CN113855655A - Application of bakuchiol in preparation of medicine for treating acute myocardial infarction - Google Patents
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/487—Psoralea
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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
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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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Abstract
The invention relates to an application of bakuchiol in preparing a medicine for treating acute myocardial infarction. The invention proves that the bakuchiol can inhibit proliferation, migration and differentiation of fibroblasts, improve early myocardial fibrosis and left ventricular remodeling after myocardial infarction, and improve the cardiac ejection fraction and contractility, so that cardiac dysfunction after myocardial infarction can be improved; the Chinese medicine monomer bakuchiol is suggested to be a potential treatment medicine for clinical treatment of acute myocardial infarction, and is expected to become one of potential treatment measures for improving cardiac dysfunction of patients suffering from acute myocardial infarction.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of bakuchiol in preparation of a medicine for treating acute myocardial infarction.
Background
Myocardial infarction has been one of the leading causes of global cardiac dysfunction, followed by heart failure and death in patients. The cardiac remodeling plays an important role in dealing with structural disorder after myocardial infarction injury and maintaining the function of cardiac pumping. Among them, in the progressive process of cardiac remodeling, the severity of myocardial fibrosis is closely related to the progressive development of heart failure, which may lead to the development of cardiac function from compensation to decompensation. Excessive fibrosis eventually leads to the development of heart failure; there is currently no clinically effective drug to reduce or reverse cardiac fibrosis.
Cardiac fibroblasts play a crucial role in the development of myocardial fibrosis after a heart has suffered an ischemic insult with myocardial infarction. Fibroblasts in the non-infarcted area migrate to the infarcted area and replace the necrotic cardiomyocytes to maintain the integrity of the cardiac structure and aid in the compensation of cardiac function. When the heart fibroblast is continuously stimulated by various signals such as chemical and mechanical signals, the activated heart fibroblast migrates, proliferates and differentiates to realize the compensation of the heart function and the maintenance of the heart structure. However, this persistent reactive hyperproliferation and differentiation of fibroblasts impairs compensatory remodeling of the heart, and at the same time, such adverse behavior further leads to deterioration of cardiac structure and function. Therefore, reducing excessive migration, proliferation and differentiation of fibroblasts in the infarct area can help improve poor cardiac remodeling, and has an important effect on the maintenance and promotion of cardiac function after myocardial infarction.
The bakuchiol is an effective component extracted from Chinese medicine bone fat supplement, and has been proved to improve mitochondrial oxidation injury of myocardial cells in isolated hearts in ischemia reperfusion injury, and in addition, the component can obviously improve pathological myocardial hypertrophy induced by aortic constriction surgery and diabetic cardiomyopathy induced by hyperglycemia. However, the effect of bakuchiol on cardiac function and myocardial fibrosis following myocardial infarction is unclear.
Disclosure of Invention
The invention aims to solve the technical problem that the application of bakuchiol in preparing a medicament for treating acute myocardial infarction discusses the regulation and control effect of bakuchiol on cardiac remodeling after myocardial infarction and the potential mechanism of bakuchiol.
The invention provides application of bakuchiol in preparation of a medicine for treating acute myocardial infarction.
The medicine is used for improving cardiac function after myocardial infarction, and protecting myocardial fibrosis and poor cardiac remodeling.
The medicine comprises bakuchiol and pharmaceutically available auxiliary materials.
Preferably, the auxiliary materials comprise fillers, binders, lubricants, dispersants, glidants, wetting agents, disintegrants, flavors or colors.
The dosage form of the medicine is oral preparation or injection.
Preferably, the form of the oral preparation includes tablets, hard or soft capsules, troches, dripping pills, pellets, aqueous or oil suspensions, emulsions, powders, granules, oral liquids or syrups.
Preferably, the injection is in the form of: sterile aqueous or oily solutions, sterile powders, liposomes, emulsions or microcapsules.
Advantageous effects
The invention proves that the bakuchiol can improve the reversion of myocardial fibrosis to left ventricle reconstruction after myocardial infarction, improve the cardiac dysfunction after myocardial infarction, improve the cardiac ejection fraction and contractility of heart by inhibiting the proliferation, migration and differentiation of fibroblasts, and prompt that the bakuchiol can be a potential strategy for treating the cardiac reconstruction and cardiac dysfunction after clinical myocardial infarction.
Drawings
FIG. 1 is an echocardiogram of bakuchiol after 7 days of continuous treatment following myocardial infarction; wherein,
a: representative pictures of each group of echocardiograms 7 days after the psoralen continuous treatment; b: histogram of left ventricular minor axis shortening rate (LVFS); c: histogram of Left Ventricular Ejection Fraction (LVEF).
FIG. 2 is an echocardiogram of psoralen on day 28 of continuous treatment following myocardial infarction; wherein, A: representative pictures of each echocardiogram group on day 28 of psoralen treatment; b: histogram of left ventricular minor axis shortening rate; c: histogram of left ventricular ejection fraction.
FIG. 3 is an analysis of the staining results of malachite with bakuchiol for different time points after myocardial infarction; wherein, A: masson stained picture, left: 20 times magnification, right: amplifying by 200 times; b: left ventricular fibrosis ratio; c: left ventricular wall thickness.
FIG. 4 shows the expression of genes related to cardiac myocyte structure and function on day 7 of continuous treatment with bakuchiol after myocardial infarction; wherein, A: gene expression of the peduncle area; b: non-infarct region gene expression.
FIG. 5 shows fibroblast differentiation and related gene expression on day 7 of continuous treatment with bakuchiol after myocardial infarction; wherein, A: gene expression of the peduncle area; b: non-infarct region gene expression; c: immunofluorescence staining of infarct areas (400-fold magnification); d: myofibroblast quantification.
FIG. 6 is a graph of the effect of bakuchiol treatment on isoproterenol-induced proliferation and migration of primary fibroblasts; wherein A: the influence of bakuchiol on the activity of primary fibroblast cells; b: effect of different concentrations of bakuchiol on isoproterenol (ISO, 20 μ M) induced cell activity of primary fibroblasts; c: transwell chamber experiments (200-fold magnification); d: fibroblast transwell chamber experimental mobility histograms.
FIG. 7 is a graph of the effect of bakuchiol treatment on TGF-. beta.1 (5ng/mL) induced proliferation of primary fibroblasts.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
1. Experiment grouping
Experimental mice were randomly divided into 4 groups, which were (1) sham-operated groups: sham surgery was performed and gavage treatment given placebo (5% sodium carboxymethylcellulose); (2) sham surgery + drug group: performing a pseudo-operation and administering bakuchiol of 60mg/kg/day for intragastric administration; (3) operation group: surgery was performed and placebo gavage treatment was given; (4) surgery + drug group: surgery was performed and the administration of bakuchiol at 60mg/kg/day for intragastric administration. The four groups of mice are subjected to echocardiography after 7 days of continuous gavage administration according to the experimental requirements and then are used for taking materials, and the four groups of mice are subjected to echocardiography detection after 28 days of gavage administration according to the experimental requirements and then are used for taking materials and then are subjected to next experiment.
2. Results of the experiment
(1) Psoraleanol improves cardiac function of mice on day 7 after myocardial infarction
After the myocardial infarction model is established, the patient is treated by continuous gavage for 7 days, then ultrasonic cardiogram detection is carried out on each experimental group, and the result shows that (table 1 and figure 1), on the 7 th day after operation, the cardiac function indexes of the operation group are obviously deteriorated (P is less than 0.05) compared with the heart function indexes of the false operation group: LVEF, LVFS, IVSs, IVSd, LVEDV, LVESV, LVIDd, LVIDs and the like. After 7 days of administration of bakuchiol for intragastric administration, the LVFS and LVEF of the surgery group and the drug group are both significantly improved (P is less than 0.05) compared with the surgery group. The other indexes are as follows: IVSs, IVSd, LVEDV, LVESV, LVIDd, LVIDs and the like, and the echocardiogram results show a trend of improvement.
Note: n-4-10/group, compared to the results of the sham group, and # compared to the results of the surgery group.
(2) Psoraleanol improves heart function of mice at 28 days after myocardial infarction
After the myocardial infarction model is established, ultrasonic cardiogram detection is carried out on the heart function and the heart structure of each group of experimental mice after 28 days of continuous gavage treatment. The test results show (table 2, fig. 2) that the heart function index was: LVEF, LVFS, IVSs, IVSd, LVEDV, LVESV, LVIDd, LVIDs, LVPWd and LVPWs all worsened significantly (P < 0.05). After the administration of bakuchiol as a myocardial infarction model for intragastric administration for 28 days, the LVEF (P is less than 0.05) and LVESV (P is less than 0.05) of the operation and drug group are obviously improved compared with those of the operation group; other indicators are as follows: LVFS, IVSs, IVSd, LVEDV, LVIDd, LVIDs, LVPWd, LVPWs and the like, echocardiogram results show an improved trend.
Note: n-4-10/group, compared to the results of the sham group, and # compared to the results of the surgery group.
(3) Bavacrol treatment for reducing left ventricular fibrosis and improving wall thickness after myocardial infarction
Left ventricular myocardial fibrosis levels and left ventricular wall thickness were measured by masson staining (figure 3). The fibrosis area of the heart tissue on the 7 th day after myocardial infarction was measured by using Image J software, and the data result showed that the fibrosis area of the left ventricle of the operation group was significantly enlarged (P < 0.01) compared with the sham operation group. In the staining results of the cardiac tissue sections on the 7 th day and the 28 th day after the treatment of gavage with bakuchiol, the level of left ventricular fibrosis in the operation group and the drug group was significantly reduced (P < 0.05 and P < 0.01, respectively) compared with the operation group. In addition, the left ventricular wall thickness of the cardiac tissue was also measured on day 7 after myocardial infarction using Image J software. After myocardial infarction operation, the left ventricular wall thickness of the operation group is obviously thinner (P is less than 0.001) compared with that of a false operation group, and the staining results of heart tissue sections at 7 days and 28 days after the treatment by the bakuchiol show that the left ventricular wall thickness can be obviously improved (P is less than 0.001 and P is less than 0.01) compared with that of the operation group after the treatment by the bakuchiol.
(4) Effect of Bavacrol treatment on myocardial cell Structure and function related Gene expression
The expression of genes related to cardiomyocyte structure and function at day 7 after myocardial infarction (FIG. 4) including α -MHC and β -MHC associated with cardiomyocyte contractile function, and ANP and BNP stimulated by cardiomyocytes when the heart was overloaded were analyzed. Experimental results show that after myocardial infarction, the gene expression of beta-MHC, ANP and BNP in an infarct area and a non-infarct area is obviously up-regulated after myocardial infarction, and meanwhile, the expression level of alpha-MHC gene is obviously reduced. After treatment with bakuchiol, gene expression of β -MHC (P < 0.05) and BNP (P < 0.01) was significantly reduced in tissue samples of the infarct area (FIG. 4A). The gene expression levels of alpha-MHC (P < 0.01) and ANP (P < 0.05) in the non-infarcted areas were significantly improved after psoralen treatment (FIG. 4B).
(5) Influence of bakuchiol on expression level of fibrosis-related gene after myocardial infarction
The gene expression of TGF-beta 1 and ERK2 genes in the infarct area at 7 days after myocardial infarction is detected, the expression level of the TGF-beta 1 and the ERK2 genes is found to be obviously up-regulated compared with that of a sham operation group, and the gene expression of TGF-beta 1(P is less than 0.01) and the ERK2(P is less than 0.01) in the infarct area after the psoralea fruit phenol is used for treating for 7 days after myocardial infarction can be obviously reduced (figure 5A, B).
In addition to cardiomyocytes, there are other important cells in the heart, such as fibroblasts, that are involved in repairing the structural and functional integrity of the heart following myocardial infarction. Detecting the expression levels of myofibroblast differentiation related genes alpha-SMA and fibrinectin, and finding that the two genes can be obviously up-regulated after myocardial infarction; the bakuchiol enables the gene expression level of the fibrinectin to have a significant reduction trend in both infarct and non-infarct areas.
(6) Bakuchiol affecting differentiation of myofibroblasts in infarct zone
To further investigate whether the differentiation of myofibroblasts in the infarct area of the heart was affected by bakuchiol treatment, the tissue sections were subjected to vimentin (VIM, a fibroblast marker) and α -SMA (a myofibroblast differentiation-related marker) immunofluorescent staining (fig. 5C, D) to facilitate observation of the differentiation of myofibroblasts. The differentiation ratio of myofibroblasts was defined as the number of cells of α -SMA (+) VIM (+) per the number of cells of VIM (+), which represents the cardiac myofibroblast differentiation level. The immunofluorescence staining result shows that the myofibroblast differentiation level is remarkably increased in the infarct area 7 days after myocardial infarction, and the myofibroblast differentiation level is remarkably reduced after the psoralea phenol treatment. In conclusion, treatment with bakuchiol significantly inhibited cardiac myofibroblast differentiation on day 7 after myocardial infarction.
(7) Psoraleal improves isoproterenol-induced proliferation and migration of primary fibroblasts
According to the in vivo experiment results, it can be speculated that the cardiac fibroblasts play an important role in the process of improving myocardial fibrosis after infarction by bakuchiol, and in the in vitro experiment, the effect of primary cardiac fibroblasts of an experimental mouse on bakuchiol is separated for further research.
In the bakuchiol drug toxicity test, the fibroblast proliferation test using CCK8 (FIG. 6A) revealed that bakuchiol did not significantly change the proliferation potency of fibroblasts at the following concentrations of 1. mu.M, 2.5. mu.M, 5. mu.M, and 7.5. mu.M. Primary fibroblasts were stimulated with isoproterenol (20 μ M) for 24 hours and then significantly upregulated in proliferative capacity (fig. 6B), and treatment with different concentrations of bakuchiol for 24 hours significantly inhibited isoproterenol-induced upregulation of cardiac fibroblast proliferation levels.
In addition, the migration capacity of the fibroblasts is detected by detecting the migration number of the fibroblasts, and the experimental result shows (fig. 6C, D) that the psoralen phenol (1 μ M) can significantly inhibit the isoproterenol-induced increase of the migration capacity of the fibroblasts within 24 hours, and the psoralen phenol can also significantly inhibit the migration capacity of the fibroblasts in a basic state.
Meanwhile, transforming growth factor TGF-beta 1(5ng/mL) is used for stimulating the proliferation of cardiac fibroblasts, and bakuchiol (7.5 mu M) is also found to remarkably inhibit the proliferation of the fibroblasts induced by the bakuchiol (figure 7).
3. Conclusion
The invention proves that the bakuchiol can improve the myocardial fibrosis reversion left ventricle reconstruction after acute myocardial infarction, improve the cardiac ejection fraction and contractility and improve the cardiac dysfunction after myocardial infarction by inhibiting the proliferation, migration and differentiation of fibroblasts, and the invention suggests that the traditional Chinese medicine monomer bakuchiol can be a potential treatment medicine for the clinical treatment of acute myocardial infarction and is expected to become one of potential treatment measures for improving the cardiac dysfunction of patients with acute myocardial infarction.
Claims (7)
1. Application of bakuchiol in preparing medicine for treating acute myocardial infarction is provided.
2. Use according to claim 1, characterized in that: the medicament is used for improving the cardiac function after myocardial infarction and protecting against poor cardiac remodeling.
3. Use according to claim 1, characterized in that: the medicine comprises bakuchiol and pharmaceutically available auxiliary materials.
4. Use according to claim 3, characterized in that: the auxiliary materials comprise a filling agent, a bonding agent, a lubricating agent, a dispersing agent, a flow aid, a wetting agent, a disintegrating agent, a spice or a pigment.
5. Use according to claim 1, characterized in that: the dosage form of the medicine is oral preparation or injection.
6. Use according to claim 5, characterized in that: the oral preparation can be in the form of tablet, hard or soft capsule, lozenge, dripping pill, pellet, aqueous or oil suspension, emulsion, powder, granule, oral liquid or syrup.
7. Use according to claim 5, characterized in that: the injection is in the form of a sterilized aqueous or oily solution, a sterile powder, a liposome, an emulsion or a microcapsule.
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Citations (1)
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| CN107050003A (en) * | 2017-03-24 | 2017-08-18 | 中国人民解放军第四军医大学 | Bakuchiol is used for the application for preparing infectious myocardial damage medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107050003A (en) * | 2017-03-24 | 2017-08-18 | 中国人民解放军第四军医大学 | Bakuchiol is used for the application for preparing infectious myocardial damage medicine |
Non-Patent Citations (3)
| Title |
|---|
| WENSHUAI MA: "《Bakuchiol Alleviates Hyperglycemia-Induced Diabetic Cardiomyopathy by Reducing Myocardial Oxidative Stress via Activating the SIRT1/Nrf2 Signaling Pathway》", 《OXIDATIVE MEDICINE AND CELLULAR LONGEVITY》, vol. 2020, pages 1 - 15 * |
| 王铮: "《补骨脂酚在心肌肥厚中的作用及机制研究》", 《中国博士学位论文全文数据库（电子期刊）》 * |
| 王铮: "《补骨脂酚在心肌肥厚中的作用及机制研究》", 《中国博士学位论文全文数据库（电子期刊）》, no. 2, 15 February 2021 (2021-02-15), pages 1 * |
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