CN116491472B - Application of phenylacetylglutamine in construction of chronic wound animal model - Google Patents
Application of phenylacetylglutamine in construction of chronic wound animal model Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
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- A—HUMAN NECESSITIES
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- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6848—Methods of protein analysis involving mass spectrometry
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/20—Animals treated with compounds which are neither proteins nor nucleic acids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of phenylacetylglutamine in constructing a chronic wound animal model. The invention provides a new application of phenylacetylglutamine, and the phenylacetylglutamine with high blood concentration can lead to the prolongation of wound healing time, the thinning of skin and the less deposition of collagen, and a chronic wound animal model is successfully constructed on the basis. The animal model of the invention can be used for screening new drugs, such as diabetic foot ulcers or hyperammemia after treatment by ammonia bypass metabolism.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of phenylacetylglutamine in constructing a chronic wound animal model.
Background
As the largest organ of the human body, the skin is a barrier protecting visceral tissues from the potential environment, and therefore the probability of skin damage is great. For healthy people, wound healing only requires a few days or even no treatment, however, in some cases, the skin tissue repair function is impaired, resulting in a failure of the wound to heal in time, or even to develop into a chronic wound.
The wound surface comprises acute wound surface and chronic wound surface. The wound healed within 1 or 2 weeks is an acute wound. The wound surface with the healing time exceeding 1 or 2 weeks is a chronic wound surface. Generally, chronic wounds develop from acute wounds. Common acute wounds include surgical incisions, skin abrasions, burns, skin areas and the like, and common chronic wounds include pressure sores, vascular (arterial/venous) ulcers of the lower limbs, diabetic foot ulcers (diable foot), other difficult-to-heal wounds (hard-to-heeling) and the like.
With the increasing prevalence of various chronic diseases, chronic wounds including pressure sores, vascular (arterial/venous) ulcers of the lower limbs, diabetic foot ulcers (diabetes foot) and the like are also becoming more common, which will seriously affect the quality of life of the patient, and if the infection spreads, will even threaten the patient's life.
Diabetic ulcers are the most common and clinically difficult wound surface as a common and serious chronic complication for diabetics. It results in 90% of non-invasive amputation, one of the main causes of hospitalization of diabetics, resulting in a cost of up to $40,000 for a uniform hospitalization. About 0.4-0.6 hundred million diabetic foot ulcers exist worldwide, the lifelong prevalence is 19-34%, the recurrence rate of ulcers after wound healing is up to 40%, the mortality risk of DFU patients for 5 years is 2.5 times that of diabetic patients without foot ulcers, and the mortality rate of 5 years after amputation is over 70%. The Wagner classification and Texas (UT) classification of the wound surface are widely used clinically at present, and the prediction rate of prognosis is not high because only the characteristics of the wound surface are focused. Generally, a wound surface which cannot heal within 90 days is called a chronic wound surface, and even if efforts are made for decades, the chronic wound surface still lacks effective treatment means, and a patient is inevitably finally in the end of amputation, so that the patient faces disability and even death, and even survival exists, and the life quality of the patient is greatly reduced. The great obstacle to chronic wound prevention and diagnosis is that the mechanism and target spot exploration are difficult to maintain due to the fact that the chronic wound is various in etiology, complex in classification and lack of an animal model capable of completely simulating chronic wound formation.
The animal chronic wound model used at present adopts a single factor design aiming at classical known causes of wound healing of damage, and comprises diabetes wound mice (gene editing induction or pharmacological induction), radiation wound mice, staphylococcus aureus infected mice and skin ischemia wound mice. Recent advances in molecular biology, genomics, transcriptomics, proteomics, metabolomics and microbiology have, however, helped identify more potential small molecules that impair wound healing in recent years. The findings can be used as biomarkers for predicting the occurrence risk of chronic wounds on one hand, can be used as important supplements based on the basic research of the traditional wound model on the other hand, and can make important prompts and contributions for further establishing a chronic wound risk prediction model combining demographic characteristics, wound characteristics, laboratory indexes and sequencing transcriptome results. The method is favorable for predicting the occurrence risk of the chronic wound and identifying the early-onset chronic wound, so that more positive treatment means are implemented for the patient with the chronic wound early, the clinical efficiency is improved, and the bad prognosis is reduced.
Disclosure of Invention
In view of the above-described drawbacks of the prior art, an object of the present invention is to provide a use of phenylacetylglutamine in constructing a chronic wound animal model, in order to solve the problems existing in the prior art.
In order to achieve the above purpose, the present invention adopts the following technical scheme.
The first aspect of the invention protects the use of phenylacetylglutamine in constructing a chronic wound animal model or in preparing a product for a chronic wound animal model.
In certain embodiments, the animal model is derived from a mammal.
Preferably, the animal is a mouse. More preferably, it is a mouse.
The second aspect of the invention provides a method for constructing a chronic wound animal model, comprising the following steps:
And (3) administering an effective dose of phenylacetylglutamine to an animal, and then creating a wound on the epidermis of the animal to obtain the animal model with the chronic wound surface.
The chronic wound animal model of the present application is particularly suitable for screening candidate drugs for prevention and/or treatment when preventing and/or treating patients suffering from hyperammonemia after treatment with a high-fat high-protein diet or with ammonia bypass metabolism.
In certain embodiments, the effective dose of phenylacetylglutamine is 40 to 60mg/kg body weight/day. So that the concentration of the phenylacetylglutamine in animal plasma is 1.82-267.07 mu M.
In certain embodiments, the phenylacetylglutamine is injected intraperitoneally into an animal.
In certain embodiments, the animal is selected from the group consisting of mammals.
Preferably, the animal is a mouse. More preferably, it is a mouse.
In certain embodiments, the creating is: two full-layer wound surfaces penetrating through the meat membrane are formed on two sides of the spinal column of the animal by using a biopsy punch, and the diameter of each wound surface is 6-10 mm.
Preferably, the diameter of the wound is 8mm.
The third aspect of the invention protects the use of the chronic wound animal model constructed by the construction method described above in screening medicines for preventing and/or treating chronic wound.
In a fourth aspect the invention provides a method of screening for a drug candidate for the prevention and/or treatment of chronic wounds, the drug candidate being administered to a chronic wound animal model as hereinbefore described.
In certain embodiments, the method further comprises: screening the candidate drugs of the chronic wound by changing the animal model of the chronic wound to which the candidate drugs are applied.
The fifth aspect of the invention protects the use of phenylacetylglutamine as a metabolic marker for the manufacture of a product for diagnosing a disease associated with a chronic wound or for assessing the risk of a disease associated with a chronic wound.
The sixth aspect of the invention provides the use of a substance for detecting phenylacetylglutamine levels in the manufacture of a product for diagnosing a disease associated with a chronic wound or for assessing the risk of a disease associated with a chronic wound.
In certain embodiments, the phenylacetylglutamine level refers to the concentration of the phenylacetylglutamine in plasma and/or urine.
In certain embodiments, the phenylacetylglutamine level is positively correlated with risk of developing a disease associated with a chronic wound.
Preferably, the increased level of phenylacetylglutamine increases the risk of developing a disease associated with a chronic wound.
In certain embodiments, the phenylacetylglutamine level is obtained by detection by liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
A seventh aspect of the invention provides a product for assessing the risk of a disease associated with a chronic wound comprising a substance for detecting phenylacetylglutamine levels.
In certain embodiments, the product comprises at least one of a kit, a membrane strip, and a chip.
In certain embodiments, the disease associated with chronic wounds is selected from diabetic foot ulcers or hyperammonemia.
The invention provides a new application of phenylacetylglutamine, which is used for inducing wound healing to be damaged and successfully constructing a chronic wound animal model. The chronic wound animal model has typical characteristics of poor wound healing, thinning skin and reduced collagen deposition, is an ideal animal model for clinical application research, and can be well applied to screening medicines for preventing and/or treating chronic wound.
Compared with the prior art, the invention has the following beneficial effects:
1) The invention discloses that the phenylacetylglutamine can lead to longer wound healing time and is sensitive to drug reaction after intraperitoneal injection for the first time, so that the method is more accurate and has higher efficiency in drug screening than the prior model.
2) The invention discovers that the high blood concentration of the phenylacetylglutamine can lead to poor skin wound healing, proves that the phenylacetylglutamine can play an important role in predicting the risk of diseases related to chronic wounds (such as diabetic foot ulcers or hyperammonemia) as a metabolic marker, and shows the potential of the phenylacetylglutamine as a treatment target of the chronic wounds (such as the diabetic foot ulcers or the hyperammonemia).
Drawings
FIG. 1 is a photograph showing the actual condition of the wound surface of a mouse in example 1 of the present invention at day 0 and day 7 after the injury by injection of PAGln and physiological saline, respectively.
FIG. 2 is a bar graph showing the unoccluded rate of the wound on day 7 of the injury caused by the injection of PAGln and normal saline into the mice in example 1 of the present invention.
FIG. 3 shows H & E and Masson's plots of the neonatal skin epithelium of example 1 of the present invention on day 7 of injury by injection of PAGln and normal saline, respectively.
Detailed Description
According to the application, through a great deal of practical research, the small molecular metabolite phenylacetylglutamine (PAGln) is unexpectedly found to be capable of damaging wound healing, and a chronic wound animal model is constructed by adopting the phenylacetylglutamine on the basis. The chronic wound animal model constructed by the application has the typical characteristics of long wound healing time, thin skin and less collagen deposition, and can simulate the occurrence and development of chronic wound in vivo. Meanwhile, the chronic wound animal model can be applied to screening candidate medicines for treating chronic wounds. The present application has been completed on the basis of this finding.
New application of phenylacetylglutamine
The first aspect of the invention provides the use of phenylacetylglutamine in constructing a chronic wound animal model or in preparing a product for a chronic wound animal model.
The inventor uses small molecular phenylacetylglutamine (PAGln) to build a chronic wound surface animal model, carries out relevant biological tests on the animal model, and finally screens the chronic wound surface model.
Typical symptoms of chronic wounds are wound persistence and chronicity. The application adopts a chronic wound model constructed by phenylacetylglutamine induction, and 60% of wounds are still not closed after 7 days. It was found by HE pathology evaluation that phenylacetylglutamine (PAGln) resulted in a significant thinning of the thickness of the new skin epithelium and a reduction of collagen deposition.
Phenylacetylglutamine
Molecular weight 264.28, molecular formula C 13H16N2O4, CAS number 28047-15-6.
Construction of animal model for chronic wound
The invention also provides a construction method of the chronic wound animal model, which comprises the following steps: injecting phenylacetylglutamine into an animal body, and making a wound on the epidermis of the animal to obtain the chronic wound animal model.
The chronic wound animal model is particularly suitable for patients with hyperlipoidemia or hyperammonemia after treatment by ammonia bypass metabolism.
According to the method of the present application, the effective dosage of phenylacetylglutamine is 40 to 60mg/kg body weight/day. Preferably 50mg/kg body weight/day. According to the method of the present application, the phenylacetylglutamine is injected into an animal body via an intraperitoneal injection, but is not limited thereto. The administration mode is sufficient as long as the concentration of phenylacetylglutamine in animal plasma is 1.82 to 267.07. Mu.M.
According to the method of the application, the animal is selected from the group consisting of mammals, such as rats and mice. More preferably, it is a mouse.
According to the method of the application, the creating is: two full-layer wound surfaces penetrating through the meat membrane are formed on two sides of the spinal column of the animal by using a biopsy punch, and the diameter of each wound surface is 6-10 mm. More preferably, the diameter of the wound is 8mm.
After induction with phenylacetylglutamine, the 7d wound has an unoccluded rate of 60%, the thickness of the new skin epithelium and skin is significantly thinner, and collagen deposition is also reduced. From the comprehensive indexes, the inventor successfully constructs a chronic wound animal model by using phenylacetylglutamine induction.
Screening for new drugs
The invention successfully constructs the chronic wound animal model by using phenylacetylglutamine induction, and the chronic wound animal model has various applications. For example, it can be used to study and elucidate the pathogenesis of diseases associated with acetylglutamine levels, including but not limited to diabetic foot or chronic wound with hyperammonemia after treatment with ammonia bypass metabolism, at the cellular or even molecular level. Can also be applied to screening medicines for preventing and/or treating chronic wound surfaces.
The invention also provides a method for screening candidate medicines for preventing and/or treating chronic wounds, which comprises the following steps: the test candidate drug is applied to the chronic wound animal model constructed by the method described above, and compared with the chronic wound animal model without the test candidate drug, wherein the test compound which leads to improvement or cure of chronic wound symptoms after application is the candidate drug for treating chronic wound.
The candidate drugs screened above may constitute a screening library, and further cell, animal, and/or clinical trials may be performed on these substances to further confirm the prevention and/or treatment of chronic wound effects of the potential substances.
The invention adopts phenylacetylglutamine for induction, the constructed model is more similar to the human morbidity process and has high consistency, so the invention has more accurate and higher efficiency in drug screening than the former model.
Marker(s)
The invention also provides the use of phenylacetylglutamine as a metabolic marker in the manufacture of a product for diagnosing a disease associated with a chronic wound or assessing the risk of a disease associated with a chronic wound.
The term "marker" in the present invention refers to a molecule that is present in an individual at different concentrations that can be used to predict the disease state of the individual. Markers may include, but are not limited to, small molecules, nucleic acids, proteins, and variants and fragments thereof.
The invention also provides the use of a substance that detects phenylacetylglutamine levels in the manufacture of a product for diagnosing a disease associated with a chronic wound or assessing the risk of a disease associated with a chronic wound.
According to the use of the present application, the phenylacetylglutamine level refers to the concentration of the phenylacetylglutamine in plasma and/or urine.
According to the use of the application, the phenylacetylglutamine level is positively correlated with the risk of suffering from a disease associated with chronic wounds.
Preferably, the increased level of phenylacetylglutamine increases the risk of developing a disease associated with a chronic wound.
The methods for detecting phenylacetylglutamine levels according to the use of the present application are well known to those skilled in the art and include, but are not limited to, detection by liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.
Preferably, the liquid chromatography comprises High Performance Liquid Chromatography (HPLC), ultra high performance liquid chromatography (UPLC) or Nano-liter liquid chromatography (Nano-LC).
More preferably, the separation conditions of the liquid chromatography include: the mobile phase A is acetic acid aqueous solution, and the mobile phase B is acetonitrile solution containing acetic acid; the chromatographic column is selected from C18 silica gel packing column, the column temperature is 35-55 ℃, and the flow rate is 0.2-0.6 mL/min.
In an exemplary embodiment, the liquid chromatography measurement conditions are as follows:
C18 column (50 mm. Times.2.1 mm;2.6 μm);
the column temperature is 35-55 ℃, and the sample injection volume is 0.8-1.2 mu L;
The mobile phase A is acetonitrile solution containing 0.1-0.2% acetic acid aqueous solution, and the mobile phase B is 0.1-0.2% acetic acid;
The flow rate of the mobile phase is 0.2-0.6 mL/min;
Adopting a gradient elution mode, wherein the mobile phase elution gradient is maintained to be 0% B for 0min, 0% B is maintained for 0-2 min, the mobile phase is changed from 0% B to 20% B for 2-5 min, the mobile phase is changed from 20% B to 60% B for 5.0-6.0 min, the mobile phase is changed from 60% B to 70% B for 6.0-7.5 min, the mobile phase is changed from 70% B to 100% B for 7.5-8.0 min, and 100% B is maintained for 8.0-9.5 min; 9.5-10 min from 100% B to 0% B; maintaining 0% B for 10.0-15.0 min.
Preferably, the mass spectrometry conditions are: multi-ion monitoring reaction mode, positive ion mode, electrospray ionization, ion source temperature 300-400 ℃, GS1 of 100-200psi, and gs2 of 200-300psi, the monitored ion pair information is as follows: PAGln quantification: m/z 265.2 →130.15, PAGln-D5: m/z 270.1→ 130.15.
Kit, membrane strip and chip
The present invention also provides a product for assessing the risk of a disease associated with a chronic wound comprising a substance that detects phenylacetylglutamine levels.
The product according to the application comprises at least one of a kit, a membrane strip and a chip.
In certain non-limiting embodiments, the present invention provides kits, chips, membrane strips for predicting the risk of chronic wounds comprising reagents for detecting the metabolic markers set forth in the preceding section. The kit, chip, membrane strip also includes instructions or support materials describing the use of the kit to determine chronic wounds, and/or mentions a website or publication describing it.
The chronic wound related diseases are selected from diabetic foot ulcer or hyperammonemia.
The invention provides application of phenylacetylglutamine in constructing a chronic wound animal model, and provides the chronic wound animal model and a constructing method thereof, wherein the animal model can prolong the wound healing time, so that the animal model can be used for promoting the research of wound healing medicines, and can save the material cost, the labor cost and the time cost; further provides the potential of the phenylacetylglutamine as a metabolic marker in chronic wound surfaces, such as diabetic foot ulcers or a target point for treating the hyperammoniacal diseases after using ammonia bypass metabolism treatment, and has good industrialization prospect.
Further advantages and effects of the present invention will become apparent to those skilled in the art from the disclosure of the present invention, which is described by the following specific examples.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention. The test methods in the following examples, in which specific conditions are not noted, are generally conducted under conventional conditions or under conditions recommended by the respective manufacturers.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, materials used in the embodiments, any methods, devices, and materials of the prior art similar or equivalent to those described in the embodiments of the present invention may be used to practice the present invention according to the knowledge of one skilled in the art and the description of the present invention.
In the following examples of the present application, the measurement conditions of the liquid chromatograph are:
C18 column (50 mm. Times.2.1 mm;2.6 μm);
The column temperature is 45 ℃, and the sample injection volume is 1.0 mu L;
Mobile phase A is acetonitrile solution containing 0.15wt% acetic acid aqueous solution, mobile phase B is 0.15wt% acetic acid;
The flow rate of the mobile phase is 0.4mL/min;
Adopting a gradient elution mode, wherein the mobile phase elution gradient is maintained to be 0% B for 0min, 0% B is maintained for 0-2 min, the mobile phase is changed from 0% B to 20% B for 2-5 min, the mobile phase is changed from 20% B to 60% B for 5.0-6.0 min, the mobile phase is changed from 60% B to 70% B for 6.0-7.5 min, the mobile phase is changed from 70% B to 100% B for 7.5-8.0 min, and 100% B is maintained for 8.0-9.5 min; 9.5-10 min from 100% B to 0% B; maintaining 0% B for 10.0-15.0 min.
The measurement conditions of the mass spectrum are as follows:
multi-ion monitoring reaction mode, positive ion mode, electrospray ionization, ion source temperature 350 ℃, GS1 of 100-200psi, and gs2 of 200-300psi, the monitored ion pair information is as follows: PAGln quantification: m/z 265.2 →130.15, PAGln-D5: m/z 270.1→ 130.15.
Example 1
In this embodiment, the method includes the following steps:
1. Experimental materials
1.1 Experimental animals and foods: male 6-8 week old c57BL/6 mice (weight 18-22 g) (purchased from Shanghai Ji Hui Biol Co., ltd.)
1.2 Reagents
PAGln is purchased from Bachem, inc., cat#4016439.0001.
2. Experimental method
2.1, Establishing a pathological model of high blood concentration PAGln
A model group (PA group, 3) of high blood concentration PAGln was prepared by intraperitoneal injection of PAGln (50 mg/kg/day) (preparation method was referred to Stanley L.Hazen, CELL,2020 (doi: 10.1016/j. Cell.2020.02.016), and dissolved PAGln in physiological saline to form an injection).
A saline group (NS group, 3) was simultaneously established, and each mouse was injected with an equal amount of saline by intraperitoneal injection.
2.2 Model mouse Back wound model establishment
When the concentration of PAGln in the blood of the mice was 1.82 to 267.07 μm, after each mouse was anesthetized, the back hair was shaved off with an electric hair clipper before wound excision, and then depilatory cream was applied. The skin was rinsed with alcohol and two full-thickness wounds penetrating the meat membrane were formed on the back side of the midline using an 8mm biopsy punch on the meat membrane to obtain a back wound model.
On the same day as the wound (day 0), every other day after the wound (i.e. day 1, day 3, day 5 and day 7), the wound surface is photographed and recorded, the area of the wound surface is quantitatively detected by ImageJ (National Institutes of Health), and the non-closure rate of the wound surface is calculated. Mice were given PAGln mg/kg/day daily within days 1-7 after the injury.
The calculation formula of the non-closure rate (x) of the wound surface is
FIG. 1 is a photograph showing the wound surface of a mouse in this example on days 0 and 7 after the mouse is injured by injection PAGln and normal saline, respectively.
As can be seen from fig. 1, wound closure was slowed in the high blood concentration PAGln group (PA group).
FIG. 2 is a bar graph showing the non-occlusion rate of the wound surface on day 0 and day 7 after the mice were injured by PAGln and normal saline injections, respectively, in this example. Wherein p <0.001 is represented.
As can be seen from fig. 2, the area of the wound surface which is not closed is about 40% 7 days after the injury of the Normal Saline (NS); wound closure was slowed in the high blood concentration PAGln group (PA group) and 60% of the wounds remained unclosed after 7 days. Indicating that the wound healing is obviously deteriorated after the intraperitoneal injection PAGln.
2.3 Histological and histopathological analysis
The lethal anesthetized mice were sacrificed by cervical dislocation 7 days after the wound. The back skin was collected, fixed with formaldehyde (at least 1 hour) and then frozen overnight with 30% sucrose, and paraffin embedded. Skin sections (5 μm) were stained with H & E and Masson's trichromatic stain.
Wherein, the HE dyeing steps are as follows: skin sections were dewaxed by 100%, 95%, 75% ethanol gradient and hydrated, then stained with hematoxylin for 5 minutes, rinsed, and hydroalcoholic differentiated for 30 seconds. Eosin staining was followed by rinsing after 2 minutes. Dehydration to wax was performed by a 75%, 95%, 100% ethanol gradient. The xylene transparent back neutral gum encapsulates the tablet.
The steps of MASSON staining are: skin sections were dewaxed by 100%, 95%, 75% ethanol gradient and hydrated. Hematoxylin staining for 5-10 min and washing with running water. Differentiation of 1% hydrochloric acid alcohol, washing with running water for several minutes. The ponceau acid fuchsin dye liquor is dyed for 5-10 minutes, and is slightly rinsed by running water. The phosphomolybdic acid solution was treated for about 5 minutes and directly counterstained with aniline blue dye for 5 minutes without washing. 1% glacial acetic acid treatment for 1 min, and dehydration of 95% alcohol for multiple times. Dehydrated in absolute alcohol, transparent xylene and sealed with neutral gum.
FIG. 3 shows H & E staining and Masson trichromatic staining of new skin epithelium 7 days after mice injected PAGln with the present examples. Wherein NS is normal saline injection+injured mice, PA is PAGln injection+injured mice.
As can be seen from fig. 3, the skin tissue of the control group (NS) has a complete and clear epidermis structure, an obvious keratinized layer, orderly and compact cell arrangement, and more compact staggered arrangement of collagen fibers in the dermis layer; while the thickness of the PA group neoskin epithelium was significantly thinner than that of the normal control group (NS), and collagen deposition at the wound site was also less than that of the normal control group. Indicating that high blood concentration PAGln results in thinning of the skin, reduced collagen and poor wound healing.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (13)
1. The application of phenylacetylglutamine in constructing a chronic wound animal model or preparing a product for the chronic wound animal model;
The animal is a mammal.
2. The use according to claim 1, wherein the animal is a mouse.
3. The method for constructing the chronic wound animal model is characterized by comprising the following steps of:
Administering an effective dose of phenylacetylglutamine to an animal, and then creating a wound on the epidermis of the animal to obtain the chronic wound animal model; the phenylacetylglutamine is injected into an animal body via the abdominal cavity.
4. A method of construction according to claim 3, wherein the animal is selected from the group consisting of mammals;
And/or, the creating is: two full-layer wound surfaces penetrating through the meat membrane are formed on two sides of the spinal column of the animal by using a biopsy punch, and the diameter of each wound surface is 6-10 mm.
5. The method of claim 4, wherein the animal is a mouse.
6. The method of claim 3, wherein the effective dosage of phenylacetylglutamine is 40 to 60mg/kg body weight/day.
7. Use of a chronic wound animal model constructed by the construction method according to any one of claims 3-6 in screening drugs for preventing and/or treating chronic wound.
8. A method of screening a drug candidate for preventing and/or treating chronic wounds, characterized in that the drug candidate is applied to a chronic wound animal model constructed by the construction method according to any one of claims 3 to 6.
9. The method as recited in claim 8, further comprising: screening the candidate drugs of the chronic wound by changing the animal model of the chronic wound to which the candidate drugs are applied.
10. Use of phenylacetylglutamine as a metabolic marker for the preparation of a product for diagnosing a disease associated with a chronic wound or for assessing the risk of a disease associated with a chronic wound.
11. Use of a substance that detects phenylacetylglutamine level in the manufacture of a product for diagnosing a disease associated with a chronic wound or evaluating the risk of a disease associated with a chronic wound.
12. A product for assessing the risk of a disease associated with a chronic wound, said product comprising a substance that detects phenylacetylglutamine levels.
13. The use according to claim 10 or 11 or the product according to claim 12, wherein the chronic wound related disease is selected from diabetic foot ulcers or hyperammonemia.
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| CN103584925A (en) * | 2013-11-12 | 2014-02-19 | 中国人民解放军第四军医大学 | Method for building chronic wound animal experiment model |
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