Application of compound Lycbarbarines in prevention and treatment of diseases related to lipid metabolism disorder

Abstract

The invention relates to an application of a compound Lycbarbarines represented by the following formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof in preparation of drugs for preventing, improving and / or treating diseases or symptoms related to lipid metabolism disorder, and belongs to the technical field of biological medicines. The medicine prepared from the Lycbarbarines compound provided by the invention has the characteristics of obvious curative effect and good safety. # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the field of biomedicine technology, and specifically relates to the use of lycibarbarines, or pharmaceutically acceptable salts or esters thereof, in the preparation of drugs for preventing, improving and / or treating obesity, metabolic-related fatty liver disease, insulin resistance, hyperglycemia and hyperlipidemia. Background Art

[0002] The compound Lycibarbarines is a class of tetrahydroquinoline alkaloid compounds with a spiroketal structure that was first isolated from the fruit of Ningxia wolfberry in 2020. This type of natural product has a unique tricyclic tetrahydroquinoline-oxazine-ketohexose fusion skeleton, which is the first new skeleton molecular structure reported in natural products. Currently, three types of Lycibarbarines compounds, Lycibarbarine A, Lycibarbarine B and Lycibarbarine C, have been reported in the Lycibarbarines compound family. Although they can be isolated and extracted from wolfberry, the natural content of Lycibarbarines is extremely low. Literature reports that only 2.5 mg of Lycibarbarine A, 1.7 mg of Lycibarbarine B and 4.7 mg of Lycibarbarine C can be isolated from 50 kg of wolfberry. In 2022, the inventor team completed the efficient chemical synthesis of Lycibarbarine A and Lycibarbarine B for the first time through a four-step reaction (CN202210636411.4), laying the foundation for our in-depth exploration of the biological activity of this class of compounds. At present, the understanding of the biological activity of Lycibarbarines is very limited at home and abroad, and the only biological activity study proves that Lycibarbarine A has a neuroprotective effect.

[0003] Diseases or conditions related to lipid metabolism disorders, such as obesity, have become one of the most serious public health problems worldwide. The World Obesity Association's latest "Global Obesity Map 2023" shows that by 2035, more than 4 billion people in the world will be obese or overweight, accounting for 51% of the world's population. The "Report on the Nutrition and Chronic Disease Status of Chinese Residents (2020)" shows that more than half of Chinese adults are overweight or obese. Obesity is closely related to a variety of metabolic diseases. Obesity can lead to metabolic-related fatty liver disease, type 2 diabetes, hypertension, hyperlipidemia and other diseases. WHO defines obesity as abnormally excessive fat accumulation in the body. The body's adipose tissue can be divided into white fat that stores energy and brown / beige fat that consumes energy according to its function. Obesity is usually accompanied by an increase in the number and volume of white fat cells.

[0004] Metabolic dysfunction-Associated Fatty Liver Disease affects a quarter of the world's population and is also the most common type of chronic liver disease in China. Currently, there are more than 150 million patients in my country. Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a chronic liver disease associated with metabolic dysfunction, with abnormal accumulation of liver fat as the main pathological change. It is closely related to overweight or obesity, type 2 diabetes, and metabolic dysfunction. Obese people are at high risk of metabolic fatty liver disease. Studies have shown that the prevalence of metabolic fatty liver disease in the overweight / obese population worldwide is as high as 50.7%, and obese patients with metabolic fatty liver disease have a higher risk of liver fibrosis and cirrhosis than non-obese patients with metabolic fatty liver disease. Obesity increases the risk of fatty hepatitis, fibrosis, and hepatocellular carcinoma in patients.

[0005] Therefore, the prior art urgently needs an agent that can be effectively used to prevent, improve and / or treat diseases or conditions related to lipid metabolism disorders (such as obesity, metabolism-related fatty liver disease, glucose and lipid metabolism disorders and hyperlipidemia). Summary of the invention

[0006] In order to solve the above problems, the inventors conducted in-depth research and found for the first time that Lycbarbarines, a compound derived from wolfberry, has good uses for weight loss, improving metabolic-related fatty liver disease and glucose and lipid metabolism disorders, and can be effectively used to prevent, improve and / or treat obesity, metabolic-related fatty liver disease, insulin resistance, hyperglycemia and hyperlipidemia. There is currently no report on the biological activity of Lycbarbarines on diseases related to glucose and lipid metabolism disorders such as obesity and metabolic-related fatty liver disease.

[0007] Specifically, the present invention is achieved through the following aspects:

[0008] In the first aspect, the present application relates to the use of a compound lycibarbarines represented by the following formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof in the preparation of a drug for preventing, improving and / or treating a disease or condition associated with lipid metabolism disorders,

[0009]

[0010] In a second aspect, the present application relates to the use of Lycibarbarines, a compound represented by the formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof, in the preparation of a food or functional health product for preventing and / or improving non-disease symptoms associated with lipid metabolism disorders.

[0011] In a third aspect, the present application relates to a pharmaceutical composition or a functional health food composition, wherein the pharmaceutical composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, and one or more pharmaceutically acceptable excipients; the functional health food composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, and one or more food-acceptable excipients. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Shown is the weight loss effect of compound Lyc-A or Lyc-B on HFHC diet-induced obese mice.

[0013] Figure 2 Compounds Lyc-A or Lyc-B were shown to inhibit HFHC diet-induced adipocyte enlargement.

[0014] Figure 3 Shown are the effects of compound Lyc-A or Lyc-B on metabolism-associated fatty liver disease in HFHC diet-induced obese mice.

[0015] Figure 4 Shown are the effects of compound Lyc-A or Lyc-B on glucose metabolism in HFHC diet-induced obese mice.

[0016] Figure 5 Shown are the effects of compound Lyc-A or Lyc-B on blood lipids in HFHC diet-induced obese mice. DETAILED DESCRIPTION

[0017] Those skilled in the art will appreciate that the following embodiments are provided for illustrative purposes only and are not intended to limit the scope of protection of the present application in any way.

[0018] In this article, unless otherwise indicated, the term "pharmaceutically acceptable" or "food science acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. For example, the term "pharmaceutically acceptable salt" used herein refers to an acid addition salt or base addition salt formed by a compound represented by formula (I) and a pharmaceutically acceptable free acid or free base. Acid addition salts are obtained from the following acids: such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, malic acid, oxalic acid, succinic acid, etc. Base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, or magnesium salts. The term "pharmaceutically acceptable ester" as used herein refers to an ester formed by a compound represented by formula (I) through a hydroxyl group therein and a pharmaceutically acceptable organic acid, such as acetate, benzoate, citrate, lactate, maleate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, tartrate, fumarate, malate, oxalate, succinate, etc.

[0019] Unless otherwise specified, solid and dashed keys ( and ) represents the absolute configuration of a stereocenter. Unless otherwise specified, stereoisomers mentioned herein include geometric isomers and enantiomers, all of which are within the scope of the present application.

[0020] In one embodiment, the present application relates to the use of a compound lycibarbarines represented by the following formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for preventing, improving and / or treating a disease or condition associated with lipid metabolism disorders,

[0021]

[0022] In some embodiments, the present application relates to the use of the compound Lycibarbarines represented by the formula (I), or its stereoisomers, or its pharmaceutically acceptable salts or esters in the preparation of food or functional health products for preventing and / or improving non-disease symptoms associated with lipid metabolism disorders. The compound Lycibarbarines represented by formula (I) is a safe and effective small molecule compound obtained from traditional Chinese medicine and natural plants (wolfberry) with medicinal and edible properties, and can be used as a safe food or functional health product without toxic side effects. Moreover, when used in food or functional health products, the use of the present invention is a non-therapeutic use.

[0023] In some embodiments, the disease or condition associated with lipid metabolism disorder is selected from one or more of the following: obesity, metabolic-related fatty liver disease, type II diabetes, and hyperlipidemia.

[0024] In some embodiments, the non-disease symptoms associated with lipid metabolism disorders are selected from one or more of the following: obesity, liver damage, abnormal blood sugar levels, and abnormal blood lipid levels.

[0025] In some embodiments, the food or functional health product is used to prevent and / or improve one or more selected from the following: weight loss (e.g., controlling body fat), liver damage (e.g., chemical liver damage related to metabolism), lowering blood sugar (e.g., maintaining healthy blood sugar levels), lowering blood lipids (e.g., maintaining healthy blood lipid (cholesterol / triglyceride) levels), or providing auxiliary effects thereon.

[0026] In some embodiments, the compound Lycbarbarines is selected from one or more of the group consisting of the following compounds: Lycbarbarine A represented by the following formula (II) (also referred to herein as "Lyc-A"), Lycbarbarine B represented by the following formula (III) (also referred to herein as "Lyc-B"),

[0027]

[0028] In some embodiments, the drug is an injection, tablet, powder, granule, pill, capsule, oral solution, ointment, cream or spray.

[0029] In some embodiments, the food or functional health product is an oral liquid, a tea, a lozenge, a capsule, a drink, an effervescent tablet or a chewable tablet.

[0030] In some embodiments, the compound Lycbarbarines is in the form of a pharmaceutical composition or a functional health food composition, wherein the pharmaceutical composition comprises the compound Lycbarbarines, or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients (e.g., normal saline); the functional health food composition comprises the compound Lycbarbarines, or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof, and one or more food-acceptable excipients (e.g., normal saline).

[0031] In some embodiments, the drug is in a form of administration by oral administration, enteral administration, injection, spraying, physical or chemical mediation, or in a form of administration after being mixed or encapsulated with other substances.

[0032] In some embodiments, the compound Lycbarbarines is a natural product extracted from wolfberry.

[0033] In some embodiments, the compound Lycbarbarines is artificially synthesized rather than derived from wolfberry.

[0034] In some embodiments, the compound Lycbarbarines is administered to the subject in an amount of 10 to 120 mg / kg (eg, 60 mg / kg) of subject body weight per day.

[0035] In some embodiments, the compound Lycbarbarines is in the form of an aqueous solution or a saline solution at 1-12 mg / ml (eg, 6 mg / ml).

[0036] In some embodiments, the compound Lycbarbarines is used for glucose metabolism disorders, hypercholesterolemia, and insulin resistance.

[0037] In one embodiment, the present application relates to a pharmaceutical composition or a functional health food composition, wherein the pharmaceutical composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, and one or more pharmaceutically acceptable excipients; the functional health food composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, and one or more food-acceptable excipients.

[0038] In some embodiments, the pharmaceutical composition or functional health food composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester as the sole active ingredient.

[0039] In some embodiments, the pharmaceutical composition or functional health food composition comprises the compound Lycbarbarines and normal saline.

[0040] In some embodiments, the pharmaceutical composition or functional health food composition further comprises other active ingredients.

[0041] The excipients described herein may be any excipients that are pharmaceutically or food-acceptable, such as, but not limited to, solvents (e.g., water, saline, glycerol, and ethanol), propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc. For other pharmaceutically acceptable excipients, see, for example, Handbook of Pharmaceutical Excipients (4th edition), by RC Luo et al., translated by Zheng Zemin, 2005, Chemical Industry Press.

[0042] In an optional embodiment, the present application relates to a method for preventing, improving and / or treating a disease or condition associated with a lipid metabolism disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, or the above-mentioned pharmaceutical composition. In an optional embodiment, the present application relates to the above-mentioned compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, or the above-mentioned pharmaceutical composition for preventing, improving and / or treating a disease or condition associated with a lipid metabolism disorder.

[0043] Unless otherwise indicated, the terms "patient," "subject," and "individual" are used interchangeably herein and refer to a human or a non-human animal (eg, primate, rodent, etc.).

[0044] Unless otherwise specified, in this article, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe the present invention, the term "about" indicates the error value that exists, for example, it indicates a change within the range of ±10%, such as ±1% of a specific value.

[0045] Unless otherwise stated, herein, singular terms include plural terms and plural terms include singular terms.

[0046] Herein, unless otherwise specified, the terms "comprises, includes and contains" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0047] Example

[0048] The present invention is further described in detail below by examples. These examples are merely illustrative and should not be construed as limiting the scope of the present invention. All technical solutions and variations thereof implemented based on the above content of the present invention fall within the scope of the present invention. In the following examples, unless otherwise specified, the reagents and materials used can be obtained commercially. Unless otherwise specified, the methods used are conventional methods in the art.

[0049] Example 1: Improvement effect of Lycibarbaines on obesity induced by high-fat diet

[0050] Compound preparation: The synthesis of Lycibarbarine A and B (referred to as "Lyc-A" and "Lyc-B", respectively) refers to the method described in the patent application with application number ZL 202210636411.4.

[0051] Animal experimental methods: 36 SPF-grade 8-week-old male C57BL / 6J mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. and were kept in a standard specific pathogen-free (SPF-grade) animal room. The breeding environment was controlled to a 12-hour dark-light cycle, humidity was 55±15%, and temperature was 23±3°C. Mice had free access to food and water. The conventional feed (ND) used in the animal experiment was purchased from Beijing Huafukang Biotechnology Co., Ltd., and high-fat high-cholesterol feed (High fat highcholesterol, HFHC) (MDDZ483, 60% calories from fat, 1.2% cholesterol added) was purchased from Jiangsu Medison Biomedicine Co., Ltd. The solvent for the intragastric fluid in the experiment was normal saline. The drug group used normal saline to dilute the Lyc-A or Lyc-B mother solution (600 mg / ml, DMSO configuration) to 6 mg / ml intragastric fluid, and then administered according to 10g body weight / 0.1ml intragastric fluid. The concentration of mice was 60 mg / Kg body weight. The solvent control group was intragastrically administered with 10 g body weight / 0.1 ml solvent (1% DMSO concentration in physiological saline).

[0052] After 1 week of adaptive feeding, the mice were randomly divided into 4 groups according to their body weight: ① Normal control group (ND+solvent): n=9, fed with normal feed (i.e., conventional feed) for 12 weeks during the experiment, and given an equal dose of solvent by oral gavage every day; ② High-fat and high-cholesterol diet control group (HFHC+solvent): n=9, fed with HFHC feed for 12 weeks during the experiment, and given an equal dose of solvent by oral gavage every day; ③ Lyc-A administration group (HFHC+Lyc-A): n=9, fed with HFHC feed for 12 weeks during the experiment, and given compound Lyc-A by gavage at a dose of 60 mg / kg body weight / day; ④ Lyc-B administration group (HFHC+Lyc-B): n=9, fed with HFHC feed for 12 weeks during the experiment, and given Lyc-B by gavage at a dose of 60 mg / kg body weight / day. Gavage was performed once a day for 12 weeks, and body weight and food intake were recorded regularly every week. After the treatment, the mice were fasted overnight (12 hours) and euthanized, serum was collected for blood biochemical analysis, adipose tissue (epididymal adipose tissue, inguinal adipose tissue, mesenteric adipose tissue, interscapular adipose tissue) was separated and accurately weighed, and the adipose tissue was divided into two parts, one fixed in 4% paraformaldehyde solution and the other frozen in a -80°C refrigerator. The fixed adipose tissue was embedded in paraffin and used for HE staining, and the morphology of adipocytes was analyzed by optical upright microscope.

[0053] Experimental results: First, Figure 1 As shown, the body weight of mice in the high-fat diet control group (HFHC+solvent) was significantly higher than that in the normal diet control group, indicating that the obese mouse model of this experiment was successfully constructed. At the same time, compared with the high-fat diet control group (HFHC+solvent), treatment with compounds Lyc-A or Lyc-B significantly reduced obesity caused by a high-fat diet. Specifically, after administration of Lyc-A or Lyc-B, compared with the high-fat diet control group, the body weight of the treated group showed a significant downward trend from the first week, and the body weight and weight gain of the mice in the Lyc-A treatment group were significantly lower than those in the HFHC diet control group ( Figure 1 ), the body weight and weight gain of the Lyc-B treated group were significantly lower than those of the HFHC diet control group ( Figure 1 ), and the significant weight loss effect lasted until the end of the experiment. Consistent with this, fasting body weight tests showed that both Lyc-A and Lyc-B treatment groups were significantly lower than the HFHC diet control group ( Figure 1 ). At the same time, there was no significant difference in food intake between the Lyc-A and Lyc-B groups compared with the high-fat diet control group ( Figure 1), indicating that compound Lyc-A or Lyc-B had no significant effect on the appetite of mice. During the experiment, no abnormalities were observed in the activity, hair, mental state, etc. of mice in the Lyc-A or Lyc-B treatment group, suggesting that Lyc-A or Lyc-B did not cause other abnormalities while reducing weight and had good biosafety.

[0054] Analysis of the effects of Lyc-A or Lyc-B on adipose tissue accumulation in vivo showed that, consistent with the decrease in body weight, the weights of epididymal white adipose tissue, inguinal white adipose tissue, mesenteric white adipose tissue, and interscapular brown adipose tissue in the Lyc-A group were significantly lower than those in the HFHC diet control group ( Figure 1 ); The weight of epididymal white adipose tissue and scapular brown adipose tissue in the Lyc-B group was also significantly lower than that in the HFHC diet control group ( Figure 1 ), while inguinal white adipose tissue and mesenteric white adipose tissue showed a significant downward trend ( Figure 1 ). The above results indicate that Lyc-A or Lyc-B has the effect of significantly reducing fat accumulation in the body.

[0055] Further analysis of the effects of Lyc-A or Lyc-B on adipose tissue at the adipocyte level showed that ( Figure 2 ), the area of ​​epididymal adipocytes and inguinal adipocytes in the Lyc-A and Lyc-B treated groups was significantly smaller than that in the HFHC diet control group, and the number of small lipid droplets in interscapular adipocytes was significantly greater than that in the HFHC diet control group ( Figure 2 ), that is, Lyc-A and Lyc-B treatment can significantly inhibit the expansion of adipocytes caused by a high-fat diet. In summary, compounds Lyc-A or Lyc-B can effectively improve obesity in mice induced by a high-fat diet.

[0056] Example 2: Improvement effect of Lycibarbaines on metabolic-related fatty liver disease induced by a high-fat diet

[0057] Experimental methods: The mice were treated in the same way as above. After the treatment, the liver tissue was separated and accurately weighed, and then divided into two parts, one fixed in 4% paraformaldehyde solution, and the other frozen in a -80°C refrigerator for the detection of liver lipid content. The fixed liver tissue was embedded in paraffin for HE staining or frozen sectioned for Oil Red O staining, and the morphology and lipid deposition of liver cells were analyzed by optical upright microscope. The lipid content in the liver was determined by extracting lipids in the liver using the modified Folch method, and the lipid content was determined according to the instructions of the kit (Beijing Pulilai, triglyceride (TG) content enzymatic determination kit, E1003; total cholesterol (TC) content enzymatic determination kit, E1005), and the lipid content of the liver was corrected by protein concentration.

[0058] Experimental results: Compared with the high-fat diet control group, compounds Lyc-A or Lyc-B can significantly improve metabolic-related fatty liver disease induced by high-fat diet in mice. Specifically, compared with the normal diet group, high-fat diet significantly increased liver weight, while Lyc-A and Lyc-B treatment significantly reduced the increase in liver weight caused by high-fat diet ( Figure 3 ); Pathological sections of liver tissue showed that compared with the high-fat diet control group, H&E staining showed that the degree of vacuolation of liver parenchymal cells in the drug-treated group was significantly reduced, and Oil Red O staining results showed that the abnormal accumulation of liver lipids caused by the high-fat diet was significantly reduced ( Figure 3 ); further quantitative analysis of the lipid content in the liver showed that Lyc-A and Lyc-B treatment significantly reduced the total cholesterol (TC) content in the liver and caused a significant decrease in the triglyceride (TG) content in the liver ( Figure 3 ); at the same time, the activity of alanine aminotransferase (ALT), a marker of liver damage, in the serum of the Lyc-A and Lyc-B treatment groups was significantly decreased ( Figure 3 ). In summary, compound Lyc-A or Lyc-B has a significant improvement effect on abnormal liver fat accumulation, liver cell damage, and liver function damage induced by a high-fat diet, indicating that compound Lyc-A and / or Lyc-B has a good preventive and therapeutic effect on metabolism-related fatty liver disease.

[0059] Example 3 Effect of Lycibarbaines on the Improvement of Glucose Metabolism Disorders Induced by High-Fat Diet in Mice

[0060] Experimental methods: The mice were treated in the same way as above. After 10 weeks of administration, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. Oral glucose tolerance test (OGTT): After fasting for 12 hours, mice were gavaged with 2g / kg body weight of glucose solution. Blood was collected from the tail vein at 0, 15, 30, 60, 90 and 120 minutes after glucose administration. Blood glucose was measured with a handheld blood glucose meter, and the blood glucose change curve was drawn to calculate the area under the curve.

[0061] Insulin tolerance test (ITT): ITT test was performed 3 days after the completion of OGTT experiment. After fasting for 4 hours, the mice were intraperitoneally injected with 0.75U / kg body weight insulin solution. Blood samples were collected from the tail vein at 0, 15, 30, 60, 90 and 120 minutes after injection to measure blood glucose, and the blood glucose change curve was plotted to calculate the area under the curve.

[0062] After the treatment, the mice were fasted overnight, and serum was collected to detect fasting blood glucose using a kit (Beijing Prilai, Glucose Content Determination Kit, E1010).

[0063] Experimental results: Compared with the high-fat diet control group (HFHC+solvent control group), compounds Lyc-A or Lyc-B can improve HFHC diet-induced type 2 diabetes in mice. Oral glucose tolerance test (OGTT) results ( Figure 4 ) showed that the blood glucose levels of the Lyc-A group were significantly lower than those of the high-fat diet control group at 0, 60, 90, and 120 minutes after glucose administration, as well as the area under the curve (AUC) calculated from the blood glucose-time curve, indicating that the glucose tolerance of the Lyc-A group was enhanced ( Figure 4 ); The blood glucose level of the Lyc-B group mice 120 minutes after glucose administration was significantly lower than that of the HFHC diet control group; compared with the high-fat diet control group, the AUC of the Lyc-B group mice showed a significant downward trend, indicating that the compound Lyc-B has an improving effect on glucose tolerance in mice ( Figure 4 ). Insulin tolerance test (ITT) results ( Figure 4 ) showed that the blood glucose and AUC of the Lyc-A group mice were significantly lower 0, 30, and 90 minutes after insulin administration than those of the high-fat diet control group, indicating that the insulin sensitivity of the Lyc-A group mice was significantly enhanced; the blood glucose of the Lyc-B group mice was significantly lower 0 minutes after insulin administration than that of the high-fat diet control group. Fasting blood glucose test results ( Figure 4 ) showed that compared with the high-fat diet control group, the fasting blood glucose of mice in the Lyc-A administration group decreased significantly (p = 0.06). In summary, compound Lyc-A has a significant improvement effect on high-fat diet-induced glucose metabolism disorders in mice, and compound Lyc-B also has an improvement effect on glucose metabolism disorders in mice.

[0064] Example 4: Improvement effect of Lycibarbaines on high-fat diet-induced hyperlipidemia in mice;

[0065] Experimental method: The mice were treated in the same way as above, and serum was collected after treatment for lipid analysis (automatic biochemical analyzer, MINDRAY, BS-360E).

[0066] Experimental results: Figure 5 The total cholesterol content in the serum of mice in the high-fat diet control group (HFHC+solvent) was significantly higher than that in the normal diet control group, indicating that the high-fat diet in this example induced a hypercholesterolemia mouse model. Based on this model, compared with the HFHC diet control group, the total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-c) content in the serum of mice in the Lyc-A or Lyc-B treatment group were significantly reduced ( Figure 5 ), indicating that Lyc-A and / or Lyc-B have a good improvement effect on hypercholesterolemia.

[0067] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. Use of a compound lycibarbarines represented by the following formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for preventing, improving and / or treating a disease or condition associated with lipid metabolism disorders, 2. Use of a compound lycibarbarines represented by the following formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof in the preparation of a food or functional health product for preventing and / or improving non-disease symptoms associated with lipid metabolism disorders, 3. The use according to claim 1, wherein The disease or condition associated with lipid metabolism disorder is selected from one or more of the following: obesity, metabolism-related fatty liver disease, type II diabetes and hyperlipidemia.

4. The use according to claim 2, wherein The non-disease symptoms associated with lipid metabolism disorders are selected from one or more of the following: obesity, liver damage, abnormal blood sugar levels, and abnormal blood lipid levels.

5. The use according to any one of claims 1 to 4, wherein The compound Lycbarbarines is selected from one or more of the group consisting of the following compounds: Lycbarbarine A represented by the following formula (II), Lycbarbarine B represented by the following formula (III), 6. The use according to any one of claims 1, 3 and 5, wherein The medicine is in the form of injection, tablet, powder, granule, pill, capsule, oral solution, ointment, cream or spray.

7. The use according to any one of claims 2 and 4-5, wherein The food or functional health product is an oral liquid, tea, lozenge, capsule, drink, effervescent tablet or chewable tablet.

8. The use according to any one of claims 1 to 7, wherein The compound Lycbarbarines is in the form of a pharmaceutical composition or a functional health food composition, wherein the pharmaceutical composition comprises the compound Lycbarbarines, or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients; the functional health food composition comprises the compound Lycbarbarines, or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof, and one or more food-acceptable excipients.

9. The use according to any one of claims 1, 3, 5-6 and 8, wherein The drug is in a form of administration by oral administration, enteral administration, injection, spraying, physical or chemical mediation, or in a form of administration after being mixed or encapsulated with other substances.

10. A pharmaceutical composition or a functional health food composition, wherein: The pharmaceutical composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester as described in any one of claims 1 to 9, and one or more pharmaceutically acceptable excipients; the functional health food composition comprises the compound Lycbarbarines, or its stereoisomer, or its pharmaceutically acceptable salt or ester, and one or more food-acceptable excipients.

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