CN114306302A - Application of selfheal extract in preparation of medicine for preventing and/or treating coronary heart disease - Google Patents
Application of selfheal extract in preparation of medicine for preventing and/or treating coronary heart disease Download PDFInfo
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Abstract
The application provides application of a selfheal extract in preparing a medicament for preventing and/or treating coronary heart disease, wherein the selfheal extract contains caffeic acid. In the application, caffeic acid and the selfheal extract containing the caffeic acid can improve myocardial ischemia or ischemia reperfusion injury, so that the caffeic acid and the selfheal extract containing the caffeic acid can be used for preventing and/or treating coronary heart disease, and further used for preparing a medicine for preventing and/or treating coronary heart disease; further, the pharmaceutical composition comprising at least one of caffeic acid or a selfheal extract can also be used for preparing a medicament for preventing and/or treating coronary heart disease.
Description
Technical Field
The application relates to the technical field of medicines, in particular to application of a selfheal extract in preparing a medicine for preventing and/or treating coronary heart disease.
Background
The number of cardiovascular disease patients in China is up to 3.3 hundred million, wherein the coronary heart disease is up to 1100 million, and the cardiovascular disease patients are the leading factor of death of residents in China. Ischemic heart disease, also known as coronary heart disease, is caused by the formation of atherosclerotic coronary plaques or coronary spasm, resulting in stenosis or occlusion of the lumen, myocardial ischemia, hypoxia or even necrosis, which in turn causes left ventricular systolic dysfunction, ventricular remodeling and ultimately heart failure and death.
The clinical treatment of coronary heart disease mostly adopts three means of drug therapy, percutaneous coronary artery interventional therapy and bypass surgery. The medicine is mainly used for improving ischemia and relieving symptoms, and comprises a beta receptor retarder, nitrates, a calcium channel retarder, an angiotensin converting enzyme inhibitor and the like. The traditional Chinese medicine is widely used in cardiovascular medicines, has the advantages of definite curative effect, small side effect and huge market potential. Therefore, the development of safe and effective medicaments for resisting myocardial ischemia and ischemia reperfusion injury has important significance for preventing and treating coronary heart disease.
The Prunellae Spica is derived from dried mature cluster of Prunellae Spica (Prunella vulgaris L.) belonging to Prunella of Labiatae. The selfheal has the efficacy of medicine and food, is the main component of the herbal tea, and is mainly used for treating diseases such as acute icterohepatitis, conjunctival congestion and swelling pain, herpes simplex virus keratitis, hypertension and the like clinically. Modern pharmacological research shows that the selfheal has the effects of immunoregulation, antioxidation and the like, but the treatment effect on coronary heart disease is not reported.
Disclosure of Invention
The present inventors have found, through intensive studies, that caffeic acid and a Prunella vulgaris extract comprising the same can improve myocardial ischemia or ischemia-reperfusion injury, and thus can be used for preventing and/or treating coronary heart disease, and have completed the present application based on this.
A first aspect of the application provides the use of caffeic acid in the preparation of a medicament for the prevention and/or treatment of coronary heart disease.
A second aspect of the present application provides use of a prunella vulgaris extract in the preparation of a medicament for preventing and/or treating coronary heart disease, wherein said prunella vulgaris extract comprises caffeic acid.
A third aspect of the present application provides a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one of caffeic acid or a selfheal extract; the Prunellae Spica extract contains caffeic acid.
A fourth aspect of the present application provides the use of the pharmaceutical composition of the third aspect of the present application in the manufacture of a medicament for the prevention and/or treatment of coronary heart disease.
The selfheal extract has the effect of protecting myocardial cells, the caffeic acid and the selfheal extract containing the caffeic acid have anti-inflammatory activity, and can inhibit ventricular remodeling, improve cardiac function and improve myocardial ischemia or ischemia-reperfusion injury in a myocardial ischemia model or an ischemia-reperfusion injury model, so that the caffeic acid and the selfheal extract can be used for preventing and/or treating coronary heart disease, and further used for preparing a medicine for preventing and/or treating coronary heart disease. Further, the pharmaceutical composition comprising at least one of caffeic acid or a selfheal extract can also be used for preparing a medicament for preventing and/or treating coronary heart disease. Furthermore, the selfheal extract can inhibit the development of atherosclerosis and the occurrence and development of coronary heart disease, so that the selfheal extract can be used for preventing and/or treating coronary heart disease and further used for preparing a medicine for preventing and/or treating coronary heart disease.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present application, and it is also obvious for a person skilled in the art to obtain other embodiments according to the drawings.
FIG. 1 is the results of ultrasonic examination of the hearts of rats of each group 4 weeks after administration in the myocardial ischemia model of example 1, wherein A is an M-type ultrasonic examination chart and B is the results of the systolic anterior wall thickness and the diastolic anterior wall thickness.
FIG. 2 shows the results of ejection fraction and short axis shortening of the heart of each group of rats after 1, 2 and 4 weeks of administration in the myocardial ischemia model of example 1.
FIG. 3 is the result of TTC staining of heart tissue of rats in groups 4 weeks after administration in the myocardial ischemia model of example 1.
FIG. 4 is the H & E staining results and partial enlarged views of myocardial tissues of rats in each group 4 weeks after administration in the myocardial ischemia model of example 1.
FIG. 5 shows the results of Masson staining and a partial enlarged image of myocardial tissue of rats in each group 4 weeks after administration in the myocardial ischemia model of example 1.
FIG. 6 is the results of ultrasonic examination of the hearts of rats of each group 4 weeks after administration in the myocardial ischemia model of example 2, wherein A is an M-type ultrasonic examination image, and B is the results of the anterior wall thickness of the left ventricle in the systolic phase and the inner diameter of the left ventricle in the systolic phase.
FIG. 7 shows the results of ejection fraction and short axis shortening of the heart of each group of rats after 1, 2 and 4 weeks of administration in the myocardial ischemia model of example 2.
FIG. 8 is the result of TTC staining of heart tissue of rats in each group 4 weeks after administration in the myocardial ischemia model of example 2, in which panel A is a graph showing staining and panel B is the result of quantifying myocardial infarction area and inflammatory area in panel A.
FIG. 9 shows the results of H & E staining and a partial enlarged view of myocardial tissue of rats in each group 4 weeks after administration in the myocardial ischemia model of example 2.
FIG. 10 shows the results of Masson staining and a partial enlarged image of myocardial tissue of rats in each group 4 weeks after administration in the myocardial ischemia model of example 2.
FIG. 11 shows the results of the amounts of inflammatory factors IL-1. beta., IL-6, and TNF-. alpha.in the serum of rats in each group 1 week after the administration in the myocardial ischemia model in example 2.
FIG. 12 is the results of the ejection fraction and the short axis shortening rate of the hearts of rats in each group in the ischemia-reperfusion injury model in example 3.
FIG. 13 is the result of Ewensky blue-TTC staining of the hearts of rats in the ischemia-reperfusion injury model of example 3, wherein A is a graph showing staining and B is a graph showing the quantitative result of myocardial infarction area in A.
FIG. 14 shows the results of H & E staining of myocardial tissue of rats in the ischemia-reperfusion injury model of example 3.
FIG. 15 shows the TUNEL staining of the hearts of rats in each group in the ischemia-reperfusion injury model of example 3, wherein A is a graph showing the staining and B is a quantitative result of apoptosis in A.
FIG. 16 shows the results of cell viability of groups of H9C2 cardiomyocytes in the glucose-deficient hypoxia-induced cardiomyocyte injury assay of example 4.
FIG. 17 shows the results of cell viability of groups of H9C2 cardiomyocytes in the hypoxia-reoxygenation-induced cardiomyocyte injury assay of example 4.
FIG. 18 shows the NO content of RAW264.7 macrophages in each group in the inflammation test of example 5.
FIG. 19 is the results of oil red O staining of RAW264.7 macrophages in each group in example 6, in which A is a graph showing staining and B is a graph showing quantification of the amount of accumulated cell lipids in A.
Detailed Description
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments that can be derived by one of ordinary skill in the art from the description herein are intended to be within the scope of the present disclosure.
A first aspect of the application provides the use of caffeic acid in the preparation of a medicament for the prevention and/or treatment of coronary heart disease.
The inventor finds that caffeic acid can inhibit ventricular remodeling, improve cardiac function and improve myocardial ischemia in a myocardial ischemia model, so that the caffeic acid can be used for preventing and/or treating coronary heart disease and further used for preparing a medicine for preventing and/or treating coronary heart disease.
In some embodiments of the first aspect of the present application, the coronary heart disease comprises at least one of asymptomatic coronary heart disease, stable angina, ischemic cardiomyopathy, sudden death, acute coronary syndrome, unstable angina, myocardial infarction, myocardial injury resulting from suspending perfusion and resuscitating the heart during cardiac surgery, perioperative myocardial injury from heart valve replacement and coronary bypass surgery, pulmonary heart disease.
A second aspect of the present application provides use of a prunella vulgaris extract in the preparation of a medicament for preventing and/or treating coronary heart disease, wherein said prunella vulgaris extract comprises caffeic acid.
The inventor finds that the selfheal extract can inhibit ventricular remodeling, improve cardiac function and improve myocardial ischemia and ischemia-reperfusion injury in a myocardial ischemia model and an ischemia-reperfusion injury model, so that the selfheal extract can be used for preventing and/or treating coronary heart disease and further used for preparing a medicine for preventing and/or treating coronary heart disease.
The inventor also finds that the selfheal extract has the function of inhibiting atherosclerosis in the early stage of atherogenesis and inhibiting the development of atherosclerosis, so that the occurrence or development of coronary heart disease is inhibited, and the selfheal extract can be used for preventing and/or treating coronary heart disease and further used for preparing medicines for preventing and/or treating coronary heart disease.
The extraction method of the selfheal extract is not particularly limited in the present application as long as the object of the present application can be achieved, and for example, the extraction can be performed by using water as a solvent by adopting an ultrasonic or heating reflux method; in some embodiments of the second aspect of the present application, the Prunella vulgaris extract may be extracted by:
taking selfheal, adding water, heating and refluxing at 80-100 ℃ for 1-3h, and filtering to obtain a first water extract and dregs, wherein the mass ratio of the selfheal to the water is 1 (15-25);
adding water into the medicine residues, heating and refluxing at 80-100 ℃ for 0.5-1.5h, and filtering to obtain a second water extract, wherein the mass ratio of the medicine residues to the water is 1 (8-12);
and (3) combining the first water extract and the second water extract, concentrating and drying to obtain the selfheal extract.
The concentration and drying method is not particularly limited in the present application as long as the object of the present application can be achieved, and the combined extract may be concentrated to a thick state by, for example, concentration under reduced pressure; the drying can be performed in a freeze drying mode, and can be performed in a refrigerator, the extracting solution is concentrated and then is placed in the refrigerator with the temperature of-70 to-90 ℃ for freezing for 22-26h, and a freeze dryer is used for drying for 1-3 days.
In some embodiments of the second aspect of the present application, the caffeic acid is the only active ingredient of the extract of Prunella vulgaris.
In some embodiments of the second aspect of the present application, the coronary heart disease comprises at least one of asymptomatic coronary heart disease, stable angina, ischemic cardiomyopathy, sudden death, acute coronary syndrome, unstable angina, myocardial infarction, myocardial injury resulting from suspending perfusion and resuscitating the heart during cardiac surgery, perioperative myocardial injury from heart valve replacement and coronary artery bypass surgery, pulmonary heart disease.
A third aspect of the present application provides a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one of caffeic acid or a selfheal extract; the Prunellae Spica extract contains caffeic acid.
In some embodiments of the third aspect of the present application, the Prunella vulgaris extract may be extracted by:
taking selfheal, adding water, heating and refluxing at 80-100 ℃ for 1-3h, and filtering to obtain a first water extract and dregs, wherein the mass ratio of the selfheal to the water is 1 (15-25);
adding water into the medicine residues, heating and refluxing at 80-100 ℃ for 0.5-1.5h, and filtering to obtain a second water extract, wherein the mass ratio of the medicine residues to the water is 1 (8-12);
and (3) combining the first water extract and the second water extract, concentrating and drying to obtain the selfheal extract.
In some embodiments of the third aspect of the present application, the caffeic acid is the only active ingredient of the extract of Prunella vulgaris.
In some embodiments of the third aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient; the pharmaceutically acceptable carrier or excipient is selected from at least one of a solvent, a diluent, a dispersing agent, a suspending agent, a surfactant, an isotonic agent, a thickening agent, an emulsifying agent, a preservative, a binder, a lubricant, a stabilizer, a hydrating agent, an emulsification accelerator, a buffer, an absorbent, a coloring agent, a flavoring agent, a sweetening agent, an ion exchanger, a mold release agent, a coating agent, a flavoring agent, or an antioxidant.
Herein, "pharmaceutically acceptable" means having no substantial toxic effect when used in the usual dosage amounts, and thus being approved by the government or equivalent international organization or approved for use in animals, more particularly in humans, or registered in the pharmacopoeia.
The "pharmaceutically acceptable carrier or excipient" useful in the pharmaceutical compositions of the present application may be any conventional carrier in the art of pharmaceutical formulation, and the selection of a particular carrier will depend on the mode of administration or the type and state of the disease used to treat a particular patient. The preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical art.
As used herein, the term "pharmaceutical composition" has its ordinary meaning. In addition, the "pharmaceutical composition" of the present application may also be present or provided in the form of a health product, a functional food, a food additive, or the like. The pharmaceutical compositions of the present application can be prepared by conventional techniques in the pharmaceutical field, particularly in the formulation field, by obtaining the active ingredients of the raw materials of the pharmaceutical compositions of the present application by extraction, separation and purification means commonly used in pharmaceutical manufacturing, optionally mixing with one or more pharmaceutically acceptable carriers or excipients, and then forming the desired dosage form. The pharmaceutical composition according to the present application is a pharmaceutical preparation which can be suitably used for oral administration, a pharmaceutical preparation (e.g., solution) suitable for parenteral injection (e.g., intravenous injection, subcutaneous injection), a pharmaceutical preparation (e.g., ointment, patch or cream) suitable for surface administration, or a pharmaceutical preparation (e.g., suppository) suitable for rectal administration, and the like. Dosage forms for oral administration may include, for example, tablets, pills, hard or soft capsules, solutions, suspensions, emulsions, syrups, powders, fine granules, pellets, elixirs and the like, without limitation. In addition to the active ingredient, these preparations may contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine), lubricants (e.g., silica, talc, stearic acid or its magnesium salt, calcium salt, and polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone. If necessary, it may further contain pharmaceutically acceptable additives such as disintegrating agents (e.g., starch, agar, alginic acid or sodium salt thereof), absorbents, coloring agents, flavoring agents, sweetening agents, and the like. Tablets may be prepared according to conventional mixing, granulating or coating methods.
A fourth aspect of the present application provides the use of the pharmaceutical composition of the third aspect of the present application in the manufacture of a medicament for the prevention and/or treatment of coronary heart disease.
In some embodiments of the fourth aspect of the present application, the coronary heart disease comprises at least one of asymptomatic coronary heart disease, stable angina, ischemic cardiomyopathy, sudden death, acute coronary syndrome, unstable angina, myocardial infarction, myocardial injury resulting from suspending perfusion and resuscitating the heart during cardiac surgery, perioperative myocardial injury from heart valve replacement and coronary artery bypass surgery, pulmonary heart disease.
In the present application, the only active ingredient refers to the only one of caffeic acid which is the active ingredient capable of preventing and/or treating coronary heart disease in the prunella vulgaris extract or the pharmaceutical composition.
In the present application, the term "treatment" has its ordinary meaning and may refer herein to the treatment of a mammalian subject (preferably a human) already suffering from coronary heart disease with the medicament of the present application in order to produce a therapeutic, curative, palliative, etc. effect on the disease. Similarly, as used herein, the term "prevention" has its ordinary meaning and can refer herein to treatment of a mammalian subject who may or is at risk of developing coronary heart disease with a medicament of the present application in an effort to prevent, hinder, abrogate, etc. the disease.
The experimental materials and methods used in the following examples are, unless otherwise specified, conventional materials and methods.
In the examples of this application, all data are expressed as Mean ± standard deviation (Mean ± s.e.m), and statistical differences between groups were calculated using One-Way ANOVA using SPSS statistical software.
Preparation of Prunellae Spica extract
Taking 2.5kg of Prunellae Spica (purchased from Guangxi Tang pharmaceutical industry, LLC of Annational City), pulverizing, adding 20 times of water, heating and reflux-extracting at 100 deg.C for 2 hr, and filtering to obtain first water extractive solution and residue; adding 10 times of water by mass into the medicine residues, heating and refluxing for extraction at 100 ℃ for 1h, and filtering to obtain a second water extract; mixing the first and second water extractive solutions, concentrating under reduced pressure to obtain thick solution, freezing in-80 deg.C refrigerator for 24 hr, drying for 2 days with freeze dryer, and weighing to obtain Prunellae Spica extract 300 g; grinding into powder, mixing, and storing in refrigerator at 4 deg.C. The selfheal extract contains caffeic acid detected by high performance liquid chromatography. Dissolving Prunellae Spica extract in water to obtain Prunellae Spica water solutions with concentrations of 50, 200, 400, and 600mg/mL respectively.
Example 1 Effect of caffeic acid on improving myocardial ischemia
Rat coronary artery left anterior descending ligation replicates the myocardial ischemia model. Taking 8-week-old healthy SD rats and 76 males, weighing 240g +/-20 g, having an SPF (specific pathogen free) grade and a qualification number of 110324200104618382, and providing the SD rats and the males by Beijing Wintolite laboratory animal technology Limited company; the rats are all raised in the experimental animal center of Tianjin Chinese medicine university at the room temperature of 20-25 ℃ and the relative humidity of 40-60%, and are raised adaptively for one week by adopting a standard raising mode and alternating light and dark environments for 12 hours respectively. Injecting 5% chloral hydrate (6ml/kg) into abdominal cavity of a rat for anesthesia, performing anterior chest surgery for skin preparation after anesthesia, fixing limbs on a rat board in a supine position, wiping and disinfecting with 75% alcohol, then smearing iodophor for secondary disinfection, performing chest opening between 3-4 ribs at the left edge of a sternum, performing blunt separation on subcutaneous tissues and muscles layer by layer, popping the heart out of a heart cavity, finding out the left anterior descending limb of a coronary artery, performing ligation at a position 2mm below the left auricle by using a 5-0 surgical thread and with the depth of 1.5mm and the width of 3mm, rapidly returning the heart to the heart cavity after ligation, pressing and extruding chamber air, closing tissues and skin by using hemostatic forceps, loosening the hemostatic forceps, suturing the skin by using a 2-0 suture line, then rapidly placing the hemostatic forceps on an electric blanket to help reviving and smearing the iodophor at the wound again; the following day after surgery, cardiac ultrasound was performed, and rat Ejection Fraction (EF) values of 30-50% were considered as successful modeling, and the modeled rats were injected subcutaneously with ketoprofen for 3 consecutive days. The 76 rats were divided into 12 control groups, 12 sham-operated groups and 52 operative groups, wherein the control groups were not operated; the false operation group performs false operation, only threading is performed without ligation; the surgical group was operated.
The 36 rats in the surgery group were divided into 3 groups: model group 12, caffeic acid group 12, nifedipine group 12. Wherein nifedipine is a conventional common medicament for treating coronary heart disease and is used as a positive control in the application. After the model building is successful, the rats in each group start to be administrated, 1 time per day, and are continuously administrated by gastric gavage for 4 weeks, wherein, the control group, the sham operation group and the model group are administrated with 4ml/kg of physiological saline per day according to the body weight; caffeic acid group, which is administered with 10mg/kg caffeic acid water solution; in the nifedipine group, 10mg/kg of an aqueous nifedipine solution was administered.
(1) Action of caffeic acid in improving cardiac function
Detecting each group of rats by using an M-type image of a small animal ultrasonic instrument (VisualSonics corporation, model 2100), measuring the values of the systolic and diastolic end-stage left ventricular anterior wall thickness (LVAW) of the hearts of each group of rats, selecting 3 cardiac cycles for each rat to measure, and calculating an average value; the cardiac echocardiography test results of the rats in each group are shown in figure 1, the M-type echocardiography test chart is shown in a chart of figure 1, the statistical results of the systolic phase LVAW and the diastolic phase LVAW are shown in a chart B of figure 1, and the results of the chart a and the chart B of figure 1 show that after 4 weeks of administration, the anterior wall of the left ventricle of the rats in the model group is thinned, the movement is weakened, the inner diameter of the left ventricle is increased, and compared with the control group, the thickness of the anterior wall of the left ventricle of the rats in the model group is obviously thinned in both the systolic phase and the diastolic phase (n is 11, and P is less than 0.01, compared with the control group); significantly increased systolic and diastolic LVAW thickness (n 6, # P < 0.05, vs. model group) following caffeic acid administration indicated that caffeic acid improved left ventricular anterior wall motion and increased anterior wall thickness.
After administration for 1, 2 and 4 weeks, the Ejection Fraction (EF) and the short axis shortening rate (FS) of the rat hearts of each group were measured by a small animal ultrasound machine, and the results of the ejection fraction and the short axis shortening rate obtained by detection are shown in fig. 2, and it can be seen from fig. 2 that the model group can significantly reduce the ejection fraction and the short axis shortening rate of the rat hearts (n-11, P < 0.01, compared with the control group); compared with the model group, the caffeic acid can improve the ejection fraction of the heart of the rat and can obviously improve the short axis shortening rate (n is 10, # P < 0.05, # P < 0.01, compared with the model group); after 2 weeks of administration, caffeic acid can remarkably improve the short axis shortening rate of rats, and the ejection fraction tends to increase; the short axis shortening rate of the caffeic acid group rats continued to increase and exceeded the positive drug nifedipine group 4 weeks after administration.
The above results indicate that caffeic acid has the effect of improving cardiac function and improving myocardial ischemia.
(2) Effect of caffeic acid on inhibiting ventricular remodeling
After 4 weeks of administration, picking up heart tissues of rats of each group, cutting 6 sections from apex to apical direction in parallel, staining by 2,3, 5-triphenyltetrazolium chloride (TTC), photographing, wherein the staining result is shown in figure 3, and the result shows that after 4 weeks of administration, compared with a control group, myocardial tissues of the left ventricle of the model group become white, which shows that myocardial tissue necrosis caused by ischemia is caused, and the myocardial infarction area of the model group is increased; after the caffeic acid group administration, the myocardial infarction area was reduced.
Embedding the myocardial tissues of each group of rats in paraffin, slicing the myocardial tissues into 5 mu m, observing the change of the myocardial tissue morphology and inflammatory cell infiltration of each group of rats by adopting H & E staining (H & E staining kit, Solebao Biotechnology Co., Ltd., product number G1120), and obtaining the H & E staining result of the myocardial tissues of each group of rats as shown in figure 4, wherein the staining result shows that the myocardial cells of a control group are arranged regularly; the model group has a large amount of inflammatory factors which are gathered, inflammatory cell infiltration occurs, arrangement of myocardial cells is loose, interstitial edema occurs, muscle fibers are broken and dissolved, and the nucleus part is shrunk; after administration, the caffeic acid group can reduce inflammatory factor aggregation, inflammatory cell infiltration, interstitial edema of cardiac muscle cells and nucleus shrinkage; the results show that caffeic acid can inhibit the morphological change of the myocardial cells.
Taking paraffin-embedded rat myocardial tissues of each group, slicing the rat myocardial tissues by 5 mu m, and evaluating myocardial fibrosis by adopting Masson staining (Masson staining kit, Shanghai, the next saint Biotech company, product number G1346) to obtain Masson staining results of the rat myocardial tissues of each group as shown in figure 5, wherein the staining results show that myocardial fibrosis is caused after myocardial cell death caused by myocardial ischemia and hypoxia of the myocardial cells of a model group, so that the front wall of the left ventricle is thinned, and the ventricle is expanded, thereby causing cardiac structural dysfunction; the caffeic acid group after administration can reduce left ventricular myocardial fibrosis and improve ventricular anterior wall motion.
The results show that caffeic acid can inhibit ventricular remodeling and improve myocardial ischemia.
The results show that caffeic acid can inhibit ventricular remodeling and improve cardiac function in the myocardial ischemia model, and the caffeic acid can improve myocardial ischemia, so that the caffeic acid can be used for preventing and/or treating coronary heart disease and further used for preparing the medicine for preventing and/or treating coronary heart disease.
Example 2 Prunellae Spica extract for improving myocardial ischemia
Rat coronary artery left anterior descending ligation replicates the myocardial ischemia model. Taking healthy SD rats and 105 males with the age of 8 weeks, weighing 240g +/-20 g, with the SPF grade and the qualification number of 1100111911060448, and providing the SD rats and the males by Beijing Wittisley laboratory animal technology Limited company; the rats are all raised in the experimental animal center of Tianjin Chinese medicine university at the room temperature of 20-25 ℃ and the relative humidity of 40-60%, and are raised adaptively for one week by adopting a standard raising mode and alternating light and dark environments for 12 hours respectively. 105 rats were divided into 11 control groups, 11 sham-operated groups and 83 operated groups, wherein the control groups were not operated; the false operation group performs false operation, only threading is performed without ligation; the operation group performs the operation, 5% chloral hydrate (6ml/kg) is injected into the abdominal cavity of a rat for anesthesia, the chest is operated for skin preparation after anesthesia, the limbs are fixed on a rat board in a supine position, 75% alcohol is used for wiping and disinfecting, secondary disinfection is performed by coating iodophor, the chest is opened between the left edges of the sternum and the sternum from 3 to 4 ribs, subcutaneous tissues and muscles are separated in a layer-by-layer blunt manner, the heart is popped out of the heart cavity, the left front descending limb of the coronary artery is found, a 5-0 operation line is used for ligation at the position 2mm below the left auricle with the depth of 1.5mm and the width of 3mm, the heart is quickly put back to the heart cavity after ligation, the air in a cavity is squeezed out by pressing, the tissues and the skin are closed by hemostatic forceps, the hemostatic forceps are loosened, the skin is sutured by 2-0 suture lines, then the hemostatic forceps are quickly put on an electric blanket to help reviving and the iodophor is coated at the wound again; the following day after surgery, cardiac ultrasound was performed, and rat Ejection Fraction (EF) values of 30-50% were considered as successful modeling, and the modeled rats were injected subcutaneously with ketoprofen for 3 consecutive days.
The 58 rats in the surgery group were divided into 5 groups: 10 models, 9 prunella vulgaris low dose groups, 13 prunella vulgaris medium dose groups, 12 prunella vulgaris high dose groups and 14 nifedipine groups; wherein nifedipine is a conventional common medicament for treating coronary heart disease and is used as a positive control in the application. After the model building is successful, the rats in each group start to be administrated, 1 time per day, and are continuously administrated by gastric gavage for 4 weeks, wherein, the control group, the sham operation group and the model group are administrated with 4ml/kg of physiological saline per day according to the body weight; in the low-dose group of the selfheal, 200mg/kg of selfheal aqueous solution is given; in the middle-dosage group of the selfheal, 400mg/kg of selfheal aqueous solution is given; in the high-dose group of the selfheal, 600mg/kg of selfheal aqueous solution is given; in the nifedipine group, 10mg/kg of an aqueous nifedipine solution was administered.
(1) Function of selfheal extract for improving cardiac function of rat with myocardial ischemia
Detecting each group of rats by using an M-type image of a small animal ultrasonic instrument (VisualSonics corporation, model 2100), measuring values of the systolic and diastolic end-stage anterior wall thickness (LVAW) and the Left Ventricular Inner Diameter (LVID) of the heart of each group of rats, selecting 3 cardiac cycles for each rat to measure, and calculating an average value; the inner diameter of the left ventricle of the ultrasonic detection model set is obviously increased in the systolic period and the diastolic period, and the thickness of the front wall of the left ventricle is obviously reduced; wherein the cardiac echocardiography test results of the rats in each group are shown in figure 6, the M-type echocardiography test chart is shown in a graph A of figure 6, the statistical results of the systolic LVAW and LVID are shown in a graph B of figure 6, and the results of the graph A and the graph B of figure 6 show that the ventricular cavity diameter of the rats in the model group is enlarged, the left ventricular anterior wall motion is weakened, and the systolic LVAW of the model group is obviously reduced and the systolic LVID of the model group is obviously increased compared with the control group and the sham operation group after 4 weeks of administration (n is 10, P is less than 0.01, and the control group is compared with the model group; P is less than 0.01, and the sham operation group is compared with the model group); compared with a model group, the selfheal middle-dose group (n is 13, # P is less than 0.05, and compared with the model group) can obviously improve the contraction phase LVAW of a rat and obviously reduce the contraction phase LVID; the selfheal high-dose group has the tendency of increasing the contraction period LVAW of a rat and reducing the contraction period LVID of the rat, and the result shows that the selfheal extract can inhibit the expansion of ventricular cavity diameter, improve the motion state of the left ventricular wall and reduce the risk of the right ventricular dysfunction.
After administration for 1, 2 and 4 weeks, the Ejection Fraction (EF) and the short axis shortening rate (FS) of the rat hearts of each group are measured by a small animal ultrasonic instrument, the ejection fraction and the short axis shortening rate of the rat hearts of each group are detected and obtained, and the results are shown in figure 7, and according to figure 7, the ejection fraction and the short axis shortening rate of the rat hearts of the model group can be obviously reduced (n is 10, P is less than 0.01, the comparison of the control group and the model group; P is less than 0.01, and the comparison of the sham operation group and the model group); compared with the model group, the selfheal medium-dose group can obviously improve the ejection fraction and the short axis shortening rate of rat hearts (n is 13, # P is less than 0.05, # P is less than 0.01, compared with the model group), and the selfheal high-dose group also shows the improvement effect on the ejection fraction and the short axis shortening rate (n is 12, # P is less than 0.05, # P is less than 0.01, compared with the model group), and the result shows that the selfheal extract can improve the ventricular contractile function.
The results show that the selfheal extract has the effect of improving the cardiac function of rats with myocardial ischemia and can improve the myocardial ischemia.
(2) Function of selfheal extract for inhibiting ventricular remodeling of myocardial ischemia rat
After 4 weeks of administration, each group of rat heart tissues was harvested, 6 sections were cut in parallel from the apex to the apex, stained with 2,3, 5-triphenyltetrazolium chloride (TTC), photographed, and the results of staining are shown in a of fig. 8, and the results of a were quantitatively analyzed using Image J software to calculate the myocardial infarction area (Scar area) and the Inflammatory area (Inflammatory area), and the results are shown in B of fig. 8; the results of graphs a and B in fig. 8 show that after 4 weeks of administration, the myocardial infarction area of the model group was significantly increased compared to the control group, and the myocardial infarction area and inflammatory area of the model group were significantly increased compared to the control group (n-5, × P < 0.01, × P < 0.001, compared to the control group); after administration treatment, the myocardial infarction area of rats in the dose group in the selfheal is reduced, the myocardial infarction area and the inflammation area are obviously improved (n is 5, # # P is less than 0.01, and # # P is less than 0.001 compared with a model group), myocardial cell necrosis and apoptosis are reduced compared with the model group, left ventricle expansion is reduced, the thickness of the front wall of the left ventricle is increased, and the infarction area is reduced.
Embedding the myocardial tissues of the rats of each group with paraffin, slicing the myocardial tissues into 5 mu m, and observing the morphological change and inflammatory cell infiltration of the myocardial tissues of the rats of each group by adopting H & E staining to obtain H & E staining results of the myocardial tissues of the rats of each group, wherein the H & E staining results show that the myocardial cells of a control group are arranged regularly; the myocardial cells in the infarct zone of the model group are loosely arranged, interstitial edema exists, muscle fibers are broken and dissolved, and the cell nucleus part is shrunk and infiltrated by inflammatory cells; after administration, the selfheal middle-dose group can improve the myocardial cell morphology and reduce inflammatory cell infiltration; the result shows that the selfheal extract can inhibit the morphological change of the myocardial cells.
Taking paraffin-embedded rat myocardial tissues of each group, slicing the rat myocardial tissues by 5 microns, and evaluating myocardial fibrosis by adopting Masson staining to obtain Masson staining results of the rat myocardial tissues of each group as shown in figure 10, wherein the staining results show that a large amount of myocardial cells of a model group die, collagen deposits, the wall of a left ventricle becomes thin, the elasticity becomes poor, and the diameter of the ventricle cavity becomes large, and the selfheal middle-dose group can obviously reduce the collagen deposits, maintain the thickness of the ventricle front wall and has no obvious expansion of the ventricle after administration, thereby improving the structure and the function of the left ventricle.
The results show that the selfheal extract can effectively inhibit ventricular remodeling of rats with myocardial ischemia and improve myocardial ischemia.
(3) Inflammation inhibiting effect of Prunellae Spica extract
After 1 week of administration, the inflammatory factors in the serum of each group of rats were measured using enzyme-linked immunosorbent assay kit (ELISA kit, purchased from R & D, USA) for IL-1 β, IL-6, TNF- α: the results of the contents of interleukin 1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) are shown in fig. 11, and the results show that the contents of the inflammatory factors IL-1 beta, IL-6 and TNF-alpha in the model group are all significantly increased compared with the control group (n is 3, P is less than 0.001 compared with the control group); compared with the model group, the contents of inflammatory factors IL-1 beta, IL-6 and TNF-alpha in the dose group in the selfheal are all obviously reduced (n is 3, # P is less than 0.05, # P is less than 0.01, and compared with the model group); the result shows that the selfheal extract has the function of inhibiting inflammation.
The results show that the selfheal extract can reduce inflammation, inhibit ventricular remodeling and further improve cardiac function in a myocardial ischemia model with ligation of left anterior descending branch of rat, and the selfheal extract can improve myocardial ischemia, so that the selfheal extract can be used for preventing and/or treating coronary heart disease and further preparing a medicine for preventing and/or treating coronary heart disease.
Example 3 Effect of Prunella vulgaris extract on ameliorating ischemia-reperfusion injury
And performing ischemia reperfusion operation to construct an ischemia reperfusion injury model. Taking 8-week-old healthy SD rats and 60 males with the weight of 240g +/-20 g and the SPF level, and providing the SD rats and the males by Beijing Wintonlihua laboratory animal technology company Limited; the rats are all bred in the experimental animal center of Tianjin Chinese medicine university at the room temperature of 20-25 ℃ and the relative humidity of 40-60%, and are bred adaptively for one week in a standard breeding mode with 12h alternation of light and dark environments. The SD rats were divided into 10 sham surgery groups, 10 model groups, 10 Prunella vulgaris low dose groups, 10 Prunella vulgaris medium dose groups, and 10 Prunella vulgaris high dose groups. Pre-administration of rats is performed by intragastric administration for 1 time every day for 7 days; wherein, the sham operation group and the model group are administered 8ml/kg of physiological saline per day according to the body weight; in the low-dose group of the selfheal, 50mg/kg of selfheal aqueous solution is given; in the middle-dosage group of the selfheal, 200mg/kg of selfheal aqueous solution is given; in the high-dose group of the selfheal, 400mg/kg of selfheal aqueous solution is given; ischemia reperfusion surgery was performed 2 hours after the last gavage.
Taking a rat in a sham operation group for a sham operation, and threading without ligation; the remaining rats in each group were subjected to ischemia reperfusion surgery: anaesthetizing with 10% chloral hydrate, performing tracheal intubation, connecting a breathing machine, adjusting the parameters to be tidal volume of 3ml, frequency of 85 and breathing ratio of 1:1, sequentially cutting open chest skin and muscles, exposing ribs, expanding the ribs, exposing heart, tearing off pericardium, inserting a needle at a position 2-3mm below a left auricle by using a 6-0 operation line, ligating the left anterior descending branch of coronary artery, and turning the heart below a ligature line from red to white to prove that the ligature is successful, suturing the muscles and the skin, sterilizing wounds, withdrawing the breathing machine, suturing trachea and neck skin, loosening a sliding knot in vitro when the heart is infarcted for 45 minutes to realize reperfusion, performing cardiac ultrasound when the reperfusion is performed for 24 hours, and measuring the ejection fraction and the short axis shortening rate of the heart.
(1) Cardiac function improving effect of selfheal extract
EF and FS values were measured for each group of rat hearts using a small animal ultrasound machine (feiyino, model VINNO 5) and the results are shown in fig. 12, which shows a significant decrease in both EF and FS values for the model group compared to the sham group (n 8, P < 0.01, compared to the sham group); compared with the model group, the medium-dose group and the high-dose group of the selfheal can obviously improve EF and FS values of rat hearts (n is 8, # P is less than 0.05, # P is less than 0.01, and compared with the model group), and the result shows that the selfheal extract has the function of improving the cardiac function and can improve the ischemia-reperfusion injury.
(2) Prunellae Spica extract for inhibiting ventricular remodeling
Taking down the hearts of each group of rats, putting the hearts into pre-cooled K-H (Krebs-Henseleit) solution at 4 ℃, quickly hanging the hearts on a langendorff isolated perfusion system, ligating coronary arteries, injecting 0.1ml of 2% Evans blue solution into the aorta, taking down the hearts, putting the hearts into a refrigerator at-40 ℃, freezing for 1H, uniformly cutting the frozen hearts into 6 to 7 pieces from the apex to the ligature line by using an operating knife, putting the cut pieces into 2% TTC solution, and reacting in a dark place for 15min to obtain Evans blue-TTC staining results of each section, wherein the Evans blue-TTC staining results are shown in a picture of fig. 13, and the results of the A picture are quantitatively analyzed by adopting Image J software to obtain quantitative results of myocardial infarction areas, and are shown in a picture B of fig. 13; the results of panels a and B of fig. 13 show that the myocardial infarction area was large and the myocardial infarction area was large in the model group; compared with the model group, the selfheal medium-dose group and the selfheal high-dose group can reduce myocardial infarction areas and can obviously reduce myocardial infarction areas (n is 4, # P is less than 0.05, # P is less than 0.01, and compared with the model group).
Embedding the rat myocardial tissues of each group in paraffin, slicing the rat myocardial tissues by 5 microns, and observing the change of the form of the rat myocardial tissues of each group by adopting H & E staining to obtain the H & E staining result of the rat myocardial tissues of each group, wherein the H & E staining result is shown in figure 14, and the staining result shows that the myocardial cells of the sham operation group are arranged in order; the myocardial cells in the infarct zone of the model group are loosely arranged and interstitial edema occurs; the selfheal middle-dose and high-dose groups can improve the morphology of cardiac muscle cells; the result shows that the selfheal extract can inhibit the morphological change of the myocardial cells.
OCT embedding is carried out on each group of rat hearts, the rat hearts are cut into frozen sections of 10 mu m, TUNEL staining is carried out to evaluate the myocardial apoptosis, the obtained result of TUNEL staining of each group of rat hearts is shown as an A picture in figure 15, Image J software is adopted to carry out quantitative analysis on the result of the A picture, and the obtained result of the apoptosis rate is shown as a B picture in figure 15; the results of panels a and B of fig. 15 show a significant increase in the number of cardiomyocytes undergoing apoptosis in the model group compared to the sham group, with a higher rate of apoptosis (n-4, P < 0.01, compared to the sham group); the selfheal middle-dose group and the selfheal high-dose group can obviously reduce myocardial apoptosis (n is 4, # # P is less than 0.01, compared with a model group).
The results show that the selfheal extract can effectively inhibit ventricular remodeling and improve ischemia-reperfusion injury.
The results show that the selfheal extract can inhibit ventricular remodeling and improve cardiac function in an ischemia-reperfusion injury model, and the selfheal extract can improve ischemia-reperfusion injury, so that the selfheal extract can be used for preventing and/or treating coronary heart disease, and further can be used for preparing a medicine for preventing and/or treating coronary heart disease.
Example 4 the effect of Prunella vulgaris extract on protecting cardiomyocytes
H9C2 cardiomyocytes (purchased from Pronospora) were cultured in DMEM medium (containing 10% fetal bovine serum, 1% diabody) at 37 ℃ with 5% CO2Cultured in an incubator.
(1) Function of selfheal extract for improving myocardial cell injury induced by lack of sugar and oxygen
Inoculating H9C2 cardiomyocytes into a 96-well plate at 6000/well, culturing for 24H, pre-administering, sequentially administering low, middle and high doses of Prunellae Spica respectively to obtain Prunellae Spica extract with final concentration of 20, 40 and 80 μ g/mL (the Prunellae Spica extract is dissolved in Phosphate Buffer Solution (PBS)), administering equal volume of PBS to control group and model group, culturing for 24H, changing D-Hank's sugar-free medium, transferring the rest groups except control group into 37 deg.C 95% N2+5％CO2The hypoxia cell of (1) was subjected to hypoxia and sugar depletion (OGD) for 18 hours, the cell viability was measured by MTT method (thiazole blue, MTT, Sigma), the absorbance (OD) value was measured at 490nm, the cell viability was expressed by OD value, and the cell viability results of the prunella vulgaris extract are shown in fig. 16; from the results of fig. 16, the model group was able to significantly reduce cardiomyocyte viability compared to the control group (n-9, P < 0.001, compared to the control group); compared with the model group, the selfheal extract pretreatment can inhibit the reduction of the activity of myocardial cells (n is 9, # # P is less than 0.01, compared with the model group); the result shows that the selfheal extract can inhibit myocardial cell injury induced by sugar deficiency and oxygen deficiency and has the effect of protecting myocardial cells.
(2) Influence of Prunellae Spica extract on myocardial cell injury induced by anoxia reoxygenation
Inoculating H9C2 cardiomyocytes into a 96-well plate at 5000/well, culturing for 24H, pre-administering, and respectively administering Prunellae Spica extract to obtain Prunellae Spica extract with final concentration of 6.1, 12.5, 25, 50, and 100 μ g/mL (dissolving Prunellae Spica extract with PBS); the control group and the model group were given an equal volume of PBS; culturing for 2h respectively; adding H to each group except the control group2O2Stimulating for 2h at 350 mu mol/L, and adding water with the same volume to the control group for culturing for 2 h; measurement of fineness by CCK8 method (CCK8 kit, Saint Corp.)Cell viability, OD value was measured at 450nm and recorded, and the cell viability was expressed as OD value, and the cell viability result of Prunellae Spica extract is shown in FIG. 17; from the results in fig. 17, the model group was able to significantly reduce cardiomyocyte viability compared to the control group (n-4, P < 0.01, compared to the control group); compared with a model group, the selfheal extract pretreatment can inhibit the reduction of the activity of myocardial cells (n is 4, # P < 0.05, # P < 0.01, compared with the model group); the result shows that the selfheal extract can inhibit myocardial cell injury induced by hypoxia reoxygenation and has the effect of protecting myocardial cells.
Example 5 anti-inflammatory Activity of caffeic acid and Prunella vulgaris extract containing the same
RAW264.7 macrophages (purchased from ATCC company, USA) were cultured in DMEM medium (containing 10% fetal bovine serum, 1% double antibody) at 37 deg.C and 5% CO2Culturing in an incubator; inoculating RAW264.7 cells into a 96-well plate at 6000/well, culturing for 24h, pre-administering, wherein the final concentration of caffeic acid after caffeic acid administration is 50 [ mu ] mol/L (caffeic acid is dissolved by PBS), the final concentration of selfheal extract after selfheal group administration is 100 [ mu ] g/mL (selfheal extract is dissolved by PBS), the model group is administered with PBS with the same volume, and culturing for 2h respectively; each group was stimulated with 10. mu.g/mL LPS (lipopolysaccharide, Sigma) for 18h, which stimulates macrophages to release nitric oxide; the NO content is measured by adopting a Nitric Oxide (NO) content detection kit (Solebao company), the NO content is taken as an inflammation evaluation index, the NO content results of each group are shown in figure 18, compared with a model group, the NO content of a selfheal group and a caffeic acid group is remarkably reduced (n is 3, and P is less than 0.05, compared with the model group), the selfheal extract and the caffeic acid can inhibit macrophage inflammation, and the results show that the selfheal extract and the caffeic acid have anti-inflammatory activity.
EXAMPLE 6 inhibition of Atherosclerosis by Prunellae Spica extract
Foam cell formation is an early event in atherogenesis; in the early stage of atherogenesis, monocytes in the blood differentiate into macrophages under the endothelium, through the endothelial space; macrophages engulf oxidized low density lipoproteins beneath the vascular endothelium, leading to intracellular lipid accumulation and conversion into foam cells; foam cells accumulate to form lipid streaks and even lipid plaques. This example investigates the effect of Prunella vulgaris extract on atherosclerosis by establishing a macrophage foaming model.
RAW264.7 macrophages (purchased from ATCC company, USA) were cultured in DMEM medium (containing 10% fetal bovine serum, 1% double antibody) at 37 deg.C and 5% CO2Culturing in an incubator; inoculating RAW264.7 cells into a 96-well plate at 10000/well, culturing for 24h, pre-administering for 2h, wherein the final concentration of the self-heal extract after the self-heal low-dose group is administered is 50 mu g/mL (the self-heal extract is dissolved with water), the final concentration of the self-heal extract after the self-heal high-dose group is administered is 200 mu g/mL (the self-heal extract is dissolved with water), and the control group and the model group are administered with water with the same volume; the pre-administration model group, the Prunella vulgaris low dose group and the Prunella vulgaris high dose group are both administered with equal volume of 50 μ g/mL oxidized low density lipoprotein (ox-LDL, Shanghai-derived leaf Biotech limited) to induce foam cell model, and cultured for 48 h; measuring lipid accumulation in RAW264.7 macrophage cell by using 0.5% prepared oil red O (Solebao) staining, wherein the staining result is shown in A of FIG. 19, the result of A is quantitatively analyzed by Image J software, the result of lipid accumulation in each group is calculated and shown in B of FIG. 19, and the result of lipid accumulation is expressed by relative expression of oil red O; based on the results of panels a and B of fig. 19, the model group had a large red-stained lipid accumulation compared to the control group, indicating that 50 μ g/mL ox-LDL successfully induced the foam cell model (n-3, P < 0.01, compared to the control group); compared with a model group, the selfheal extract pretreatment can inhibit lipid accumulation (n is 3, # # P is less than 0.01, compared with the model group), and the result shows that the selfheal extract can reduce the lipid accumulation in RAW264.7 macrophages, and the selfheal extract has the function of slowing down the macrophage from being converted into foam cells, so that the selfheal extract can inhibit the development of atherosclerosis.
In summary, the selfheal extract has the effect of protecting cardiac muscle cells, the caffeic acid and the selfheal extract containing the caffeic acid have anti-inflammatory activity, and can inhibit ventricular remodeling, improve cardiac function and improve myocardial ischemia or ischemia-reperfusion injury in a myocardial ischemia or ischemia-reperfusion injury model, so that the caffeic acid can be used for preventing and/or treating coronary heart disease and can be used for preparing a medicine for preventing and/or treating coronary heart disease. Further, the pharmaceutical composition comprising at least one of caffeic acid or a selfheal extract can also be used for preparing a medicament for preventing and/or treating coronary heart disease. Furthermore, the research of the inventor of the present application finds that the selfheal extract of the present application can inhibit the development of atherosclerosis and the occurrence and development of coronary heart disease, so that the selfheal extract can be used for preventing and/or treating coronary heart disease, and further can be used for preparing a medicine for preventing and/or treating coronary heart disease.
The above description is only for the preferred embodiment of the present application and is not intended to limit the scope of the present application. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application are included in the protection scope of the present application.
Claims (10)
1. Application of caffeic acid in preparing medicine for preventing and/or treating coronary heart disease is provided.
2. The use of claim 1, wherein the coronary heart disease comprises at least one of asymptomatic coronary heart disease, stable angina, ischemic cardiomyopathy, sudden death, acute coronary syndrome, unstable angina, myocardial infarction, myocardial injury resulting from suspending perfusion and resuscitating the heart during cardiac surgery, perioperative myocardial injury from heart valve replacement and coronary bypass surgery, pulmonary heart disease.
3. The application of the prunella vulgaris extract in preparing a medicine for preventing and/or treating coronary heart disease, wherein the prunella vulgaris extract contains caffeic acid.
4. Use according to claim 3, wherein caffeic acid is the only active ingredient of the Prunella vulgaris extract.
5. The use of claim 3, wherein the coronary heart disease comprises at least one of asymptomatic coronary heart disease, stable angina, ischemic cardiomyopathy, sudden death, acute coronary syndrome, unstable angina, myocardial infarction, myocardial injury resulting from suspending perfusion and resuscitating the heart during cardiac surgery, perioperative myocardial injury from heart valve replacement and coronary bypass surgery, pulmonary heart disease.
6. A pharmaceutical composition, wherein the pharmaceutical composition comprises at least one of caffeic acid or a selfheal extract; the Prunellae Spica extract contains caffeic acid.
7. The pharmaceutical composition of claim 6, wherein the caffeic acid is the only active ingredient of the Prunella vulgaris extract.
8. The pharmaceutical composition of claim 6 or 7, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient; the pharmaceutically acceptable carrier or excipient is selected from at least one of a solvent, a diluent, a dispersing agent, a suspending agent, a surfactant, an isotonic agent, a thickening agent, an emulsifying agent, a preservative, a binder, a lubricant, a stabilizer, a hydrating agent, an emulsification accelerator, a buffer, an absorbent, a coloring agent, a flavoring agent, a sweetening agent, an ion exchanger, a mold release agent, a coating agent, a flavoring agent, or an antioxidant.
9. Use of a pharmaceutical composition according to any one of claims 6 to 8 for the preparation of a medicament for the prevention and/or treatment of coronary heart disease.
10. The use of claim 9, wherein the coronary heart disease comprises at least one of asymptomatic coronary heart disease, stable angina, ischemic cardiomyopathy, sudden death, acute coronary syndrome, unstable angina, myocardial infarction, myocardial injury resulting from suspending perfusion and resuscitating the heart during cardiac surgery, perioperative myocardial injury from heart valve replacement and coronary bypass surgery, pulmonary heart disease.
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