Application of fisetin in preparation of medicine for treating heart-related diseases

Abstract

The invention discloses application of fisetin or a salt thereof in medicine preparation, the compound is used for treating or preventing obesity cardiomyopathy, preferably heart diseases caused by hyperlipidemia, but is not limited to the inducer, and specifically, the medicine can inhibit or improve various obesity cardiomyopathy.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to the use of a compound of formula (I) (code name Fisetin) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing heart diseases caused by chronic diseases.

[0002] Background Art

[0003] Obesity cardiomyopathy is a cardiac pathological condition caused by obesity, characterized by long-term obesity leading to abnormal cardiac structure and function, which may eventually lead to heart failure. In an obese state, the patient's blood lipids, blood sugar and other levels are elevated, causing the body to be in a persistent hyperlipidemia, hypertension or hyperglycemia environment, resulting in persistent chronic damage to tissues or organs, especially the heart, an important organ. Under the stimulation of these risk factors, myocardial muscle fiber disorder, myocardial fibrosis, increased expression of myocardial cell fibrosis proteins, cardiac systolic and diastolic dysfunction, and eventually develop into heart failure or even irreversible myocardial infarction, seriously affecting the patient's quality of life and even endangering his life. Summary of the invention

[0004] Based on many years of research on pharmacology and pathological mechanisms, the inventors have discovered that Fisetin can effectively treat chronic metabolic diseases such as obese heart disease induced by hyperlipidemia, and heart-related pathological changes can be significantly improved.

[0005] The object of the present invention is to provide a new use of a compound of fisetin, codenamed (Fisetin).

[0006] Specifically, the present invention provides the use of a compound of formula (I) (Fisetin) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing obese cardiomyopathy.

[0007]

[0008] The active ingredient of the medicine comprises fisetin or a pharmaceutically acceptable salt thereof.

[0009] The present invention also provides the use of the compound of formula (I) (Fisetin) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving obese cardiomyopathy.

[0010]

[0011] There are many causes of heart disease, including hyperlipidemia, hyperglycemia, hypertension, autoimmunity, drug toxicity, congenital development, viral infection, etc. Different causes have different treatments. Among them, high-salt and high-fat diet, hypertension, hyperglycemia, poor management of hyperlipidemia, and obesity are common causes of heart disease, such as the most common coronary heart disease, and myocardial infarction and heart failure caused by its deterioration. Considering the mechanism of disease occurrence, the present invention is mainly aimed at heart diseases caused by hyperlipidemia, but is not limited to the above-mentioned pathogenic factors; most preferably, it is used to treat pathological changes in cardiac tissue under hyperlipidemia.

[0012] Preferably, in the use of the present invention, the main pathological features of heart disease are myocardial cell hypertrophy, fibrosis and changes in cardiac function.

[0013] The medicine used in the present invention contains an effective dose of the compound of formula (I) (Fisetin). The effective dose can be the content of the medicine in a unit dosage form (such as a tablet, a needle, a pill or a dose), or it can be the unit dose (such as a unit body weight dose) of the patient to be treated / prevented. In the present invention, the effective dose (in terms of content) can be 10μg-1g, preferably 0.1mg-500mg, and more preferably 1mg-100mg.

[0014] The drugs used in the present invention usually also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier used refers to a non-toxic filler, stabilizer, diluent, adjuvant or other formulation excipient. For example, diluents, excipients, such as water, physiological saline, etc.; fillers, such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginates, gelatin and / or polyvinyl pyrrolidone; wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate and / or sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants, such as hexadecanol; adsorption carriers, such as kaolin and / or soap clay; lubricants, such as talc, calcium / magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition of the present invention may further contain other excipients, such as flavoring agents, sweeteners, etc. According to the known technology in the art, the pharmaceutical composition can be prepared into various dosage forms according to the needs of the treatment purpose and the route of administration. Preferably, the composition is a unit dosage form, such as a lyophilized agent, a tablet, a capsule, a powder, an emulsion, an aqueous injection or a spray, and more preferably, the pharmaceutical composition is an injection form (such as a lyophilized powder injection) or an oral dosage form (such as a tablet, a capsule). The drug can be administered by conventional routes, particularly enteral, such as oral, such as in the form of a tablet or capsule, or parenteral, such as in the form of an injectable solution or suspension, topically, such as in the form of a lotion or gel, or in the form of a nasal agent or a test agent.

[0015] The present invention will be described in detail below through specific embodiments and drawings. It should be particularly pointed out that these descriptions are only partial exemplary descriptions and do not constitute a limitation on the scope of the present invention. According to the discussion of this specification, many changes and modifications of the present invention are obvious to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The invention relates to the effect of the compound of formula (I) (Fisetin) on the diffuse infiltration of inflammatory cells in the myocardial tissue and the down-regulation of the expression of inflammatory genes in the myocardial tissue of mice with obese cardiomyopathy.

[0017] Figure 2 The compound of formula (I) (Fisetin) has an alleviating effect on the structural disorder of myocardial tissue in mice with obese cardiomyopathy.

[0018] Figure 3 The compound of formula (I) (Fisetin) has a down-regulating effect on myocardial tissue fibrosis and the expression of myocardial tissue fibrosis genes in mice with obese cardiomyopathy.

[0019] Figure 4 The compound of formula (I) (Fisetin) improves the cardiac function of mice with obese cardiomyopathy. DETAILED DESCRIPTION

[0020] The present invention is further described in the following examples. These examples are only for the purpose of illustrating the present invention, but are not intended to limit the scope of the present invention.

[0021] Example 1 The compounds of the present invention can significantly inhibit the diffuse infiltration of inflammatory cells in myocardial tissue and the down-regulation of the expression of inflammatory genes in myocardial tissue caused by hyperlipidemia (obesity).

[0022] C57BL / 6J mice were randomly divided into 4 groups (6 mice in each group), namely:

[0023] Control group: healthy C57BL / 6J mice;

[0024] Hyperlipidemia (obesity) group (HFD): C57BL / 6J mice were fed a high-fat diet (HFD) for 16 weeks to establish a hyperlipidemia (obesity) mouse model;

[0025] Compound treatment group (HFD + Fisetin 10 mg / kg or 20 mg / kg): After the construction of hyperlipidemic (obese) mice, the compound of formula (I) (Fisetin) was gavaged to the mice at a dose of 10 mg / kg or 20 mg / kg after the 16th week, and the administration was continued for 8 weeks.

[0026] The body weight of mice was monitored weekly and it was found that Fisetin had no effect on body weight. Figure 1 A). After 24 weeks of modeling, the mice were killed and their heart tissues were fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness for immunohistochemical (F4 / 80 and Ly6G) staining and microscopic examination. The results of immunohistochemical (F4 / 80 and Ly6G) staining showed that obesity caused cardiac tissue structural disorder, which was alleviated by Fisetin administration ( Figure 1 A). At the same time, we detected the expression of VCAM-1 protein and gene in cardiac tissue ( Figure 1 C and Figure 1 D), the results showed that obesity caused a significant upregulation of the protein and gene of intercellular adhesion molecule 1 (VCAM-1) in cardiac tissue, which was significantly alleviated by administration of Fisetin. (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0027] Example 2 The compounds of the present invention can significantly improve the alleviation effect of myocardial tissue structural disorder caused by hyperlipidemia (obesity).

[0028] The samples were fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness before hematoxylin & eosin (H&E) staining and microscopic examination. The results of H&E staining showed that hyperlipidemia (obesity) caused cardiac tissue structural disorder, which was significantly alleviated by Fisetin ( Figure 2 A). At the same time, we detected the expression of myosin heavy chain 6 (Myh6) protein and gene in cardiac tissue ( Figure 2 B and Figure 2 C), the results showed that obesity caused a significant upregulation of myosin heavy chain 6 (Myh6) protein and gene expression in cardiac tissue, which was significantly alleviated by Fisetin administration. (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0029] Example 3 The compounds of the present invention can significantly inhibit myocardial tissue fibrosis and down-regulation of the expression of myocardial tissue fibrosis genes caused by hyperlipidemia (obesity).

[0030] The samples were fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness for Masson staining and microscopic examination. The results of Masson staining showed that hyperlipidemia (obesity) caused cardiac tissue fibrosis, which was significantly alleviated by Fisetin ( Figure 3 A). At the same time, we detected the expression of fibrotic proteins and fibrotic genes in cardiac tissue ( Figure 3 B and Figure 3 C), the results showed that obesity caused a significant upregulation of cardiac fibrosis proteins and fibrosis genes, which was significantly alleviated by Fisetin administration. (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0031] Example 4 The compounds of the present invention can significantly inhibit changes in cardiac function caused by hyperlipidemia (obesity).

[0032] After 24 weeks of modeling, the mouse chest was depilated with depilatory cream, and the cardiac function of the mouse was analyzed under isoflurane anesthesia using a high-resolution small animal ultrasound imaging system (Vevo LAB 3.1.1). The results showed that obesity caused changes in the cardiac function of mice, which were significantly alleviated after administration of Fisetin ( Figure 4 A). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

Claims

1. An application of fisetin in drug preparation, characterized in that: The drug is used to treat or prevent heart-related diseases; The structure of fisetin is shown in formula (I): The active ingredient of the medicine comprises fisetin or a pharmaceutically acceptable salt thereof.

2. The use of fisetin in drug preparation according to claim 1, characterized in that: The heart-related disease is obesity-related cardiomyopathy.

3. The use of fisetin in drug preparation according to claim 1, characterized in that: The heart-related diseases are heart tissue function and pathological damage caused by hyperlipidemia.

4. The use of fisetin in drug preparation according to any one of claims 1 to 3, characterized in that: The heart-related diseases are changes in cardiac tissue function and pathological damage.

5. The use of fisetin in drug preparation according to claim 4, characterized in that: The functional changes and pathological damages of cardiac tissue include diffuse infiltration of inflammatory cells in myocardial tissue, hypertrophy of myocardial cells, increased expression of fibrin, disordered myocardial tissue structure, myocardial fibrosis and remodeling, and disordered cardiac systolic and diastolic function.

6. The use of fisetin in drug preparation according to claim 1, characterized in that: The drug also contains a pharmaceutically acceptable carrier.

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