CN111686097A - Application of LMK235 in medicine for inhibiting scar formation - Google Patents
Application of LMK235 in medicine for inhibiting scar formation Download PDFInfo
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- CN111686097A CN111686097A CN202010760223.3A CN202010760223A CN111686097A CN 111686097 A CN111686097 A CN 111686097A CN 202010760223 A CN202010760223 A CN 202010760223A CN 111686097 A CN111686097 A CN 111686097A
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- lmk235
- scar
- medicament
- treatment
- scar formation
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides application of LMK235 in a medicament for inhibiting scar formation. The invention firstly provides the application of LMK235 as a medicament for treating hypertrophic scars. The injection of LMK235 in scar can inhibit hyperplastic scar formation. The drug related to the invention has clear treatment target, and avoids the defects of unknown treatment mechanism, low efficiency, easy side effect and the like; a series of side effects possibly brought by hormone are avoided; the possibility of damaging normal cells of a human body is avoided; the defect of shallow treatment depth and the possibility of inducing new scar formation are avoided; can be used for treating large-area pathological scar, and avoids the defect of small treatment range.
Description
Technical Field
The invention relates to the application field of LMK235, in particular to application of LMK235 in a medicament for inhibiting scar formation.
Background
Hypertrophic scars are a fibrotic disease of the skin, a fibrometabolic disease of the dermal layer of the skin characterized by uncontrolled proliferation of fibroblasts and excessive production and deposition of large amounts of extracellular matrix such as collagen. It affects the physical and mental health of millions of people worldwide. Often secondary to trauma, burns and surgery. Reports show that the incidence rate of the Chinese medicinal preparation in patients after conventional operations is 36-64%, and the incidence rate in patients with deep burns can reach 91%. Hyperplastic scars not only affect the appearance of patients, but also produce contractures which can cause dysfunctions of different degrees and seriously reduce the quality of life of patients.
Clinical evidence shows that hypertrophic scars often appear in places with high skin tension of the body, such as the chest, the shoulders, the outer side of the upper arm and the like. Severe scars rarely appear on the scalp and the front part of the lower leg, and the two parts are characterized in that bones are directly positioned under the skin, and the skin is not easily affected by tension. Studies have shown that stressors can alter the conformation of TGF-beta 1 (pro-fibrotic cytokine) precursors, facilitating the release of activated TGF-beta 1 from the extracellular matrix. Another study shows that the tension can directly activate a TGF-beta/Smad 2/3 signal channel in the fibroblast and promote the activation of the fibroblast. Meanwhile, the tension stimulation can also change the conformation of the G protein on the cell membrane, so as to activate Protein Kinase C (PKC) and promote the release of downstream fibrosis-related growth factors. It is readily apparent from the above studies that local skin tone is an important factor in hypertrophic scarring and that prevention and treatment of pathologic scarring is of great value by targeting specific targets for tone-regulated scarring.
HDAC5 is a histone deacetylase, belongs to the type II histone deacetylase family, and plays an important role in the regulation and control of hypertrophic scars by tension as a mechanically sensitive protein. The fluid shear force can promote the activity of a transcription factor MEF2 by promoting calcium ion pathway dependent phosphorylation of HDAC5 in vascular endothelial cells to cause the enucleation of HDAC 5; down-regulation of HDAC5 expression could inhibit renal fibrosis by interfering with the P38/MAPK signaling pathway; it has been found that HDAC5 has increased expression in idiopathic sclerosis of skin and inhibits angiogenesis by inhibiting the expression of pro-angiogenic factor genes.
LMK235, (N- [ [6- (hydroxyyamino) -6-oxohexyl ] oxy ] -3, 5-dimethyllbenzamide), is a selective inhibitor of HDAC4 and HDAC5 in the HDAC family II with an IC50 of 11.9nM and 4.2nM, respectively. It is used in the patent US2015290168A1 for the treatment of bacterial infections and in the patent WO2018160356A1 for the treatment of Friedreich ataxia, a mutated FXN gene.
At present, various methods for treating and preventing pathological scars are available, and the method is mainly focused on removing various factors causing scar hyperplasia before scar formation and in an immature stage after the wound surface is covered on the epithelium, so as to prevent various deformities and dysfunctions of the organism caused by the scar. The limitations of the existing methods for preventing and treating pathological scars are mainly: 1. the operation therapy has painful treatment process and high recurrence rate and can not be suitable for patients with large-area scars; 2. the compression treatment and the silica gel product treatment have good effect on patients with large-area burn, but the patients need to wear the elastic compression device for a long time, and the life is seriously inconvenient; 3. radiotherapy, which has limited treatment effect and often causes permanent radioactive damage to the whole body and parts of a patient; 4. the freezing treatment is only suitable for scars with small areas, and can treat complications such as deepening of skin pigments and mild skin atrophy; 5. glucocorticoid therapy can produce complications such as skin atrophy, depigmentation, telangiectasia, female menstrual disorder, ulceration or calcification of injection site, etc.; 6. the laser therapy has low clinical effective rate and is easy to induce new scars; 7. the treatment of the anti-tumor drugs has high toxicity to local and general normal cells, and the clinical value is not exact; 8. the clinical curative effect of the tacrolimus, the statins, the tamoxifen and other medicines is limited, and the therapeutic target point is not exact.
Disclosure of Invention
The invention provides application of LMK235 in a medicament for inhibiting scar formation.
The technical scheme of the invention is realized as follows:
use of LMK235 in a medicament for inhibiting scarring.
In some embodiments, the drug is a drug that targets the HDAC5 gene and/or its encoded protein as a drug.
In some embodiments, the mode of administration is topical injection or painting.
In some embodiments, the drug is an injectable injection.
In some embodiments, the concentration of LMK235 in the injectable injection is 50 ug/ml. The solvent is physiological saline.
The inhibition of scarring described above HDAC5 inhibits scarring.
The chemical structural general formula of the LMK235(N- [ [6- (hydroxyyamino) -6-oxohexyl ] oxy ] -3, 5-dimethyllbenzamide) is as follows:
compared with the prior art, the invention has the following beneficial effects:
(1) the invention firstly provides the application of LMK235 as a medicament for treating hypertrophic scars.
(2) The injection of LMK235 in scar can inhibit hyperplastic scar formation.
(3) Compared with medicaments such as tacrolimus, statins, tamoxifen and the like, the medicament has definite treatment target points, and avoids the defects of unknown treatment mechanism, low efficiency, easy side effect and the like; compared with glucocorticoid medicaments, the compound avoids a series of side effects possibly brought by hormone; compared with anti-tumor drugs and radiotherapy, the possibility of damaging normal cells of a human body is avoided; the disadvantage of shallow treatment depth and the possibility of inducing new scarring are circumvented relative to laser treatment; compared with operation treatment and cryotherapy, the medicament can treat large-area pathological scars, and avoids the defect of small treatment range.
(4) Compared with the existing medicines, the medicine provided by the invention has the obvious advantage of cost and is low in synthesis cost.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive exercise.
Figure 1 is a graph of the inhibition of HDAC5 mediated histone acetylation by LMK 235; western blot of histone acetylation in human hypertrophic scar fibroblasts at different LMK235 drug concentrations.
FIG. 2 shows that LMK235 inhibits the expression of human primary hypertrophic scar-derived fibroblast fibrosis marker; a, the relative expression levels of mRNA of Col1a1, Col3a1 and alpha-SMA in human hypertrophic scar fibroblasts under different LMK235 drug concentrations; b, the relative expression levels of the proteins of Col1a1, Col3a1 and alpha-SMA in human hypertrophic scar fibroblasts under different LMK235 drug concentrations.
FIG. 3 shows that LMK235 inhibits the activity of human primary hypertrophic scar-derived fibroblasts; activity of human hypertrophic scar fibroblasts at different LMK235 drug concentrations (CCK8 method).
FIG. 4 shows that LMK235 can inhibit hypertrophic scar formation in mice; representative pictures of HE staining of scars on mice in the solvent control group and LMK235 group, and statistical data of cross-sectional areas of scars.
Figure 5 is a graph showing that LMK235 can inhibit the expression of fibrosis markers in scar tissue in a mouse hypertrophic scar model: A. the relative expression levels of mRNA of Col1a1, Col3a1 and alpha-SMA in the scar tissues of the skin of mice in the solvent control group and the LMK235 group; and B, the relative expression levels of the proteins of Col1a1, Col3a1 and alpha-SMA in the scar tissues of the skins of the mice in the solvent control group and the LMK235 group.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention intervenes HDAC5 to inhibit the formation of skin hypertrophic scar, inhibit the biological behaviors of skin fibroblast such as excessive proliferation and secretion of a large amount of extracellular matrix, and the like, thereby achieving the effect of treating hypertrophic scar and fibrosis related diseases.
Example 1
Use of LMK235 in a medicament for inhibiting scarring.
1. Experimental Material
1.1 the preparation method of the LMK235 solution is as follows:
LMK235 was purchased from Selleck (#7569) and dissolved in physiological saline to prepare solutions of LMK235 concentration of 5ng/ml,10ng/ml,25ng/ml and 50ug/ml, respectively.
2. Experimental methods
2.1 extraction and culture of human scar-derived fibroblasts
Clinical specimens (human hypertrophic scar tissue, patient signed informed consent) were soaked with dispaseII (2mg/ml, Life technologies, ThermoFisher) overnight at 4 ℃ and the epidermis was peeled off and removed. Mincing tissue under sterile environment, soaking with 4mg/ml collagenase, digesting at 37 deg.C for 2-4 hr by shaking table, filtering cell suspension with filter screen, centrifuging at 1500rpm for 5min, removing supernatant, suspending cell precipitate with culture medium, and inoculating into DMEM culture medium. The solution was changed every 2 days.
2.2 establishment of mouse hypertrophic scar model
The mouse hypertrophic scar model is referenced to Geoffrey C Gurtner, faeb J, 2007. Briefly, 12-week-old C57/BL6 mice were anesthetized and dorsal skin was prepared. On the first day, a 2 cm incision was made in the dorsal midline of the mice, which was then reapproximated with 6-0 nylon suture. After the rat skin healed, a special mechanical stretching device is sewn at the incision part, mechanical load is generated on scars of the incision by adjusting a screw knob, and the stretching is kept at a tension of 4mm every other day. After 2 weeks of stress, mice were euthanized and the material was taken.
2.3LMK235 injection
On the day when the scar of the mouse is built, LMK235 injection is started, and the injection method is intradermal injection. Divided into a normal saline injection group and a 50ug/ml LMK administration group. The injection is carried out once a day, 8 points are injected, 50ul of medicine is injected at each point until the model is established and the materials are obtained.
2.4 addition of LMK235 to cells cultured in vitro
When the cell density reached about 70%, the cells were changed and 5ng/ml,10ng/ml,25ng/ml of LMK235 solution was added. And (5) carrying out related detection on the fibrosis marker after 24h of culture.
2.5 real-time quantitative PCR
Total RNA from tissues or cells was extracted by Trizol (Invitrogen, Grand Island, NY, USA), and the RNA concentration and purity were measured by UV spectrophotometry (ND-1000, Thermo, Rockford, IL, USA). The extracted total RNA was subjected to reverse transcription reaction using RT-PCR kit (TaKaRa, Shiga, Japan) and ABI HT7900PCR instrument (applied biosystems, Foster City, Calif., USA) to synthesize cDNA. Real-time quantitative PCR was performed using the above cDNA as a template, and 20. mu.l of the reaction system was used.
2.6 tissue sections and HE staining
Clinical specimens and animal tissues are taken, then are fixed, dehydrated and embedded in paraffin by a conventional method, and 6 mu m slices are prepared. Before dyeing, the paraffin in the slices is removed by xylene, and then the slices are dyed by high-concentration to low-concentration alcohol and finally distilled water. And HE staining, namely, placing the section into a hematoxylin water solution for staining for a plurality of minutes after the distilled water is added. The acid water and ammonia water are separated in color for several seconds each. The water is flushed for 1 hour and then distilled water is added for a moment. Dehydrating in 70% and 90% ethanol for 10 min. Dyeing for 2-3 minutes in alcohol eosin staining solution. And (4) dehydrating and transparency, namely dehydrating the dyed slices by pure alcohol, enabling the slices to be transparent by dimethylbenzene, and sealing the slices by gum. And (6) taking a picture.
2.7 extraction and quantification of total cellular proteins:
and (3) total protein extraction: (1) the cell culture fluid was aspirated and washed twice with pre-cooled PBS; (2) adding a proper amount of RIPA lysate (containing 1% PMSF), and cracking for 15 minutes on ice; (3) the cells were scraped off with a cell scraper, transferred into a pre-cooled EP tube and centrifuged at 12,000rpm for 15 minutes at 4 ℃; (4) collecting supernatant to obtain total protein, and packaging at-80 deg.C. Quantification (BCA method): (1) mixing the solution A and the solution B of the BCA at a ratio of 50:1, and adding 200 mu L of solution A to a 96-well enzyme label plate in each empty; (2) adding 10 μ L/well of cell (or tissue) lysate, RIPA as blank control, and incubating at 37 deg.C for 30 min; (3) the absorbance was measured at 562nm and the protein content in the sample was calculated from the BCA standard curve.
2.8Western blot
(1) Sample preparation: 20 ug of Protein was taken, added to 4 XProtein SDS PAGE Loading Buffer,
mixing, heating at 95 deg.C for 10min to denature protein, and opening disulfide bond;
(2) preparing a separation gel: mixing the above materials uniformly according to the system (10% gel) in the following table, adding into the middle of the cleaned rubber plate, and immediately adding isopropanol to seal;
(3) preparing concentrated glue: after the separation gel is solidified, pouring off the isopropanol, uniformly mixing according to the system in the following table, adding into a rubber plate, and quickly inserting into a comb;
(4) electrophoresis: adding a proper amount of electrophoresis buffer solution into an electrophoresis tank, adding 8 mu L of protein marker and denatured protein into a sample loading hole, carrying out 80V electrophoresis for about 30min until bromophenol blue enters separation gel, changing the voltage to 120V, and carrying out electrophoresis for about 1 hour;
(5) film transfer: carefully taking down the SDS-PAGE gel, putting the PVDF membrane (which needs to be pre-soaked in methanol for 30 seconds for activation), qualitative filter paper and a fiber pad into a membrane transferring buffer solution of an electrophoresis tank, firmly clamping the PVDF membrane, the qualitative filter paper, the gel, the PVDF membrane, the qualitative filter paper and the fiber pad in a sandwich manner (the fiber pad, the qualitative filter paper, the gel, the PVDF membrane, the qualitative filter paper and the fiber pad are sequentially arranged from a negative electrode to a positive electrode), completely removing bubbles, putting the PVDF membrane, the qualitative filter paper and the fiber pad into a transfer tank filled with the membrane transferring buffer solution, putting the SDS-PAGE gel;
(6) and (3) sealing: taking out the PVDF membrane with the protein, immersing the PVDF membrane into fresh blocking solution (5% BSA), and incubating the PVDF membrane on a shaking table for 1 hour at room temperature to block the nonspecific protein binding sites;
(7) a first antibody: cutting the PVDF membrane according to the molecular weight of the needed protein, adding primary antibody, slowly shaking on a shaking table, and incubating overnight at 4 ℃;
(8) washing the membrane: absorbing primary antibody, washing the membrane for 3 times with TBST on a shaking table, 10 minutes each time;
(9) secondary antibody: adding a horseradish peroxidase-labeled secondary antibody, slowly shaking on a shaking table, and incubating for 1 hour at room temperature;
(10) washing the membrane: absorbing the secondary antibody, washing the membrane for 3 times with TBST on a shaking table, 10 minutes each time;
(11) and (3) developing: mixing the developer solution 1:1, dripping the mixture onto a membrane, opening a chemiluminescence imaging analysis system (Tanon5200S), exposing and developing, and observing a protein band;
(12) and (3) analysis: the bands were analyzed using Image J software.
2.9CCK-8 cell Activity assays
For the cells cultured in vitro, the activity of the cells was examined by the CCK-8 method. The CCK-8 kit was purchased from Dojindo (Tokyo, Japan) and the experimental procedures were carried out strictly according to the kit instructions.
3. Results of the experiment
3.1LMK235 inhibits HDAC5 Activity
Addition of LMK235 to the culture broth inhibited HDAC5 activity, thereby increasing human hypertrophic scar primary fibroblast histone acetylation levels (see figure 1).
3.2LMK235 can inhibit the expression of fibrosis marker in human hypertrophic scar fibroblast
LMK235 was added to the culture and the mRNA and protein levels of the fibrosis markers COL1A, COL3A and α -SMA were measured by real-time quantitative PCR (q-PCR) and Western Blot. The results show that the addition of LMK235 to the culture broth significantly reduced the expression of the fibrosis markers COL1A, COL3A and α -SMA (see fig. 2), which is positively correlated with drug concentration.
3.3LMK235 Activity for inhibiting human hypertrophic scar fibroblast
Separating and culturing human hypertrophic scar fibroblast, adding LMK235 into the culture solution, and detecting the proliferative activity of the human hypertrophic scar fibroblast by adopting a CCK-8 method. The results show that the cell activity after intervention is significantly lower than that of the control group by adding LMK235 to the culture solution, and the cell activity is lower with higher drug concentration (see fig. 3).
3.4LMK235 can inhibit the formation of hypertrophic scar in mice
A classical mouse hypertrophic scar model was established to mimic the pathological changes in human hypertrophic scars (figure 4). HE staining was performed on the scar of the mouse after the material was taken. The results show that the cross-sectional area of the mouse skin hypertrophic scar is obviously reduced (p is less than 0.001) after LMK235 is injected, and the mouse hypertrophic scar is inhibited.
3.5LMK235 can inhibit the expression of mouse skin fibrosis marker
The obtained skin samples were subjected to q-PCR and WB assays, and the results showed that the expression of collagen I, collagen III and α -SMA at the mRNA and protein levels (p < 0.001) was significantly reduced by injecting LMK235 (see fig. 5).
The invention firstly provides the application of LMK235 as a medicament for treating hypertrophic scars. The injection of LMK235 in scar can inhibit hyperplastic scar formation.
Claims (6)
- Use of LMK235 in a medicament for inhibiting scarring.
- 2. The use according to claim 1, wherein the medicament is a medicament targeting HDAC5 gene and/or its encoded protein as a drug action target.
- 3. Use according to claim 1 or 2, wherein the administration is by local injection or by painting.
- 4. The use of claim 1 or 2, wherein the medicament is an injectable solution.
- 5. The use of claim 4, wherein the concentration of LMK235 in the injectable solution is 50 ug/ml.
- 6. The use according to claim 1, wherein the inhibition of scarring is HDAC5 inhibition of scarring.
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