CN116139160A - Application of verbena glycoside in treating diabetes and/or diabetic complications - Google Patents

Abstract

The invention provides application of verbena glycoside in preparing a medicament for treating diabetes mellitus, application of verbena glycoside in preparing a medicament for treating diabetic heart disease and application of verbena glycoside in preparing a medicament for treating diabetic nephropathy. The invention discovers that the verboside has the function of preventing and treating diabetes and heart and kidney injury of diabetes for the first time through researches: in terms of blood glucose, verbena glycosides can improve glucose tolerance levels by improving blood glucose metabolic levels; in the aspect of heart injury involved in diabetes mellitus, verbena glycoside can improve heart dysfunction and left ventricle reconstruction, and inhibit fibrosis of heart tissues; in terms of kidney injury, verbena glycosides can improve renal function levels and inhibit renal fibrosis levels. The invention provides powerful experimental foundation and theoretical basis for the verboside to be used for preventing and treating diabetes and heart and kidney injury thereof, and widens the application prospect.

Description

Application of verbena glycoside in treating diabetes and/or diabetic complications

Technical Field

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to application of verbena glycoside in treating diabetes and/or diabetic complications.

Background

Diabetes is a group of life-long metabolic diseases caused by multiple causes characterized by persistent chronic hyperglycemia, which has become an increasingly serious health problem. Diabetes is one of the most known complications, and most diabetics die from diabetes complications, and long-term blood sugar increases, and large blood vessels and micro blood vessels are damaged and endanger heart, kidney, peripheral nerves, eyes, feet and the like. Currently, diabetic heart disease and diabetic nephropathy are the leading causes of death for diabetics.

Clinically, the treatment scheme of patients with diabetes complicated with heart and kidney complications is very limited, and mainly comprises the steps of actively treating the primary disease of diabetes, strictly controlling blood sugar, carrying out diet treatment, using insulin and other hypoglycemic drugs. However, there is still a lack of effective therapeutic agents to protect diabetes and its associated heart and kidney damage. The threat of diabetes to human health can be reduced to some extent by intervention in the high-sugar state and heart and kidney injury caused by the disease. Thus, diabetes mellitus and its heart and kidney complications are increasingly emphasized, and the diabetes mellitus and the heart and kidney complications are urgent problems to be solved in the related field of heart and kidney.

At present, a large number of oral medicines for preventing and treating diabetes mellitus are available in the markets at home and abroad, and common diabetes mellitus treatment medicines can be divided into eight types. Mainly comprises insulin analogues, metformin compounds, sulfonylurea drugs, glucosidase inhibitors, thiazolidinedione drug sensitizers, DPP-4 enzyme inhibitors, receptor agonists and the like. The medicines play a great role in treating and preventing diabetes and relieving pains of diabetics. However, the currently marketed drugs for treating diabetes have various kinds, and most of them are biological products or synthetic monomer compounds, and have side effects. And along with the diversification of diabetic complications, particularly heart and kidney injury, the human health is seriously threatened, so that the development of safer and more effective medicaments for treating diabetes (hyperglycemia) and heart and kidney injury thereof is still a very significant work.

At present, a plurality of traditional Chinese medicines are widely applied to the prevention and treatment of diabetes and complications thereof, and the traditional Chinese medicines play a role in efficacy through multiple ways, multiple targets and integration and regulation mechanisms, and have systematic characteristics. However, the traditional Chinese medicine has complex chemical components, undefined drug effect substance basis and difficult quality control. The efficacy of the effective parts of various traditional Chinese medicines for treating diabetes and complications is different and is emphasized, and the effective chemical components of the traditional Chinese medicines are used for replacing the traditional Chinese medicines, so that the quality control of the medicines is facilitated, and the complexity is reduced. Therefore, the method for providing the effective chemical components of the traditional Chinese medicine has important clinical significance.

Disclosure of Invention

Based on the above, the invention aims to provide the application of the verbena glycoside in treating diabetes and/or diabetic complications, the verbena glycoside has the function of preventing and treating diabetes and diabetic heart and kidney injury, and the verbena glycoside can be used for preparing medicines for treating diabetes, diabetic heart disease and diabetic nephropathy.

In order to achieve the above purpose, the present invention adopts the following technical scheme.

Application of verbena glycoside in preparing medicine for treating diabetes is provided.

In some embodiments, the medicament has at least one of the following effects: reducing blood sugar content and improving sugar tolerance level.

The invention also provides application of verboside in preparation of a medicament for treating diabetic heart disease.

In some embodiments, the medicament has at least one of the following effects: improving cardiac dysfunction, left ventricular remodeling, and cardiac fibrosis.

The invention also provides application of verboside in preparation of a medicament for treating diabetic nephropathy.

In some embodiments, the medicament has at least one of the following effects: improving renal function level, protecting kidney structure, and improving kidney fibrosis.

The invention also provides a medicine for treating diabetes and/or diabetic heart disease and/or diabetic nephropathy, which comprises verbena glycoside and pharmaceutically acceptable auxiliary materials.

In some embodiments, the pharmaceutical dosage form is a solution, granule, tablet, pill, drop, injection, capsule, powder, or decoction.

The invention discovers that the verboside has the function of preventing and treating diabetes and heart and kidney injury of diabetes for the first time through researches: in terms of blood glucose, verbena glycosides can improve glucose tolerance levels by improving blood glucose metabolic levels; in the aspect of heart injury involved in diabetes mellitus, verbena glycoside can improve heart dysfunction and left ventricle reconstruction, and inhibit fibrosis of heart tissues; in terms of kidney injury, verbena glycosides can improve renal function levels and inhibit renal fibrosis levels. The verbena glycoside has the advantages of stable blood sugar reduction, complication consideration, definite curative effect, definite composition components, no obvious toxic or side effect, convenient administration, low price and the like. Compared with the traditional Chinese medicine for treating diabetes and complications, the traditional Chinese medicine has simple and clear chemical components, is easier to clarify the action mechanism in pharmacological research, and is easier to control the quality of the medicine in production. The invention provides powerful experimental foundation and theoretical basis for the verboside to be used for preventing and treating diabetes and heart and kidney injury thereof, and widens the application prospect.

Drawings

FIG. 1 is a graph showing experimental results of verbena glycoside for improving general conditions and blood glucose levels in diabetic mice; wherein A is the weight detection result of the mice; b is the detection result of the fasting blood glucose level of the mice; c is the oral glucose tolerance test result of the mice.

FIG. 2 is a graph of experimental results of verbena glycoside improvement of cardiac dysfunction, left ventricular remodeling and cardiac fibrosis in diabetic model mice; wherein A is an echocardiographic result; b is the WGA staining result of the heart; c is the red staining result of sirius of heart.

FIG. 3 is a graph showing experimental results of verbena glycoside in improving renal function levels and renal fibrosis in a diabetic model mouse; wherein A is the creatinine (SCr) level detection result of the diabetic mice; b is the staining result of kidney PAS; c is the kidney Masson staining result.

Detailed Description

The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.

In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.

The following description is made with reference to specific embodiments.

Example 1

1. Experimental method

1. Medicament

The verbenaoside standard is purchased from Chengdoman Biotechnology Co.

2. Animal model preparation

SPF-grade C57/BL male mice (35-42 days, body weight 16-20 g) were randomly divided into Normal group (Normal group) and diabetic group (DN group). Mice in group DN were fed high fat diet and Normal diet was given to Normal diet. All mice received intraperitoneal injections after 2 months: sodium citrate (pH 4.5, NC group) or 50mg/kg STZ (dissolved in sodium citrate, pH4.5, DN group) for 5 consecutive days. After one week, mice with DN group having a hollow abdominal blood glucose level higher than 16.7mmol/L were used for the subsequent experiments. After successful molding, the DN component is divided into 2 groups: model group (Model group), verboside 50mg/kg lavage treatment group (Cornin group). The stomach is irrigated once a day, and the volume of each time of the stomach irrigation is 0.2mL; wherein, normal group and Model group irrigate the stomach with equal volume of physiological saline. The lavage time was 4 weeks. Throughout the experimental session, each group of mice was observed daily for systemic conditions, including general, mental and hair conditions, urination and changes in dietary intake.

3. General index

During the administration process, the change of feeding, drinking and excretion of the mice is carefully observed every day, and the general conditions of mental state, hair change, death and the like of the mice in each group are compared, and the change of weight and death are recorded.

4. Blood glucose level determination

All experimental mice were assayed for fasting blood glucose 12 hours per week and four groups of mice were observed for body weight and fasting blood glucose levels. After the end of the experiment, mice were subjected to an Oral Glucose Tolerance Test (OGTT), blood glucose values of 30, 60, 90 and 120min after gastric lavage were measured, and the area under the blood glucose curve within 120min was calculated using Graphpad. After 24 hours of last administration, the eyeballs of each group of mice are removed for blood sampling, and relevant biochemical indexes such as serum and the like are detected.

5. Echocardiography (UGV)

After the completion of the lavage, the heart function of the mice was evaluated by ultrasound in the small animals. Short axis view of papillary muscle level, cardiac contractility index, including Left Ventricular Ejection Fraction (LVEF), left ventricular short axis shortening (LVFS) index, were measured for each test and quantified. And analyzing the parameters by applying a related module.

6. Determination of Biochemical index of renal function

After the completion of the stomach lavage, the kidney function of the mice is evaluated by the detection kit. Injecting 10mL/kg of 5% chloral hydrate before taking materials of experimental animals for anesthesia, taking blood by adopting an eyeball blood taking method, standing for 4 hours at room temperature, centrifuging for 15min at a temperature of 3000r & min < -1 >, taking supernatant, and sub-packaging and storing at a temperature of minus 80 ℃ for detecting the kidney function index urea nitrogen (SCr) of the mice.

7. Pathological conditions of the heart and kidneys

After 4 weeks of continuous administration, all mice were anesthetized excessively, hearts and kidneys of the mice were dissociated, hearts and kidneys on one side were placed in a paraformaldehyde solution of 4% of a fixing solution, paraffin embedding was performed after the fixation was completed, and experiments such as sirius red staining, WGA staining, PAS staining, masson staining, and the like of heart tissues were performed, respectively.

2. Experimental results

1. Verbena glycoside for improving general condition of mice

After molding, the Normal group mice have glossy and smooth hair color, good mental state, free movement, continuous weight increase, normal food intake, water intake and urination and defecation, and dry padding without obvious bad smell. The Model group and Cornin group diabetic mice have gradually sallow and shiny hair color, are easy to fall off, have poor spirit, little activity and sleepiness, have emaciation and weight loss, have typical symptoms of polyphagia, polydipsia and diuresis, and have easily moist padding and obvious peculiar smell. After 4 weeks of administration, the Cornin group mice had a well-conditioned state, the hair was gradually clean and shiny, and the drinking water excretion was reduced. The body weight of each group of mice varied during the administration period, and the body weight of the Model group of mice was maximally reduced except for the Normal group of mice, and the body weight of the Cornin group of mice was reduced, and the difference was statistically significant (P < 0.01) as compared with the Model group (fig. 1A). The result shows that after the treatment, the verbena glycoside can improve the general condition of diabetes, can relieve the three more and one less symptoms of the diabetic mice, and has a certain protection effect on the weight loss of the diabetic mice.

2. Verbena glycoside improves Fasting Blood Glucose (FBG) and glucose tolerance (OGTT) levels in diabetic model mice

The fasting blood glucose level (FBG) of mice after STZ induction is obviously increased (P is less than 0.0001), while verbena glycoside can obviously reduce blood glucose level, and the difference has statistical significance (P is less than 0.0001) (figure 1B), which shows that the verbena glycoside can effectively regulate and improve blood glucose level.

According to the results of the Oral Glucose Tolerance Test (OGTT) of mice and the statistical analysis of the area under the curve by t test, the glucose tolerance of the Model group is seriously impaired, and the blood glucose level is obviously higher than that of other groups in 0min and is rapidly increased in 30 min. AUC was significantly reduced in Cornin group compared to Model group, and the difference was statistically significant (P < 0.0001) (fig. 1C), indicating that verboside was able to increase the glucose tolerance level effect upon oral administration and thereby potentially exert a therapeutic effect on diabetes.

3. Verboside improves cardiac dysfunction, left ventricle reconstruction and cardiac fibrosis of diabetic model mice

Echocardiography showed that STZ-induced diabetic mice could cause the occurrence of systolic dysfunction of the heart, and verbena glycosides could improve the LVEF value level (P < 0.05) and the LVFS value level (P < 0.01) in diabetic model mice (fig. 2A).

Cardiac WGA staining showed that STZ-induced diabetic mice could cause myocardial hypertrophy, and 4 weeks verbena glycoside intervention of diabetic mice had significantly improved myocardial hypertrophy, and could effectively inhibit myocardial hypertrophy, significantly reduce the cross-sectional area of cardiomyocytes (fig. 2B).

Heart sirius red staining showed that STZ-induced diabetic mice had significantly increased levels of myocardial fibrosis, while verbascoside could effectively ameliorate heart fibrosis (fig. 2C).

4. Verbenaoside can improve renal function level and renal fibrosis of diabetic model mice

As shown in fig. 3A, STZ-induced creatinine (SCr) levels were significantly elevated in diabetic mice, indicating impaired renal function in the STZ-induced diabetic mice. The intervention of verbena glycoside can improve the renal function level, and the difference has statistical significance (P is less than 0.01).

Kidney PAS staining shows that the STZ induced cavitation degeneration of tubular epithelial cells of diabetic mice, the broadening of the kidney membranous region is more obvious than that of normal groups, and the expansion of part of tubular is generated in renal interstitium, the tubular epithelial cells fall off and regenerate, and the change is obviously relieved after the treatment of verbena glucoside. Thus, verbena glycoside has obvious protective effect on the kidney structure of diabetic nephropathy mice (figure 3B).

Kidney Masson staining showed that glomerular collagen deposition was clearly visible in STZ-induced diabetic mice. Vernicin can significantly improve this situation. Such results indicate that post-STZ-induced renal fibrosis levels in diabetic mice are aggravated and that verboside intervention can be effective in improving renal fibrosis levels (fig. 3C).

In conclusion, verbena glycoside can improve the glucose tolerance level by improving the blood glucose metabolism level in terms of blood glucose. In the aspect of heart injury involved in diabetes mellitus, verbena glycoside can improve heart dysfunction and left ventricle reconstruction, and inhibit fibrosis of heart tissues; in the aspect of kidney injury, the verbena glycoside can improve the level of kidney function and inhibit the fibrosis level of kidney, thereby playing a role in treating diabetes and heart and kidney injury thereof.

The technical features of the above embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (8)

1. Application of verbena glycoside in preparing medicine for treating diabetes is provided.

2. The use of claim 1, wherein the medicament has at least one of the following effects: reducing blood sugar content and improving sugar tolerance level.

3. Application of verbena glycoside in preparing medicine for treating diabetic heart disease is provided.

4. The use according to claim 3, wherein the medicament has at least one of the following effects: improving cardiac dysfunction, left ventricular remodeling, and cardiac fibrosis.

5. Application of verbena glycoside in preparing medicine for treating diabetic nephropathy is provided.

6. The use according to claim 5, wherein the medicament has at least one of the following effects: improving renal function level, protecting kidney structure, and improving kidney fibrosis.

7. A medicament for treating diabetes and/or diabetic heart disease and/or diabetic kidney disease, characterized in that the medicament comprises verbascoside and pharmaceutically acceptable auxiliary materials.

8. The medicament of claim 7, wherein the medicament is in the form of a solution, granule, tablet, pill, drop, injection, capsule, powder or decoction.

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