasts, endothelial cells, etc., and mesoderm. It has been reported that Vimentin has high expression and has a scar-promoting effect.
Disclosure of Invention
The object of the present invention is to provide a polypeptide ADSCP8.
It is a further object of the invention to provide the use of the polypeptide.
It is a further object of the present invention to provide a cell culture broth comprising the polypeptide.
The aim of the invention can be achieved by the following technical scheme:
the amino acid sequence of the polypeptide ADSCP8 is shown as SEQ ID NO. 1.
The polypeptide can be obtained by a solid phase synthesis method according to the amino acid sequence; or by cloning and expressing a DNA fragment carrying a nucleotide sequence encoding one of said polypeptides in a host microorganism or cell, prepared by existing recombinant DNA techniques. The expression vectors and host cells used are known to the public as recombinant technology. Expression vectors such as pET vectors, pGEX vectors; host cells such as E.coli (E.coli), actinomycetes (Actinomyces), bacillus (Bacillus) and Streptomyces (Streptomyces) are isolated from the host cells by conventional methods of digestion, and may be isolated and purified by conventional liquid chromatography, which methods are well known to those skilled in the art.
The invention also provides a nucleotide sequence for encoding the polypeptide, which is a nucleotide sequence shown as SEQ ID NO. 2.
Recombinant expression vectors containing the genes of the present invention.
Host microbial cells transfected with the expression vectors of the present invention.
The application of the polypeptide ADSCP8 in preparing a medicament or a reagent for reducing the collagen content of scar dermis fibroblast is provided.
The application of the polypeptide ADSCP8 in preparing a medicament or reagent for reducing myofibroblast amount is provided.
A cell culture broth comprising said polypeptide ADSCP8.
The invention also provides a composition containing the polypeptide.
The polypeptides of the invention may be used alone or in combination with other polypeptides. The polypeptide composition comprises a polypeptide with a sequence of SEQ ID NO. 1.
The medicinal composition is in the form of any one of capsules, tablets, lozenges, pills, dripping pills, suppositories, sprays, cream and patches.
The pharmaceutical composition comprises pharmaceutical excipients for preparing the polypeptide ADSCP8 into the dosage form.
The beneficial effects are that:
polypeptide ADSCP8 (LIKTVETRDGQVINETSQHHDDLE), the precursor protein is VIME, and the precursor protein consists of 24 amino acids, and no related function report exists at present. The bioinformatics analysis and experimental results show that: (1) ADSCP8 is derived from 443-466 amino acids of the carboxyl end of Vimentin protein; (2) ProtParam online analysis shows that the instability coefficient (Instability index) of ADSCP8 is 10.93, belongs to stable polypeptide and can exist stably; the fat coefficient (aliphatics index) was 89.17 and the average hydrophilic-hydrophobic (Grand average ofhydropathicity) was-1.025; (3) ADSCP8 is added into the cell culture solution, and quantitative PCR experiments prove that the ADSCP8 can reduce the mRNA expression quantity of collagen genes COL1A1, COL1A2, COL3A1 and a main marker ACTA2 of myofibroblast in scar dermis fibroblast; western blot experiments prove that ADSCP8 can reduce the protein expression amount of type I collagen (comprising COL1A1 and COL1A 2) and COL3A1 and a main myofibroblast marker ACTA 2. Thus, ADSCP8 can be used in the preparation of medicaments or agents for reducing the collagen content of scar dermis fibroblast and reducing the myofibroblast amount.
Drawings
FIG. 1 is a graph showing that ADSCP8 inhibits the expression level of mRNA of collagen genes COL1A1, COL1A2, COL3A1 and myofibroblast main marker ACTA2 in scar dermis fibroblast in test example 1. * P <0.05.
FIG. 2 is a graph showing that ADSCP8 inhibits the protein expression levels of type I collagen (including COL1A1, COL1A 2), COL3A1 and ACTA2, a main marker of myofibroblasts in test example 2.
Detailed Description
Example 1
The sequence shown in SEQ ID NO.1 was synthesized by solid phase method by Shanghai peptide biotechnology Co., ltd:
Leu Ile Lys Thr Val Glu ThrArgAsp Gly Gln Val IleAsn Glu Thr Ser Gln His His AspAsp Leu Glu
this is a 24 amino acid polypeptide, and the main biological parameters of the aforementioned polypeptide sequence obtained by an on-line tool are as follows:
isoelectric Point (PI) is 4.57, molecular weight (Molecular weight) 2777.98Da.
The above sequence is a natural sequence from human adipose-derived stem cell culture supernatant, and can be obtained by chemical solid phase synthesis, biological enzyme digestion technology of long-chain polypeptide, cloning and expressing DNA fragment carrying nucleotide sequence encoding one of the polypeptides in host microorganism or cell, and preparing by existing recombinant DNA technology. The nucleotide sequence for encoding the polypeptide is as follows:
ctgattaagacggttgaaactagagatggacaggttatcaacgaaacttctcagcatcacgatgaccttgaa(SEQ ID NO.2)。
the expression vectors and host cells used are known to the public as recombinant technology. Expression vectors such as pET vectors, pGEX vectors; host cells such as E.coli (E.coli), actinomycetes (Actinomyces), bacillus (Bacillus) and Streptomyces (Streptomyces) are isolated from the host cells by conventional methods of digestion, and may be isolated and purified by conventional liquid chromatography, which methods are well known to those skilled in the art.
Example 2
The polypeptides described in example 1 may be used alone or in combination with other polypeptides. The polypeptide composition comprises a polypeptide with a sequence of SEQ ID NO. 1.
Example 3
This example provides a polypeptide as described in the foregoing example 1, or a polypeptide composition as described in example 2, which can be formulated into a pharmaceutically acceptable carrier, such as: in the form of capsule, tablet, lozenge, pill, dripping pill, suppository, spray, cream, patch, etc.
Example 4
1. Test materials
RNA reverse transcription kit, RNA detection kit, etc. were purchased from Nanjinopran, inc., and fibroblast medium was purchased from Sciencell, USA.
2. Synthesis and dilution of ADSCP8 polypeptides
The polypeptide ADSCP8 obtained by solid phase synthesis in this experimental example 1 is exemplified. 10mg of the polypeptide was diluted with sterile double distilled water to 50mM-40℃and stored for further use.
3. Real-time quantitative PCR (RT-PCR) detection of the influence of polypeptide ADSCP8 on the mRNA expression of collagen genes COL1A1, COL1A2, COL3A1 and the primary myofibroblast marker ACTA2 in human scar dermal fibroblasts
At 37℃with 5% CO 2 Culturing human scar dermis fibroblast in incubator according to 10 5 Inoculating the cells into a 6-hole plate at a density of/mL, adding polypeptide ADSCP8 (the final concentration is 25 mu M) into human scar dermis fibroblasts when the cell fusion degree reaches about 60%, after 24 hours, growing the cells, discarding the culture medium, sucking the culture medium as much as possible, and directly adding Trizol 1mL respectively; cracking at room temperature for 5 minutes, adding 200 mu L of chloroform, fully vortex shaking and uniformly mixing for 15 seconds, standing at room temperature for 2 minutes, centrifuging at 12000rpm and 4 ℃ for 15 minutes; gently sucking the upper aqueous phase into an RNase-free EP tube of 450. Mu.L, adding 450. Mu.L of isopropanol, standing overnight at-20 ℃, centrifuging at 12000rpm at 4 ℃ for 15min, and allowing a fine flaky precipitate to be seen at the bottom of the tube; washing the precipitate with 75% ethanol (DEPC water formulation), centrifuging at 12000rpm at 4deg.C for 5min, and carefully discarding the supernatant; centrifuging at 12000rpm at 4deg.C for 2min, and carefully sucking off the supernatant with a yellow gun head; placing into an ultra clean bench or a fume hood for drying for 10-15min; RNA was dissolved using 30. Mu.L of DEPC water.
The extracted RNA is subjected to reverse transcription by using a reverse transcription kit of Nanjinouzan company, and the method is implemented according to the specific steps of the specification as follows: (1) possible genomic DNA was removed and the total volume of the reaction system was 16. Mu.L, as follows:
after the above reagents were added to an EP tube, the pipette was gently blown to mix them, and placed in a 42℃water bath for 2min. (2) A reverse transcription reaction system was prepared in a total volume of 20. Mu.L, that is, 4. Mu.L of a reverse transcription reaction solution (5X HiScript III qRT SuperMix) containing a reverse transcriptase was added to the EP tube in the previous step, and the mixture was gently stirred with a pipette. (3) Reverse transcription was performed at 37℃for 15min and 85℃for 5s. The product can be used immediately for qPCR reactions or stored at-20℃and used within half a year.
The primers used were synthesized by Shanghai Ind. The primer sequences were as follows:
real-time fluorescent quantitative PCR (qRT-PCR) was performed using the ChamQ Universal SYBR qPCR Master Mix kit from Nanjinopran.
The following mixture was prepared in qPCR tube:
setting according to a standard program of PCR amplification by a two-step method default by a PCR instrument: pre-denaturation at 95℃for 10s; PCR reaction is carried out for 40 cycles at 95 ℃ for 5s and 60 ℃ for 31 s; the melting curve acquisition procedure is default Dissociation Stage. After the reaction, it was confirmed that the amplification curve of qRT-PCR and the melting curve of the primer were normal, and the obtained data were analyzed by the 2-DeltaCt method.
Test results: as shown in fig. 1, the real-time quantitative PCR experiment shows that the mRNA expression amounts of the collagen genes COL1A1, COL1A2, COL3A1 and the myofibroblast main marker ACTA2 in the scar dermis fibroblast of the ADSCP8 polypeptide treatment group (25 μm) are significantly reduced, which indicates that the polypeptide ADSCP8 can significantly inhibit the mRNA expression amounts of the collagen genes COL1A1, COL1A2, COL3A1 and the myofibroblast main marker ACTA2 in the scar dermis fibroblast. 4. Western blot method for detecting influence of polypeptide ADSCP8 on expression quantity of type I collagen (comprising COL1A1 and COL1A 2) and COL3A1 and main marker ACTA2 protein of myofibroblast in human scar dermis fibroblast
Human scar dermal fibroblasts from the polypeptide treated group (final concentration 25. Mu.M) and the control group were collected, respectively, and the following procedure was performed:
mu.L of RIPA cell lysate (containing protease inhibitor) was added and lysed on ice for 30min, and during lysis, a bomb was often used to lyse the cells. Then, the mixture was centrifuged at 12000rpm at 4℃for 5 minutes, and the supernatant of the lysate was dispensed into 1.5mL EP tubes and stored at-80 ℃. The protein content was determined by BCA (Bicinchoninic acid) method, specifically as follows: first, a standard curve of a BSA protein standard was prepared, and the protein concentration was measured on an enzyme-labeled instrument.
After the protein was obtained, 5 XSDS (Sodium dodecyl sulfate, sodium dodecyl sulfonate) loading buffer was added, and the protein was denatured by boiling in boiling water for 5 min. The experiment was performed by preparing SDS-PAGE separating gel and concentrating gel, and loading the same amount of protein into each well. Electrophoresis was stopped after the just-run out of bromophenol blue (typically 1-2 h) at 80V for 1.5h, followed by transfer. Transferring for 2h by 60V, sealing for 1h, and adding primary antibody (diluted with TBST (Tris-Buffered Saline andTween 20) at the antibody dilution ratio of 1:1000); after incubation for 1-2h at room temperature, washing twice with TBST for 10min each time on a decolorizing shaking table at room temperature; after which it was washed once with TBS for 10min. Adding corresponding secondary antibodies (diluted by TBST, the dilution ratio of the antibodies is 1:5000) according to the sources of the primary antibodies, incubating for 1-2 hours at room temperature, and washing twice by TBST on a decolorizing shaking table at room temperature for 10min each time; after which it was washed once with TBS for 10min. The chemiluminescent reaction is then carried out using a ECL (Efficient chemiluminescence kit) kit or the like. Photographing, and carrying out gray analysis on the strip by using an Image J.
Antibody information was purchased from the corresponding company as follows:
test results: as shown in fig. 2, western blot experiments show that the protein expression levels of type I collagen (including COL1A1, COL1 A2), COL3A1 and the primary myofibroblast marker ACTA2 in the scar dermis fibroblasts of the ADSCP8 polypeptide-treated group are reduced, indicating that the polypeptide ADSCP8 can inhibit the protein expression levels of collagen and the primary myofibroblast marker ACTA2 in the scar dermis fibroblasts.
The foregoing is only a preferred embodiment of the invention, it being noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (9)
1. Polypeptide ADSCP8, which is characterized in that the amino acid sequence is shown in SEQ ID NO. 1.
2. A gene encoding the polypeptide ADSCP8 of claim 1.
3. The gene according to claim 2, wherein the nucleotide sequence is shown in SEQ ID NO. 2.
4. A recombinant expression vector comprising the gene of claim 2.
5. A host microbial cell transfected with the expression vector of claim 4.
6. Use of polypeptide adccp 8 according to claim 1 for the preparation of a medicament or agent for reducing collagen content of scar dermis fibroblasts.
7. A composition comprising the polypeptide ADSCP8 of claim 1.
8. The composition of claim 7, characterized in that the polypeptide adccp 8 of claim 1 is present in the composition in a therapeutically effective amount.
9. A cell culture broth comprising the polypeptide adccp 8 of claim 1.
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| CN114790234A (en) * | 2022-04-08 | 2022-07-26 | 南京市妇幼保健院 | Adipose-derived stem cell secreted endogenous polypeptide ADSCP5 and application thereof |
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| CN110903376A (en) * | 2019-11-08 | 2020-03-24 | 上海交通大学 | Bioactive polypeptide RISLPLPTFSSL, and preparation method and application thereof |
| CN112826922A (en) * | 2020-12-24 | 2021-05-25 | 广州医科大学附属第一医院（广州呼吸中心） | Drug for treating or preventing fibroproliferative diseases |
| CN113817042A (en) * | 2021-08-13 | 2021-12-21 | 南京市妇幼保健院 | Human adipose-derived stem cell secreted polypeptide ADSCP2 and application thereof |
| CN114790234A (en) * | 2022-04-08 | 2022-07-26 | 南京市妇幼保健院 | Adipose-derived stem cell secreted endogenous polypeptide ADSCP5 and application thereof |
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