Application of germacrone and medicine of germacrone

Abstract

The invention relates to the technical field of medicines, and discloses application of germacrone and a medicine of germacrone. According to the invention, germacrone can be used for preparing medicines related to cardiovascular diseases, including medicines for improving heart failure, inhibiting cardiac hypertrophy, improving vascular endothelial function and reducing blood pressure, and further used for preparing medicines for reducing expression of vascular cell adhesion molecules 1 and intercellular adhesion molecules 1 and / or improving serum NO level; germacrone can also be used for preparing medicines for regulating abnormal lipid metabolism, including medicines for reducing triglyceride and total cholesterol levels; germacrone can also be used for preparing medicines for relieving liver injury, including medicines for reducing the level of glutamic-pyruvic transaminase and glutamic oxalacetic transaminase; germacrone 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 specifically to an application of germacron and a medicine thereof. Background Art

[0002] Cardiovascular disease (CVD), also known as circulatory system disease, kills 17.9 million people each year, accounting for 31% of the world's total deaths, and is a major cause of death worldwide. The most common cardiovascular diseases include heart failure, coronary heart disease, hypertension, atherosclerosis, arrhythmia, etc.

[0003] At present, the commonly used therapeutic drugs mainly include a variety of anti-inflammatory drugs, antioxidant drugs, lipid-lowering drugs, and drugs that enhance blood circulation and dissolve blood clots. Drugs can control the occurrence and development of the disease to a certain extent, but they cannot cure it. They can only be maintained by long-term drugs. Once the drug is stopped or drug resistance occurs, cardiovascular disease may recur. Many drugs can only relieve symptoms alone, but cannot solve the fundamental problem. For example, lipid-lowering drugs can regulate blood lipids to normal, but blood clots in blood vessels will not be eliminated due to normal blood lipids. The efficacy of drugs for cardiovascular disease is limited, and long-term medication often causes more adverse reactions. For example, although aspirin can resist platelet aggregation, prevent thrombosis, and reduce the risk of myocardial infarction, it often causes gastrointestinal discomfort and aggravates bleeding tendency. ACE inhibitors such as captopril can be used to treat hypertension and heart failure, dilate blood vessels, and lower blood pressure, but they can also cause adverse reactions such as irritating cough, hypotension, liver and kidney damage. At present, there are few drugs that can control the onset of cardiovascular disease for a long time without toxic side effects. Therefore, the development of effective and low-toxic anti-cardiovascular disease drugs is of great clinical significance.

[0004] Germacrone is a sesquiterpenoid compound, mostly found in plants of the Geranium family, Ericaceae family and Zingiberaceae family. Germacrone has a wide range of pharmacological activities, can reduce inflammation and inhibit bacteria, effectively kill certain influenza viruses; can induce cell apoptosis and inhibit its proliferation; and has the effect of promoting the degradation of fibrotic tissue.

[0005] The article "Germacrone mitigates cardiac remodeling by regulating PI3K / AKT-mediated oxidative stress, inflammation, and apoptosis" shows that germacrone mitigates cardiac remodeling by regulating the PI3K / AKT signaling pathway. Although this study proves the potential role of germacrone in cardiac remodeling, it also has certain limitations. For example, this study focuses on the treatment of cardiac remodeling and heart failure (HF), using 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) in the clinic. This study mainly focuses on the fibrosis, hypertrophy and functional recovery of myocardial tissue, and does not involve indicators related to metabolic cardiovascular diseases (such as lipid metabolism, endothelial function, etc.). In addition, the scope of indications of this article is also limited. This article mainly focuses on the treatment of cardiac remodeling and lacks applicability research on a wider range of metabolic diseases (such as hyperlipidemia and cardiovascular diseases 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 solution of the present invention is as follows:

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

[0009] Preferably, it is used for preparing a medicament 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 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.

[0016] Preferably, the method 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 case of heart failure.

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

[0020] Preferably, it 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 for preparing 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 case of heart failure.

[0025] Furthermore, it is used to prepare drugs for reducing the levels of alanine aminotransferase and aspartate aminotransferase.

[0026] Preferably, it is used for preparing a drug for reducing the levels of alanine aminotransferase and aspartate aminotransferase in 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 amount of germacron used in 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 germacruin for the above diseases is 10mg / kg.

[0031] Preferably, the cardiovascular diseases include myocardial hypertrophy, abnormal endothelial function, increased 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 mainly emphasize that germacron 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, including inhibiting the production of reactive oxygen species (ROS) and reducing oxidative damage; regulating inflammatory factors and apoptosis signaling molecules such as NF-κB and Bax; and maintaining cell survival and tissue repair through the activation of PI3K / AKT. The research model is mainly based on acute isoproterenol (ISO)-induced cardiac remodeling, which simulates the recovery process after myocardial injury and fails to cover the interaction of multiple signaling pathways in complex pathological mechanisms.

[0034] The present invention proposes that the use of jemacron can achieve multi-pathway synergistic effects, surpassing the single signal mechanism, including endothelial function regulation, lipid metabolism regulation and bidirectional regulation of 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 the endothelial function, the microcirculation disorders caused by endothelial damage, the pathological changes of increased vascular permeability, and platelet and thrombin dysfunction are alleviated. Jemacron significantly reduces the levels of triglycerides (TG) and total cholesterol (TC), and this metabolic improvement effect forms a synergistic mechanism through coordination. Unlike the prior art that focuses on single-pathway regulation, the present invention reveals that jemacron simultaneously regulates the expression of VCAM-1 and ICAM-1 to form a multi-dimensional anti-inflammatory protective effect.

[0035] In addition, the prior art 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 a chronic metabolic cardiovascular disease model induced by L-NAME to successfully simulate myocardial hypertrophy: manifested as increased ventricular mass and thickening of the ventricular wall, reflecting the myocardial pathological changes associated with metabolic syndrome; hypertension: through significant increases in blood pressure and impaired endothelial function, the core pathology of hypertensive cardiovascular disease is simulated; lipid metabolism disorders: triglyceride and total cholesterol levels are significantly increased, reflecting the impact of metabolic syndrome on the cardiovascular system; liver function damage: elevated levels of alanine aminotransferase and aspartate aminotransferase, indicating the metabolic burden of chronic diseases on the liver. Through comprehensive model verification, germacron 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 metabolism-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 jemacron can exert a comprehensive therapeutic effect under low-dose (10 mg / kg) conditions through multi-pathway synergy. Through the experimental study of the present invention, low-dose jemacron can significantly improve relevant indicators (such as ventricular mass, blood pressure, blood lipid levels, etc.), and the effect is equivalent 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 jemacron 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, and verifies the role of jemacron under complex chronic disease conditions, further highlighting its low-dose comprehensive efficacy. 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 technical solution of the present invention has the following beneficial effects:

[0039] 1. Improve cardiac function. The present invention shows that germacron can significantly improve the problem of myocardial hypertrophy caused by cardiac dysfunction. By reducing ventricular mass and reducing ventricular wall thickness, germacron shows a significant protective effect and helps to restore normal cardiac structure and function. This effect not only inhibits myocardial hypertrophy, but also provides a guarantee for maintaining normal cardiac ejection capacity, demonstrating its potential for application in heart failure-related treatments.

[0040] 2. Lower blood pressure and protect vascular function. The results of the present invention show that germacron can significantly lower blood pressure, including systolic pressure, diastolic pressure and mean arterial pressure. At the same time, by increasing the level of nitric oxide in serum, germacron effectively improves vasodilation and restores vascular function. Its mechanism of action includes fundamentally improving the state of blood vessels by enhancing the function of vascular endothelial cells, providing a potential treatment option for patients with hypertension.

[0041] 3. Increase blood perfusion and improve microcirculation. Germacron has shown excellent effects in improving vascular microcirculation and can significantly increase tissue blood perfusion levels. By alleviating vascular dysfunction and promoting blood circulation, Germacron effectively solves the problem of insufficient blood flow caused by poor microcirculation and provides a new direction for the intervention of diseases related to microcirculation disorders.

[0042] 4. Repair vascular endothelial damage. The present invention shows that germacron can significantly inhibit the expression of vascular inflammation-related molecules, 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. The significant vascular protective effect of germacron is of great significance in preventing arteriosclerosis and improving vascular pathological conditions.

[0043] 5. Regulate lipid metabolism. The present invention shows that germacron has a significant effect in regulating lipid metabolism and can significantly reduce the levels of triglycerides and total cholesterol in serum. By restoring the balance of lipid metabolism, germacron provides a potential therapeutic strategy for preventing atherosclerosis and other lipid metabolism-related diseases.

[0044] 6. Relieve liver damage. The present invention shows that germacron can effectively reduce the levels of alanine aminotransferase and aspartate aminotransferase in serum, significantly reducing liver dysfunction and liver cell damage. This protective effect gives germacron a unique advantage in solving liver damage caused by metabolic disorders or other reasons.

[0045] 7. Improve systemic inflammatory response and abnormal activation of platelets and thrombin. The present invention shows that germacron can significantly reverse the surge in the number of white blood cells and monocytes in the blood of mice with heart failure with preserved ejection fraction, and reduce the number of platelets and the average platelet volume. This improvement of germacron may be of great significance in systemic inflammatory response and platelet and thrombin dysfunction diseases.

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

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

[0048] Figure 2 Blood pressure indexes 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 A. Blood perfusion volume of the feet of mice in each group; A. Pictures of blood perfusion volume of the feet of mice in each group; B. Statistical results of 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 levels of mice in each group; B. Serum total cholesterol levels of mice in each group; C. Serum alanine aminotransferase levels of mice in each group; D. Aspartate aminotransferase levels of mice in each group.

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

[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. Number of platelets in the blood of mice in each group. DETAILED DESCRIPTION

[0054] The present invention is 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 are commercially available.

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

[0057] Example 1

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

[0059] Detection Methods

[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 pulsed Doppler (E / A ratio) were used to evaluate the cardiac chamber size and cardiac function of the mice.

[0062] 2. Blood pressure detection

[0063] After 10 weeks of administration, the blood pressure of mice in each group was tested using a small animal non-invasive blood pressure measuring instrument. During the measurement, the mouse was fixed with a sleeve and the tail was exposed. After the fixed sleeve was placed on a heating plate and heated for about 5-10 minutes, the corresponding model of the ring was put into the base of the mouse's tail to start measuring blood pressure. The blood pressure meter automatically and continuously measured, and the average of 6 valid blood pressure values ​​was taken as the measured blood pressure value.

[0064] 3. Foot blood flow detection

[0065] After 10 weeks of administration, the mice were anesthetized and the blood flow of the mouse feet was detected using a laser speckle blood flow imaging system. After the mice were anesthetized, they were placed in a suitable position to expose the part to be tested. The camera focus was adjusted under visible light to obtain a clear image, and then various parameters were adjusted according to different parts. After recording, the ROI area of ​​the part to be tested was selected using LSCI software (Shenzhen RWD) to calculate the average perfusion volume.

[0066] 4. Cardiovascular endothelial function test

[0067] After continuous oral administration for 10 weeks, the mice were killed after anesthesia, and the mouse heart tissue was collected for frozen sectioning and stained using immunofluorescence staining. First, the slice was taken out and rinsed with 0.02% PBST three times, then the slice was placed in acetone and fixed at -20°C for 20 minutes, then the slice was taken out, 0.02% PBST was added and allowed to stand for 3 minutes, repeated 3 times, and the excess liquid around the tissue was wiped with lens paper, and a circle of appropriate size was drawn around the tissue with an immunohistochemistry pen, and the blocking solution was added for blocking 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 allowed to stand for 5 minutes, and repeated three times. The PBST was dried, 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 stand for 5 min, repeat three times, wipe off the excess water around the tissue and the traces of immunohistochemistry pen, 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 the mice were anesthetized, their eyeballs were removed to collect blood, which was placed in a centrifuge tube and left at room temperature for 2 hours to allow the blood to coagulate. The coagulated blood was then centrifuged at 3000 rpm for 15 minutes at 4°C, and the supernatant was collected as serum. The kit was then used to detect the levels of nitric oxide, total cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase in the serum of each group of mice.

[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 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 photographed using a laser confocal microscope (LSM 800, Zeiss, Germany) in a timely manner.

[0072] 7. Complete blood cell analysis

[0073] Routine blood tests require anticoagulated whole blood. Take about 0.5 mL of blood from mice. Mix gently immediately after blood collection to prevent platelet adhesion and aggregation. Be careful not to shake vigorously to prevent bubbles and hemolysis. Check the sample for clots. Send blood for testing in time after blood collection, and complete it within 2 hours. This experiment uses a fully automatic blood cell analyzer for analysis.

[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 gemacron 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 gemacron and empagliflozin, the myocardial cross-sectional area of ​​mice with heart failure was significantly reduced. The above results show that gemacron can reduce left ventricular mass, left ventricular posterior wall thickness and left atrial anteroposterior diameter, and inhibit myocardial hypertrophy. The effect of gemacron is close to that of empagliflozin and even better in some indicators, showing 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 show that the significantly increased DBP indicates 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 jemacron and empagliflozin, the DBP, SBP, and MBP of the mice were significantly downregulated, and the level of NO in the serum increased significantly. Jemacron can relieve the symptoms of hypertension in mice with heart failure with preserved ejection fraction, and shows antihypertensive effects at different doses, and the effect is comparable to that of the positive control empagliflozin group. Jemacron 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 heart failure mice

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

[0081] 4. Germacron improves endothelial damage in the heart vessels of 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 The results showed that when mice were treated with a high-fat diet and L-NAME, endothelial damage occurred in the heart and blood vessels of the mice, the expression of VCAM-1 and ICAM-1 in the heart microvascular endothelium increased significantly, and the fluorescence signal was significantly enhanced. Compared with the normal group, jemacron significantly reduced the expression of VCAM-1 and ICAM-1 at all doses and restored them to near normal levels, and even showed better effects at low doses. The effect of jemacron at all doses was comparable to that of empagliflozin, indicating that jemacron has similar or even better vascular protection potential than existing drugs.

[0083] 5. Germacron improves abnormal lipid metabolism 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. From the perspective of triglycerides and total cholesterol, jemacron 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 jemacron may be close to saturation at 10 mg / kg. As a positive control drug, empagliflozin has the same effect as jemacron in various indicators, indicating that jemacron 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 high-fat diet and L-NAME, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the mouse serum increased significantly, leading to liver cell damage and dysfunction. After intervention with jemacron and empagliflozin, the levels of ALT and AST in the mouse serum decreased significantly, and the effect of the jemacron 10mg / kg group was better than that of the empagliflozin group, showing better liver protection, indicating that jemacron 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 were exposed to a high-fat diet and L-NAME, the number of white blood cells and monocytes in the blood of mice 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 blood of mice 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 activation of platelets and thrombin. 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 activation of platelets and thrombin in heart failure with preserved ejection fraction.

[0089] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. An application of germacron, characterized in that, Used for preparing drugs related to cardiovascular diseases.

2. The use of germacron according to claim 1, characterized in that Used to prepare drugs for improving heart failure.

3. The use of germacrone according to claim 1, characterized in that: Used for preparing drugs related to inhibiting myocardial hypertrophy.

4. The use of germacron according to claim 1, characterized in that: Used to prepare drugs for improving vascular endothelial function and lowering blood pressure.

5. The use of germacrone according to claim 4, characterized in that: Used for preparing drugs that reduce the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 and / or increase serum NO levels.

6. The use of germacrone according to claim 1, characterized in that: Used for preparing drugs for improving systemic inflammation and / or platelet and thrombin dysfunction.

7. An application of germacron, characterized in that, Used to prepare drugs for regulating abnormal lipid metabolism and alleviating liver damage.

8. The use of germacrone according to claim 7, characterized in that: Used to prepare drugs for lowering triglyceride and total cholesterol levels.

9. The use of germacrone according to claim 7, characterized in that: Used to prepare drugs that reduce alanine aminotransferase and aspartate aminotransferase levels.

10. A drug, characterized in that The drug comprises germacron and is used for treating cardiovascular diseases, systemic inflammation, abnormal lipid metabolism and liver-related diseases.

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