CN113209099A - Application of magnoflorine in preparing medicine for regulating hyperappetite or treating obesity - Google Patents

Application of magnoflorine in preparing medicine for regulating hyperappetite or treating obesity Download PDF

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CN113209099A
CN113209099A CN202110650962.1A CN202110650962A CN113209099A CN 113209099 A CN113209099 A CN 113209099A CN 202110650962 A CN202110650962 A CN 202110650962A CN 113209099 A CN113209099 A CN 113209099A
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magnoflorine
obesity
application
hyperappetite
regulating
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陶枫
刘珍秀
朱蕴华
陈易
冯怡莹
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SHANGHAI HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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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Abstract

The invention relates to the technical field of medicines, in particular to application of magnoflorine in preparation of medicines for regulating hyperappetite or treating obesity. Provides a new treatment way for patients with the hyperphagia/obesity, has strong practicability and wide application prospect.

Description

Application of magnoflorine in preparing medicine for regulating hyperappetite or treating obesity
Technical Field
The invention relates to the technical field of medicines, in particular to application of magnoflorine in preparing a medicine for regulating hyperappetite or treating obesity.
Background
Obesity, which is a condition of excess fat accumulation in the body, refers to a certain degree of significant overweight and excessive thickness of the fat layer. It does not mean a simple weight gain, but a state in which an excess of adipose tissues is accumulated in the body. Excessive accumulation of fat in the body due to excessive food intake or altered metabolism of the body causes excessive weight gain and causes pathological, physiological changes or latency in the human body. Obesity can increase the risk of cardiovascular disease, affect the function of the digestive system, affect the function of the endocrine system, increase the risk of cancer, cause joint soft tissue injury, reproductive capacity reduction and psychological disorders, heart disease, diabetes, atherosclerosis, fatty liver, gall stone, edema, gout complications, and is a source of tens of thousands of diseases. Obesity not only affects the beauty of the body, but also brings inconvenience to life.
Obesity is mainly classified into simple obesity, abdominal obesity, puffiness, fat obesity, qi-fat obesity and pathological obesity. Simple obesity: congenital or caused by an over-diet; abdominal obesity: constipation and hypertension are often accompanied by excessive liver qi; puffiness of deficiency type: the symptoms of irregular menstruation and cold hands and feet are often caused by too strong or too weak kidney function; fat obesity: heart disease is easily caused by excessive blood and qi; qi fat: obesity due to mental stress caused by abnormal triple energizer meridian; pathological obesity: mainly is obesity caused by diseases, and when the simple obesity has more serious complications, the simple obesity gradually changes into pathological obesity.
Causes of pathological obesity: 1. the Kexing syndrome: mainly, the adrenal cortex is hyperfunction, the cortisol is secreted too much, the face, the neck and the body are hypertrophic, but the four limbs are not much fat; 2. pancreatic source: the excessive insulin secretion and the reduction of the metabolic rate lead to the reduction of lipolysis and the increase of body weight and the obesity of the whole body; 3. decreased sexual function: cerebral obesity with loss of sexual function or decreased libido, obesity in the vicinity of the breast, lower abdomen and genitals; 4. verticality: hypophysis pathological changes cause excessive secretion of anterior pituitary, and hyperplasia and hypertrophy of bones, soft tissues and visceral tissues of the whole body; 5. hypothyroidism: hypothyroidism, obesity and myxoedema; 6. medicine source property: the side effects of drugs, such as obesity, in patients with allergic diseases, rheumatoid diseases, and asthma, occur after a certain period of time.
Through relevant data queries, current drugs for treating obesity include: 1. amphetamine has the effects of inhibiting nerves and reducing appetite, but has obvious drug resistance, so that a user can have emotional excitement and hallucination reaction, and the drug is very easy to addict and difficult to quit; 2. the fenfluramine has obvious weight-reducing effect, but can cause serious cardiovascular diseases after long-term use; 3. senna leaf is a traditional Chinese medicine, but slight patients vomit, nausea and diarrhea after taking the medicine, and serious patients can cause visceral hemorrhage to endanger life; 4. caffeine, ingested in large doses over a long period of time, can cause tachycardia, sleep disorder, and induce various types of mental disorders; 5. capsaicin stimulates sympathetic nerves, promotes blood circulation, and accelerates metabolism, but fat is not directly burned, and chronic high dose administration of capsaicin causes renal toxicity.
The medicament containing the components is used for treating obesity, has side effects after being taken into a human body as an oral medicament, mainly enters liver, kidney, lung and spleen, increases the burden of the liver, and can cause gastrointestinal dysfunction and malnutrition of the human body through the functions of suppressing appetite, accelerating metabolism and promoting urination, and serious patients can cause mental diseases or deterioration of liver and kidney functions to threaten life after being taken for a long time.
With the progress of science, incretin endocrine effects are gradually discovered and applied to clinical medicine. Glucagon-like peptide-1 (GLP-1), a representative incretin, has various physiological effects such as glucose-dependent incretin secretion, inhibition of pancreatic β -cell fibrosis, promotion of proliferation thereof, inhibition of gastric emptying, reduction of food intake, and reduction of glomerular filtration pressure. Various GLP-1 receptor agonists have been discovered and gradually used clinically to service patients.
Aiming at the defects, the invention creatively provides a novel glucagon-like peptide-1 receptor agonist, namely magnoflorine for the first time, provides a novel treatment method for patients with bulimia/obesity, and has no report about the application of magnoflorine in the preparation of medicines for regulating bulimia or treating obesity.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel medicament for regulating hyperphagia or treating obesity.
In order to achieve the purpose, the invention adopts the technical scheme that:
in a first aspect, the invention provides the use of magnoflorine in the preparation of glucagon-like peptide-1 receptor agonists.
In a second aspect, the invention provides the use of magnoflorine as the sole active ingredient in the manufacture of a medicament for suppressing bulimia.
In a third aspect, the invention provides the use of magnoflorine as the sole active ingredient in the manufacture of a medicament for the treatment of obesity.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier.
In a fourth aspect, the invention provides a medicament for increasing the expression level of glucagon-like peptide-1, which is prepared from magnoflorine and a pharmaceutically acceptable carrier.
In a fifth aspect, the invention provides a medicament for suppressing hyperphagia, which is prepared from magnoflorine and a pharmaceutically acceptable carrier.
In a sixth aspect, the invention provides a medicament for treating obesity, which is prepared from magnoflorine and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier of the invention is: the carrier for the administration of the therapeutic agent comprises various excipients, diluents and the like. The term refers to such pharmaceutical carriers: they are not essential active ingredients per se and are not unduly toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A thorough discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (mackpub.co., n.j.1991). Pharmaceutically acceptable carriers in the compositions may comprise liquids such as water, saline, glycerol and ethanol. In addition, auxiliary substances such as emulsifiers, fillers, binders, wetting agents, disintegrants, absorption enhancers, flavoring agents, colorants, cosolvents and the like may also be present in these carriers. The emulsifier is selected from acetylated monoglyceride, acetylated diglyceride, sucrose ester, sorbitol ester, soybean phospholipid, lauric monoglyceride, propylene glycol fatty acid ester, calcium stearoyl lactylate, diacetyl tartaric acid, glyceryl monostearate, modified soybean phospholipid, etc. Such as magnesium stearate, microcrystalline cellulose, lactose, milk sugar, high molecular weight polyethylene glycols, and the like. Such as starch, mannitol, silicic acid, dextrin, calcium hydrogen phosphate, cellulose, etc. Such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, gum arabic, starch slurry, hydroxypropyl starch, modified starch, pregelatinized starch, dextrin, microcrystalline cellulose, polyvinyl pyrrolidone mucilage, gelatin mucilage. Such as glycerin and the like. The disintegrating agent is agar, calcium carbonate, potato starch, tapioca starch, alginic acid, hydroxypropyl starch, modified starch, sodium carboxymethyl starch, microcrystalline cellulose, guar gum, xanthan gum, etc. The absorption enhancer is such as quaternary ammonium compound, effervescent agent, cyclodextrin, vitamin D and its derivatives, piperine, etc. The flavoring agent can be sour agent, sweetener, such as phosphoric acid, lactic acid, tartaric acid, malic acid, fumaric acid, acetic acid, succinic acid, xylitol, steviosin, sodium cyclamate, aspartame, oleum Menthae Dementholatum, etc. The colorant may be a plant colorant, an animal colorant or a microbial colorant, such as beet red, turmeric, chlorophyll, shellac, cochineal, red yeast colorant, and the like. Such as beta-cyclodextrin, maltodextrin, tween, ethanol, span, sodium dodecyl sulfate, propylene glycol, polyethylene glycol, glycerol, etc. However, it will be appreciated by those skilled in the art that the pharmaceutically acceptable carriers useful in the present invention are not limited to the above-mentioned types.
The molecular formula of magnoflorine is as follows: c20H24NO4；
The molecular weight of the magnoflorine is as follows: 341;
magnoflorine structure diagram:
Figure BDA0003111139280000041
the invention has the advantages that:
as is well known to those skilled in the art, the appetite increase refers to the condition of easy hunger, food intake and obvious increase of food intake, and is caused by reasons of excessive body heat energy consumption, excessive metabolism or insulin secretion increase, the body weight of a patient often rapidly increases within a short time, and obesity symptoms and corresponding complications appear.
Drawings
Figure 1 is a standard graph.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
Example 1 cell experiments
1 method
The NCI-H716 cell culture model was established by the relevant method In the reference (Yunli Yu, Li Liu, Xinting Wang, et al.modulation of glucose-like peptide-1release by bergenine: In vivo and In vitro students. biochemical Pharmacology 79(2010) 1000-.
And respectively randomly dividing the constructed cell models into two groups, wherein one group uses small corydaline for the cells, the other group uses magnoflorine for the cells, cell supernatant is collected after the experiment is finished, and the concentration of GLP-1 is detected by an ELISA method. (KRB buffer was used for induction).
The ELISA method comprises the following experimental steps:
1) the kit was removed and left at room temperature (18-25 ℃) for 30 minutes.
2) Grouping: and taking out the 96-well plate, determining the number of required battens according to the data of the samples to be detected and the number of the standard substances, continuously refrigerating the rest battens, and respectively setting the standard substances (8 concentrations), blank holes and sample groups to be detected.
3) Sample adding: respectively adding 100ul of standard solution into the blank micropores according to the sequence of the standard; add 100ul of distilled water to the blank control well; 100ul of the sample to be tested was added to the remaining microwells. The reaction wells were sealed with a sealing plate of gummed paper and incubated at room temperature for 2.5h or gently shaken overnight at 4 ℃.
4) Washing the plate: the plate was washed 4 times and patted dry on thick absorbent paper for the last time.
5) Biotinylated antibody working solution (100 ul/well) was added. The reaction wells were sealed with a sealing plate of gummed paper and incubated at room temperature for 60 minutes with gentle shaking.
6) Washing the plate: the plate was washed 4 times and patted dry on thick absorbent paper for the last time.
7) Adding an enzyme standard solution: 100ul of enzyme labeling solution (except for blank control wells) is added to each well of the standard sample group and the sample group to be detected. Incubate with gentle shaking at room temperature for 45 minutes.
8) Washing the plate: the plate was washed 4 times and patted dry on thick absorbent paper for the last time.
9) Color development: add color reagent TMB100 ul/well and incubate for 20 minutes at room temperature in the dark.
10) And (4) terminating: add 50ul stop solution, mix well and measure OD450 value.
11) Reading a plate: the OD of each well was read at a wavelength of 450 nm. Note: the residual liquid and finger traces on the bottom of the plate must be wiped off when the plate is read, and the plate reading time is controlled to be 30 after the reaction is stopped
12) And (6) analyzing the data.
2 results
The results are shown in FIG. 1 and tables 1-2.
TABLE 1
Name of curve Formula of curve A B C R2
Standard curve Y＝C*X^2+B*X+A 0.16 0.91 -0.08 0.99
TABLE 2
Figure BDA0003111139280000051
Figure BDA0003111139280000061
Relative concentration of berberine and GLP-1
3 conclusion
The results show that the magnoflorine and the small firewood alkali can promote the cells to secrete GLP-1 without influencing IV-type dipeptidyl peptidase (which plays the role of inactivating GLP-1 and is related to multiple physiological activities in a human body), and the magnoflorine can act on a GLP-1 target spot and can be used as an agonist of the GLP-1 target spot.
Example 2 Effect verification
1 method
An NCI-H716 cell model was constructed according to the method described in example 1, using small bupleurum base as a positive control, 3 concentrations were set for each monomer, 3 wells were repeated for each concentration, and verification was performed using GLP-1 secretion as an indicator (the ELISA method is the same as in example 1, and details are not repeated here).
2 results
2.1 Standard Curve
The standard curve obtained is as described in table 1.
2.2 is shown in Table 3.
TABLE 3
Figure BDA0003111139280000062
Figure BDA0003111139280000071
Relative concentration of berberine and GLP-1
3 conclusion
The above results indicate that magnoflorine has comparable results to small magnoflorine and is also useful as a GLP-1 agonist.
Example 3 animal experiments
1 method
1 method
This example is intended to evaluate the effect of magnoflorine on the degree of obesity and related indicators in diet-induced obese rats.
1.1 materials
30 general-grade Wister rats, male, 4-week-old, 150-200 g in body weight.
Basic feed: 30% of corn, 30% of wheat, 20% of soybean meal, 10% of wheat bran, 0.05% of salt, 0.05% of cod-liver oil and 9.9% of fish meal.
High-fat nutritional feed: 80% of basic feed, 20% of lard oil and 7% of cane sugar.
1.2 Molding
After 1 week of adaptive feeding of Wister rats, 10 rats were randomly selected as a blank control group, and basal diet was given, and the rest were given high-fat nutritional diet as experimental groups.
And molding for 10 weeks. After the molding is successful, the high-fat nutrition feed group rats are given 2.5g of magnoflorine solvent per kg/d, and the blank control group is given 10 weeks based on normal saline (10 mL/kg). The rats were observed daily for growth, diet, resolution, and body weight recording.
At the end of the experiment, the rats were fasted without water deprivation, anesthetized after 12h, and the body weight of each group was measured. And (3) carrying out conventional dissection, taking blood from the abdominal main vein, measuring fasting blood glucose, carrying out low-temperature centrifugation, and separating serum to be measured.
2 results
2.1 the degree of obesity for each group is shown in Table 4.
TABLE 4
Figure BDA0003111139280000072
Figure BDA0003111139280000081
2.2 post-treatment blood glucose values and cholesterol values for each group are shown in Table 5.
TABLE 5
Group of Blood sugar (mmol/L) Cholesterol (mmol/L)
Blank control group 6.19±0.86 1.19±0.26
Model set 6.50±0.75 1.55±0.19
Experimental group 6.22±0.77 1.29±0.64
3 conclusion
The results show that the magnoflorine solvent can obviously reduce the weight, the blood sugar and the cholesterol of a rat after being administered to the obesity model rat, and prove that the magnoflorine has the curative effect of treating the obesity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and additions can be made without departing from the principle of the present invention, and these should also be considered as the protection scope of the present invention.

Claims (7)

1. Application of magnoflorine in preparing glucagon-like peptide-1 receptor agonist is provided.
2. Application of magnoflorine as the only active ingredient in preparing a medicament for suppressing hyperphagia.
3. Use of magnoflorine as the sole active ingredient in the manufacture of a medicament for the treatment of obesity.
4. The use of any one of claims 2-3, wherein the medicament further comprises a pharmaceutically acceptable carrier.
5. A medicine for improving the expression quantity of glucagon-like peptide-1 is characterized in that the medicine is prepared from magnoflorine and a pharmaceutically acceptable carrier.
6. The medicament for inhibiting the hyperappetite is prepared from magnoflorine and a pharmaceutically acceptable carrier.
7. The medicine for treating obesity is characterized by being prepared from magnoflorine and a pharmaceutically acceptable carrier.
CN202110650962.1A 2021-06-10 2021-06-10 Application of magnoflorine in preparing medicine for regulating hyperappetite or treating obesity Pending CN113209099A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114832004A (en) * 2022-04-24 2022-08-02 河北医科大学 Pharmaceutical composition for treating metabolic disorder and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ESTERA OKON等: "Advances in Chemistry and Bioactivity of Magnoflorine and Magnoflorine-Containing Extracts", 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114832004A (en) * 2022-04-24 2022-08-02 河北医科大学 Pharmaceutical composition for treating metabolic disorder and preparation method thereof
CN114832004B (en) * 2022-04-24 2023-08-22 河北医科大学 Pharmaceutical composition for treating metabolic abnormality and preparation method thereof

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