CN117883457A - Application of 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester in preparation of liver protection medicine - Google Patents
Application of 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester in preparation of liver protection medicine Download PDFInfo
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester in preparing liver-protecting medicaments. The compound has obvious functions of reducing blood fat and resisting liver fibrosis, and has the advantages of good safety, simple and convenient administration, easy absorption and convenient preservation and transportation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel hypolipidemic and anti-hepatic fibrosis medicine, in particular to an application of 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester in preparation of hypolipidemic medicines.
Background
Hyperlipidemia refers to hyperlipidemia, such as elevation of Total Cholesterol (TC) and Triglyceride (TG) and low density lipoprotein (LDL-C) in serum, which can directly cause diseases seriously harmful to human health, such as atherosclerosis, coronary heart disease, etc. Hyperlipidemia can also cause fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, hyperuricemia, etc. Liver fibrosis is a pathological process in the human body that occurs in the early stages of cirrhosis. Generally refers to the pathological process of abnormal hyperplasia of connective tissue in the liver, leading to excessive deposition of diffuse cells in the liver. Normally, the normal liver causes hyperlipidemia, acute hepatitis, chronic hepatitis and liver fibrosis due to drinking, high-fat high-sugar high-salt diet, virus infection, autoimmunity, heredity, metabolism, medicine and the like, and finally, liver cirrhosis, thereby causing ascites, hepatic encephalopathy, other complications and the like. Clinical studies have shown that most sudden cardiac death has a coronary arteriosclerotic lipid abnormality and that coronary arteriosclerotic lipid abnormality may play an important role in ischemic cardiovascular and cerebrovascular events. Lipid metabolism disorders exacerbate the disorder of glucose metabolism on the one hand and increase the incidence of macrovascular complications of diabetes and mortality on the other hand.
Most of clinically used lipid regulating drugs are chemical synthesis preparations, and various statin drugs such as simvastatin and lovastatin are required to be taken for a long time, so that the statin drugs can prevent cardiovascular and cerebrovascular accidents while treating hyperlipidemia. However, the long-term or large-dose use of statin drugs may cause serious adverse reactions such as biochemical changes of liver tissue cells or dissolution of striated muscle of heart, and the long-term administration of statin drugs is limited. The main treatment method for the liver fibrosis clinically only takes the liver burden reduction and a few liver protection medicines and Chinese herbal medicines as main medicines, no specific medicines for treating the liver fibrosis exist clinically at present, the common liver protection medicines comprise magnesium isoglycyrrhetate, silymarin, obeticholic acid and the like, the Chinese herbal medicines mainly comprise an Anluo chemical pill, a compound turtle shell liver softening tablet and the like, but the current liver protection medicines and the Chinese herbal medicines still have a plurality of adverse reactions, common adverse reactions mainly comprise abdominal pain, diarrhea, nausea, cough and the like, and the specific treatment medicines for treating the pathological process of long-term hyperlipidemia and inducing hepatitis and liver fibrosis still have research and development hot spots and difficult problems.
Therefore, the research and development of safe and effective novel liver protection drugs, in particular to drugs for regulating blood lipid and drugs for resisting liver fibrosis have important significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a medicament with remarkable liver protection effect, good safety and simple and convenient administration.
In order to achieve the above purpose, the invention provides application of 1, 2-dihydroxyethyl 2-acetoxybenzoate in preparing liver-protecting medicines.
The molecular formula of the 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester is C 13 H 16 O 5 The molecular weight is 252, and the chemical structural formula is as follows:
the 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester is a derivative of aspirin, and is prepared by modifying aspirin, and a preparation method and identification thereof refer to Chinese patent application CN110668947A. 1, 2-dihydroxyethyl 2-acetoxybenzoate is also referred to herein as "Gankang".
Preferably, the liver-protecting drug is a hypolipidemic drug.
More preferably, the hypolipidemic agent reduces total cholesterol, triglycerides and low density lipoproteins in the serum of a hyperlipidemic animal, reduces total cholesterol and triglyceride levels in the liver and liver diameter.
Preferably, the liver protecting drug is an anti-liver fibrosis drug.
More preferably, the anti-liver fibrosis agent reduces liver fibrosis, reduces liver weight ratio, serum, and ALT and AST levels in liver tissue homogenates.
Preferably, the liver protection medicament is a capsule, a tablet, a powder, a granule, a sustained release agent, an injection or any other pharmaceutically acceptable preparation.
Compared with the prior art, the invention has the following beneficial technical effects: the hypolipidemic effect is remarkable: the 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester can obviously regulate blood fat, can obviously reduce serum TC, TG and LDL-C compared with the most commonly used atorvastatin in clinic under the maximum clinical dosage, and can be used as a safe and effective medicament for preventing and treating hyperlipidemia; (2) the anti-hepatic fibrosis effect is remarkable: the 2-acetoxybenzoic acid 1, 2-dihydroxyethyl ester can obviously improve the hepatic fibrosis area of mice, and can be used as a safe and effective medicament for preventing and treating hepatic fibrosis; (3) good safety, no obvious toxic or side effect; (4) the medicine is simple and convenient to take and easy to absorb; (5) The raw material of the medicine is aspirin, the finished product has strong drug property, low price and high cost performance; (6) convenient transportation and storage.
Drawings
FIG. 1 shows the effect of Gankang on TC (A), TG (B) and LDL-C (C) levels in blood, TC (D) and TG (E) levels in liver, and liver diameter (F, G) of hyperlipidemic golden mice.
FIG. 2 shows the effect of Gankang on hyperlipidemia C57BL/6 mice blood lipid TC (A), TG (B) and LDL-C (C) levels, TC (D) and TG (E) levels in the liver, and liver diameter (F, G).
FIG. 3 is the effect of Gankang on TC (A) and TG (B) levels in oleic acid-induced high-fat HepG2 cells.
Fig. 4 is a schematic diagram of experimental procedures of liver health anti-hepatic fibrosis animals.
FIG. 5 is a graph showing the effect of Gankang on liver morphology in liver fibrosis mice.
FIG. 6 is a graph showing the effect of Gankang on liver weight to weight ratio in liver fibrosis mice.
FIG. 7 shows the effect of Gankang on the markers of liver injury, glutamic pyruvic transaminase ALT (A) and glutamic oxaloacetic transaminase AST (B), in serum of liver fibrosis mice.
FIG. 8 shows the effect of Gankang on liver injury markers ALT (A) and AST (B) in liver tissue of liver fibrosis mice.
FIG. 9 is a graph showing the effect of Gankang on hepatic fibrosis mouse α -SMA protein expression.
Detailed Description
The advantages and features of the present invention will become more apparent from the following description of the invention, taken in conjunction with the accompanying drawings and detailed description. The embodiments are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Unless otherwise indicated, the experimental reagents or operation techniques used in the embodiments of the present invention are conventional experimental reagents or operation techniques known and available in the art, and are not described in detail for the sake of brevity, but do not affect implementation of the technical solution. Each experimental data is expressed as mean ± standard deviation.
Example 1: efficacy test of Gankang on golden yellow mice animal model
1. Experimental materials
Experimental animals: 42 of SPF grade male golden yellow mice (Mesocricetus auratus)
Test drug: 2-Acetoxybenzoic acid 1, 2-dihydroxyethyl ester (Gankang)
Maintaining feed: purchased from the company Tianjin feed limited, the company of the family australia.
High-fat feed: the feed formula comprises 20.0% sucrose, 15% lard, 1.2% cholesterol, 0.2% sodium cholate, proper amount of casein, calcium hydrophosphate, stone powder and the like. Besides crude fat, the water content, crude protein, crude fat, crude fiber, crude ash, calcium and phosphorus of the high-fat feed all reach the national standard of maintaining the feed. The feed is clean, vacuum packaged, and stored at 4deg.C. The above percentages (%) are all weight percentages.
2. Principle of experiment
The animal model of lipid metabolism disorder can be formed by feeding animals with the above-mentioned high-fat feed containing cholesterol, sucrose, lard and sodium cholate, and then the animal drug can be administered, so that the influence of the test drug on hyperlipidemia can be detected, and the influence of the test drug on lipid absorption, lipoprotein formation, lipid degradation or excretion of the animal can be determined.
Determination of animal model of hyperlipidemia: after the modeling period is finished, the serum triglyceride, the total cholesterol or the low-density lipoprotein cholesterol is increased in the hyperlipidemia model group compared with the blank control group, the difference is significant, and the model is judged to be established.
3. Experimental method
3.1 grouping of animals
First random grouping: after animals are received, the animals are adaptively fed for 5-7 days, the appearance and general state of the animals are observed during the domestication period, and the animal formulas which are qualified after inspection can enter the experiment. After the end of the adaptation period, animals were weighed and randomly divided into a placebo group (ND) and a high fat model group.
Second random grouping: after the completion of the establishment of the animal hyperlipidemia model, the animal blood lipid was examined, and the hyperlipidemia model group was randomly divided into a hyperlipidemia model control group (HFD), a test drug low dose group (25 ml/kg body weight) (HFD-GK-L), a test drug medium dose group (50 mg/kg body weight) (HFD-GK-M), a test drug high dose group (100 mg/kg body weight) (HFD-GK-H), a positive control group (atorvastatin calcium group, 2mg/kg body weight) (HFD-ATV).
3.2 model establishment period of hyperlipidemia
As shown in table 1, in each experimental group, a blank group was fed with a maintenance feed, and the other groups were fed with a high fat feed, and the levels of triglyceride, total cholesterol, and low density lipoprotein in the serum of animals were measured.
The animals in the blank control group and the high-fat model group fasted the canthus to collect blood, and serum was separated after blood collection to determine the levels of TC, TG and LDL-C in the serum. The high-fat model groups were randomly grouped according to TC, TG, and LDL-C levels, and TC, TG, and LDL-C were compared to the blank.
TABLE 1 dosing and diet of animals of each group
| Group of | Frequency of administration | Period of administration | Dosage of medicine | Diet and food | Number of golden mice |
| Blank control group | Gastric lavage 1 time/day | For 10 days | 10ml/kg body weight | Normal state | 7 pieces of |
| Hyperlipidemia model control group | Gastric lavage 1 time/day | For 10 days | 10ml/kg body weight | High fat | 7 pieces of |
| Low dose group of test drugs | Gastric lavage 1 time/day | For 10 days | 25mg/kg body weight | High fat | 7 pieces of |
| Dose group in test drug | Gastric lavage 1 time/day | For 10 days | 50mg/kg body weight | High fat | 7 pieces of |
| High dose group of test drugs | Gastric lavage 1 time/day | For 10 days | 100mg/kg body weight | High fat | 7 pieces of |
| Positive control group | Gastric lavage 1 time/day | For 10 days | 2mg/kg body weight | High fat | 7 pieces of |
3.3 dosing period
Animals in the successfully grouped test drug (high, medium, low dose) groups and the positive control group (atorvastatin calcium group) were given daily intragastric administration, and the blank control group and the hyperlipidemia model control group were given corresponding doses of the solvent (blank control group: distilled water; hyperlipidemia model control group: olive oil). The amounts administered in each group are shown in Table 1.
The feed administration condition is unchanged, blood is taken from the canthus 10 days after administration, the levels of TC, TG and LDL-C in animal serum and the levels of TC and TG in liver tissue homogenate are measured, the influence of test drugs on the TC and TG in animal serum TC, TG, LDL-C and liver is observed, and the liver diameter of the animal is detected by ultrasonic.
3.4 observation period
General vital sign observations were made during the experiment.
3.5 main detection index
(1) Serum TC, TG and LDL-C levels.
(2) And ultrasonically detecting the liver diameter of the animal.
(3) After sampling, TC and TG levels in liver homogenates were determined.
4. Experimental data and results
4.1 data processing
Analysis of variance is adopted, but the variance alignment is firstly checked according to the program of the analysis of variance, the variance is aligned, the F value is calculated, the 36F value is less than 0.05, and the conclusion is that: the difference between the average numbers of the groups is not significant; f is more than or equal to 0.05, P is less than or equal to 0.05, and statistics is carried out by a pairwise comparison method of average numbers between a plurality of experimental groups and a control group; proper variable conversion is carried out on the data with non-normal or variance, and statistics is carried out on the converted data after the normal or variance alignment requirement is met; if the normal or variance alignment purpose is not achieved after the variable conversion, the rank sum test is used for statistics.
4.2 animal Experimental results determination
Judging the functional result of reducing blood fat: compared with a blank control group, the hyperlipidemia model control group has the advantages that the serum triglyceride is increased, the serum total cholesterol is increased, the low-density lipoprotein is increased, the difference is obvious, and the judgment model is established.
And compared with a control group of a hyperlipidemia model, each dose group of the tested medicament has obviously reduced serum total cholesterol, triglyceride and low-density lipoprotein, and the difference is obvious, so that the positive test result of the tested medicament in the animal with the function of reducing blood fat can be judged.
Compared with a control group of a hyperlipidemia model, each dosage group of the test drug has the advantages that the cholesterol and triglyceride levels in liver tissue homogenate are reduced, the difference is significant, meanwhile, the cholesterol and triglyceride of each dosage group of the test drug is not significantly higher than that of the control group of the hyperlipidemia model, and the test result of the test drug for reducing the cholesterol and triglyceride functional animals can be judged to be positive.
Compared with a control group of the hyperlipidemia model, each dose group of the tested medicine has the advantages that the liver diameter of any dose group of the tested medicine is reduced, the difference is remarkable, meanwhile, the liver diameter of each dose group of the tested medicine is not remarkably higher than that of the control group of the hyperlipidemia model, and the test result of the tested medicine for reducing triglyceride can be judged to be positive.
4.3 experimental results
As shown in FIG. 1, after 10 days of administration, the hyperlipidemic model control group golden yellow mice had total cholesterol in serum [ (] compared with the blank control group golden yellow mice ** P<0.01vs. ND), triglycerides ** P<0.01 vs.ND) and low density lipoprotein ** P<0.01 vs.ND) level is significantly increased, and the establishment of the judgment model is successful.
Compared with the control group of the hyperlipoidemia model, the TC in serum of the golden mice with hyperlipoidemia can be obviously reduced by the low, medium and high doses of the tested medicament and the atorvastatin calcium # P<0.05vs.HFD， ## P<0.01vs.HFD)、TG( ## P<0.01vs. HFD) and LDL-C ## P<0.01vs.HFD)。
Compared with the golden yellow mice in the blank control group, the golden yellow mice in the hyperlipidemic model group have total cholesterol in the liver @ ** P<0.01vs. ND) and triglycerides ** P<0.01 vs.ND) level is significantly increased, and the establishment of the judgment model is successful.
Compared with the control group of the hyperlipoidemia model, the low, medium and high doses of the tested medicament can reduce TC in liver tissue homogenate of the golden yellow mice with hyperlipoidemia ## P<0.01vs. HFD) and TG # P<0.05vs.HFD， ## P<0.01vs.HFD)。
Compared with the golden yellow mice in the blank control group, the golden yellow mice in the hyperlipoidemia model group are prepared ** P<0.01 vs.ND), the liver diameter is remarkably increased, and the establishment of a judgment model is successful.
Compared with the control group of the hyperlipoidemia model, the liver diameter of the golden yellow rats with hyperlipoidemia can be reduced by the low, medium and high doses of the tested medicament and the atorvastatin calcium ## P<0.01vs.HFD)。
Example 2: efficacy test of Gankang on C57BL/6 mouse animal model
1. Experimental materials
Experimental animals: 28 animals of uniform body weight (healthy male C57BL/6 mice (22.+ -.1 g)).
Test drug: 2-Acetoxybenzoic acid 1, 2-dihydroxyethyl ester (Gankang)
Maintaining feed: purchased from the company Tianjin feed limited, the company of the family australia.
High-fat feed: the feed formula comprises 20.0% sucrose, 15% lard, 1.2% cholesterol, 0.2% sodium cholate, proper amount of casein, calcium hydrophosphate, stone powder and the like. Besides crude fat, the water content, crude protein, crude fat, crude fiber, crude ash, calcium and phosphorus of the high-fat feed all reach the national standard of maintaining the feed. The feed is clean, vacuum packaged, and stored at 4deg.C. The above percentages (%) are all weight percentages.
2. Principle of experiment
The animal model of lipid metabolism disorder can be formed by feeding animals with the above-mentioned high-fat feed containing cholesterol, sucrose, lard and sodium cholate, and then the animal drug can be administered, so that the influence of the test drug on hyperlipidemia can be detected, and the influence of the test drug on lipid absorption, lipoprotein formation, lipid degradation or excretion of the animal can be determined.
Determination of animal model of hyperlipidemia: after the modeling period is finished, the serum triglyceride, the total cholesterol or the low-density lipoprotein cholesterol is increased in the hyperlipidemia model group compared with the blank control group, the difference is significant, and the model is judged to be established.
3. Experimental method
3.1 grouping of animals
First random grouping: after animals are received, the animals are adaptively fed for 5-7 days, the appearance and general state of the animals are observed during the domestication period, and the animal formulas which are qualified after inspection can enter the experiment. After the end of the adaptation period, animals were weighed and randomly divided into a placebo group (ND) and a high fat model group.
Second random grouping: after the establishment of the animal hyperlipidemia model, the animal hyperlipidemia is detected, and the hyperlipidemia model group is randomly divided into a hyperlipidemia model control group (HFD), a test drug group (HFD-GK) and a positive control group (atorvastatin calcium group) (HFD-ATV).
3.2 model establishment period of hyperlipidemia
As shown in table 2, in each experimental group, the blank group was fed with a maintenance feed, the remaining groups were fed with a high fat feed, and the levels of triglyceride, total cholesterol, and low density lipoprotein in the serum of animals were measured.
The animals in the blank control group and the high-fat model group fasted the canthus to collect blood, and serum was separated after blood collection to determine the levels of TC, TG and LDL-C in the serum. The high-fat model groups were randomly grouped according to TC, TG, and LDL-C levels, and TC, TG, and LDL-C were compared to the blank.
TABLE 2 dosing and diet of animals of each group
| Group of | Frequency of administration | Period of administration | Dosage of | Diet and food | Number of C57BL/6 mice |
| Blank control group | Gastric lavage 1 time/day | 8 weeks of | 10ml/kg body weight | Normal state | 7 pieces of |
| Hyperlipidemia model control group | Gastric lavage 1 time/day | 8 weeks of | 10ml/kg body weight | High fat | 7 pieces of |
| Test drug group | Gastric lavage 1 time/day | 8 weeks of | 100mg/kg body weight | High fat | 7 pieces of |
| Positive control group | Gastric lavage 1 time/day | 8 weeks of | 20mg/kg body weight | High fat | 7 pieces of |
3.3 dosing period
Animals in the successfully grouped test drug group and the positive control group (atorvastatin calcium group) were administered daily by gastric lavage, and the blank control group and the hyperlipidemia model control group were administered with corresponding doses of the solvent (blank control group: distilled water; hyperlipidemia model control group: olive oil). The amounts administered in each group are shown in Table 2.
The feed administration condition is unchanged, blood is taken from the canthus after 8 weeks of administration, the levels of TC, TG and LDL-C in animal serum and the levels of TC and TG in liver tissue homogenate are measured, the influence of test drugs on the TC and TG in animal serum TC, TG, LDL-C and liver is observed, and the liver diameter of the animal is detected by ultrasonic.
3.4 observation period
General vital sign observations were made during the experiment.
3.5 main detection index
(1) Serum TC, TG and LDL-C levels.
(2) And ultrasonically detecting the liver diameter of the animal.
(3) After sampling, TC and TG levels in liver homogenates were determined.
4. Experimental data and results
4.1 data processing
Analysis of variance is adopted, but the variance alignment is firstly checked according to the program of the analysis of variance, the variance is aligned, the F value is calculated, the 36F value is less than 0.05, and the conclusion is that: the difference between the average numbers of the groups is not significant; f is more than or equal to 0.05, P is less than or equal to 0.05, and statistics is carried out by a pairwise comparison method of average numbers between a plurality of experimental groups and a control group; proper variable conversion is carried out on the data with non-normal or variance, and statistics is carried out on the converted data after the normal or variance alignment requirement is met; if the normal or variance alignment purpose is not achieved after the variable conversion, the rank sum test is used for statistics.
4.2 animal Experimental results determination
Judging the functional result of reducing blood fat: compared with a blank control group, the hyperlipidemia model control group has the advantages that the serum triglyceride is increased, the serum total cholesterol is increased, the low-density lipoprotein is increased, the difference is obvious, and the judgment model is established.
Compared with a control group of a hyperlipidemia model, the serum total cholesterol, the triglyceride and the low-density lipoprotein are reduced, and the differences are obvious, so that the positive result of the animal experiment with the blood lipid reducing function of the tested drug can be judged.
Compared with a control group of a hyperlipidemia model, the cholesterol and triglyceride levels in liver tissue homogenate are reduced, the difference is remarkable, and meanwhile, the cholesterol and triglyceride of each dosage group is not remarkably higher than that of the control group of the hyperlipidemia model, so that the positive experimental results of the functional animal of the cholesterol and triglyceride reduction of the test drug can be judged.
Compared with the control group of the hyperlipidemia model, the liver diameter of the test drug group is reduced, the difference is remarkable, and meanwhile, the liver diameter of the test drug group is not remarkably higher than that of the control group of the hyperlipidemia model, so that the test drug can be judged to be positive in the experimental result of the animal with triglyceride reducing function.
4.3 experimental results
The results are shown in FIG. 2, which shows the effect of Gankang on the blood lipid TC (A), TG (B) and LDL-C (C) levels, TC (D) and TG (E) levels in the liver, and liver diameter (F, G) in hyperlipidemic C57BL/6 mice, where G is an ultrasound image of the liver.
As can be seen from the graph, after 8 weeks of administration, the total cholesterol (P <0.01vs. nd), triglyceride (P <0.05vs. nd) and low-density lipoprotein (P <0.01vs. nd) levels in serum were significantly increased in the control group C57BL/6 mice of the hyperlipidemia model compared to the control group C57BL/6 mice, and successful model establishment was judged.
Compared with the control group of the hyperlipidemia model, the TC in serum of the C57BL/6 mice with hyperlipidemia can be obviously reduced by the test drug group and the atorvastatin calcium (positive control group) ## P<0.01vs.HFD),TG( ## P<0.01vs. HFD) and LDL-C # P<0.05vs.HFD)。
The total cholesterol (P <0.01vs. nd) and triglyceride (P <0.05vs. nd) levels in the liver were significantly increased in the hyperlipidemic model control group C57BL/6 mice compared to the placebo group C57BL/6 mice, and the model was judged to be successful.
Compared with the control group of the hyperlipoidemia model, the tested drug group can reduce TC in liver tissue homogenate of the hyperlipoidemia C57BL/6 mice # P<0.05vs. HFD) and TG ## P<0.01vs.HFD)。
The liver diameter of the control group C57BL/6 mice of the hyperlipidemia model is obviously increased compared with that of the control group C57BL/6 mice of the blank group (P is less than 0.01vs. ND), and the establishment of the model is judged to be successful.
Compared with the control group of the hyperlipoidemia model, the liver diameter of the C57BL/6 mice with hyperlipoidemia can be reduced by the test drug group and the atorvastatin calcium (positive control group) ## P<0.01vs.HFD)。
Example 3: efficacy test of Gankang on HepG2 cell line
1. Experimental materials
Experimental cells: hepG2 cell lines
Test drug: 2-Acetoxybenzoic acid 1, 2-dihydroxyethyl ester (Gankang)
2. Principle of experiment
And (3) administering a cell test drug into the cultured HepG2 cells for half an hour, and adding oleic acid to induce and prepare a cell high-lipid model, so that the influence of the test drug on the lipid level of the cells can be detected.
3. Experimental method
3.1 cell grouping
After the cell fusion degree reaches about 80%, the oleic acid of 800 mu mol/L is added into the other groups except the normal group, and then the groups are divided into five groups: normal (Ctrl), oleic acid-induced hyperlipidemia (OA), liver-healthy low-dose (oa+gk2.5 μmol/L), liver-healthy medium-dose (oa+gk5 μmol/L) and liver-healthy high-dose (oa+gk10 μmol/L). After 24 hours, cellular cholesterol (TC) and Triglyceride (TG) levels were measured.
3.2 detection method
3.2.1 cell collection: the cells were scraped off with PBS, cell suspensions were prepared, centrifuged at 3000 rpm for 10min, the supernatant was discarded, cell pellet was left, washed 1-2 times with PBS, centrifuged at 3000 rpm for 10min, the supernatant was discarded, and cell pellet was left.
3.2.2 cell disruption: 30. Mu.L of PBS was added and sonicated.
3.2.3 assay method: firstly, the protein concentration of a sample is measured by using the Biyun kit. Then 250. Mu.L of working solution is added into a 96-well plate, 2.5. Mu.L of distilled water is added into a blank well, 2.5. Mu.L of calibration solution is added into a calibration well, 2.5. Mu.L of sample is added into a sample well, incubation is carried out for 10 minutes at 37 ℃, and OD value is measured by an enzyme-labeled instrument at 510 nm.
3.2.4 calculation formula:
cholesterol content= (sample OD value-blank OD value)/(calibration OD value-blank OD value) ×5.17/protein concentration of sample to be tested
Triglyceride content = (sample OD value-blank OD value)/(calibration OD value-blank OD value) ×2.26/protein concentration of sample to be tested
4. Experimental data and results
4.1 data processing
Analysis of variance is adopted, but the variance alignment is firstly checked according to the program of the analysis of variance, the variance is aligned, the F value is calculated, the 36F value is less than 0.05, and the conclusion is that: the difference between the average numbers of the groups is not significant; f is more than or equal to 0.05, P is less than or equal to 0.05, and statistics is carried out by a pairwise comparison method of average numbers between a plurality of experimental groups and a control group; proper variable conversion is carried out on the data with non-normal or variance, and statistics is carried out on the converted data after the normal or variance alignment requirement is met; if the normal or variance alignment purpose is not achieved after the variable conversion, the rank sum test is used for statistics.
4.2 experimental results
As shown in FIG. 3, to effect Gankang on TC (A) and TG (B) levels in oleic acid-induced high-fat HepG2 cells, oleic acid-induced high-fat cells (OA) were compared with control cells (Ctrl), total cholesterol [ ** P<0.01vs. Ctrl) and triglycerides [ (] ** P<0.01vs. ctrl) level was significantly increased, judging that the model was successfully built. Induction of high lipidomic cells with oleic acidCompared with the low, medium and high dosage groups of Gankang, the TC of oleic acid induced high-fat cells can be obviously reduced ## P<0.01vs. OA) and TG ## P<0.01vs. oa). This shows that Gankang has the effect of reducing blood lipid, in particular reducing total cholesterol, triglyceride and low density lipoprotein in serum of animals with hyperlipidemia, and reducing the level of total cholesterol and triglyceride in liver and liver diameter.
Example 4: efficacy test of Gankang on liver fibrosis C57BL/6 mouse model
1. Experimental materials
Experimental animals: 60C 57BL/6 mice of uniform body weight.
Test drug: 2-Acetoxybenzoic acid 1, 2-dihydroxyethyl ester (Gankang).
2. Principle of experiment
Carbon tetrachloride (CCl) was injected intraperitoneally 4 ) A mouse model of liver fibrosis can be formed in 8 weeks, and the effect of the test drug on the liver fibrosis can be detected by administering the drug to the mice by intragastric administration for 4 weeks.
3. Experimental method
3.1 grouping of animals
Random grouping: after animal reception, the animals were fed adaptively for 3 days, and after the end of the adaptation period, the C57BL/6 mice were randomly weighed and randomly divided into 5 groups, namely a control group (Ctrl) and a hepatic fibrosis model group (CCl) 4 ) Gankang low dose group (CCl) 4 +GK-L), gankang middle dose group (CCl) 4 +GK-M), gankang high dose group (CCl) 4 +GK-H)。
3.2 liver fibrosis model establishment
The hepatic fibrosis model of the mice is established by intraperitoneal injection of carbon tetrachloride. Healthy male C57BL/6 mice (22.+ -.1 g) were intraperitoneally injected with carbon tetrachloride (2 mg/kg) twice weekly for 8 weeks. Fig. 4 is a schematic diagram of experimental procedures of liver health anti-hepatic fibrosis animals.
3.3 dosing and modeling period:
the adaptively fed SPF-grade C57BL/6 mice were randomly weighed and randomly divided into 5 groups, namely a control group (Ctrl) and a hepatic fibrosis model group (CCl) 4 ) Gankang low dose group (CCl) 4 +GK-L), gankang middle dose group (CCl) 4 +GK-M), gankang high dose group (CCl) 4 +GK-H), hepatic injury is detected by drawing materials after 4 consecutive weeks, after starting to administer Gankang and olive oil by intragastric administration in the fifth week induced by carbon tetrachloride. The dosage of the Gankang low dose group is 25mg/kg, the dosage of the Gankang medium dose group is 50mg/kg, and the dosage of the Gankang high dose group is 100mg/kg. The administration (distilled water) dose of the control group was 10ml/kg body weight; the dose of the control group of the hyperlipidemia model was 10ml/kg body weight.
3.4 observation period
General vital sign observations were made during the experiment.
3.5 main detection index
(1) After drawing the materials, the mouse liver was observed for graininess and lesions.
(2) After sampling, the liver weight to weight ratio, serum and ALT and AST levels in the liver were determined.
(3) Measurement of alpha-SMA protein.
4. Experimental data and results
4.1 data processing
Adopting analysis of variance, but firstly carrying out a variance alignment test according to the program of the analysis of variance, calculating an F value, wherein the F value is less than 0.05, and conclusion is that: the difference between the average numbers of the groups is not significant; f is more than or equal to 0.05, P is less than or equal to 0.05, and statistics is carried out by a pairwise comparison method of average numbers between a plurality of experimental groups and a control group; proper variable conversion is carried out on the data with non-normal or variance, and statistics is carried out on the converted data after the normal or variance alignment requirement is met; if the normal or variance alignment purpose is not achieved after the variable conversion, the rank sum test is used for statistics.
4.2 experimental results
The results are shown in FIG. 5, which shows the effect of Gankang on liver morphology (liver morphology at the beginning of the apical behavioral experiment and liver morphology at the end of the basal behavioral experiment) in liver fibrosis mice. As can be seen from the graph, the model group has serious liver granule feel, and liver granule feel of liver rehabilitation administration groups (comprising low, medium and high dose groups) is obviously reduced.
As shown in FIG. 6, the effect of Gankang on the liver weight ratio of liver fibrosis mice was demonstrated. As can be seen from the graph, the liver weight ratio was significantly increased in the liver fibrosis model group compared to the control group; compared with liver fibrosis model group, liver weight ratio of liver health administration group (including low dose, medium dose and high dose) is significantly reduced, and the reduction degree is proportional to the dose.
As shown in fig. 7, the effects of liver health on liver injury markers ALT (a) and AST (B) in serum of liver fibrosis mice are shown. As can be seen from the figure, the liver fibrosis model group has significantly increased ALT and AST in serum compared with the control group; compared to the liver fibrosis model group, the liver health administration group (including low dose, medium dose and high dose) had significantly reduced ALT and AST levels.
As shown in fig. 8, the effects of liver health on liver injury markers ALT (a) and AST (B) in liver tissue of liver fibrosis mice are shown. As can be seen from the figure, ALT and AST in liver tissue homogenates were significantly increased in the liver fibrosis model group compared to the control group; compared with liver fibrosis model group, ALT and AST levels of liver health administration group are significantly reduced.
As shown in fig. 9, the effect of liver health on the expression of alpha-SMA protein in liver fibrosis mice is shown, wherein the upper panel shows western blot results for determining the expression of alpha-SMA protein, and the lower panel shows a bar graph of the expression level of alpha-SMA protein. As can be seen from the figure, the liver fibrosis model group has significantly increased α -SMA protein expression compared to the control group; compared with liver fibrosis model group, liver health administration group (including low dose, medium dose and high dose) has significantly reduced expression level of alpha-SMA protein.
The experimental results show that the Gankang has the function of resisting hepatic fibrosis, especially reducing hepatic fibrosis, decreasing the weight-to-weight ratio of liver, and reducing ALT and AST levels in serum and liver tissue homogenates.
Claims (7)
1, 2-dihydroxyethyl 2-acetoxybenzoate is used in preparing liver protecting medicine.
2. The use according to claim 1, wherein the chemical structural formula of the 1, 2-dihydroxyethyl 2-acetoxybenzoate is as follows:
3. the use according to claim 1, wherein the liver protecting drug is a hypolipidemic drug.
4. The use according to claim 3, wherein the hypolipidemic agent reduces total cholesterol, triglycerides and low density lipoproteins in the serum of a hyperlipidemic animal, reduces total cholesterol and triglyceride levels in the liver and liver diameter.
5. The use according to claim 1, wherein the liver protecting drug is an anti-liver fibrosis drug.
6. The use according to claim 5, wherein the anti-liver fibrosis drug reduces liver fibrosis, reduces liver weight ratio, serum and ALT and AST levels in liver tissue homogenates.
7. The use according to any one of claims 1 to 6, wherein the liver-protecting medicament is in the form of a capsule, tablet, powder, granule, slow release formulation, injection or any other pharmaceutically acceptable formulation.
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