Use of givinabactm and pharmaceuticals thereof

Abstract

The application relates to the technical field of medicines, and discloses application of gymnemon and a medicine thereof.According to the application, the gymnemon can be used for preparing medicines related to cardiovascular diseases, including medicines for improving heart failure, inhibiting myocardial hypertrophy, improving vascular endothelial function and reducing blood pressure, and further used for preparing medicines for reducing expressions of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 and / or increasing serum NO level; the gymnemon can also be used for preparing medicines for regulating abnormal lipid metabolism, including medicines for reducing triglyceride and total cholesterol level; the gymnemon can also be used for preparing medicines for relieving liver injury, including medicines for reducing glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase level; and the gymnemon can also be used for preparing medicines for improving systemic inflammation and / or platelet and thrombin dysfunction.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more particularly to an application of germacron and a medicine thereof. Background Art

[0002] Cardiovascular disease (CVD), also known as circulatory system disease, claims 17.9 million lives annually, accounting for 31% of the world's total mortality and is a leading cause of death worldwide. The most common cardiovascular diseases include heart failure, coronary heart disease, hypertension, atherosclerosis, and arrhythmias.

[0003] Currently, commonly used treatments include various anti-inflammatory drugs, antioxidants, lipid-lowering drugs, and drugs that enhance blood circulation and dissolve blood clots. While medications can control the onset and progression of the disease to a certain extent, they cannot cure it completely and require long-term maintenance. Once the medication is discontinued or drug resistance develops, cardiovascular disease may recur. Many medications only alleviate symptoms but fail to address the underlying cause. For example, lipid-lowering drugs can normalize blood lipids, but normalizing blood lipids does not eliminate blood clots in blood vessels. Cardiovascular medications have limited efficacy, and long-term use often causes numerous adverse reactions. For example, while aspirin can inhibit platelet aggregation, prevent thrombosis, and reduce the risk of myocardial infarction, it often causes gastrointestinal discomfort and increases bleeding tendency. ACE inhibitors, such as captopril, are used to treat hypertension and heart failure by dilating blood vessels and lowering blood pressure, but they can also cause adverse reactions such as irritating cough, hypotension, and liver and kidney damage. Currently, few drugs can effectively control cardiovascular disease attacks without toxic side effects over the long term, making the development of effective and low-toxic cardiovascular medications of great clinical significance.

[0004] Germacrone is a sesquiterpenoid compound found in plants of the Geraniaceae, Ericaceae, and Zingiberaceae families. Germacrone exhibits a wide range of pharmacological activities, including anti-inflammatory and antibacterial properties, effective against certain influenza viruses, inducing cell apoptosis and inhibiting cell proliferation, and promoting the degradation of fibrotic tissue.

[0005] The article "Germacrone mitigates cardiac remodeling by regulating PI3K / AKT-mediated oxidative stress, inflammation, and apoptosis" demonstrates that germacrone mitigates cardiac remodeling by regulating the PI3K / AKT signaling pathway. While this study demonstrates the potential role of germacrone in cardiac remodeling, it also has certain limitations. For example, the study focused on the treatment of cardiac remodeling and heart failure (HF), employing an isoproterenol (ISO)-induced cardiac remodeling model and focusing on pathological recovery after myocardial injury. The ISO model is an acute myocardial injury model and may not fully reflect the pathological mechanisms of complex chronic cardiovascular diseases (such as hypertensive heart disease and metabolic cardiovascular disease) seen in clinical practice. This study primarily focused on myocardial fibrosis, hypertrophy, and functional recovery, and did not address metabolic cardiovascular disease-related markers (such as lipid metabolism and endothelial function). Furthermore, the article's scope of indications is limited, focusing primarily on the treatment of cardiac remodeling and lacking research on its applicability to a wider range of metabolic diseases (such as hyperlipidemia and cardiovascular disease associated with hypertension). Summary of the Invention

[0006] The present invention provides an application of germacron to overcome the defects of the above-mentioned prior art that do not involve heart failure with preserved ejection fraction and its pathological characteristics (such as myocardial hypertrophy, microcirculatory disorders, endothelial dysfunction, platelet and thrombin dysfunction), systemic inflammation, regulation of lipid metabolism and relief of liver damage.

[0007] In order to solve the above technical problems, the technical solutions of the present invention are as follows:

[0008] An application of germacron for preparing drugs related to cardiovascular diseases.

[0009] Preferably, it is used for preparing a drug for improving blood microcirculation.

[0010] Furthermore, it is used to prepare drugs for improving heart failure.

[0011] Furthermore, it is used to prepare drugs related to inhibiting myocardial hypertrophy.

[0012] Preferably, it is used to prepare drugs for inhibiting myocardial hypertrophy in cases of heart failure.

[0013] Furthermore, it is used to prepare drugs for improving vascular endothelial function.

[0014] Preferably, it is used to prepare a drug for improving vascular endothelial function in the case of heart failure.

[0015] Furthermore, the invention can be used to prepare a drug for reducing the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 and / or increasing the serum NO level.

[0016] Preferably, the invention is used for preparing a drug for reducing the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 and / or increasing the serum NO level in the case of heart failure.

[0017] Furthermore, it is used to prepare drugs for lowering blood pressure.

[0018] Preferably, it is used to prepare a drug for lowering blood pressure in cases of heart failure.

[0019] Furthermore, the invention is used to prepare a drug for improving systemic inflammation and / or platelet and thrombin dysfunction.

[0020] Preferably, the invention is used for preparing a drug for improving systemic inflammation and / or platelet and thrombin dysfunction in the case of heart failure.

[0021] An application of germacron is used to prepare a medicine for regulating abnormal lipid metabolism and alleviating liver damage.

[0022] Preferably, it is used to prepare a drug for regulating abnormal lipid metabolism and alleviating liver damage in the case of heart failure.

[0023] Furthermore, it is used to prepare drugs for lowering triglyceride and total cholesterol levels.

[0024] Preferably, it is used to prepare a drug for lowering triglyceride and total cholesterol levels in the case of heart failure.

[0025] Furthermore, the invention can be used to prepare drugs for reducing the levels of alanine aminotransferase and aspartate aminotransferase.

[0026] Preferably, the invention is used for preparing a drug for reducing the levels of alanine aminotransferase and aspartate aminotransferase in the case of heart failure.

[0027] A medicine comprising germacron is used for treating cardiovascular diseases, abnormal lipid metabolism, systemic inflammatory response, and liver-related diseases.

[0028] Preferably, the dosage of germacron for the above diseases is greater than 10 mg / kg.

[0029] Preferably, the dosage of germacron for the above diseases is greater than 10-40 mg / kg.

[0030] The dosage of germacron for the above diseases is 10 mg / kg.

[0031] Preferably, the cardiovascular disease includes myocardial hypertrophy, vascular endothelial dysfunction, elevated blood pressure, abnormal activation of platelets and thrombin, and heart failure.

[0032] Preferably, the liver-related diseases include abnormal liver function and liver damage.

[0033] Existing technologies primarily emphasize that germaquinone exerts its effects by regulating the PI3K / AKT signaling pathway. This mechanism focuses on three aspects: anti-oxidative stress, anti-inflammation, and inhibition of cell apoptosis. These include inhibiting the production of reactive oxygen species (ROS) to reduce oxidative damage; regulating inflammatory factors and apoptosis signaling molecules such as NF-κB and Bax; and maintaining cell survival and tissue repair through PI3K / AKT activation. The research model is primarily based on acute isoproterenol (ISO)-induced cardiac remodeling, simulating the recovery process after myocardial injury and failing to capture the interactions of multiple signaling pathways in complex pathological mechanisms.

[0034] The present invention proposes that the use of germacrone can achieve multi-pathway synergistic effects, surpassing the single signal mechanism, including bidirectional regulation of endothelial function regulation, lipid metabolism regulation and inflammatory factors. By increasing the level of nitric oxide and reducing the expression of VCAM-1 and ICAM-1, the integrity and function of the vascular endothelium are restored. While repairing endothelial function, it alleviates microcirculatory disorders caused by endothelial damage, pathological changes of increased vascular permeability, and platelet and thrombin dysfunction. Germacrone significantly reduces the levels of triglycerides (TG) and total cholesterol (TC), and this metabolic improvement effect forms a synergistic mechanism through coordination. Unlike the existing technology that focuses on single-pathway regulation, the present invention reveals that germacrone simultaneously regulates the expression of VCAM-1 and ICAM-1, forming a multi-dimensional anti-inflammatory protective effect.

[0035] In addition, the existing technology uses an acute myocardial injury model (ISO-induced cardiac remodeling) to simulate the early recovery process of heart disease. This model cannot fully reflect chronic metabolic disorders (such as hyperlipidemia, hypertension) and their complex interactions with cardiovascular diseases, and ignores the comprehensive verification of multi-system pathological mechanisms. The present invention uses a high-fat diet combined with L-NAME-induced chronic metabolic cardiovascular disease model to successfully simulate myocardial hypertrophy: manifested as increased ventricular mass and thickening of ventricular wall thickness, reflecting the myocardial pathological changes associated with metabolic syndrome; hypertension: through significantly increased blood pressure and impaired endothelial function, simulating the core pathology of hypertensive cardiovascular disease; lipid metabolism disorders: triglyceride and total cholesterol levels are significantly increased, reflecting the impact of metabolic syndrome on the cardiovascular system; liver function damage: increased alanine aminotransferase and aspartate aminotransferase levels, indicating the metabolic burden of chronic diseases on the liver. Through comprehensive model verification, geramarin showed a comprehensive protective effect under the above-mentioned multiple pathological conditions, which is significantly different from the single model study in the prior art.

[0036] The existing technology focuses on the treatment of "cardiac remodeling" and "traditional heart failure (HFrEF)", and does not involve heart failure with preserved ejection fraction (HFpEF) or metabolic-related cardiovascular diseases. HFpEF is a special type of heart failure, and its pathological mechanisms include myocardial stiffness, microcirculatory disorders and endothelial dysfunction. The present invention proposes for the first time the potential of jemacron in the preparation of HFpEF drugs. The present invention also expands the application of jemacron in metabolic disorders (such as hyperlipidemia, hypertension and metabolic syndrome), filling the gap not covered by the existing technology. By significantly reducing ALT and AST levels, the present invention also proposes the potential application value of jemacron in the preparation of drugs for alleviating diseases related to liver metabolic burden.

[0037] The application of the present invention to germacron, through the synergistic effect of multiple pathways, enables germacron to exert a comprehensive therapeutic effect under low-dose (10 mg / kg) conditions. Through the experimental study of the present invention, low-dose germacron can significantly improve relevant indicators (such as ventricular mass, blood pressure, blood lipid levels, etc.), and the effect is comparable to the control drug empagliflozin 10 mg / kg, and even better in some indicators. Low-dose medication can significantly reduce the risk of adverse drug reactions, especially in long-term treatment or chronic disease management. The comparative document uses an isoproterenol (ISO)-induced cardiac remodeling model, which mainly evaluates the effect of germacron on myocardial fibrosis and functional recovery, and focuses more on the repair process after acute myocardial injury. The present invention uses a high-fat diet combined with L-NAME-induced ejection fraction-preserved heart failure model, covering multidimensional pathological states such as hypertension, hyperlipidemia, and liver function damage, verifying the role of germacron under complex chronic disease conditions, and further highlighting its comprehensive therapeutic effect at a low dose. This low-dose sensitivity to metabolic cardiovascular diseases associated with heart failure has not been reflected in the prior art. The reduction in drug dosage also reduces the cost of production and clinical use, making it more economically feasible in practical applications.

[0038] Compared with the prior art, the beneficial effects of the technical solution of the present invention are:

[0039] 1. Improve cardiac function. Research conducted in this study demonstrates that germacron can significantly improve myocardial hypertrophy caused by cardiac dysfunction. By reducing ventricular mass and ventricular wall thickness, germacron exhibits a significant protective effect, helping to restore normal cardiac structure and function. This effect not only inhibits myocardial hypertrophy but also ensures normal cardiac ejection capacity, demonstrating its potential for use in the treatment of heart failure.

[0040] 2. Lower blood pressure and protect vascular function. The results of the present invention demonstrate that germacron can significantly lower blood pressure, including systolic, diastolic, and mean arterial pressure. Simultaneously, by increasing serum nitric oxide levels, germacron effectively improves vasodilation and restores vascular function. Its mechanism of action involves enhancing endothelial cell function, fundamentally improving vascular health, and providing a potential treatment option for patients with hypertension.

[0041] 3. Increase blood perfusion and improve microcirculation. Germacone demonstrates remarkable effectiveness in improving vascular microcirculation, significantly increasing tissue blood perfusion. By alleviating vascular dysfunction and promoting blood circulation, germacone effectively addresses the problem of insufficient blood flow caused by poor microcirculation, providing a new approach for intervention in diseases associated with microcirculatory disorders.

[0042] 4. Repair vascular endothelial damage. The present invention shows that germacron can significantly inhibit the expression of molecules related to vascular inflammation, including vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1). By reducing the release of these inflammatory factors, germacron effectively repairs vascular endothelial function and protects vascular integrity and permeability. Germacron's significant vascular protective effect is of great significance in preventing arteriosclerosis and improving vascular pathology.

[0043] 5. Regulate lipid metabolism. Studies have shown that germacrone is highly effective in regulating lipid metabolism, significantly reducing serum triglyceride and total cholesterol levels. By restoring lipid metabolism, germacrone offers a potential therapeutic strategy for preventing atherosclerosis and other lipid metabolism-related diseases.

[0044] 6. Alleviate liver damage. Research in this study demonstrates that germacron can effectively reduce serum levels of alanine aminotransferase and aspartate aminotransferase, significantly alleviating liver dysfunction and hepatocellular damage. This protective effect gives germacron a unique advantage in addressing liver damage caused by metabolic disorders or other causes.

[0045] 7. Improves systemic inflammatory responses and abnormal platelet and thrombin activation. Studies in this study have shown that germacron can significantly reverse the surge in white blood cell and monocyte counts in the blood of mice with preserved ejection fraction heart failure, and reduce platelet count and mean platelet volume. This improvement may be of great significance in diseases of systemic inflammatory responses and platelet and thrombin dysfunction.

[0046] 8. High efficacy at low doses. The present invention found that germacrone can achieve significant effects at low doses (e.g., 10 mg / kg), including improving cardiac function, regulating blood pressure, repairing endothelial function, and regulating lipid metabolism. This high efficacy at low doses further highlights the safety and clinical potential of germacrone, providing an important basis for optimizing treatment options. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The following are the cardiac function indicators of mice in each group; A. M-mode ultrasound results of parasternal short-axis section of mice in each group; B. Left ventricular ejection fraction of mice in each group; C. Left ventricular mass of mice in each group; D. Left ventricular anterior wall thickness at end-diastole of mice in each group; E. Left ventricular posterior wall thickness at end-diastole of mice in each group; F. Pulse Doppler of apical four-chamber section of mice in each group; Ratio of GE peak to A peak.

[0048] Figure 2 Blood pressure indicators and serum nitric oxide concentrations of mice in each group; A. diastolic blood pressure of mice in each group; B. systolic blood pressure of mice in each group; C. mean arterial pressure of mice in each group; D. serum nitric oxide concentration of mice in each group.

[0049] Figure 3 The blood perfusion volume of the feet of mice in each group; A. Pictures of the blood perfusion volume of the feet of mice in each group; B. Statistical results of the blood perfusion volume of the feet of mice in each group.

[0050] Figure 4 The expression of VCAM-1 and ICAM-1 in the cardiac vascular endothelium of each group of mice; A. The expression of VCAM-1 in the cardiac vascular endothelium of each group of mice and the fluorescence statistical results; B. The expression of ICAM-1 in the cardiac vascular endothelium of each group of mice and the fluorescence statistical results.

[0051] Figure 5 Serum triglyceride, total cholesterol, alanine aminotransferase and aspartate aminotransferase levels of mice in each group; A. Serum triglyceride level of mice in each group; B. Serum total cholesterol level of mice in each group; C. Serum alanine aminotransferase level of mice in each group; D. Aspartate aminotransferase level of mice in each group.

[0052] Figure 6 Representative graphs and statistical results of the myocardial cross-sectional area of ​​mice in each group.

[0053] Figure 7 Results of whole blood cell analysis of mice in each group; A. Number of monocytes in the blood of mice in each group; B. Platelet volume in the blood of mice in each group; C. Platelet volume in the blood of mice in each group; D. Platelet number in the blood of mice in each group. DETAILED DESCRIPTION

[0054] The present invention will be further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0055] Unless otherwise specified, the reagents and materials used in the following examples were commercially available.

[0056] The reagents and materials used in this invention were obtained from: Germacone (source leaf, B20589); L-NAME (Sigma aldrich, N5751); Empagliflozin (Boehringer Ingelheim, Germany, 14202853284); and high-fat diet (Huafukang, H10060). Experimental animals were purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd., animal production certificate number: SCXK (Yue) 2022-0063.

[0057] Example 1

[0058] 8-week-old SPF-grade C57BL / 6N mice were randomly divided into normal group, model group, and drug group. The drug groups included low-dose germacron group, medium-dose germacron group, high-dose germacron group, and positive drug group (empagliflozin). The mice in the normal group were given normal feed and normal drinking water. The mice in the model group and drug group were given a free diet of high-fat feed and drinking water containing L-NAME (0.5g / L) every day. The low-dose germacron group was gavaged with 10mg / kg germacron every day, the medium-dose germacron group was gavaged with 20mg / kg germacron every day, the high-dose germacron group was gavaged with 40mg / kg germacron every day, and the positive drug group was gavaged with 10mg / kg empagliflozin every day for 10 consecutive weeks. The normal group and model group were intervened with the same volume of normal saline.

[0059] Detection method

[0060] 1. Heart function test

[0061] Ten weeks after administration, the mice were anesthetized and three cardiac cycles were continuously measured using M-mode echocardiography. The average value was calculated, and the left ventricular mass (LV Mass), left ventricular anterior wall thickness at end-diastole (LVAWD), left ventricular posterior wall thickness at end-diastole (LVPWD), left ventricular ejection fraction (LVEF), and the ratio of the E peak to the A peak of the apical four-chamber view pulsed Doppler (E / A ratio) were used to evaluate the cardiac chamber size and cardiac function of the mice.

[0062] 2. Blood pressure testing

[0063] After 10 weeks of dosing, blood pressure was measured in each group of mice using a small animal non-invasive blood pressure meter. For measurement, the mice were secured with a sleeve, exposing their tails. The sleeve was heated on a heating plate for approximately 5-10 minutes. A corresponding size snare was then placed around the base of the tail to begin blood pressure measurement. The blood pressure meter automatically and continuously measured blood pressure, and the average of the six valid blood pressure values ​​was used as the measured blood pressure value.

[0064] 3. Foot blood flow detection

[0065] Ten weeks after administration, the mice were anesthetized and the blood flow in their feet was measured using a laser speckle blood flow imaging system. After the mice were anesthetized, they were placed in a suitable position to expose the area to be measured. The camera focus was adjusted under visible light to obtain a clear image, and then various parameters were adjusted according to different parts of the body. After recording, the ROI area of ​​the area to be measured was selected using LSCI software (Shenzhen RWD) and the average perfusion volume was calculated.

[0066] 4. Cardiovascular endothelial function test

[0067] After 10 weeks of continuous gavage administration, mice were anesthetized and sacrificed. Heart tissue was collected for frozen sectioning and stained using immunofluorescence staining. First, the slides were removed and rinsed three times with 0.02% PBST. The slides were then placed in acetone and fixed at -20°C for 20 minutes. The slides were then removed and incubated with 0.02% PBST for 3 minutes. This was repeated three times. Excess liquid around the tissue was wiped dry with lens paper. An immunohistochemistry pen was used to draw a circle of appropriate size around the tissue. Blocking solution was added and blocked at room temperature for 1 hour. The blocking solution was discarded, and the primary antibody (anti-VWF / anti-ICAM-1 / anti-ZO-1) was added and incubated at 4°C overnight. The primary antibody was discarded, and 0.02% PBST was added and incubated for 5 minutes. This was repeated three times. The PBST was shaken dry, and the fluorescent secondary antibody was added and incubated at room temperature in the dark for 2 hours. Discard the secondary antibody, add 0.02% PBST and let it stand for 5 minutes, repeat three times, wipe off the excess water and immunohistochemistry pen marks around the tissue, seal the slide in the dark, and take pictures under an immunofluorescence microscope.

[0068] 5. Serum nitric oxide, total cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase levels

[0069] After anesthesia, the mice's eyes were removed and blood was collected. The blood was placed in a centrifuge tube and allowed to clot at room temperature for 2 hours. The clotted blood was then centrifuged at 3000 rpm for 15 minutes at 4°C, and the supernatant was collected as serum. The serum levels of nitric oxide, total cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase in each group of mice were then measured using a kit.

[0070] 6. WGA staining method to detect myocardial cross-sectional area

[0071] Mouse heart tissue sections were fixed with acetone at -20°C for 20 min and then washed three times with PBS solution for 10 min each time. Wheat lectin (WGA) staining solution was then added dropwise and stained at room temperature in the dark for 30 min. The sections were then washed three times with PBS solution for 10 min each time. After sealing, the sections were immediately photographed using a laser confocal microscope (LSM 800, Zeiss, Germany).

[0072] 7. Complete blood cell analysis

[0073] Routine blood testing requires anticoagulated whole blood. Collect approximately 0.5 mL of blood from mice and gently mix immediately after collection to prevent platelet adhesion and aggregation. Avoid vigorous shaking to prevent air bubbles and hemolysis. Inspect the sample for clots. Blood should be promptly submitted for testing within 2 hours. This experiment was performed using a fully automated hematology analyzer.

[0074] Test results

[0075] 1. Germacron improves cardiac function in mice with heart failure

[0076] from Figure 1 The results showed that when mice were treated with a high-fat diet and L-NAME, their cardiac function was damaged and they showed symptoms of heart failure with preserved ejection fraction. Compared with the normal group, the mice in the model group had increased left ventricular mass (LVmass), left ventricular anterior wall thickness at end-diastole (LVAWD), left ventricular posterior wall thickness (LVPWD) and E / A ratio. After intervention with geramalin and empagliflozin, the left ventricular mass (LVmass), left ventricular anterior wall thickness at end-diastole (LVAWD, posterior wall thickness (LVPWD), and E / A ratio of heart failure mice decreased. In addition, the WGA staining results showed that ( Figure 6 ) After intervention with gemacrone and empagliflozin, myocardial cross-sectional area in mice with heart failure was significantly reduced. These results indicate that gemacrone can reduce left ventricular mass, left ventricular posterior wall thickness, and left atrial anteroposterior diameter, inhibiting myocardial hypertrophy. The efficacy of gemacrone is comparable to that of empagliflozin, and in some cases even surpasses it, demonstrating a significant protective effect in improving myocardial hypertrophy and cardiac function.

[0077] 2. Germacron lowers blood pressure in mice with heart failure

[0078] from Figure 2The results showed that the significantly increased DBP indicated that the experimental model induced by high-fat diet combined with L-NAME successfully caused a pathological state of hypertension. Compared with the mice in the normal group, the diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MBP) of the mice in the model group increased significantly, and the content of nitric oxide (NO) in the serum decreased significantly. After intervention with geramalin and empagliflozin, the DBP, SBP, and MBP of the mice were significantly downregulated, and the level of NO in the serum increased significantly. Germacone can alleviate the symptoms of hypertension in mice with heart failure with preserved ejection fraction, and showed antihypertensive effects at different doses, and the effect was comparable to that of the positive control empagliflozin group. Germacone can also significantly increase the level of NO, a marker of endothelial cell function, indicating that it achieves the antihypertensive effect by improving endothelial function.

[0079] 3. Germacron increases foot blood perfusion in mice with heart failure

[0080] from Figure 3 The results showed that compared with the normal group, the model group mice, after receiving the dual treatment of high-fat diet and L-NAME, had microcirculatory disorders and vascular function damage, resulting in a significant decrease in blood perfusion in the limbs. Figure 3 In A, it can be seen that the red area is significantly reduced, and a large area appears blue. Figure 3 B shows that after intervention with gemacron and the positive drug empagliflozin, the foot blood perfusion of mice with heart failure with preserved ejection fraction was significantly restored. Gemacron can fully alleviate vascular perfusion deficiency at a low dose by significantly increasing NO levels and improving endothelial function.

[0081] 4. Germacron improves cardiac vascular endothelial damage in mice with heart failure

[0082] Vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) are important adhesion molecules that mediate adhesion reactions. VCAM-1 and ICAM-1 are expressed at low levels on resting vascular endothelial cells. When blood vessels are damaged, the expression of VCAM-1 and ICAM-1 will be significantly upregulated. Figure 4 Results showed that when mice were treated with a high-fat diet and L-NAME, endothelial damage occurred in their heart vessels, with a significant increase in the expression of VCAM-1 and ICAM-1 in the cardiac microvascular endothelium, and a significant enhancement in the fluorescence signal. Compared with the normal group, germacrucin significantly reduced the expression of VCAM-1 and ICAM-1 at all doses and restored them to near-normal levels, even showing a superior effect at low doses. The effect of germacrucin at all doses was comparable to that of empagliflozin, indicating that germacrucin has similar or even superior vascular protection potential to existing drugs.

[0083] 5. Germacron improves lipid metabolism abnormalities in mice with heart failure with preserved ejection fraction

[0084] from Figure 5 The experimental results show that when mice were treated with a high-fat diet and L-NAME, triglyceride levels increased significantly, indicating abnormal lipid metabolism. In terms of triglycerides and total cholesterol, germacron has shown significant improvement effects at low doses, and the effect is even better than that of the empagliflozin group, and the difference between different doses is small, indicating that the efficacy of germacron may be close to saturation at 10 mg / kg. As a positive control drug, empagliflozin has the same effect as germacron in various indicators, indicating that germacron has similar potential as existing clinical drugs in improving metabolism and liver function, and even has more advantages in some indicators.

[0085] 6. Germacron improves liver damage in mice with heart failure with preserved ejection fraction

[0086] from Figure 5 The experimental results show that when mice were treated with a high-fat diet and L-NAME, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in their serum increased significantly, leading to liver cell damage and dysfunction. After intervention with germaquinone and empagliflozin, the levels of ALT and AST in the mice's serum decreased significantly. The effect of the 10mg / kg germaquinone group was better than that of the empagliflozin group, showing a better liver protection effect, indicating that germaquinone can better improve liver damage in mice with heart failure with preserved ejection fraction at a low dose.

[0087] 7. Germacron reduces the number of white blood cells, monocytes, platelets and mean platelet volume in the blood of mice with heart failure with preserved ejection fraction

[0088] from Figure 7 The whole blood cell analysis showed that when mice received a double attack of high-fat diet and L-NAME, the number of white blood cells and monocytes in the mouse blood increased significantly, indicating that mice with heart failure with preserved ejection fraction had a systemic inflammatory response. After intervention with gemacron and empagliflozin, the number of white blood cells and monocytes in the mouse blood decreased, indicating that gemacron can improve the systemic inflammatory response of mice with heart failure with preserved ejection fraction. In addition, compared with the normal group of mice, the number of platelets in the blood of mice with heart failure with preserved ejection fraction increased significantly, and the average platelet volume increased, indicating that mice with heart failure with preserved ejection fraction had abnormal platelet and thrombin activation. After intervention with gemacron and empagliflozin, the number of platelets in the blood of mice decreased, and the average platelet volume decreased, indicating that gemacron can improve abnormal platelet and thrombin activation in heart failure with preserved ejection fraction.

[0089] Obviously, the above embodiments of the present invention are merely examples for the purpose of clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the claims of the present invention.

Claims

1. An application of germacrone, characterized in that, Used for preparing drugs related to cardiovascular diseases; the drugs used for preparing drugs related to cardiovascular diseases include drugs used for preparing drugs related to inhibiting myocardial hypertrophy, drugs used for preparing drugs for improving vascular endothelial function and lowering blood pressure, drugs used for preparing drugs for reducing the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 and increasing serum NO levels, drugs used for preparing drugs for improving systemic inflammation and platelet and thrombin dysfunction, and drugs used for preparing drugs for improving blood microcirculation; the cardiovascular diseases are caused by heart failure with preserved ejection fraction.

2. An application of germacrone, characterized in that, Used to prepare drugs for regulating abnormal lipid metabolism and alleviating liver damage; the abnormal lipid metabolism and liver damage are caused by heart failure with preserved ejection fraction.

3. The use of germacrone according to claim 2, wherein Used to prepare drugs for lowering triglyceride and total cholesterol levels.

4. The use of germacrone according to claim 2, wherein Used to prepare drugs that lower alanine aminotransferase and aspartate aminotransferase levels.

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