Application of ellagic acid in prevention of heart injury caused by long-term diving

Abstract

The invention discloses application of ellagic acid to prevention of heart injury caused by long-term diving. A medicine for preventing heart injury caused by long-term diving is a medicine composition taking ellagic acid as a unique active ingredient or containing ellagic acid. According to the application of ellagic acid in prevention of heart injury caused by long-term phreatic water, animal in-vivo experiment results show that the morbidity of myocardial infarction of a long-term simulated phreatic water rat model is reduced to 23.8% from 44.8% through ellagic acid administration, the infarction area is remarkably reduced to 4.6 + / -3.3% from 14.9 + / -7.7%, the right ventricular hypertrophy index is reduced to 23.3 + / -6.5% from 34.5 + / -12.2%, and the curative effect is remarkable. The ellagic acid can effectively prevent rat heart injury caused by long-term diving. Therefore, ellagic acid has a good application prospect in prevention of heart injury caused by long-term diving.

Description

[0001] TECHNICAL FIELD

[0002] The present application relates to the field of medicine, in particular to application of ellagic acid in preventing heart injury caused by long-term diving. BACKGROUND

[0003] With the development of economy and the progress of technology, diving has rapidly expanded from commercial and national defense fields such as fishery, underwater engineering and special combat to leisure, exploration and scientific research, and has become an increasingly popular activity. The number of participants is increasing, and at the same time, its safety is increasingly concerned. When entering underwater, divers will be affected by environmental factors such as hydrostatic pressure, low temperature and immersion, and their operation must follow certain rules to avoid special diseases such as decompression sickness and barotrauma. In order to improve the safety of diving, the acute effects of these underwater environmental factors have been intensively studied, but in addition to inducing diseases and accidents at the work site, long-term diving also produces chronic effects, especially changes in cardiovascular system function. Practice shows that the incidence of cardiovascular disease in divers is higher than that in the general population, and it has become the first major factor in the life cycle of divers, among which myocardial infarction and myocardial hypertrophy are the most common. The mechanism of heart injury in divers is relatively complex. During diving, high pressure and immersion can cause changes such as decreased cardiac output, increased peripheral resistance, elevated diastolic pressure and reduced pulse pressure difference, leading to increased cardiac load, increased myocardial oxygen consumption and reduced blood supply; when ascending out of water after diving, the dissolved physiological inert gas (nitrogen, helium, etc.) in the body of the diver will exceed the saturation limit to form bubbles, which may not only cause decompression sickness, but also enter the coronary artery to directly form gas emboli, and the inflammatory response and endothelial damage caused by gas emboli can also lead to heart injury. The repeated effects of the above factors during long-term diving are an important mechanism for myocardial infarction and myocardial hypertrophy.

[0004] Ellagic acid belongs to polyphenols, which exists in many fruits, nuts and vegetables, and has good antioxidant, anti-inflammatory and anticancer effects (Landete J M. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health [J]. Food research international, 2011, 44(5): 1150-1160). Its chemical structural formula is shown as formula (I):

[0005]

[0006]

[0007] Ellagic acid has more phenolic hydroxyl groups in its structure, which can directly scavenge reactive oxygen and nitrogen free radicals, and can also enhance the expression and activity of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, and reduce the generation of lipid peroxide and reactive oxygen species. Studies have found that its antioxidant activity is 50 times that of vitamin E. Ellagic acid can inhibit the activity of transcription factor NF-κB and protein kinase MAPK, reduce the expression of cyclooxygenase-2 and nitric oxide synthase, and reduce the synthesis and secretion of pro-inflammatory factors such as transforming growth factor-β and interleukin-6. The main anti-tumor mechanism of ellagic acid is related to the inhibition of tumor cell proliferation and tumor angiogenesis, induction of tumor cell apoptosis, removal of DNA chain carcinogens, and delay of anti-tumor drug resistance. It has been found to be effective against prostate cancer, colon cancer, breast cancer, bladder cancer, skin cancer, etc. In addition, ellagic acid has also been found to have vascular endothelial and nerve protection, antibacterial, antiviral and other effects (Ríos J L, Giner R M, Marin M, et al. A pharmacological update of ellagic acid [J]. Planta medica, 2018, 84(15): 1068-1093; Larrosa M, Garcia-Conesa M T, Espín J C, et al. Ellagitannins, ellagic acid and vascular health [J]. Molecular aspects of medicine, 2010, 31(6): 513-539; Ahmed T, N Setzer W, Fazel Nabavi S, et al. Insights into effects of ellagic acid on the nervous system: a mini review [J]. Current Pharmaceutical Design, 2016, 22(10): 1350-1360.).

[0008] Currently, ellagic acid has been widely used in health products, cosmetics, beverages and other fields. Its medicinal reports mainly involve the above-mentioned tumors, viral hepatitis, fatty liver, diabetes, sepsis, atherosclerosis, arrhythmia, hypertension and other aspects (Sharifi-Rad J, Quispe C, Castillo C M S, et al. Ellagic acid: A review on its natural sources, chemical stability, and therapeutic potential [J]. Oxidative medicine and cellular longevity, 2022, 2022: 3848084; Amor A J, Gómez-Guerrero C, Ortega E, et al. Ellagic acid as a tool to limit the diabetes burden: Updated evidence [J]. Antioxidants, 2020, 9(12): 1226; W R, Zazueta C. Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection [J]. Pharmacological Research, 2015, 97: 84-103). Due to its antioxidant, anti-inflammatory and vascular endothelial protection effects, ellagic acid also has potential therapeutic effects on myocardial infarction induced by isoproterenol and coronary artery ligation (Larrosa M, Garcia-Conesa M T, Espin J C, et al. Ellagitannins, ellagic acid and vascular health [J]. Molecular aspects of medicine, 2010, 31(6): 513-539), but the mechanism of this type of myocardial infarction is quite different from that caused by long-term diving. There is no relevant literature report on the preventive effect of ellagic acid on heart injury caused by long-term diving. SUMMARY

[0009] The purpose of the present application is to provide an application of ellagic acid in preventing heart injury caused by long-term diving.

[0010] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0011] One aspect of the present application provides a use of ellagic acid in preventing heart injury caused by long-term diving.

[0012] The drug for preventing heart injury caused by long-term diving is a drug composition containing ellagic acid as the only active ingredient.

[0013] The drug composition containing ellagic acid refers to a drug composition of ellagic acid and one or more excipients allowed in pharmacy.

[0014] The excipient is at least one of diluent, excipient (such as physiological saline, edible oil, etc.), flavoring agent, sweetening agent.

[0015] The rat dose of ellagic acid is 50-150 mg / kg, and the human dose is 8-24 mg / kg, taken at one time, which can be changed according to the age, condition, etc. of the individual.

[0016] The ellagic acid can be prepared into a pharmaceutical preparation with conventional pharmaceutical excipients in pharmacy.

[0017] The pharmaceutical preparation is at least one of capsule, suspension, emulsion, solution or syrup, etc.

[0018] The animal in-vivo experimental results of the present application show that ellagic acid administration can effectively reduce the incidence of myocardial infarction of long-term simulated diving rats, reduce the infarction area and right ventricular hypertrophy index, indicating that ellagic acid can effectively prevent heart injury caused by long-term diving.

[0019] The heart injury described in the present application refers to functional and organic lesions of the heart of divers engaged in long-term diving due to factors such as pressure, immersion, low temperature, etc., and myocardial infarction and right ventricular hypertrophy are most common.

[0020] Due to the above technical solutions, the present application has the following advantages and beneficial effects:

[0021] The present application provides a use of ellagic acid in a drug for preventing heart injury caused by long-term diving, and ellagic acid can effectively prevent heart injury caused by long-term diving, which is of great significance for the health maintenance of divers. And ellagic acid itself is a plant extract active ingredient, which widely exists in various vegetables, fruits and nuts. According to the current data, there is no obvious side effect, and the safety as a drug is very high, and the treatment window is wide. Therefore, ellagic acid has a good application prospect in preventing heart injury caused by long-term diving. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is a schematic diagram of the comparison of myocardial infarction incidence of the administration group and the control group of rats in the embodiment of the present application.

[0023] Figure 2is a comparison schematic diagram of myocardial infarction areas of the administration group and the control group of rats in the embodiment of the present application.

[0024] Figure 3 is a comparison schematic diagram of right ventricular hypertrophy indexes of the administration group and the control group of rats in the embodiment of the present application. DETAILED DESCRIPTION

[0025] In order to more clearly illustrate the present application, the present application will be further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the specific description below is illustrative rather than limiting, and should not limit the protection scope of the present application.

[0026] The experimental methods in the following examples not specifically indicated are generally according to the conventional conditions, or according to the conditions suggested by the manufacturers. The reagents used in the embodiments of the present application can be obtained from the sales companies, unless otherwise specified.

[0027] Example 1

[0028] Rat administration: ellagic acid and powdered feed were mixed in a certain proportion to prepare granular rat feed. The rats were given the special rat feed at a dose of 100 mg / kg per day from one week before the first simulated diving, and the administration was continued until the last simulated diving.

[0029] The control group of rats was given ordinary feed without ellagic acid.

[0030] The rats were subjected to simulated diving every 72 hours, for a total of 10 times. Each simulated diving process was as follows: the rats were placed in a pressurized cabin, and sodium lime was placed at the bottom of the cabin to absorb carbon dioxide. First, the pressure was increased to 4 ATA at a rate of 1 ATA / min, and then the pressure was increased to 7 ATA at a rate of 1.5 ATA / min, and maintained for 90 minutes, during which ventilation was maintained. After the end, the pressure was reduced to normal pressure at a rate of 0.5-2 ATA / min according to the body weight of the rats (the rate of pressure reduction was gradually slowed down as the body weight increased, and the body weight and the rate of pressure reduction were important factors affecting the formation of gas bubbles in the rats' bodies, and gradually slowing down the rate of pressure reduction could maintain the level of gas bubbles in the rats' bodies relatively stable). Since the rats in the experiment might suffer from acute myocardial infarction and decompression sickness, both of which could be fatal, the experiment ended when the number of surviving rats in both groups reached 20 after 10 consecutive simulated dives. During the experiment, the hearts of the dead rats were immediately removed and rinsed with phosphate buffer to remove blood in the heart cavity, and then subjected to 2,3,5-triphenyltetrazolium chloride (TTC) staining according to the standard method. The surviving rats were randomly divided into two equal groups, one group was subjected to TTC staining as described above, and the other group of rats had their hearts removed, the right ventricular free wall was isolated, the weight of the right ventricle and the total weight of the left ventricle and interventricular septum were measured, and then the fixed solution was used for fixation, sectioning and hematoxylin-eosin (HE) staining.

[0031] First, the effect of ellagic acid on the incidence of myocardial infarction in long-term simulated diving rats

[0032] The number of myocardial infarction in TTC-stained sections and HE-stained sections was observed, and the incidence of myocardial infarction in rats was calculated as the sum of the two. The experimental results are shown in Table 1, Figure 1 Figure 1 is a comparison diagram of the myocardial infarction incidence of the administration group and the control group of rats in the embodiment of the present application. As can be seen from Figure 1 , the myocardial infarction incidence of the control group of rats is 44.8%, and the myocardial infarction incidence of the administration group of rats is 23.8%. Compared with the control group, the myocardial infarction incidence of the administration group of rats is significantly reduced, indicating that β-aescin can prevent myocardial infarction in rats caused by long-term simulated diving.

[0033] Second, the effect of ellagic acid on the myocardial infarction area of long-term simulated diving rats

[0034] The TTC-stained heart sections were scanned, and the pixel area of infarction and the pixel area of tissue in each section were measured using Image-Pro Plus 6.0 image analysis software, and the infarction area was calculated as = infarction pixel area / tissue pixel area*100%. The experimental results are shown in Table 2, Figure 2 Figure 2 is a comparison diagram of the myocardial infarction area of the administration group and the control group of rats in the embodiment of the present application. As can be seen from Figure 2 , the myocardial infarction area of the control group of rats is 14.9±7.7%, and the myocardial infarction area of the administration group of rats is 4.6±3.3%. Compared with the control group, the myocardial infarction area of the administration group of rats is significantly reduced, indicating that β-aescin can reduce myocardial infarction in rats caused by long-term simulated diving.

[0035] Third, the effect of ellagic acid on right ventricular hypertrophy in long-term simulated diving rats

[0036] The right ventricular hypertrophy index of rats = right ventricular weight / (left ventricular weight+interventricular septum weight)*100%, and the right ventricular hypertrophy index of rats in the two groups was calculated according to the formula, and the experimental results are shown in Table 3, Figure 3 Figure 3 is a comparison diagram of the right ventricular hypertrophy index of the administration group and the control group of rats in the embodiment of the present application. As can be seen from Figure 3 , the right ventricular hypertrophy index of the control group of rats is 34.5±12.2%, and the right ventricular hypertrophy index of the administration group of rats is 23.3±6.5%. Compared with the control group, the right ventricular hypertrophy index of the administration group of rats is significantly reduced, indicating that ellagic acid can prevent right ventricular hypertrophy in long-term simulated diving rats.

[0037] ​​​Experimental data description: the incidence of myocardial infarction in rats was tested by Chi-square test, the myocardial infarction area was tested by t test of two independent samples, the right ventricular hypertrophy index was tested by one-way ANOVA, and P<0.05 was statistically significant. All statistical analysis was performed by SPSS11.5 software, and the comparison between groups was as follows Figure 1 , Figure 2 and Figure 3 wherein: *P<0.05, # P<0.05.

[0038] It can be seen that the administration of ellagic acid can effectively reduce the incidence of myocardial infarction in long-term simulated diving rats, reduce the myocardial infarction area and the degree of right ventricular hypertrophy, indicating that ellagic acid can effectively prevent heart damage caused by long-term diving.

[0039] The above shows and describes the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. Use of ellagic acid in preventing heart injury caused by long-term diving.

2. Use of ellagic acid according to claim 1 for preventing cardiac damage caused by long-term diving, characterized in that: The medicine for preventing heart injury caused by long-term diving is a medicine composition containing ellagic acid as the only active ingredient or containing ellagic acid.

3. The use of ellagic acid in preventing heart damage caused by long-term diving according to claim 2, characterized in that: The medicine composition containing ellagic acid refers to a medicine composition of ellagic acid and one or more pharmaceutically acceptable adjuvants.

4. Use of ellagic acid according to claim 3 for preventing cardiac damage caused by long-term diving, characterized in that: The adjuvant is at least one of diluent, excipient, flavoring agent, and sweetening agent.

5. Use of ellagic acid according to any one of claims 1 to 4 for the prevention of cardiac damage induced by long-term diving, characterized in that: The dose of ellagic acid for rats is 50-150 mg / kg, and the dose for humans is 8-24 mg / kg, taken at one time.

6. Use of ellagic acid according to claim 1 for preventing cardiac damage caused by long-term diving, characterized in that: The ellagic acid can be prepared into a medicine preparation with conventional pharmaceutical adjuvants.

7. Use of ellagic acid according to claim 6 for the prevention of cardiac damage induced by long-term diving, characterized in that: The medicine preparation is at least one of capsule, suspension, emulsion, solution, and syrup.

8. Use of ellagic acid according to claim 7 for the prevention of cardiac damage induced by long-term diving, characterized in that: The medicine preparation is administered orally.

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