CN117017972A - Activation of AMPK by lignum Aquilariae Resinatum component - Google Patents
Activation of AMPK by lignum Aquilariae Resinatum component Download PDFInfo
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- CN117017972A CN117017972A CN202311047918.7A CN202311047918A CN117017972A CN 117017972 A CN117017972 A CN 117017972A CN 202311047918 A CN202311047918 A CN 202311047918A CN 117017972 A CN117017972 A CN 117017972A
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Abstract
The invention discloses a use of a compound of formula I or a compound of formula II or pharmaceutically acceptable salt thereof in preparing a medicament, food, beverage or dietary supplement for preventing and/or treating diabetes, obesity and/or complications thereof related to AMPK activation, wherein R 1 Is hydroxy or C 1‑12 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1‑12 Alkoxy, R 4 Is hydrogen. The compound provided by the invention can remarkably activate the in vitro activity of the AMPK and promote glucose uptake, and can be applied to preparation of medicines, foods, beverages or dietary supplements for diabetes mellitus, obesity and/or complications thereof related to the activation of the AMPK.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an activation effect of agilawood components on AMPK.
Background
Agalloch eaglewood is resin-containing wood formed under an injury-inducing defensive reaction by agalloch eaglewood (Aquilaria lam.) or agalloch eaglewood-like plants (Gyrinops gaertn.) of the family daphnaceae. In China, the agilawood medicinal material mainly comes from aquilaria sinensis (Aquilaria sinensis (Lour.) Gilg) which is a clinically common and traditional rare medicinal material, has the effects of promoting qi circulation, relieving pain, warming middle-jiao, relieving vomiting, relieving asthma and the like, and is widely applied to Chinese patent medicines, tibetan medicines and Japanese Han prescription medicines.
AMPK (adenosine monophosphate activated protein kinase, adenosin 5' -monophosphate (AMP) -activated protein kinase) is a serine/threonine kinase that is widely present in eukaryotic cells. AMPK has been found to be an important drug target for treating various diseases, which is a major effector of metformin, a first-line clinical drug for treating diabetes, and is also considered as an important therapeutic target for controlling human diseases such as metabolic syndrome, cancer and the like. AMP-activated protein kinase (AMPK) agonists have long been used as international hot spots for the study of metabolic diseases such as obesity and diabetes.
Specifically, the AMPK signal pathway is an energy sensor and regulator, and plays an important role in promoting ATP production in various tissues and suppressing ATP consumption. The kinase is activated in response to stress that depletes cellular ATP supplies, such as hypoglycemia, hypoxia, ischemia, and heat shock. AMPK acts as a cellular energy sensor capable of efficiently responding to low ATP levels, and activation of AMPK can actively regulate and supplement the signaling pathway of cellular ATP supply. For example, AMPK activation is effective in promoting GLUT4 transcription and translocation, which in turn leads to increased glucose uptake by the body stimulated by insulin.
AMPK is considered as a key therapeutic target for the treatment of obesity, type two diabetes and cancer as a central regulator of lipid and sugar metabolism. AMPK down-regulates several core proteins during ATP consumption, such as CREB transcriptional coactivator (TORC 2) and glycogen synthase, can ultimately lead to gluconeogenesis, down-regulation or inhibition of glycogen, lipid and protein synthesis. AMP-activated protein kinase (AMPK) plays an important role in regulating cellular energy homeostasis. This enzyme is activated under low ATP conditions, typically caused by various stresses, and modulates signal pathways that increase the available ATP supply.
In recent years, there have been many new findings on both AMPK activation and AMPK signal paths. The new findings suggest that AMPK can be activated before ATP levels drop when glucose levels drop, timely supplementing potential ATP deficiency.
There are two main indirect activation modes of AMPK known at present. More importantly, the ratio of AMP/ATP in cells, such as berberine hydrochloride and metformin, is increased by inhibiting respiratory chain to achieve the effect of indirectly activating AMPK, thereby generating curative effect.
AMPK is an important kinase in the process of regulating energy of a body, and maintains energy supply and nutrition supply of the cell by sensing the level of ATP in the body. Under the condition of low energy supply, the AMPK phosphorylates specific enzyme and site, can increase ATP generation and reduce ATP consumption. In mammals, when AMPK is activated, its regulation acts on almost the whole physiological metabolic process of living bodies, and has an indispensable important role in four major physiological metabolic activities of protein metabolism, lipid metabolism, carbohydrate metabolism, autophagy, and mitochondrial homeostasis. Genetic and pharmacological studies have shown that AMPK is essential for the body to maintain glucose balance. The activation of AMPK can actively improve the metabolic imbalance caused by type two diabetes mellitus, however, the molecular mechanism for activating AMPK is very complex, and the activation of AMPK through drug molecules, the finding of AMPK activators which can activate AMPK with high efficiency and low side effect, is a great challenge for treating diabetes mellitus.
Whereas, the megalopseed-2-2 phenethyl chromones (FTPECs) and the 5,6,7, 8-tetrahydroxy-2- (2-phenethyl) chromones (THPECs) in the agilawood have no report on diabetes, obesity and/or complications related to AMPK activation.
Disclosure of Invention
Based on this, the present invention provides the use of a compound of formula I or a compound of formula II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation,
wherein R is 1 Is hydroxy or C 1-12 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-12 Alkoxy, R 4 Is hydrogen.
Further, R 1 Is hydroxy or C 1-8 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-8 Alkoxy, R 4 Is hydrogen;
further, R 1 Is hydroxy or C 1-3 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-3 Alkoxy, R 4 Is hydrogen.
Further, the compound of formula I has a structure selected from the group consisting of:
according to another aspect of the present invention there is provided the use of a composition comprising a compound as described above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation.
Further, the composition further comprises one or more drugs and/or extracts.
Further, the medicament comprises a hypoglycemic agent.
Further, the hypoglycemic agent is selected from one or more of the following: glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, acarbose, voglibose, pioglitazone, sitagliptin, saxagliptin, vildagliptin, metformin, rosiglitazone and insulin.
According to another aspect of the present invention there is provided the use of a formulation comprising a compound as defined above or a pharmaceutically acceptable salt thereof or a composition as defined above in the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation.
Further, the formulation further comprises one or more pharmaceutically acceptable excipients.
Further, the auxiliary material is selected from one or more of the following: dispersing agents, wetting agents, binders, diluents, glidants, lubricants, slow-release agents, plasticizers, disintegrants, inclusion agents, flavoring agents, opacifiers and antioxidants.
Further, the preparation is in the form of tablet, dripping pill, capsule, powder, injection, film, lozenge, granule or oral liquid.
Further, the diabetes includes type I diabetes and/or type II diabetes.
Further, the complications are acute complications and/or chronic complications.
Further, the acute complication is diabetic ketoacidosis, hypertonic non-ketotic diabetic coma and/or lactic acidosis.
Further, the chronic complications are macrovascular complications, microvascular complications, neuropathy and/or diabetic foot.
Further, the macrovascular complications are cardiovascular and cerebrovascular diseases, coronary heart disease, cerebral apoplexy and/or lower limb gangrene.
Further, the microvascular complication is diabetic retinopathy and/or diabetic nephropathy.
Further, the cells associated with diabetes and/or complications thereof associated with AMPK activation are human kidney epithelial cell line cells.
Further, the human kidney epithelial cell line cell is a HEK293T cell.
Further, the compound is obtained from eaglewood or an eaglewood extract.
Further, the AMPK activation is an indirect activation mechanism.
Further, the AMPK contains an α2 subunit, a β1 subunit and a γ1 subunit.
Further, the activation of AMPK occurs in muscle, liver and/or kidney tissues.
The invention has the beneficial effects that:
the compound provided by the invention can remarkably activate the in vitro activity of the AMPK and promote glucose uptake, and can be applied to preparation of medicines, foods, beverages or dietary supplements for diabetes mellitus, obesity and/or complications thereof related to the activation of the AMPK.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, and it will be apparent that the drawings in the following description are only some embodiments of the present invention, and that other drawings can be obtained according to these drawings by those skilled in the art without departing from the scope of the claimed invention.
FIG. 1 is a graph showing the results of in vitro activity of ethanol extract of Aquilaria sinensis for activating AMPK in 293T cells. Where the results are presented as mean ± SD (n=3), p <0.01, p <0.001 compared to solvent control (DMSO).
FIG. 2 is a schematic representation of the results of HEK293T cells treated with varying concentrations of PECs monomer and detecting pAMPK and AMPK levels in cell lysates using SDS-PAGE and Western Blot. P <0.01, p <0.001 compared to solvent control (DMSO).
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains or to which this term applies. Although any methods, conditions, materials, or materials similar or equivalent to those disclosed herein can be used in the practice of the present invention, the preferred methods, conditions, materials, or materials are described herein.
The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the art of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials.
As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
In the present invention, the term "comprising" is synonymous with "including". The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.
As described in the background section, the megalopum-2-2 phenethyl chromone compounds and 5,6,7, 8-tetrahydroxy-2- (2-phenethyl) chromone compounds in agilawood have no reported problems associated with diabetes, obesity and/or complications thereof associated with AMPK activation. In order to solve the above problems, the present invention provides a use of a compound of formula I or a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament, food, beverage or dietary supplement for preventing and/or treating diabetes, obesity and/or complications thereof associated with AMPK activation,
wherein R is 1 Is hydroxy or C 1-12 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-12 Alkoxy, R 4 Is hydrogen.
In a preferred embodiment, R 1 Is hydroxy or C 1-8 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-8 Alkoxy, R 4 Is hydrogen.
In a preferred embodiment, R 1 Is hydroxy or C 1-3 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-3 Alkoxy, R 4 Is hydrogen.
In a preferred embodiment, the compound of formula I has a structure selected from the group consisting of:
the above compounds of the present invention are derived from commercial sources, or from extraction and isolation from plants such as agalloch eaglewood, or from chemical organic synthesis.
According to another aspect of the present invention there is provided the use of a composition comprising a compound as described above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation.
In the present invention, the term "treatment" also includes "prophylaxis" unless there is a specific description of the contrary. The terms "therapeutic" and "therapeutic" should be understood accordingly.
In the present invention, the term "treatment" includes alleviation, inhibition or amelioration of symptoms or conditions of the disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a composition or formulation, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration of the condition. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
In a preferred embodiment, the composition further comprises one or more drugs and/or extracts.
In a preferred embodiment, the medicament comprises a hypoglycemic agent.
In a preferred embodiment, the hypoglycemic agent is selected from one or more of the following: glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, acarbose, voglibose, pioglitazone, sitagliptin, saxagliptin, vildagliptin, metformin, rosiglitazone and insulin.
According to another aspect of the present invention there is provided the use of a formulation comprising a compound as defined above or a pharmaceutically acceptable salt thereof or a composition as defined above in the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation.
In a preferred embodiment, the formulation further comprises one or more pharmaceutically acceptable excipients.
In a preferred embodiment, the formulation of the invention contains 0.00001 to 50wt.%, or 0.0001 to 10wt.%, or 0.0001 to 5wt.%, or 0.005 to 1wt.%, or 0.1 to 20wt.%, or 0.5 to 15wt.%, or 1 to 5wt.% of at least one pharmaceutically acceptable auxiliary material, calculated to the weight of the formulation.
In the present invention, the term "pharmaceutically acceptable" refers herein to a material, such as a carrier or diluent, that does not diminish the biological activity or properties of the compound and is relatively non-toxic, e.g., the administration of a material to an individual does not cause unwanted biological effects or interact in a deleterious manner with any of the components thereof in which it is contained.
In the present invention, the term "pharmaceutically acceptable excipients" refers to carriers and/or excipients that are pharmacologically and/or physiologically compatible with the subject and active ingredient (i.e., capable of eliciting a desired therapeutic effect without eliciting any undesired local or systemic effects), as is well known in the art (see, e.g., remington's Pharmaceutical sciences. Mediated by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995).
In a preferred embodiment, the adjuvant is selected from one or more of the following: dispersing agents, wetting agents, binders, diluents, glidants, lubricants, slow-release agents, plasticizers, disintegrants, inclusion agents, flavoring agents, opacifiers and antioxidants.
The person skilled in the art will know how to select a specific chemical within the above-mentioned auxiliary material category. For example, the dispersant may be selected from one or more of the following: croscarmellose sodium, sodium starch glycolate and pregelatinized corn starch. The wetting agent may be selected from one or more of the following: polyoxymethylene stearate, poloxamer, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polysorbates such as polysorbate 80, cetyl alcohol, glycerin fatty acid esters (such as triacetin, glycerin monostearate and the like), polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, sodium lauryl sulfate, sorbitol fatty acid esters, sucrose fatty acid esters, polyoxyethylene ethers, benzalkonium chloride, polyoxyethylene castor oil, and sodium docusate. The binder may be selected from one or more of the following: polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol and methylcellulose. The diluent may be selected from one or more of the following: sugar powder, starch, compressible starch, lactose, dextrin, mannitol, sorbitol, microcrystalline cellulose, calcium sulfate and calcium carbonate. The glidant is micro powder silica gel. The lubricant may be selected from one or more of the following: calcium stearate, talc, magnesium stearate, stearic acid and colloidal silicon dioxide. The slow release agent can be selected from one or more of the following: sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, hydroxyethyl cellulose, acacia, gelatin, and shellac. The plasticizer may be dibutyl sebacate and/or various citrates. The disintegrant may be selected from one or more of the following: carboxymethyl cellulose, carboxymethyl cellulose calcium salt, and sodium carboxymethyl cellulose. The inclusion agent is hydroxypropyl betacyclodextrin. The flavouring agent may be selected from one or more of the following: sorbitol, glucose, mannose, sucrose and lactose. The opacifier is titanium dioxide. The antioxidant may be selected from one or more of the following: sodium bisulphite, sodium metabisulfite, sodium sulfite and sodium thiosulfate.
The auxiliary materials are preferably inert to drugs or can have synergistic or additive effects to enhance the therapeutic activity of the pharmaceutical composition, and the auxiliary materials are only listed, so that the auxiliary materials actually used in the invention are not limited to the auxiliary materials and can be adjusted according to the actual situation, and the effects of the invention can be achieved.
In a preferred embodiment, the formulation is in the form of a tablet, drop pill, capsule, powder, injection, film, lozenge, granule or oral liquid.
In a preferred embodiment, the diabetes comprises type I diabetes and/or type II diabetes.
In a preferred embodiment, the complication is an acute complication and/or a chronic complication.
In a preferred embodiment, the acute complication is diabetic ketoacidosis, hypertonic non-ketotic diabetic coma and/or lactic acidosis.
In a preferred embodiment, the chronic complication is macrovascular complications, microvascular complications, neuropathy and/or diabetic foot.
In a preferred embodiment, the macrovascular complication is cardiovascular and cerebrovascular disease, coronary heart disease, cerebral apoplexy and/or lower limb gangrene.
In a preferred embodiment, the microvascular complication is diabetic retinopathy and/or diabetic nephropathy.
In a preferred embodiment, the cells associated with diabetes mellitus and/or complications thereof associated with AMPK activation are human kidney epithelial cell line cells.
In a preferred embodiment, the human kidney epithelial cell line cell is a HEK293T cell.
In a preferred embodiment, the compound is obtained from eaglewood or an extract of eaglewood.
In a preferred embodiment, the AMPK activation is an indirect activation mechanism.
In a preferred embodiment, the AMPK comprises an α2 subunit, a β1 subunit and a γ1 subunit.
In a preferred embodiment, the activation of AMPK occurs in muscle, liver and/or kidney tissue.
According to another aspect of the present invention there is provided a compound as defined above, a composition as defined above or a formulation as defined above for use in the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation in a subject.
According to another aspect of the present invention, there is provided a method for preventing and/or treating diabetes, obesity and/or complications thereof associated with AMPK activation, comprising administering to the subject an effective amount of the above compound, the above composition or the above formulation.
In the present invention, the term "subject" is a mammal. The mammal may be a human, non-human primate, mouse, rat, dog, cat, horse or cow, but is not limited to these examples. Mammals other than humans may be advantageously used as subjects representing models of diabetes, obesity and/or complications thereof associated with AMPK activation. Preferably, the subject is a human.
An "effective amount" of a composition or formulation used in the present invention may achieve the desired therapeutic and/or prophylactic effect. The amount effective for this use will depend, for example, on the pharmaceutical composition, the mode of administration, the stage and severity of the disease being treated, the weight and general health of the individual, and the discretion of the prescribing physician. The dose may be administered once a week, or for two days or once a day, or even several times a day. Dosage units may be administered for a short period (e.g., weeks to months) or longer period (months to years).
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are generally according to conventional conditions or conditions suggested by manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this patent specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
Examples
1. Materials and instruments
1.1 materials
Human kidney embryo epithelial cell line HEK293T cells (deposited at the university of Qinghai university, prop. From American type culture Collection, american Type Culture Collection, ATCC) and 3T3-L1 mouse fat precursor cells (from American type culture Collection, american Type Culture Collection, ATCC); anti-AMPK phosphorylation and anti-AMPK total antibodies (Cell signaling, usa); antibodies against beta-actin (Beijing BI Co.); PBS phosphate buffer (Hyclone); south america fetal bovine serum (Gibco); a mixture of green streptomycin and double antibody (Hyclone); trypsin (trypsin); PVDF membrane (Millipore, usa); glucose uptake kit (Promega); DMEM high sugar medium (Gibco); OPTI-MEM medium (Hyclone); mycoplasma inhibitors (scientific); dexamethasone (DEX), dimethyl sulfoxide (DMSO), insulin (Insulin), 1-methyl-3-isobutanol xanthine (IBMX), 5' -ATP disodium salt, 5' -AMP disodium salt, 5' -ADP disodium salt, metformin (Met), berberine hydrochloride (BBR), and Compund C were all derived from Sigma, USA. The agilawood sample is identified by a Zhang Zhijie researcher of Chinese traditional medicine institute of Chinese traditional medicine department and then stored in a crude drug center medicine storage room of the Chinese traditional medicine institute.
Linalool (lot number: 111980-201904, purity. Gtoreq.98%, MW:318.32g/mol, number A130) was purchased from China food and drug inspection institute.
8-chloro-2- (2-phenethyl) -5,6, 7-trihydroxy-5, 6,7, 8-tetrahydrochromone (batch No. AF210328076, purity not less than 98%, MW:336.8g/mol, accession number A124) was purchased from Chengdu Angstrom Biotechnology Co.
6-hydroxy-2- (2-phenethyl) chromone (batch number: AF21042704, purity. Gtoreq.98%, MW:266.29g/mol, number A83) was purchased from Shanghai Shiadad Biotechnology Co.
6-methoxy-2- (2-phenethyl) chromone (batch number: STC6680105, purity. Gtoreq.98%, MW:280.3g/mol, number A84) was purchased from Shanghai Shiadad Biotechnology Co.
6-methoxy-2- [2- (3' -methoxyphenyl) ethyl ] chromone (batch No. STC6690105, purity not less than 98%, MW:310.3g/mol, no. A86) was purchased from Shanghai Shiadad Biotechnology Co.
1.2 instruments
scintz-IID ultrasonic cell disruption apparatus (Ningbo new ganoderma organism company), DYCZ-24DN electrophoresis apparatus (Beijing Liuyi instrumentation), ELITE type II carbon dioxide incubator (Revco company).
2. Experimental method
2.1 pharmaceutical preparation
Accurately weighing 5g of agilawood sample, adding 500ml of 95% ethanol, soaking for half an hour at room temperature, and extracting for 1 hour by micro-boiling reflux. Filtering with 8 layers of gauze and 0.45 μm microporous membrane after cooling, rotary evaporating the filtrate to remove solvent, adding DMSO, dissolving, and making into 250mg/ml lignum Aquilariae Resinatum extractive solution, and refrigerating in refrigerator. When the cells are administrated, the agilawood extract is dissolved in DMSO, and the final concentration of DMSO is 0.1% and is nontoxic to the cells.
10mg of each monomer compound (A130, A84, A124, A83, A86, BBR) was precisely weighed, dissolved in DMSO solution, and the volume was fixed to a 10ml volumetric flask to prepare 1mg/ml test sample.
2.2 culture and pharmaceutical treatment of human Kidney epithelial cell line HEK293T cells
HEK293T cells were cultured in pre-formulated DMEM complete medium containing 10% fetal bovine serum and 1% diabody, CO 2 The temperature in the cell incubator is 37 ℃, the carbon dioxide content is 5 percent, the culture medium is replaced every 24 hours in the cell culture process, and the medicine treatment can be carried out when the cell density reaches about 80 percent. In the treatment of cells, the individual monomer compounds (A130, A84, A124, A83, A86, BBR) were added to a complete medium (DMEM+0.5% free of fatty acid Bovine Serum Albumin (BSA) +1% diabody) prepared in advance and cultured for 1 hour, and the cells were collected.
2.3 SDS-polyacrylamide gel electrophoresis and Western blot detection
After the administration, cells were collected and lysed by adding a cell lysate containing a protease inhibitor and a phosphatase inhibitor at 4℃for 2 hours, and then the cell lysate was centrifuged to obtain a supernatant, and the supernatant was subjected to a treatment with beta-mercaptoethanol for 30 minutes and boiled for 5 minutes to denature proteins. The Cell lysate was subjected to SDS-PAGE gel electrophoresis separation, the separated proteins were transferred onto PVDF membrane by wet transfer method, then blocked with 5% skimmed milk powder TBST solution for 2h at room temperature, then incubated overnight at 4℃with anti-AMPK antibody (Cell Signaling) and anti-p-AMPK antibody (Cell Signaling), then incubated with goat anti-rabbit horseradish peroxidase-labeled secondary antibody (Santa Cruz) for 1h at room temperature, after full washing of the membrane, the luminophore was added, the photographic film was exposed in darkroom, and the image data was photographed and processed.
The total amount of AMPK is used as a reference, the NIH Image J software is used for analyzing and obtaining the gray values of the western blotting strips of pAMPK and AMPK at different concentration points, the ratio pAMPK/AMPK is used for representing the phosphorylation level of AMPK, the GraphPad Prism 6.0 is used for carrying out statistical analysis on pAMPK/AMPK, namely p <0.01 and p <0.001, which indicate that the difference has obvious statistical significance.
2.4 glucose uptake-in vitro analysis
Glucose uptake assay was performed using Promega glucose uptake assay kit, and the glucose uptake capacity of mature 3T3-L1 adipocytes treated with each of the monomer compounds (A130, A84, A124, A83, A86) was measured using the kit. The kit was removed from the-20 ℃ refrigerator and thawed. According to the use instructions of the kit, the neutralizing buffer solution and the stopping buffer solution in the kit are stored at 4 ℃, and the rest components are stored at-20 ℃. The experimental method is as follows:
(1) Cell treatment
3T3-L1 cells were induced to mature adipocytes by day 7. Changing liquid, removing maintenance liquid, adding whole culture medium containing medicine, treating for 24 hr, and treating at 37deg.C with 5% CO 2 Is cultured in a cell culture box.
(2) Desugaring treatment
After 24h treatment of the cells with the respective monomer compounds (A130, A84, A124, A83, A86), the medium was removed, and the cells were starved with sugar-free, serum-free, and anti-bacterial medium containing the respective monomer compounds (A130, A84, A124, A83, A86) for 2-3h at 37℃with 5% CO 2 And (5) culturing the cells in a cell culture box.
(3) Insulin activation
Removing the culture medium in (2), adding PBS solution containing 10 μg/mL insulin, and heating at 37deg.C with 5% CO 2 Is activated for 10min, insulin is removed and washed 2-3 times with PBS.
(4) Preparing 2DG6P detection reaction liquid
The reaction solution was prepared 1h in advance. The preparation was carried out in accordance with the respective set of ratios provided in the kit instructions, in accordance with a volume of 100. Mu.L/sample.
(5) Preparing cell reaction liquid
Insulin treated cells and unactivated cells were carefully washed with PBS. Using 1mM2DG solution at 37℃and 5% CO 2 The cells were incubated in an incubator for 20 minutes and half of the volume of 2DG was addedThe stop buffer stops the glucose uptake reaction of the cells and lyses the cells. After shaking several times and complete lysis of the cells, the same volume of neutralization buffer as the stop buffer is added. All the above-mentioned liquids were collected in a centrifuge tube, centrifuged at 5000g for 5min at room temperature, and the supernatant was collected as a cell reaction solution required for the experiment.
(6) Detection of glucose uptake
100 mu L of cell reaction liquid and 100 mu L of 2DG6P detection reaction liquid are taken and placed into a 96-well plate to be fully mixed, incubated for 1h (room temperature) in a dark place, and the fluorescence intensity of each experimental group is detected on an Enspire multi-mode micro-well plate detector.
2.5 data processing and statistical analysis
Western blot banding analysis statistical analyses including one-way analysis of variance (ANOVA) and mean comparison were performed using NIH Image J Image analysis software using GraphPad Prism 6.0. * P <0.01 and P <0.001 indicate significant statistical differences.
3. Results
3.1 agilawood Activity verification
To examine whether the eaglewood extract was able to activate AMPK, we treated HEK293T cells with different concentrations of eaglewood alcohol extract for 1 hour, and then examined pAMPK (Thr-172) and AMPK levels in cell lysates using SDS-PAGE and Western Blot. As shown in FIG. 1, pAMPK levels in cells were dose-dependently elevated after treatment with linalool extract. Western Blot analysis results showed that linalool extracts were both able to activate AMPK in HEK293T cells in vitro, both with AMPK activating activity and in an active-dose dependent manner. AMPK activating ability of ethanol extract of agilawood at a concentration of 120 μg/ml was similar to that of metformin, a positive drug.
3.2 verification and comparison of the Activity of the monomer components of FTPECs and THPECs
The experiment further compares the activity difference of the agalloch eaglewood FTPECs component and the THPECs component obtained by component analysis and screening, selects 4 FTPECs monomer components and 2 THPECs to carry out in vitro activity verification of AMPK agonistic activity, respectively processes cells with the selected FTPECs monomer components according to the '2.2 and 2.3' under-item methods, detects pAMPK (Thr-172) and AMPK levels in cell lysate by SDS-PAGE and Western Blot (Western Blot), and as shown in figure 2, compounds A84, A124, A83 and A86 all show dose-dependent relationship, and the higher the administration concentration is, the higher the phosphorylation level of threonine at position AMPK172 is, which indicates that the compounds have obvious AMPK activating capacity, and compound A130 does not show AMPK activating capacity.
3.3 glucose uptake-in vitro analysis
The compounds A84, A124, A83 and A86 of the invention can promote glucose uptake of 3T3-L1 fat cells at the concentration of 1-600 mM, and the glucose uptake (%) is more than 100% and less than 350% relative to a DMSO control group.
The foregoing has outlined rather broadly the more detailed description of embodiments of the invention in order that the detailed description of the principles and embodiments of the invention may be implemented in conjunction with the detailed description of embodiments of the invention that follows. Meanwhile, based on the idea of the present invention, those skilled in the art can make changes or modifications on the specific embodiments and application scope of the present invention, which belong to the protection scope of the present invention. In view of the foregoing, this description should not be construed as limiting the invention.
Claims (10)
1. The use of a compound of formula I or a compound of formula II or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation,
wherein R is 1 Is hydroxy or C 1-12 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-12 Alkoxy, R 4 Is hydrogen.
2. According to claim 1Is characterized in that R 1 Is hydroxy or C 1-8 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-8 Alkoxy, R 4 Is hydrogen;
preferably, R 1 Is hydroxy or C 1-3 Alkoxy, R 2 Is hydrogen, R 3 Is hydrogen or C 1-3 Alkoxy, R 4 Is hydrogen.
3. The use according to claim 1, wherein the compound of formula I has a structure selected from the group consisting of:
4. use of a composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation;
preferably, the composition further comprises one or more drugs and/or extracts;
more preferably, the medicament comprises a hypoglycemic agent;
still preferably, the hypoglycemic agent is selected from one or more of the following: glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, acarbose, voglibose, pioglitazone, sitagliptin, saxagliptin, vildagliptin, metformin, rosiglitazone and insulin.
5. Use of a formulation comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a composition according to claim 4 for the manufacture of a medicament, food, beverage or dietary supplement for the prevention and/or treatment of diabetes, obesity and/or complications thereof associated with AMPK activation;
preferably, the formulation further comprises one or more pharmaceutically acceptable excipients;
more preferably, the auxiliary material is selected from one or more of the following: dispersing agents, wetting agents, binders, diluents, glidants, lubricants, slow-release agents, plasticizers, disintegrants, inclusion agents, flavoring agents, opacifiers and antioxidants;
still preferably, the formulation is in the form of tablet, dripping pill, capsule, powder, injection, film, lozenge, granule or oral liquid.
6. The use according to any one of claims 1 to 5, wherein the diabetes comprises type I diabetes and/or type II diabetes;
preferably, the complications are acute complications and/or chronic complications;
more preferably, the acute complication is diabetic ketoacidosis, hypertonic non-ketotic diabetic coma and/or lactic acidosis;
still more preferably, the chronic complications are macrovascular complications, microvascular complications, neuropathy and/or diabetic foot;
particularly preferably, the macrovascular complication is cardiovascular and cerebrovascular diseases, coronary heart disease, cerebral apoplexy and/or lower limb gangrene;
particularly preferably, the microvascular complication is diabetic retinopathy and/or diabetic nephropathy.
7. The use according to any one of claims 1 to 5, wherein the cells associated with diabetes and/or complications thereof associated with AMPK activation are human kidney epithelial cell line cells, such as HEK293T cells.
8. Use according to any one of claims 1 to 5, wherein the compound is obtained from agilawood or an agilawood extract.
9. The use according to any one of claims 1 to 5, wherein the AMPK activation is an indirect activation mechanism;
preferably, the AMPK comprises an α2 subunit, a β1 subunit and a γ1 subunit.
10. The use according to any one of claims 1 to 5, wherein the activation of AMPK occurs in muscle, liver and/or kidney tissue.
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| CN202311047909.8A Pending CN117323323A (en) | 2022-08-21 | 2023-08-18 | Activation of AMPK by Phoebe cheilis component |
| CN202311047370.6A Pending CN117137981A (en) | 2022-08-21 | 2023-08-18 | Activation of AMPK by agilawood extract |
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