CN111514124B - Application of 3-hydroxyphenylacetic acid in preparation of medicine for improving pathologic ventricular remodeling and/or heart failure after myocardial infarction - Google Patents
Application of 3-hydroxyphenylacetic acid in preparation of medicine for improving pathologic ventricular remodeling and/or heart failure after myocardial infarction Download PDFInfo
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- CN111514124B CN111514124B CN202010284844.9A CN202010284844A CN111514124B CN 111514124 B CN111514124 B CN 111514124B CN 202010284844 A CN202010284844 A CN 202010284844A CN 111514124 B CN111514124 B CN 111514124B
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention provides application of 3-hydroxyphenylacetic acid in preparing a medicine for improving ventricular pathological reconstruction and/or heart failure after myocardial infarction, and belongs to the technical field of biological medicines. The 3-hydroxyphenylacetic acid can improve the cardiac function after myocardial infarction, reduce the cardiac fibrosis after myocardial infarction and improve the size of myocardial cells after myocardial infarction. Mouse animal model experiments show that: 3-hydroxyphenylacetic acid can improve the cardiac function of mice subjected to myocardial infarction mouse antibiotic treatment and intestinal flora elimination, reduce cardiac fibrosis of mice subjected to myocardial infarction mouse antibiotic treatment and intestinal flora elimination, and inhibit myocardial hypertrophy of mice subjected to myocardial infarction mouse antibiotic treatment and intestinal flora elimination.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of 3-hydroxyphenylacetic acid in preparing a medicine for improving the pathologic remodeling of ventricles and/or heart failure after myocardial infarction.
Background
Myocardial infarction is a serious disease that seriously harms human health. With the progress of treatment methods such as Percutaneous Coronary Intervention (PCI) reperfusion, the mortality rate of myocardial infarction in the acute stage is greatly reduced, but the subsequent pathological ventricular remodeling and heart failure of a large number of myocardial infarction patients bring huge burden to a medical security system. Therefore, it is of great interest to explore new approaches to the treatment of pathological ventricular remodeling after myocardial infarction and heart failure.
Disclosure of Invention
The invention aims to provide application of 3-hydroxyphenylacetic acid in preparing a medicament for improving the pathological ventricular remodeling and/or heart failure after myocardial infarction, and the 3-hydroxyphenylacetic acid has the effect of treating the pathological ventricular remodeling and heart failure after myocardial infarction.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides application of 3-hydroxyphenylacetic acid in preparing a medicament for improving the pathologic remodeling of ventricles and/or heart failure after myocardial infarction.
Preferably, the myocardial infarction comprises cardiovascular disease-induced myocardial infarction.
Preferably, the cardiovascular and cerebrovascular diseases comprise hypertension or coronary heart disease.
Preferably, the medicament also comprises pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutically acceptable auxiliary materials are selected from one or more of diluents, buffers, suspensions, emulsions, granules, encapsulating agents, excipients, fillers, adhesives, sprays, transdermal absorbents, wetting agents, disintegrants, absorption promoters, surfactants, colorants, flavors and adsorption carriers.
Preferably, the dosage form of the medicine comprises tablets, powder, granules, capsules, decoction, oral liquid, injection or suppository.
The invention has the beneficial effects that: the invention provides application of 3-hydroxyphenylacetic acid in preparing a medicament for improving the pathologic remodeling of ventricles and/or heart failure after myocardial infarction. The 3-hydroxyphenylacetic acid can improve the cardiac function after myocardial infarction, reduce the cardiac fibrosis after myocardial infarction, inhibit the myocardial hypertrophy after myocardial infarction, inhibit the pathological remodeling of ventricles and improve the heart failure. Mouse animal model experiments show that: 3-hydroxyphenylacetic acid can improve the cardiac function of mice subjected to myocardial infarction mouse antibiotic treatment and intestinal flora elimination, reduce cardiac fibrosis of mice subjected to myocardial infarction mouse antibiotic treatment and intestinal flora elimination, and inhibit myocardial hypertrophy of mice subjected to myocardial infarction mouse antibiotic treatment and intestinal flora elimination.
Drawings
FIG. 1 is a representation of ultrasonic cardiac images of a myocardial infarction mouse; wherein A in figure 1 is a cardiac ultrasound representative diagram of a saline-fed group after antibiotic treatment of a myocardial infarction mouse; b in figure 1 is a cardiac ultrasound representation of a 6mg/kg 3-hydroxyphenylacetic acid-fed group after antibiotic treatment in myocardial infarction mice; FIG. 1C is a cardiac ultrasound representation of a 25mg/kg 3-hydroxyphenylacetic acid group after antibiotic treatment in myocardial infarction mice;
FIG. 2 shows the Ejection Fraction (EF) statistics of mouse cardiac ultrasound;
FIG. 3 is a Fractional Shortening (FS) statistic of mouse cardiac ultrasound; wherein, p < 0.01; p < 0.001;
FIG. 4 is a representation of cardiac fibrosis in a myocardial infarction mouse; FIG. 4A is a graph showing representative cardiac fibrosis in a saline-fed group after antibiotic treatment in a myocardial infarction mouse; b in FIG. 4 is a representative diagram of cardiac fibrosis in a group fed with 6mg/kg 3-hydroxyphenylacetic acid after antibiotic treatment in a myocardial infarction mouse; FIG. 4C is a graph showing representative cardiac fibrosis in the 25mg/kg 3-hydroxyphenylacetic acid group after antibiotic treatment in myocardial infarction mice;
FIG. 5 is a statistical result of mouse heart fibrosis; wherein, p < 0.01; p < 0.001;
FIG. 6 is a cross-sectional representation of a heart of a myocardial infarction mouse; a in FIG. 6 is a cross-sectional representation of the heart in the saline-fed group after antibiotic treatment in a myocardial infarction mouse; b in FIG. 6 is a representative diagram of a cross-sectional view of the heart fed with 6mg/kg of 3-hydroxyphenylacetic acid after antibiotic treatment in a myocardial infarction mouse; FIG. 6C is a cross-sectional representation of the heart of the 25mg/kg 3-hydroxyphenylacetic acid group after antibiotic treatment in myocardial infarction mice;
FIG. 7 is a statistical result of cell sizes of myocardial cross-sections; wherein, p < 0.001.
Detailed Description
The invention provides application of 3-Hydroxyphenylacetic acid (3_ Hydroxyphenylacetic acid, 3-HPA) in preparation of a medicine for improving ventricular pathological reconstruction and/or heart failure after myocardial infarction.
In the present invention, the myocardial infarction preferably includes myocardial infarction induced by cardiovascular diseases. In the present invention, the cardiovascular and cerebrovascular diseases preferably include hypertension or coronary heart disease.
In the invention, the 3-hydroxyphenylacetic acid can improve the cardiac function after myocardial infarction, reduce cardiac fibrosis after myocardial infarction and improve the size of myocardial cells after myocardial infarction.
The source of the 3-hydroxyphenylacetic acid is not particularly limited in the invention, and the 3-hydroxyphenylacetic acid can be obtained by chemical synthesis or microbial metabolism.
In the invention, the medicine also comprises pharmaceutically acceptable auxiliary materials. In the present invention, the pharmaceutically acceptable adjuvant is preferably one or more selected from the group consisting of diluents, buffers, suspensions, emulsions, granules, encapsulating agents, excipients, fillers, adhesives, sprays, transdermal absorbents, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavors, and adsorptive carriers.
In the invention, the dosage form of the medicine comprises tablets, powder, granules, capsules, decoction, oral liquid, injection or suppository.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. 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.
Example 1
1. Mouse myocardial infarction model establishment
1) 4% chloral hydrate (0.01ml/g) was intraperitoneally injected into mice until the anesthetic exerted its effect (the tail and limbs of the mouse were clamped with forceps, and no reflex reaction was observed, and it was confirmed that the anesthetic was sufficiently anesthetized.
2) Placing a fully anesthetized mouse on a constant-temperature pad at 37 ℃, performing depilation treatment on the neck and the chest of the mouse, exposing the neck of the mouse, sterilizing the mouse with 75% alcohol, separating the neck skin, muscle and tissue covered on the trachea along a straight line under a microscope, cutting a small hole between two tracheal cartilage rings under the glottis after the trachea is exposed, inserting a tracheal cannula, and fixing.
3) Checking the movement of the thorax to ensure good ventilation of the two lungs (breathing frequency of 120 times/min), then under a microscope, using small scissors to make a transverse incision at the fourth, fifth, intercostal position at the left edge of the left sternum of the mouse, wherein the incision is about 1.2cm long, separating the muscles of the chest wall layer by layer until the intercostal muscles are exposed, using microscopic forceps to separate the intercostal muscles obtusely, exposing the heart, and ligating the left anterior descending artery (between the left auricle and the cone of the pulmonary artery, wherein the ligation success depends on the ischemia (whitening) of the lower apex of the heart due to invisible eyes).
4) Sterilizing the wound after operation with iodine tincture, timely injecting sterile physiological salt into the abdominal cavity if dehydration is observed after operation, taking down the mouse from the constant temperature pad until the mouse is revived, and putting the mouse back into the mouse cage; the sham group (sham) procedure was identical to the procedure described above except that the ligation portion was not performed.
2. Method for eliminating intestinal flora of mice by using antibiotics
To exclude the effects of the mice's own metabolism, the intestinal microbes were first removed and the mice were treated with antibiotics for one week. The specific method comprises the following steps:
four antibiotics ampicillin (0.25mg/ml), neomycin (0.25mg/ml), vancomycin (0.125mg/ml) and metronidazole (0.25mg/ml) were mixed together and abbreviated as ABX. The water bottle is wrapped by aluminum foil paper and is protected from light, so that strong light is avoided. The water is changed every two days, so that the water body is prevented from going bad.
3. Preparation and treatment of 3-hydroxyphenylacetic acid
3-Hydroxyphenylacetic acid powder was purchased, and 3-hydroxyphenylacetic acid was prepared at high and low concentrations (25mg/kg and 6mg/kg) using physiological saline. After mouse myocardial infarction surgery and ABX treatment, the two concentrations of 3-hydroxyphenylacetic acid are respectively used for intragastric administration for treatment for 4 weeks. Based on the effective amount of the 3-hydroxyphenylacetic acid, the mice are subjected to intragastric gavage according to the dosages of 6mg/kg/d and 25mg/kg/d respectively. Gavage for 4 weeks.
4. Cardiac ultrasound of small animals
After 4 weeks of administration, 1.5% -2% of the drug is taken% Isoflurane mice were anesthetized and then Visual Sonics was applied at 30MHz
A 2100 small animal ultrasound imaging system was used to perform cardiac function mouse evaluations.
Collecting the left ventricle cardiogram (major axis and minor axis) of the B model, and collecting the cardiogram of the M model at the maximum diameter of the left ventricle, and adopting LV wall trace to carry out measurement. Left ventricular Ejection Fraction (EF) and left ventricular shortening rate (FS), Left Ventricular Internal Diameter (LVID) in diastole or systole, ventricular septum (IVS) and Left Ventricular Posterior Wall (LVPW) were determined. Each experimental index was measured 3 times per mouse and averaged. The measurement result is shown in fig. 1-3, wherein fig. 1 is a representation of myocardial heart ultrasonic representation of a myocardial infarction mouse; a in figure 1 is a cardiac ultrasound representative diagram of a saline-fed group after antibiotic treatment of a myocardial infarction mouse; b in figure 1 is a cardiac ultrasound representation of a 6mg/kg 3-hydroxyphenylacetic acid-fed group after antibiotic treatment in myocardial infarction mice; FIG. 1C is a cardiac ultrasound representation of a 25mg/kg 3-hydroxyphenylacetic acid group after antibiotic treatment in myocardial infarction mice; FIG. 2 shows the Ejection Fraction (EF) statistics of mouse cardiac ultrasound; FIG. 3 is a Fractional Shortening (FS) statistic of mouse cardiac ultrasound; wherein, p < 0.01; p < 0.001. It can be seen from FIGS. 1 to 3 that 3-hydroxyphenylacetic acid can improve cardiac function of mice with myocardial infarction.
5. Histopathological examination
Mouse heart tissue sections were harvested and fixed in 4% paraformaldehyde, followed by tissue dehydration, infiltration and paraffin embedding. Paraffin sections, each paraffin section having a thickness of 5 μm.
And (3) dyeing the masson, slicing the paraffin, placing the sliced masson in a 65 ℃ oven for 1h, dewaxing and hydrating, using a masson dyeing kit to organize collagen fibers, using hematoxylin to stain cell nucleuses, and finally adopting glycerol to seal the slices. The collagen fiber content was analyzed by observation and photographing under a microscope using Image J software. The results are shown in fig. 4 and fig. 5, wherein fig. 4 is a representation of cardiac fibrosis of a myocardial infarction mouse; FIG. 4A is a graph showing representative cardiac fibrosis in a saline-fed group after antibiotic treatment in a myocardial infarction mouse; b in FIG. 4 is a representative diagram of cardiac fibrosis in a group fed with 6mg/kg 3-hydroxyphenylacetic acid after antibiotic treatment in a myocardial infarction mouse; FIG. 4C is a graph showing representative cardiac fibrosis in the 25mg/kg 3-hydroxyphenylacetic acid group after antibiotic treatment in myocardial infarction mice; FIG. 5 is a statistical result of mouse heart fibrosis; wherein, p < 0.01; p < 0.001. It can be seen from FIGS. 4 and 5 that 3-hydroxyphenylacetic acid can reduce cardiac fibrosis in mice with myocardial infarction.
And (3) HE dyeing, namely taking a paraffin section of the heart of the mouse, baking the paraffin section in an oven at 65 ℃ for 1h, dewaxing and hydrating, and dyeing the tissue section by hematoxylin-eosin dye. Hematoxylin can stain cell nucleus, and eosin counterstain. After mounting, observing and photographing under a microscope, evaluating the histopathological form, and analyzing the cell size of the myocardial cross section by using Image J software. The results are shown in fig. 6 and 7, in which the myocardial infarction mouse of fig. 6 is a cross-sectional representation of the heart; a in FIG. 6 is a cross-sectional representation of the heart in the saline-fed group after antibiotic treatment in a myocardial infarction mouse; b in FIG. 6 is a representative diagram of a cross-sectional view of the heart fed with 6mg/kg of 3-hydroxyphenylacetic acid after antibiotic treatment in a myocardial infarction mouse; FIG. 6C is a cross-sectional representation of the heart of the 25mg/kg 3-hydroxyphenylacetic acid group after antibiotic treatment in myocardial infarction mice; FIG. 7 is a statistical result of cell sizes of myocardial cross-sections; wherein, p < 0.001. It can be seen from FIGS. 6 and 7 that 3-hydroxyphenylacetic acid can reduce myocardial hypertrophy in myocardial infarction mice.
From the above examples, it can be seen that the 3-hydroxyphenylacetic acid can improve pathological ventricular remodeling and heart failure after myocardial infarction of mice by detecting cardiac function through cardiac ultrasound and myocardial structure and cardiac fibrosis through histological staining after 3-hydroxyphenylacetic acid with high concentration (25mg/kg) and low concentration (6mg/kg) is treated by the mouse model based on myocardial infarction. Accordingly, 3-hydroxyphenylacetic acid can be applied to a therapeutic drug for pathological ventricular remodeling and heart failure after myocardial infarction.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
- Use of 3-hydroxyphenylacetic acid for the preparation of a medicament for improving the pathological remodeling of the ventricles and/or heart failure after myocardial infarction.
- 2. The use of claim 1, wherein the myocardial infarction comprises a cardiovascular disease-induced myocardial infarction.
- 3. Use according to claim 2, wherein the cardiovascular disease comprises hypertension or coronary heart disease.
- 4. The use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable excipient.
- 5. The use according to claim 4, wherein the pharmaceutically acceptable excipient is selected from one or more of a buffer, a capsule, a filler, an adhesive, a transdermal absorbent, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, a colorant, a flavoring agent, and an adsorptive carrier.
- 6. The use of claim 1, wherein the medicament is in the form of tablets, powders, granules, capsules, decoctions, oral liquids, injections or suppositories.
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| CN111743885B (en) * | 2020-08-17 | 2022-03-15 | 山东省科学院生物研究所 | Application of p-hydroxyphenylacetic acid in preventing and/or treating cardiovascular diseases |
| CN115350174B (en) * | 2022-09-29 | 2024-04-26 | 上海大学 | Application of L-norvaline in preparing medicines for treating ventricular remodeling after myocardial infarction |
| CN116459242B (en) * | 2023-06-20 | 2023-09-01 | 北京大学第三医院（北京大学第三临床医学院） | Application of 3-hydroxyphenylacetic acid in preparation of medicines for preventing and/or treating reproductive dysfunction of aged men |
Citations (2)
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|---|---|---|---|---|
| US6623730B1 (en) * | 1999-09-14 | 2003-09-23 | Tepha, Inc. | Therapeutic uses of polymers and oligomers comprising gamma-hydroxybutyrate |
| US20070197650A1 (en) * | 2006-02-21 | 2007-08-23 | University Of Maryland, Baltimore | Ethers of 3-hydroxyphenylacetic acid as selective gamma-hydroxybutyric acid receptor ligands |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6623730B1 (en) * | 1999-09-14 | 2003-09-23 | Tepha, Inc. | Therapeutic uses of polymers and oligomers comprising gamma-hydroxybutyrate |
| US20070197650A1 (en) * | 2006-02-21 | 2007-08-23 | University Of Maryland, Baltimore | Ethers of 3-hydroxyphenylacetic acid as selective gamma-hydroxybutyric acid receptor ligands |
Non-Patent Citations (1)
| Title |
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| 3-Hydroxyphenylacetic acid induces the Burkholderia cenocepacia phenylacetic acid degradation pathway – toward understanding the contribution of aromatic catabolism to pathogenesis;Ijeme A. Imolorhe等;《Frontiers in Cellular and Infection Microbiology》;20111231;第1卷(第14期);第1-7页 * |
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