CN112691089B

CN112691089B - Application of 1-phenyl-1-propanol in preparation of medicine for treating hyperlipidemia and/or diabetes

Info

Publication number: CN112691089B
Application number: CN202011559708.2A
Authority: CN
Inventors: 张利生; 朱可玮
Original assignee: Huazhong Agricultural University
Current assignee: Huazhong Agricultural University
Priority date: 2020-12-25
Filing date: 2020-12-25
Publication date: 2022-03-18
Anticipated expiration: 2040-12-25
Also published as: CN112691089A

Abstract

The invention provides the application of 1-phenyl-1-propanol in preparing a medicine for treating hyperlipidemia and/or diabetes, and belongs to the field of medicine. The drug for treating hyperlipidemia and/or diabetes prepared by the 1-phenyl-1-propanol provided by the present invention has good hypolipidemic and hypoglycemic effects, and at the same time, has little toxic and side effects on the liver, and no adverse reactions occur; It is low in price, slightly fragrant, and sweet in taste, and can be used as a health product or food additive in production and life in the future to improve the health of the people. The results of the examples show that 1-phenyl-1-propanol can simultaneously reduce the efficacy of triglyceride, blood sugar and aspartate aminotransferase in the plasma of high-fat diet mice; The metabolic pathway of acid conversion to secondary bile acid has no obvious effect, and the effect of lowering blood lipid and blood sugar is mainly achieved by specifically increasing the content of plasma glycine-binding bile acid.

Description

Application of 1-phenyl-1-propanol in preparation of medicine for treating hyperlipidemia and/or diabetes

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of 1-phenyl-1-propanol in preparation of a medicine for treating hyperlipidemia and/or diabetes.

Background

The high-fat and low-carbohydrate diet structure is gradually popular, and the rise of overweight rate and obesity rate year by year and the increase of patients with hyperlipidemia, cardiovascular diseases, diabetes and other diseases are accompanied. Hyperlipidemia mainly includes hypercholesterolemia, hypertriglyceridemia and mixed hyperlipidemia. Hyperlipidemia has been identified as a major risk factor for cardiovascular and cerebrovascular diseases such as atherosclerosis and myocardial infarction.

Meanwhile, studies show that patients with hyperlipidemia often have other complications, such as type 2 diabetes (Yang jin Qu et al, 2002). In clinical manifestations, patients with hyperlipidemia often have large fat accumulations in their bodies, so patients are complicated by compensatory hyperinsulinemia and glucose intolerance (Reaven GM 1978, Reaven GM 1988, Einhorn D et al 2003). In the patients, because the sensitivity of the body to insulin is reduced, the beta-cells need to secrete excessive insulin in a compensatory manner to maintain the state of blood sugar balance, and the beta-cells secrete high insulin for a long time, so that the function of the beta-cells is reduced, and after the function of the beta-cells is reduced to a certain degree, the beta-cells cannot secrete enough insulin to maintain the stability of blood sugar, so that the blood sugar concentration is higher, and type 2 diabetes is formed. Therefore, hyperlipidemia is often associated with diseases such as insulin resistance and type 2 diabetes in many ways, so that various indexes and reasons in many ways need to be considered as much as possible when screening drugs.

Although the existing medicine for treating hyperlipidemia has the effect of relieving hyperlipidemia, the use of the medicine is limited to a certain extent in the aspect of treatment and side effects. Statins mainly inhibit the in vivo cholesterol synthase, HMG-coA reductase, thereby limiting cholesterol synthesis, stimulating accelerated cellular low density lipoprotein receptor synthesis, increasing the number of such receptors, enhancing the activity of such receptors, accelerating the clearance of low density lipoprotein and Very Low Density Lipoprotein (VLDL) remnant in the blood, and decreasing the levels of blood glucose and triglycerides, but have adverse effects such as increased transaminase, myalgia, and myositis when administered in large doses (Xucheng et al, 2001). The bebyttyric acid medicine not only has the function of reducing blood fat and blood sugar, but also can reduce the morbidity risk of coronary heart disease, but can obviously increase the morbidity of gallstone of a patient who takes the medicine, and also can obviously increase the mortality of non-coronary heart disease, such as gallstone, tumor and other causes, so that the medicine taking group has higher mortality than the control group. Nicotinic acid drugs have a regulating effect on blood fat and blood sugar reduction, but have serious side effects, and the use of hydrochloric acid drugs can activate peptic ulcer, aggravate ulcer diseases, reduce sugar tolerance of organisms, aggravate diabetes, increase blood uric acid and even cause gout. Therefore, a medicament for reducing blood fat and blood sugar with small toxic and side effect and good treatment effect is urgently needed at present.

Disclosure of Invention

In order to solve the problems, the invention provides application of 1-phenyl-1-propanol in preparing a medicament for treating hyperlipidemia and/or diabetes. The medicament for treating hyperlipemia and/or diabetes mellitus prepared from the 1-phenyl-1-propanol provided by the invention has good effects of reducing blood fat and blood sugar, and has small toxic and side effects on liver and no adverse reaction.

In order to achieve the above purpose, the invention provides the following technical scheme:

the invention provides application of 1-phenyl-1-propanol in preparation of a medicament for treating hyperlipidemia and/or diabetes.

The invention provides application of 1-phenyl-1-propanol in preparing a medicine for reducing triglyceride.

The invention provides application of 1-phenyl-1-propanol in preparation of a blood sugar reducing medicine.

The invention provides an application of 1-phenyl-1-propanol in preparing a medicine for reducing aspartate aminotransferase.

The invention provides application of 1-phenyl-1-propanol in preparation of a medicament for improving the content of glycine-conjugated bile acid.

Preferably, the administration dose of the medicine in any one of the technical schemes is 10-50 mg/kg body weight.

Has the advantages that:

the invention provides application of 1-phenyl-1-propanol in preparation of a medicament for treating hyperlipidemia and/or diabetes. The medicament for treating hyperlipidemia and diabetes prepared from 1-phenyl-1-propanol provided by the invention has good effects of reducing blood fat and blood sugar, and meanwhile, has small toxic and side effects on liver and no adverse reaction; and because of low price, slight fragrance and pungent and sweet taste, the product can be used as a health care product or a food additive to be applied to production and life in the future, and the health level of the national body is improved. The results of the examples show that 1-phenyl-1-propanol can simultaneously reduce the efficacy of triglycerides and blood glucose in the plasma of high-fat diet mice; meanwhile, the concentration of aspartate aminotransferase in the plasma of a high-fat diet mouse can be reduced, and the liver protection function is potential; the 1-phenyl-1-propanol has no obvious influence on the metabolic pathways of generating bile acid by cholesterol and converting primary bile acid into secondary bile acid, and the effects of reducing blood fat and blood sugar are achieved mainly by specifically increasing the content of glycine-conjugated bile acid in plasma.

Drawings

FIG. 1 shows biochemical indicators of glucose, triglyceride, aspartate aminotransferase, total cholesterol, and high density lipoprotein cholesterol in plasma of mice in normal and high-fat diet groups; wherein A is the content of triglyceride in the blood plasma of mice of each treatment group; b is the content of glucose in the blood plasma of the mice of each treatment group; c is the content of aspartate aminotransferase in the plasma of the mice of each treatment group; d is the content of total cholesterol in the blood plasma of the mice of each treatment group; e is the content of high-density lipoprotein cholesterol in the blood plasma of the mice of each treatment group; p < 0.05; p < 0.01;

FIG. 2 shows the biochemical indicators of triglyceride, glucose and aspartate aminotransferase in the plasma of control mice and drug mice; wherein A is the content of triglyceride in the blood plasma of mice of each treatment group; b is the content of glucose in the blood plasma of the mice of each treatment group; c is the content of aspartate aminotransferase in the plasma of the mice of each treatment group; p < 0.05; p <0.01

FIG. 3 shows the contents of 36 bile acids in the plasma of mice in the control group and the drug group;

FIG. 4 shows the total bile acid and total cholesterol levels in the plasma of control and drug mice, where A is the total bile acid level; b is the content of total cholesterol.

Detailed Description

The invention provides application of 1-phenyl-1-propanol in preparation of a medicament for treating hyperlipidemia and/or diabetes. The present invention has no particular requirement on the source of 1-phenyl-1-propanol, and any commercially available product that is conventional in the art may be used. The invention has no special requirements on the dosage form of the medicament for treating the hyperlipemia and/or the diabetes, and the medicament can be prepared by adopting the dosage forms which are well known to the technicians in the field, and is not limited to aqueous solution injection, powder injection, pills, powder, tablets, patches, suppositories, emulsion, cream, gels, granules, capsules, aerosol, sprays, powder sprays, sustained-release agents, controlled-release agents and the like. In the invention, the medicine for treating hyperlipemia and/or diabetes also comprises auxiliary materials, and the invention has no special requirement on the types of the auxiliary materials and can adopt the auxiliary materials well known by the technical personnel in the field. In the invention, the administration dosage of the medicament for treating hyperlipemia and/or diabetes is preferably 10-50 mg/kg body weight; more preferably 25mg/kg body weight. The medicine prepared from the 1-phenyl-1-propanol provided by the invention has good effects of reducing blood fat and blood sugar, has small toxic and side effects on the liver, does not cause adverse reaction, can treat hyperlipidemia and diabetes at the same time, and has a remarkable treatment effect.

The invention provides application of 1-phenyl-1-propanol in preparing a medicine for reducing triglyceride. The present invention has no particular requirement on the source of 1-phenyl-1-propanol, and any commercially available product that is conventional in the art may be used. The invention has no special requirements on the dosage form of the drug for reducing triglyceride, and the drug can be prepared by adopting the dosage forms which are well known to the technicians in the field, and is not limited to aqueous solution injection, powder injection, pills, powder, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder mists, sustained release agents, controlled release agents and the like. In the invention, the triglyceride reducing medicine also comprises auxiliary materials, and the invention has no special requirement on the types of the auxiliary materials and can adopt the auxiliary materials well known by the technical personnel in the field. In the invention, the administration dosage of the triglyceride-reducing drug is preferably 10-50 mg/kg body weight; more preferably 25mg/kg body weight. The medicine prepared from the 1-phenyl-1-propanol provided by the invention has good effect of reducing triglyceride in serum.

The invention provides application of 1-phenyl-1-propanol in preparation of a blood sugar reducing medicine. The present invention has no particular requirement on the source of 1-phenyl-1-propanol, and any commercially available product that is conventional in the art may be used. The invention has no special requirements on the dosage form of the medicine for reducing blood sugar, and the medicine can be prepared by adopting the dosage forms which are well known to the technicians in the field, and is not limited to aqueous solution injection, powder injection, pills, powder, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder mists, sustained-release agents, controlled-release agents and the like. In the invention, the medicine for reducing blood sugar also comprises auxiliary materials, and the invention has no special requirement on the types of the auxiliary materials and can adopt the auxiliary materials well known by the technical personnel in the field. In the invention, the administration dosage of the hypoglycemic drug is preferably 10-50 mg/kg body weight; more preferably 25mg/kg body weight. The diabetes mellitus is preferably diabetes mellitus caused by hyperglycemia complications existing in nutritional fat patients. The medicine for reducing blood sugar prepared from the 1-phenyl-1-propanol provided by the invention has good effect of reducing blood sugar in serum.

The invention provides an application of 1-phenyl-1-propanol in preparing a medicine for reducing aspartate aminotransferase. The present invention has no particular requirement on the source of 1-phenyl-1-propanol, and any commercially available product that is conventional in the art may be used. The invention has no special requirements on the dosage form of the medicine for reducing aspartate aminotransferase, and the dosage form is known by the technical personnel in the field, and is not limited to aqueous solution injection, powder injection, pill, powder, tablet, patch, suppository, emulsion, cream, gel, granule, capsule, aerosol, spray, powder spray, sustained release agent, controlled release agent and the like. In the invention, the medicine for reducing aspartate aminotransferase also comprises auxiliary materials, and the invention has no special requirement on the types of the auxiliary materials and can adopt the auxiliary materials well known by the technical personnel in the field. In the invention, the dosage of the medicament for reducing aspartate aminotransferase is preferably 10-50 mg/kg body weight; more preferably 25mg/kg body weight. The medicine prepared from the 1-phenyl-1-propanol provided by the invention has good effect of reducing the content of aspartate aminotransferase in serum.

The invention provides application of 1-phenyl-1-propanol in preparation of a medicament for improving the content of glycine-conjugated bile acid. The present invention has no particular requirement on the source of 1-phenyl-1-propanol, and any commercially available product that is conventional in the art may be used. The invention has no special requirements on the dosage form of the medicament for improving the content of the glycine-conjugated bile acid, and the medicament can be prepared by adopting the dosage forms known by the technical personnel in the field, and is not limited to aqueous solution injection, powder injection, pills, powder, tablets, patches, suppositories, emulsion, cream, gels, granules, capsules, aerosol, sprays, powder sprays, sustained-release agents, controlled-release agents and the like. In the invention, the medicine for improving the content of the glycine-conjugated bile acid also comprises auxiliary materials, and the invention has no special requirement on the types of the auxiliary materials and can adopt the auxiliary materials well known by the technical personnel in the field. In the invention, the administration dosage of the drug for improving the content of the glycine-conjugated bile acid is preferably 10-50 mg/kg body weight; more preferably 25mg/kg body weight. The medicine prepared from the 1-phenyl-1-propanol provided by the invention has a good effect of improving the content of glycine-conjugated bile acid in serum.

To further illustrate the present invention, the following examples are provided to describe in detail the use of 1-phenyl-1-propanol in the preparation of a medicament for the treatment of hyperlipidemia and/or diabetes, but should not be construed as limiting the scope of the present invention.

Example 1

1. Experimental animal and feed

Experimental animals 3 weeks old, C57BL/6J mice, all male, were selected and purchased from the center of Experimental animals at the university of Huazhong agriculture.

The common feed comprises basic feed, and the high fat feed is prepared by mixing 73.8% of basic feed, 15% of egg yolk powder, 10% of lard, 1% of cholesterol and 0.2% of sodium cholate. The nutritional indexes comprise 21.46 percent of crude protein, 22.75 percent of crude fat, 2.68 percent of crude fiber, 1.32 percent of calcium, 0.88 percent of phosphorus, calcium: the phosphorus was 1.5: 1. High-fat feed and ordinary feed were purchased from Experimental animals center of university of agriculture in Huazhong.

2. Experimental methods

The 3-week-old C57BL/6J mice were randomly divided into a normal diet group and a high-fat diet group (control group) by body weight. After feeding for 6 weeks with high fat, tail vein blood sampling is carried out to detect whether the obese mouse model of the high fat feed group is successful; the mice successfully modeled by obese mice were then divided into two groups: drug treated group and solvent control group. The drug group mice were fed with 1-phenyl-1-propanol at 25mg/kg body weight once a day for 6 weeks; the solvent control group was gavaged daily with the same amount of normal saline.

After the administration is finished, blood of each group of mice is taken, the blood is collected at 1000g/10min, plasma is obtained after centrifugation, the biochemical index of the detected plasma is calibrated, and the result is subjected to t test. Plasma biochemical indexes are as follows:

triglyceride (TG): detecting according to the kit specification, wherein the kit is purchased from Nanjing to build a bioengineering research institute Co., Ltd;

aspartate aminotransferase (AST/GOT): detecting according to the kit specification, wherein the kit is purchased from Nanjing to build a bioengineering research institute Co., Ltd;

glucose: detecting according to the kit specification, wherein the kit is purchased from Nanjing to build a bioengineering research institute Co., Ltd;

total cholesterol: detecting according to the kit specification, wherein the kit is purchased from Nanjing to build a bioengineering research institute Co., Ltd;

total bile acid: the detection is carried out according to the kit specification, and the kit is purchased from Nanjing to build a bioengineering research institute Co.

3. Results of the experiment

3.1 high fat mouse model index detection

In order to examine whether the high-fat mouse model is successfully established, 5 mice are randomly extracted from a normal feed group and a high-fat feed group respectively, and glucose, triglyceride, aspartate aminotransferase, total cholesterol and high-density lipoprotein cholesterol in the plasma of the mice are detected, and the detection results are shown in a figure 1 and a table 1.

TABLE 1 detection of Biochemical indicators related to high fat model mice

As can be seen from fig. 1 and table 1, the plasma glucose, triglyceride, aspartate aminotransferase, total cholesterol, and high-density lipoprotein cholesterol of the mice in the high-fat diet group are all significantly increased, which indicates that the establishment of the high-fat mouse model is successful.

Evaluation of blood lipid-lowering Effect of 3.21-phenyl-1-propanol

In order to examine the effect of 1-phenyl-1-propanol on blood fat, the influence of 1-phenyl-1-propanol on the content of triglyceride in the plasma of an obese model mouse after the obese model mouse is established by feeding a mouse high-fat feed is examined, and the detection result is shown in a figure 2 and a table 2.

TABLE 2 plasma triglyceride, glucose, aspartate aminotransferase levels and statistical differences in the treatment groups

As can be seen from FIG. 2 and Table 2, the plasma triglyceride level of the mice in the drug group was very significantly reduced, indicating that 1-phenyl-1-propanol had the effect of reducing the blood lipid level of the mice with a high-fat diet.

Evaluation of hypoglycemic Effect of 31-phenyl-1-propanol

To examine the effect of 1-phenyl-1-propanol on blood lipids, the effect of each treatment on glucose in mouse plasma was examined, and the results are shown in FIG. 2 and Table 2.

As can be seen from FIG. 2 and Table 2, the plasma glucose content of the mice in the drug group is significantly reduced compared with that in the control group, which indicates that the 1-phenyl-1-propanol has a relieving effect on the hyperglycemia of the mice caused by high-fat diet, and can be used for solving the hyperglycemia complications existing in nutritional obese patients and treating diabetes.

Effect of 41-phenyl-1-propanol on aspartate aminotransferase

To examine the effect of 1-phenyl-1-propanol on blood lipids, the effect of each treatment on aspartate aminotransferase in the plasma of mice was examined, and the results are shown in FIG. 2 and Table 2.

As can be seen from FIG. 2 and Table 2, the aspartate aminotransferase was significantly reduced in the drug group mice. In clinical manifestations, obese patients not only have a large amount of subcutaneous fat accumulated, but also may have a large amount of fat accumulated around their internal organs, and the excessively accumulated fat may interfere with the normal function of the visceral cells, for example, the liver, and the fat excessively accumulated around the liver may cause the occurrence of fatty liver, and further cause a certain degree of damage to the liver cells, and finally, the content of aspartate aminotransferase in the blood is increased. The reduction of aspartate aminotransferase in the drug group mice is associated with the alleviation of liver damage caused by fat accumulation, indicating that 1-phenyl-1-propanol has a potential protective function for the liver.

Effect of 3.51-phenyl-1-propanol on the content of bile acids of various species

The bile acid has many different types and combination forms, the affinity of different bile acids to different receptors is different, the effect is different, in order to observe the influence of 1-phenyl-1-propanol on the composition of bile acid in the plasma of the mouse, the LC-MS method is adopted in the experiment to separate and measure different types of bile acid in the plasma sample of the mouse, and the concentration change of different types of bile acid is observed. The concentration of 36 different bile acids was determined in this experiment, and the results are shown in FIG. 2.

From the results of fig. 3, it can be seen that: free primary bile acids in plasma: cholic Acid (CA), chenodeoxycholic acid (CDCA) and alpha/beta-murine cholic acid (alpha/beta-MCA) have no obvious change, and the results of the change of the contents of cholesterol and total bile acid in figure 4 show that 1-phenyl-1-propanol has little influence on the direction and the pathway of primary bile acid generated by cholesterol. In secondary bile acids, LCA exists mainly in free form, and a small amount of LCA circulating to the liver undergoes sulfocoupling at the 3-hydroxyl position by sulfotransferase (SULT2a1) and is rapidly secreted into bile, while most of LCA is excreted without being reabsorbed. Therefore, the plasma levels of LCA were very low, which may be the reason why LCA could not be detected in this test; other secondary bile acids, such as: the content of DCA and HDCA has no obvious change, which shows that 1-phenyl-1-propanol has little influence on the catalytic 7 alpha-dehydroxylation of the bacterial flora in the intestinal tract, and 1-phenyl-1-propanol has no obvious influence on the environment of the intestinal flora of mice. In summary, 1-phenyl-1-propanol had no significant effect on the metabolic pathways by which cholesterol generates bile acids and the conversion of primary bile acids to secondary bile acids.

Of the conjugated bile acids present in plasma, 4% are present in glycine-conjugated form and 9% are present in taurine form. As can be seen from FIG. 3, the plasma levels of glycine-binding bile acids were significantly increased in the mice administered with the agent. The number of glycine-binding bile acids tested at this time was 8. Among these, 5 conjugated bile acids, which were significantly increased statistically, were removed, namely: GHDCA, GUDCA, GCDCA, GDHCA, lambda-GMCA; the remaining three, namely: plasma contents of GLCA (p is 0.051), GDCA (p is 0.104) and GCA (p is 0.665) are all higher than those of a control group; in the taurine-conjugated bile acid of the mice of the administration group and the mice of the control group, the content of the primary bile acid and the content of the secondary bile acid are not obviously changed. The 1-phenyl-1-propanol has specific promotion effect on the generation and secretion of glycine-conjugated bile acid, and further plays roles in reducing blood fat and blood sugar.

The results of the above examples show that 1-phenyl-1-propanol can simultaneously lower the efficacy of triglycerides and blood glucose in the plasma of mice on a high-fat diet; meanwhile, the concentration of aspartate aminotransferase in the plasma of a high-fat diet mouse can be reduced, and the liver protection function is potential; the 1-phenyl-1-propanol has no obvious influence on the metabolic pathways of generating bile acid by cholesterol and converting primary bile acid into secondary bile acid, and the effects of reducing blood fat and blood sugar are achieved mainly by specifically increasing the content of glycine-conjugated bile acid in plasma. The medicament for treating hyperlipidemia and diabetes mellitus prepared from 1-phenyl-1-propanol provided by the invention has good effects of reducing blood fat and blood sugar, has small toxic and side effects on liver, does not cause adverse reaction, and is suitable for treating hyperlipidemia and complications thereof caused by high-fat diet.

Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.

Claims

1.1-phenyl-1-propanol in the preparation of medicine for treating hyperlipemia and/or diabetes.

2. The use according to claim 1, wherein the medicament is administered in a dose of 10 to 50mg/kg body weight.