CN112353810B - Use of compound F-B in preparation of products for preventing and/or treating heart injury - Google Patents
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Abstract
The invention discloses application of a compound F-B in preparing a product for preventing and/or treating heart injury, and the activity research is carried out on the compound F-B, so that the compound F-B is proved to be capable of reducing the ratio of heart to body weight, inhibiting myocardial cell fibrosis by reducing the content of hydroxyproline, inhibiting proliferation of myocardial extracellular matrix, obviously inhibiting apoptosis induced by myocardial toxic effect, and relieving H9c2 myocardial cytotoxicity effect by downregulating the expression level of p-JNK and/or clear-Caspase-3, thereby realizing the effect of preventing and/or treating myocardial cytotoxicity, and being applicable to preparing medicaments for preventing or treating myocardial injury related diseases.
Description
Technical Field
The invention relates to the field of medical application of flavonoid compounds, in particular to application of flavonoid compounds F-B.
Background
Currently, many drugs cause side effects of myocardial toxicity during treatment, especially in chemotherapy of malignant tumors, and the cytostatics used cause serious cardiotoxicity, which adversely affects prognosis and rehabilitation of patients.
Anthracyclines are reported to be generally cardiotoxic, and such drugs are widely used in clinic due to their superior antitumor activity. Taking the most successfully applied anthracycline antitumor drug Doxorubicin (DOX) as an example, the accumulation and dose-dependent cardiomyocyte toxicity of doxorubicinSex is a major problem which has plagued the practice of tumor therapy from drug development to clinical use, in that the therapeutic dose is greater than 550mg/m 2 When the congestive heart failure is induced, the incidence rate is as high as 11% -30%, and the mortality rate is as high as 50% -60%.
Therefore, development of a substance capable of reducing damage to the heart and resisting cardiotoxicity by a cardiotoxic substance is of great importance.
Disclosure of Invention
The invention provides an application of flavonoid compound F-B extracted from sea buckthorn seed meal in preparing a product for preventing and/or treating heart injury, wherein the compound F-B has the effects of inhibiting proliferation of extracellular matrix of cardiac muscle, preventing and/or treating cardiac fibrosis, delaying apoptosis of cardiac muscle cells and preventing and/or treating heart injury or reducing injury caused by cardiotoxic substances.
The invention provides an application of a compound F-B in preparing a product for preventing and/or treating heart injury, wherein the compound F-B has the following structural formula:
in a specific embodiment of the invention, the product is an anti-cardiotoxicity product.
The term "anti-cardiotoxicity" means that damage to the heart caused by substances having cardiotoxicity can be prevented or ameliorated.
In a specific embodiment of the invention, the cardiac injury is selected from cardiac tissue fibrosis and/or myocardial apoptosis.
Further, according to the above use, the product is a product which can reduce the ratio of heart to body weight.
Further, according to the above use, the product is a product for reducing the hydroxyproline content in heart tissue.
Further, according to the above use, the product is a product for delaying or inhibiting apoptosis of myocardial cells.
In a specific embodiment of the invention, the product is a product that down-regulates the expression level of p-JNK and/or clear-Caspase-3;
further, the product is a p-JNK inhibitor and/or a clear-Caspase-3 inhibitor.
The p-JNK inhibitor is a product capable of reducing the content of p-JNK in vivo; the Cleaved-Caspase-3 inhibitor is a product which can reduce the content of Cleaved-Caspase-3 in vivo. Carrying out
In a specific embodiment of the invention, the dosage form of the product is selected from the group consisting of tablets, granules, capsules, suppositories, pills, solutions, suspensions, preferably tablets, solutions; further, the solution is selected from injection solutions.
In the specific embodiment of the invention, the raw materials of the tablet comprise the following components in parts by weight: 10-50 parts of F-B, 100-200 parts of lactose, 10-20 parts of starch, 50-80 parts of microcrystalline cellulose, 1-10 parts of magnesium stearate and 1-10 parts of talcum powder; further comprises 20 parts of F-B, 150 parts of lactose, 15 parts of starch, 65 parts of microcrystalline cellulose, 5 parts of magnesium stearate and 5 parts of talcum powder;
further, the tablet has a specification of 250mg per tablet total mass;
the raw materials of the solution comprise the following components in parts by weight: 1-10 parts of F-B, 30-70 parts of glucose, 6-12 parts of sodium chloride and 900-1000 parts of water; further comprises 5 parts of F-B, 50 parts of glucose, 9 parts of sodium chloride and 940.5 parts of water;
further, the specification of the solution is 1-5 mL, preferably 1mL, per dose.
Anthracyclines, which are drugs containing an anthracycline structure, are a class of chemotherapeutic drugs derived from Streptomyces peucetius varives (caesius), mainly doxorubicin, epirubicin, pirarubicin, epirubicin, daunorubicin, and aclacinomycin, etc., and are widely used for treating hematological malignancies and solid tumors, such as acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarcoma, ovarian cancer, etc. Anthracyclines can also be used in combination with other chemotherapeutic agents and molecular targeted drugs, and anthracycline-based combination therapies are often the standard regimen for first-line therapy.
The anthracycline has wide anti-tumor spectrum, strong anti-tumor effect and definite curative effect, but can cause toxic and side effects such as alopecia, myelosuppression, cardiotoxicity and the like, wherein the cardiotoxicity is the most serious toxic and side effect of the anthracycline.
The cardiac injury described in the use of the present invention is caused by anthracyclines.
The invention has the following beneficial effects:
experiments prove that the compound F-B can reduce the heart to body weight ratio of mice with heart damaged caused by Doxorubicin (DOX) and reduce the hydroxyproline content in heart tissues, and the compound F-B can inhibit the myocardial fibrosis process caused by the action of anthracyclines and inhibit the proliferation of myocardial extracellular matrixes; meanwhile, the compound F-B can down regulate the expression level of p-JNK and clear-Caspase-3 in a DOX-induced myocardial apoptosis model, and inhibit apoptosis induced by myocardial toxic action. The compound F-B has good anti-cardiotoxicity and can be used for preparing products for preventing and/or treating heart injury caused by cardiotoxic substances.
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FIG. 1 shows the toxic effect of flavonoids on H9c2 cardiomyocytes.
FIG. 2 shows the effect of flavonoids on DOX-induced H9c2 myocardial cytotoxicity.
FIG. 3 is a graph showing the effect of flavonoids on DOX-induced activation of H9c2 cardiomyocyte Caspase-3.
FIG. 4 shows the effect of flavonoids on DOX-induced H9c2 cardiomyocytes p-JNK/JNK.
In fig. 3 and 4, the #p <0.05, #p <0.01, #p <0.001, as compared with the Con group; p <0.05, < P <0.01, < P <0.001, compared to the DOX model group; mean±sd, n=3.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments made by those skilled in the art based on the embodiments of the invention without making any inventive effort are within the scope of the invention.
The experimental methods in the examples of the present invention, unless specified, were all conventional methods, and the experimental materials used, unless specified, were all purchased from conventional biochemical reagent companies, and the data in the examples were all average values.
The chemical structural formulSub>A of F-A is as follows:
the chemical structural formula of F-B is:
the chemical structural formula of F-C is as follows:
EXAMPLE 1 therapeutic Effect of Compounds F-B on doxorubicin-induced cardiotoxicity
Rabbit test method for doxorubicin-induced cardiomyopathy (this experiment meets the relevant ethical regulations):
(1) The test was performed with rabbits of both sexes with a starting body weight of 2.3±0.2kg, with untreated animals in group a (control animals, n=8), animals treated with doxorubicin in group b (+placebo instead of test substance, n=8), animals treated with doxorubicin and test substance in group C (n=8), and with flavonoids F-A, F-B, F-C in groups C1, C2, C3, respectively.
(2) Groups b, c were given 2 times a week of 1mg/kg each time for 4 weeks with oral administration of 20mg/kg body weight of the test substance per day, starting on the first day of doxorubicin treatment, while feeding.
(3) After 4 weeks, hearts were isolated and weighed and the hydroxyproline content in heart tissue was measured (according to the liquid chromatography-mass spectrometry/mass spectrometry method for measuring L-hydroxyproline in SN/T3929-2014 outlet foods) and the measurement results are shown in Table 1.
TABLE 1 Effect of flavonoids of formula I on heart failure and alteration in rabbits
Note that: *** : p <0.001, compared to group a; + : p <0.05, compared to group b.
An increase in hydroxyproline content in heart tissue compared to normal values indicates a decline and change in heart.
The test results are shown in table 1, with respect to the heart to body weight ratio, the statistics of heart to body weight ratio for the group c test substance animals (group c1, group c2, group c 3) were significantly reduced compared to the group b doxorubicin-treated animals and reached levels that were not significantly different from the untreated control animals of group a; group b significantly increased the heart to body weight ratio compared to group a and reached very significant levels. The concentration of hydroxyproline in group c is significantly lower than that in group b in terms of hydroxyproline content, reaching a very significant level, indicating that the degree of fibrosis is inhibited to some extent; the concentration of hydroxyproline in group b was significantly higher than in group a, indicating that doxorubicin could induce fibrosis in heart tissue.
Therefore, by the administration of the test substance, the flavonoid compound can obviously reduce the change process of the extracellular myocardial matrix, inhibit the proliferation of the extracellular myocardial matrix and have preventive and/or therapeutic effects on myocardial toxic effects.
EXAMPLE 2 therapeutic Effect of Compounds F-B on doxorubicin-induced cardiotoxicity
Inhibition test of myocardial apoptosis in center of H9c2 myocardial toxicity model:
(1) After H9C2 cells are incubated for 24 hours by using flavonoid compounds F-A, F-B, F-C with different concentrations, the toxic effect of the flavonoid compounds on myocardial cells is evaluated by adopting an MTT colorimetric method, the H9C2 cells are incubated for 1 hour by using the flavonoid compounds in advance, 2.5 mu M DOX is added for culturing for 24 hours, and the apoptosis activity of the flavonoid compounds on Doxorubicin (DOX) induced myocardial cells is screened by adopting an MTT colorimetric method, so that the optimal action concentration range is determined.
(2) Treating different tested seabuckthorn flavonoids with H9c2 myocardial cells for 1H, extracting protein with 2.5 mu M DOX for 24H, cracking, scraping, collecting cell lysate, centrifuging 12000g for 15min, collecting supernatant, discarding precipitate, preserving at-80deg.C, and quantifying protein by BCA method for use; SDS-PAGE electrophoresis (Step 1, 80V,30min; step2,120V,180 min), 5% concentrate gel; transferring film, PVDF film, 30min,80mA; blocking and hybridizing, wherein 5% skimmed milk powder is blocked for 1h, the primary antibody is incubated overnight, and the secondary antibody is incubated for 1-2 h at room temperature in a light shaking way; development, ECL reagent development, gel imaging system observed intracellular Caspase-3 and p-JNK/JNK protein expression.
The results of the test are shown in FIG. 1, and the flavonoid compounds have no statistical difference (0.1-40 mu M) compared with the Con group in a certain concentration range, but have significant difference compared with the Con group when the flavonoid compounds reach 80 mu M, so that the flavonoid compounds can have a certain toxic effect on the activity of H9c2 cells at the concentration.
The results in FIG. 2 show that the flavonoid compound groups in different concentration ranges all show inhibition of DOX-induced myocardial cytotoxicity compared with the DOX model group, and show certain concentration dependence, and the concentration has obvious difference or extremely obvious difference compared with the model group in the range of 5-80 mu M.
The results in FIG. 3 show that the DOX model group can greatly increase the clear-Caspase-3 expression level compared with the Con group, and the low, medium and high dosage groups (10 mu M, 20 mu M and 40 mu M) of flavonoid compounds can reduce the clear-Caspase-3 level elevation caused by DOX to different degrees compared with the DOX model group, and obvious concentration dependence exists; as shown in fig. 4, the DOX model group was able to extremely significantly increase p-JNK expression levels compared to the Con group. There was no statistical difference in p-JNK expression levels between the low dose group (10 μm) and the DOX model group for flavonoids, but there was very significant difference between the medium dose group (20 μm) and the high dose group (40 μm) and a clear concentration dependence. Therefore, the flavonoid compound can down regulate the expression level of p-JNK in a DOX-induced myocardial apoptosis model, and the analysis of the influence of the flavonoid compound on the expression level of clear-Caspase-3 proves that the flavonoid compound can down regulate the expression level of p-JNK/clear-Caspase-3 to inhibit DOX-induced myocardial apoptosis so as to relieve myocardial cytotoxicity.
Therefore, by administering the test substance, the flavonoid compound can inhibit apoptosis induced by myocardial toxic action by down-regulating the expression level of p-JNK/clear-Caspase-3, thereby realizing the prevention and/or treatment effect.
In summary, the flavonoid compound has the effects of inhibiting myocardial fibrosis, myocardial extracellular matrix proliferation and apoptosis induced by myocardial toxicity, and relieving myocardial cytotoxicity, and can be used for preparing medicaments for preventing and/or treating heart injury.
The flavonoid compounds are suitable for being used as medicaments for mammals, particularly human bodies, and are used for preventing and/or treating the damage influence caused by medicaments with cardiotoxic doses and heart damage conditions caused by other chemical substances, particularly heart decay and change, such as myocardial toxicity, myocardial fibrosis and the like of anthracyclines. The flavonoid compounds of the invention can be used as medicaments, in particular as auxiliary treatment in the treatment process of medicaments with toxic side effects on the heart. Depending on the type of treatment regime, the substances used and the form of administration, the use may be made of intravenous, oral or the like, the amounts used being variable and variable.
EXAMPLE 3 tablet containing flavonoid Compound
Each tablet was produced from the following components:
the above components are mixed according to the dosage, granulated, and totally mixed and pressed into tablets of 250 mg.
EXAMPLE 4 injection containing flavonoid Compound
An injection having the following composition per 1ml was produced:
the solid material was dissolved in purified water, and the solution was aseptically filled into 1ml ampoules.
The foregoing description is only exemplary embodiments of the present invention and is not intended to limit the scope of the present invention, and any equivalent processes or modifications using the present invention, or direct or indirect application in other related technical fields, should be considered as included in the scope of the present invention.
Claims (10)
1. Use of a compound F-B for the preparation of a product for the prevention and/or treatment of heart damage, said compound F-B having the formula:
；
the heart injury is caused by the anthracycline doxorubicin.
2. The use according to claim 1, wherein the product is an anti-cardiotoxic product.
3. Use according to claim 1, wherein the cardiac injury is selected from cardiac tissue fibrosis and/or myocardial apoptosis.
4. Use according to any one of claims 1 to 3, wherein the product is a heart to body weight ratio lowering product.
5. Use according to any one of claims 1 to 3, wherein the product is a product for reducing the hydroxyproline content in heart tissue.
6. The use according to any one of claims 1 to 3, wherein the product is a product for delaying or inhibiting myocardial apoptosis.
7. The use according to claim 6, wherein the product is a product which down-regulates the expression level of p-JNK and/or clear-Caspase-3.
8. The use according to claim 1, wherein the product is in a dosage form selected from the group consisting of tablets, granules, capsules, suppositories, pills, solutions, suspensions.
9. The use according to claim 8, wherein the raw materials of the tablet comprise the following components in parts by weight: 10-50 parts of F-B, 100-200 parts of lactose, 10-20 parts of starch, 50-80 parts of microcrystalline cellulose, 1-10 parts of magnesium stearate and 1-10 parts of talcum powder.
10. The use according to claim 8, wherein the raw materials of the solution comprise the following components in parts by weight: 1-10 parts of F-B, 30-70 parts of glucose, 6-12 parts of sodium chloride and 900-1000 parts of water.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102274236A (en) * | 2010-06-13 | 2011-12-14 | 上海市第六人民医院 | Drug for prevention and treatment of cardiotoxicity induced by anthracycline antibiotics, and application thereof |
| CN103585166A (en) * | 2012-08-14 | 2014-02-19 | 上海医药工业研究院 | Medical applications of flavonol derivatives |
| CN111714508A (en) * | 2020-06-29 | 2020-09-29 | 中国科学院西北高原生物研究所 | Application of neoflavonoid Hip B and Hip C |
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- 2020-11-23 CN CN202011325315.5A patent/CN112353810B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102274236A (en) * | 2010-06-13 | 2011-12-14 | 上海市第六人民医院 | Drug for prevention and treatment of cardiotoxicity induced by anthracycline antibiotics, and application thereof |
| CN103585166A (en) * | 2012-08-14 | 2014-02-19 | 上海医药工业研究院 | Medical applications of flavonol derivatives |
| CN111714508A (en) * | 2020-06-29 | 2020-09-29 | 中国科学院西北高原生物研究所 | Application of neoflavonoid Hip B and Hip C |
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