CN117357512A - Application of kaurene in preparation of medicines for preventing and/or treating metabolic syndrome - Google Patents
Application of kaurene in preparation of medicines for preventing and/or treating metabolic syndrome Download PDFInfo
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- CN117357512A CN117357512A CN202311571749.7A CN202311571749A CN117357512A CN 117357512 A CN117357512 A CN 117357512A CN 202311571749 A CN202311571749 A CN 202311571749A CN 117357512 A CN117357512 A CN 117357512A
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- ONVABDHFQKWOSV-UHFFFAOYSA-N 16-Phyllocladene Natural products C1CC(C2)C(=C)CC32CCC2C(C)(C)CCCC2(C)C31 ONVABDHFQKWOSV-UHFFFAOYSA-N 0.000 title claims abstract description 110
- ONVABDHFQKWOSV-HPUSYDDDSA-N ent-kaur-16-ene Chemical compound C1C[C@H](C2)C(=C)C[C@@]32CC[C@@H]2C(C)(C)CCC[C@@]2(C)[C@@H]31 ONVABDHFQKWOSV-HPUSYDDDSA-N 0.000 title claims abstract description 110
- 239000003814 drug Substances 0.000 title claims abstract description 95
- 208000001145 Metabolic Syndrome Diseases 0.000 title claims abstract description 32
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 title claims abstract description 30
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- 238000002360 preparation method Methods 0.000 title claims description 12
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 21
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 16
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 229960004329 metformin hydrochloride Drugs 0.000 description 9
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 9
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- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Child & Adolescent Psychology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides application of kaurene in preparing a medicament for preventing and/or treating metabolic syndrome, and belongs to the technical field of biological medicines. The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating metabolic syndrome. The invention discovers for the first time that the medicine taking kaurene as the active ingredient has the functions of obviously resisting obesity, insulin resistance, hyperlipidemia, intestinal barrier integrity improvement, intestinal endotoxemia resistance, nonalcoholic fatty liver resistance and the like and relieving metabolic syndrome, and can be used for treating obesity, insulin resistance, hyperlipidemia, intestinal injury diseases, intestinal endotoxemia resistance, nonalcoholic fatty liver and other metabolic syndromes. The kaurene can be mixed with pharmaceutically acceptable, inert and nontoxic excipients or carrier auxiliary materials to prepare the clinical medicine for resisting the metabolic syndrome, which is convenient for oral administration or intravenous application, and has the characteristics of safety and small toxic and side effects.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of kaurene in preparation of a medicament for preventing and/or treating metabolic syndrome.
Background
In recent years, the prevalence of metabolic syndrome characterized by obesity, insulin resistance, hyperglycemia, hyperlipidemia, and nonalcoholic fatty liver has rapidly increased, and has become a significant public health problem. The metabolic syndrome is related to type 2 diabetes, hypertension and cardiovascular and cerebrovascular diseases, the mortality and disability rate are high, the selection of clinical antimetabolite syndrome drugs is few, and corresponding treatment is mainly carried out aiming at each characteristic of the clinical antimetabolite syndrome drugs, and certain side effects exist, so that the development of new, safer and more effective antimetabolite syndrome drugs has important significance.
Kaurene (Agath flavvon) is a flavonoid compound extracted from leaves, fruits and bark of plants of Cunninghamiaceae, rhus verniciflua, oleraceae, guttiferae and Jinlieaceae, and has chemical name of 8- [5,7-dihydroxy-2- (4-hydroxy-phenyl) -4-oxochromen-6-yl]-5,7-dihydroxy-2-(4-hydr oxyphenyl) chrome-4-one with CAS number 28441-98-7 and molecular formula C 30 H 18 O 10 Molecular weight 538.46; it has antioxidant, antiinflammatory, antiviral, antiparasitic, cytotoxic, neuroprotective and hepatoprotective activities. At present, the application of medicinal materials taking kaurene as an effective component in preparing medicaments for preventing or treating metabolic syndrome is completely unknown.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating metabolic syndrome.
The invention aims at realizing the following technical scheme:
the invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating metabolic syndrome.
Preferably, the metabolic syndrome comprises one or more of obesity, insulin resistance, hyperlipidemia, intestinal injury disease, enterogenic endotoxemia and nonalcoholic fatty liver.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in any one or more than two of the following (1) - (7):
(1) Use in the manufacture of a medicament for reducing weight gain and/or body fat deposition;
(2) The application in preparing the medicine for reversing glucose tolerance damage;
(3) The application in preparing the medicine for reducing blood sugar;
(4) The application in preparing the medicine for preventing and/or treating the hyperlipidemia;
(5) The application in preparing the medicine for preventing and/or treating the non-alcoholic fatty liver disease;
(6) Application in preparing medicines for preventing and/or treating intestinal injury diseases;
(7) The application of the composition in preparing medicines for preventing and/or treating enterogenic endotoxemia.
Preferably, the hyperlipidemia comprises hypercholesterolemia and/or hypertriglyceridemia.
The invention provides a medicine for preventing and/or treating metabolic syndrome, which comprises kaurene or a medicine taking kaurene as an effective component.
Preferably, the medicament further comprises an auxiliary material.
Preferably, the excipients include pharmaceutically acceptable, inert, non-toxic excipients or carrier excipients.
Preferably, the auxiliary materials comprise one or more than two of solvents, cosolvents, coating materials, absorbents, stabilizers, antioxidants, solubilizers and binders.
Preferably, the medicament comprises an oral formulation or an injectable formulation.
Preferably, the dosage form of the oral preparation comprises granules, tablets, powder, capsules, oral liquid or other slow release agents; the dosage form of the injection preparation comprises injection or sterile powder.
The invention has the beneficial effects that:
the invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating metabolic syndrome. The medicine taking kaurene as an effective component has the effects of remarkably resisting obesity, insulin resistance, hyperlipidemia, improving intestinal barrier integrity, reducing intestinal endotoxin, resisting nonalcoholic fatty liver and the like and relieving metabolic syndrome for the first time, and can be used for treating obesity, insulin resistance, hyperlipidemia, intestinal injury diseases, intestinal endotoxemia, nonalcoholic fatty liver and other metabolic syndromes. The invention mixes kaurene with pharmaceutically acceptable, inert and nontoxic excipient or carrier auxiliary materials to prepare the clinical medicine which is convenient for oral administration or intravenous application and is used for resisting metabolic syndrome with safety and small toxic and side effect. The results of the embodiment show that kaurene can obviously reduce weight increase and/or body fat deposition caused by high fat; can reverse glucose tolerance damage caused by high fat; the effect of reducing blood sugar can be achieved; can be used for preventing and/or treating hyperlipidemia caused by high fat diet, such as hypercholesterolemia and/or hypertriglyceridemia; can improve intestinal barrier integrity; can reduce enterogenic endotoxin; can be used for preventing and/or treating nonalcoholic fatty liver disease caused by high fat diet.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions of the prior art, the drawings that are needed in the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a structural diagram of kaurene bisapigenin;
FIG. 2 is a graph showing the detection results of the CK-MB markers of myocardial damage of mice in each experimental group;
FIG. 3 is a graph showing the detection results of the liver injury marker ALT of mice in each experimental group;
FIG. 4 is a graph showing the detection results of the kidney injury marker Cr of mice in each experimental group;
FIG. 5 is a graph showing the effect of kaurene on the body weight of high fat mice;
FIG. 6 is a graph showing the effect of kaurene on weight gain in high fat mice;
FIG. 7 is a graph showing the effect of kaurene on lipid content in high fat mice;
FIG. 8 is a graph showing the results of glucose tolerance and fasting blood glucose measurements in mice of each experimental group;
FIG. 9 is a graph showing the results of serum total cholesterol concentration detection in mice of each experimental group;
FIG. 10 is a graph showing the results of serum LDL cholesterol concentration measurements in mice of each experimental group;
FIG. 11 is a graph showing the results of serum triglyceride concentration detection in mice of each experimental group;
FIG. 12 is a graph showing the results of serum free fatty acid concentration detection in mice of each experimental group;
FIG. 13 is a graph showing liver staining results of mice in each experimental group;
FIG. 14 is a graph showing the results of liver triglyceride level detection in mice of each experimental group;
FIG. 15 is a graph showing the results of liver cholesterol level detection in mice of each experimental group;
FIG. 16 is a graph showing the results of detection of the expression levels of the zonal Occludin and ZO-1 proteins in the colonic mucosa of mice in each experimental group;
FIG. 17 is a gray scale bar graph of the expression levels of the tight junction proteins Occlutin and ZO-1 in the colonic mucosa of mice of each experimental group;
FIG. 18 is a graph showing the results of measurement of Lipopolysaccharide (LPS) endotoxin content in blood of mice of each experimental group.
Detailed Description
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating metabolic syndrome. In the present invention, the metabolic syndrome includes one or more of obesity, insulin resistance, hyperlipidemia, intestinal injury disease, enterogenic endotoxemia and nonalcoholic fatty liver.
In the present invention, the kaurene may be abbreviated as AGT; the molecular formula of kaurene is C 30 H 18 O 10 Molecular weight 538.46; the structural formula of kaurene is shown in figure 1. The source of the kaurene is not particularly limited, and the source is conventional in the art. In the present invention, the kaurene is preferably purchased from MedChemexpress company under the trade designation HY-118383. According to the research, the kaurene can not cause obvious toxicity to heart, liver and kidney when being applied to preventing and/or treating metabolic syndrome, and has safe and efficient effects.
The invention discovers for the first time that the medicine taking kaurene as the active ingredient has the effects of remarkably resisting obesity, insulin resistance, hyperlipidemia, improving the integrity of intestinal barriers, reducing enterogenic endotoxin, resisting nonalcoholic fatty liver and the like and relieving metabolic syndrome.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in any one or more than two of the following (1) - (7):
(1) Use in the manufacture of a medicament for reducing weight gain and/or body fat deposition;
(2) The application in preparing the medicine for reversing glucose tolerance damage;
(3) The application in preparing the medicine for reducing blood sugar;
(4) The application in preparing the medicine for preventing and/or treating the hyperlipidemia;
(5) Application in preparing medicines for preventing and/or treating intestinal injury diseases;
(6) Use in the manufacture of a medicament for maintaining the structural integrity of the intestinal barrier;
(7) The application of the composition in preparing medicines for preventing and/or treating enterogenic endotoxemia.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for reducing weight rise and/or body fat deposition. In the present invention, the weight gain and/or body fat deposition preferably comprises a high fat diet. In the invention, the kaurene or the medicine taking the kaurene as the effective component can obviously reduce the weight increase caused by high-fat diet. In the invention, kaurene or a medicine taking kaurene as an effective component can obviously reduce body fat deposition caused by high-fat diet. The results of the examples show that kaurene can obviously reduce the weight increase and body fat deposition of mice caused by high-fat diet.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for reversing glucose tolerance injury. In the present invention, the glucose tolerance damage preferably includes glucose tolerance damage caused by a high-fat diet. In the invention, the kaurene or the medicine taking the kaurene as the effective component can obviously improve glucose tolerance caused by high-fat diet, improve insulin sensitivity and reverse glucose tolerance injury caused by high-fat diet. The results of the examples show that kaurene remarkably improves glucose tolerance of mice caused by high-fat diet, and remarkably reduces Area Under Curve (AUC) formed by blood sugar and time.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for reducing blood sugar. In the invention, the kaurene or the medicine taking the kaurene as the effective component can achieve the effect of obviously reducing blood sugar. The results of the embodiment show that the kaurene can obviously reduce the rise of fasting blood glucose caused by high-fat diet, which indicates that the kaurene has the function of reducing blood glucose.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating hyperlipidemia. In the present invention, the hyperlipidemia preferably includes hypercholesterolemia and/or hypertriglyceridemia. In the present invention, the hyperlipidemia preferably includes hyperlipidemia caused by a high fat diet. In the invention, the kaurene or the medicine taking the kaurene as the effective component can obviously reduce the rise of the blood lipid level caused by high-fat diet. In the invention, the kaurene or the medicine taking the kaurene as the effective component can obviously reduce the total TC and LDL in blood and reduce the level of TG and FFAs in blood. The results of the examples show that the kaurene can obviously reduce the rise of the total TC and LDL levels of mice blood caused by high-fat diet and reduce the blood TG and FFAs levels.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating non-alcoholic fatty liver. In the present invention, the non-alcoholic fatty liver disease preferably includes a high-fat diet-induced non-alcoholic fatty liver disease. In the invention, the kaurene or the medicine taking the kaurene as the effective component can obviously inhibit liver lipid deposition and the rise of TG and TC levels caused by high-fat diet. The results of the examples show that the kaurene can significantly inhibit lipid deposition and increase of TG and TC levels of the liver of mice caused by high-fat diet.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating intestinal injury diseases. In the invention, the kaurene or the medicine taking the kaurene as the active ingredient preferably achieves the effect of preventing and/or treating intestinal injury diseases by maintaining the structural integrity of intestinal barriers. In the present invention, the intestinal barrier structural integrity preferably comprises colon barrier structural integrity. The present invention preferably maintains the structural integrity of the colon barrier by maintaining the expression levels of the claudin Occludin and ZO-1 proteins in the colonic mucosa. The results of the embodiment show that the kaurene can obviously improve the expression level of the closely connected proteins Occlutin and ZO-1 protein in the colon mucosa of the mice caused by high-fat diet and restore to the normal level, thereby achieving the effect of maintaining the structural integrity of the colon barrier and further achieving the effect of preventing and/or treating intestinal injury diseases.
The invention provides application of kaurene or a medicine taking kaurene as an effective component in preparing a medicine for preventing and/or treating enterogenic endotoxemia. In the invention, the kaurene or the medicine taking the kaurene as the effective component has positive effect on reducing lipopolysaccharide. The results of the embodiment show that the kaurene can obviously improve the rise of the blood lipopolysaccharide content caused by high-fat diet, so that the content of the blood lipopolysaccharide in normal mice is recovered, and the effect of preventing and/or treating enterogenic endotoxemia is achieved.
In the embodiment of the invention, kaurene is used for reducing weight increase and/or body fat deposition caused by high fat; or for reversing glucose tolerance damage; or for lowering blood glucose; or for the prevention and/or treatment of hyperlipidemia; or for preventing and/or treating intestinal injury diseases; or for the prevention and/or treatment of enterogenic endotoxemia; or when the kaurene is used for preventing and/or treating the non-alcoholic fatty liver, the consumption of the kaurene is preferably 0.002% -0.20%, more preferably 0.020% -0.20%, and even more preferably 0.20% of the ration.
The invention provides a medicine for preventing and/or treating metabolic syndrome, which comprises kaurene or a medicine taking kaurene as an effective component.
In the present invention, the medicament preferably further comprises an auxiliary material. In the present invention, the excipients preferably include pharmaceutically acceptable, inert, non-toxic excipients or carrier excipients. In the present invention, the auxiliary material preferably includes one or more of a solvent, a cosolvent, a coating material, an absorbent, a stabilizer, an antioxidant, a solubilizer, and a binder. In the present invention, the drug preferably includes an oral preparation or an injectable preparation; the dosage forms of the oral preparation comprise granules, tablets, powder, capsules, oral liquid, injection or other slow release agents; the dosage form of the injection preparation comprises injection or sterile powder.
The technical solutions provided by the present invention are described in detail below with reference to the drawings and examples for further illustrating the present invention, but they should not be construed as limiting the scope of the present invention.
In the examples of the present invention, specific experimental animals, experimental materials and experimental reagents are as follows:
the experimental animal is specifically as follows: healthy male C57BL/6N mice with age of 6 weeks are purchased from Beijing Veitway Lihua laboratory animal technology Co., ltd, raised in IVC laboratory animal systems of Jiangxi university animal science and technology university, the room temperature is controlled at 23+/-2 ℃, the relative humidity is controlled at 40% -70%, 12h illumination and 12h dark period change, and free feeding and drinking water are realized.
The experimental materials specifically comprise: normal mouse Diet (ND for short) was purchased from Research Diet company under the trade code D12450J, fat energy supply accounting for 10%; high fat mice Diet (HFD for short) was purchased from Research Diet company under the trade code D12492 with a fat energy supply ratio of 60%. Kaurene (AGT for short, CAS number: 28441-98-7, molecular formula: C) 30 H 18 O 10 Molecular weight: 538.46,the verification purity is more than 95%, the structural formula is shown in figure 1) is purchased from MedChemexpress company, and the commodity number is HY-118383; metformin hydrochloride (Metformin, purity > 97%) was purchased from Sigma-Aldrich under the trade designation 317240.
The experimental reagent specifically comprises the following components: creatine kinase-MB isoenzyme (CK-MB), alanine aminotransferase (alanine aminotransferase, ALT), creatinine (Cr), glucose (glucose), total cholesterol (total cholesterol, TC), low density lipoprotein cholesterol (low density lipoprotein cholesterol, LDL), and Triglyceride (TG) detection kits were purchased from the institute of bioengineering, made in tokyo; free fatty acid detection kits were purchased from BioAssay Systems company; lipopolysaccharide (LPS) detection kit was purchased from Cusabio company. Tight-junction protein (Occlutin, ZO-1) and beta-actin (internal control protein) antibodies were purchased from Proteintech.
The differences in the letters in the following examples are significant, and the differences in the following examples are significant between the two groups, P < 0.05; * Represents a very significant difference between the two groups, P < 0.01.
Example 1
Drug safety assessment of kaurene
1. Design of experiment
After 6-week-old male C57BL/6N mice were subjected to adaptive feeding for 1 week, the mice were randomly divided into 4 groups of 10 mice each, specifically into a normal control group (normal mice diet, abbreviated as ND), a low-dose kaurene group (normal mice diet containing 0.002% AGT by mass, abbreviated as AGT 0.002%), a medium-dose kaurene group (normal mice diet containing 0.02% AGT by mass, abbreviated as AGT 0.02%), and a high-dose kaurene group (normal mice diet containing 0.20% AGT by mass, abbreviated as AGT 0.20%). Male C57BL/6N mice respectively receive equal amounts of normal mouse daily ration and normal mouse daily ration mixed with 0.002%, 0.020% and 0.20% AGT respectively for 12 weeks, and then the levels of a mouse blood central muscle injury marker CK-MB, a liver injury marker ALT and a kidney injury marker Cr are detected, so that the safety of medicinal materials taking kaurene as an effective component for a long time is specifically studied.
2. Experimental results
After detecting that male C57BL/6N mice respectively receive equal amounts of daily ration of normal mice and daily ration of normal mice mixed with 0.002%, 0.020% and 0.20% AGT for 12 weeks, blood central muscle injury marker CK-MB, liver injury marker ALT and kidney injury marker Cr levels of the mice are shown in table 1 and figures 2-4.
TABLE 1 influence of kaurene on heart, liver and kidney function in mice
As shown in Table 1 and figures 2-4, with the increase of the addition amount of kaurene, the levels of CK-MB, ALT and Cr in the mice are not significantly different from those in the control group, which indicates that the kaurene has no significant effect on CK-MB, ALT and Cr, and the long-term intake of kaurene with the concentration can not cause obvious heart, liver and kidney toxicity.
Example 2
Pharmacodynamic effects of kaurene on high-fat diet-induced metabolic syndrome
1. Animal model construction
The mice were randomly divided into 6 groups of 10 mice each, specifically into a normal control group (normal mice diet, abbreviated as ND), a simple high fat group (high fat mice diet, abbreviated as HFD), a high fat+low dose kaurene group (high fat mice diet containing 0.002% AGT, abbreviated as hfd+agt 0.002%), a high fat+medium dose kaurene group (high fat mice diet containing 0.02% AGT, abbreviated as hfd+agt 0.02%), a high fat+high dose kaurene group (high fat mice diet containing 0.20% AGT, abbreviated as hfd+agt 0.20%), and a metformin hydrochloride treatment group (high fat mice diet, simultaneously, a daily gavage was given with 0.25g/kg body weight/day of metformin hydrochloride treatment, abbreviated as hfd+metformin0.25 g/kg).
2. Design of experiment
After 6-week-old healthy male C57BL/6N mice are acclimatized for 1 week, the daily ration feeding is respectively given for 12 weeks, metformin hydrochloride is used as a first line medicament for treating diabetes and metabolic syndrome, a metformin hydrochloride treatment group is used as a positive control medicament, and 0.25g/kg body weight/day of gastric lavage is provided. Mice were tested for body weight every two weeks, and mice were plotted for body weight, and weight gain was calculated. At experiment week 12, body fat content of living mice was detected by a body composition analyzer (QMR 06-090H, suzhou New ly Michael) and Glucose Tolerance Test (GTT) was performed on each group of mice after 6 hours of fasting, glucose tolerance curve was measured, and Area Under Curve (AUC) formed by blood glucose and time of each group of mice was calculated; after the mice are sacrificed at the end of the experiment, fasting blood glucose, blood total cholesterol, blood low density lipoprotein cholesterol, blood triglycerides, blood lipid polysaccharides and blood free fatty acid levels are detected; detecting liver lipid drop size of mice in each group by adopting a hematoxylin-eosin (HE) staining method, and detecting liver triglyceride and cholesterol levels; the immunoblotting method is adopted to detect the levels of the closely connected proteins Occludin and ZO-1 protein in colon mucosa of each group of mice, and the effect of medicinal materials taking kaurene as an effective component in the preparation of the medicament for resisting the metabolic syndrome is specifically studied.
3. Experimental results
(1) The effect of kaurene on the body weight of high fat mice is shown in table 2 and fig. 5; the effect of kaurene on the weight gain of high fat mice is shown in table 3 and fig. 6; the effect of kaurene on body fat content in high fat mice is shown in table 3 and fig. 7.
TABLE 2 influence of kaurene on the body weight of high fat mice (Unit: g)
TABLE 3 influence of kaurene on body weight gain and body fat content in high fat diet mice
As can be seen from tables 2, 3 and fig. 5 to 7, the mice in the medium dose group (hfd+agt 0.02%) and the high dose group (hfd+agt 0.20%) had significantly reduced body weight compared to the simple high fat group (HFD), wherein the high dose group (hfd+agt 0.20%) had a weight loss effect similar to that of Metformin hydrochloride treatment group (hfd+metaformin 0.25 g/kg) and were not significantly different. Compared with the simple high-fat group, the body fat content of the mice in the medium-dose group and the high-dose group is obviously reduced, which proves that the AGT has the effect of obviously reducing the weight rise and the obesity of the mice caused by high-fat diet.
(2) Each group of mice was subjected to Glucose Tolerance Test (GTT) after 6 hours on an empty stomach, and the glucose tolerance curve was measured, and the detection results are shown as a in fig. 8; the area under the curve (AUC) formed by blood glucose versus time was calculated for each group of mice as shown in table 4 and B in fig. 8; after mice were sacrificed at the end of the experiment, fasting blood glucose was measured, and the fasting blood glucose values of each group of mice are shown as C in table 4 and fig. 8.
TABLE 4 influence of kaurene on the area under the glucose tolerance curve and the fasting blood glucose values of high-fat diet mice
As can be seen from table 4 and fig. 8, ingestion of medium and high doses of AGT significantly improved glucose tolerance in mice compared to the simple high fat group (HFD), significantly reduced the area under the curve (AUC) formed by blood glucose versus time; the high fat diet significantly increased fasting blood glucose levels compared to the normal control group, which was effectively reversed by medium and high doses of AGT. The effect of reducing blood sugar and improving glucose tolerance of the high-dose group is equivalent to that of a metformin hydrochloride treatment group, which shows that kaurene has good effects of reducing blood sugar and improving insulin sensitivity.
(3) The results of measuring the total blood cholesterol, the blood low density lipoprotein cholesterol, the blood triglyceride and the blood free fatty acid level of each experimental group are shown in Table 5. Wherein, the detection result of the serum total cholesterol concentration of each experimental group of mice is shown in figure 9; the results of serum low density lipoprotein cholesterol concentration measurements for mice of each experimental group are shown in fig. 10; the results of serum triglyceride concentration detection of mice of each experimental group are shown in fig. 11; the results of the serum free fatty acid concentration measurements of the mice of each experimental group are shown in FIG. 12.
TABLE 5 influence of kaurene on serum lipid levels in high fat diet mice
As can be seen from table 5 and fig. 9-12, the high fat diet resulted in significantly elevated blood lipid levels in mice compared to the normal control group; intake of medium dose (hfd+agt 0.02%) and high dose (hfd+agt 0.20%) of AGT significantly reduced total TC and LDL in mice blood, and reduced blood TG and FFAs levels compared to the simple high fat group (HFD). The effect of cholesterol and triglyceride reducing effect of the high-dose group is similar to that of the metformin hydrochloride treatment group, which shows that kaurene can obviously reduce the hypercholesterolemia and hypertriglyceridemia of mice caused by high-fat diet.
(4) The liver lipid drop size of each group of mice was measured by hematoxylin-eosin (HE) staining method, the measurement results are shown in FIG. 13, wherein the scale in FIG. 13 is 100 μm; liver triglyceride levels for each group of mice are shown in table 6 and fig. 14; the liver cholesterol levels of each group of mice are shown in table 6 and fig. 15.
TABLE 6 influence of kaurene on liver lipid levels in high fat diet mice
As can be seen from table 6 and fig. 13-15, liver lipid deposition was aggravated in the single high fat group (HFD) mice compared to the normal control group (ND), liver TG and TC levels were significantly upregulated, whereas medium and high dose AGT significantly inhibited liver lipid deposition and TG and TC levels elevation in mice caused by the high fat diet, wherein the anti-non-alcoholic fatty liver effect of the high dose AGT was similar to that of the metformin hydrochloride treated group, demonstrating that kaurenin had the effect of significantly alleviating the non-alcoholic fatty liver in mice caused by the high fat diet.
(5) Test for verifying the expression level of Tight-junction protein in colon tissue of mice with increased Metabolic syndrome in each group of mice
The expression levels of the zonal Occidin and ZO-1 proteins in the colonic mucosa of the mice of each experimental group are shown in Table 7 and FIG. 16 and FIG. 17.
TABLE 7 expression levels of the zonal Occlutin and ZO-1 proteins in the colonic mucosa of mice of each experimental group
As can be seen from table 8, fig. 16 and fig. 17, the protein expression levels of ZO-1 and Occludin were significantly higher for both medium and high doses of AGT than for the model group, wherein the medium dose of AGT increased the expression levels of Occludin and ZO-1 proteins back to 1.05 and 0.96, respectively; the high dose of AGT raised the expression levels of Occludin and ZO-1 protein back to 0.98 and 1.10, respectively, indicating that kaurene has a good effect in maintaining the structural integrity of the colon barrier, and can be used for the treatment of intestinal injury diseases.
(6) The results of measuring the Lipopolysaccharide (LPS) content in the blood of mice of each experimental group are shown in Table 8 and FIG. 18.
TABLE 8 results of measurement of Lipopolysaccharide (LPS) content in blood of mice of each experimental group
As can be seen from table 8 and fig. 18, lipopolysaccharide in blood of mice of the simple high fat group (HFD) was significantly elevated compared to the normal control group (ND). Whereas medium and high doses of AGT significantly inhibited the increase in lipopolysaccharide content in the blood of mice caused by a high fat diet. The kaurene-bisapigenin has positive effect on lipopolysaccharide-induced inflammation, and can be used for improving enterogenic endotoxemia.
In conclusion, the medicine taking kaurene as the active ingredient has the effects of remarkably resisting obesity, resisting insulin resistance, reducing blood sugar, resisting hyperlipidemia and nonalcoholic fatty liver, improving intestinal injury diseases, improving enterogenic endotoxemia and the like and relieving metabolic syndrome.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. Application of kaurene or medicine containing kaurene as effective component in preparing medicine for preventing and/or treating metabolic syndrome is provided.
2. The use according to claim 1, wherein the metabolic syndrome comprises one or more of obesity, insulin resistance, hyperlipidemia, intestinal injury disease, enterogenic endotoxemia and nonalcoholic fatty liver disease.
3. Application of kaurene or a medicine taking kaurene as an effective component in any one or more than two of the following (1) - (7):
(1) Use in the manufacture of a medicament for reducing weight gain and/or body fat deposition;
(2) The application in preparing the medicine for reversing glucose tolerance damage;
(3) The application in preparing the medicine for reducing blood sugar;
(4) The application in preparing the medicine for preventing and/or treating the hyperlipidemia;
(5) Application of medicine for preventing and/or treating non-alcoholic fatty liver disease
(6) Application in preparing medicines for preventing and/or treating intestinal injury diseases;
(7) The application of the composition in preparing medicines for preventing and/or treating enterogenic endotoxemia.
4. Use according to claim 3, wherein the hyperlipidemia comprises hypercholesterolemia and/or hypertriglyceridemia.
5. A medicament for preventing and/or treating metabolic syndrome, which is characterized by comprising kaurene or a medicament taking kaurene as an active ingredient.
6. The medicament of claim 5, further comprising an adjuvant.
7. The medicament according to claim 6, wherein the excipients comprise pharmaceutically acceptable, inert, non-toxic excipients or carrier excipients.
8. The medicament according to claim 6, wherein the auxiliary materials comprise one or more of solvents, cosolvents, coating materials, absorbents, stabilizers, antioxidants, solubilizers and binders.
9. The medicament of claim 5, wherein the medicament comprises an oral formulation or an injectable formulation.
10. The medicament according to claim 9, wherein the dosage form of the oral preparation comprises granules, tablets, powders, capsules, oral liquids or other sustained release agents; the dosage form of the injection preparation comprises injection or sterile powder.
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Non-Patent Citations (3)
| Title |
|---|
| HASYA NAZLI GÖK，等: "Activity-guided isolation of α-amylase, α-glucosidase, and pancreatic lipase inhibitory compounds from Rhus coriaria L", J FOOD SCI, vol. 85, no. 10, 12 October 2020 (2020-10-12), pages 3220 * |
| RAVENA P DO NASCIMENTO, 等: "agathisflavone as a Single Therapy or in Association With Mesenchymal Stem Cells Improves Tissue Repair in a Spinal Cord Injury Model in Rats", FRONT PHARMACOL, no. 13, 5 April 2022 (2022-04-05), pages 858190 * |
| SABINA SHRESTHA ；等: "Rhus parviflora and its biflavonoid constituent, rhusflavone, induce sleep through the positive allosteric modulation of GABA(A)-benzodiazepine receptors", J ETHNOPHARMACOL., vol. 142, no. 1, 26 June 2012 (2012-06-26), pages 213, XP028519055, DOI: 10.1016/j.jep.2012.04.047 * |
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