WO2021182896A1 - Composition de différenciation de graisse brune induite comprenant un dérivé d'isoliquiritigénine - Google Patents
Composition de différenciation de graisse brune induite comprenant un dérivé d'isoliquiritigénine Download PDFInfo
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- WO2021182896A1 WO2021182896A1 PCT/KR2021/003043 KR2021003043W WO2021182896A1 WO 2021182896 A1 WO2021182896 A1 WO 2021182896A1 KR 2021003043 W KR2021003043 W KR 2021003043W WO 2021182896 A1 WO2021182896 A1 WO 2021182896A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/29—Saturated compounds containing keto groups bound to rings
- C07C49/303—Saturated compounds containing keto groups bound to rings to a six-membered ring
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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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
- A61K31/335—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
Definitions
- the present invention relates to a novel isoliquiritgenin derivative, a method for preparing the same, a brown fat-derivatized differentiation composition comprising the isoricuritigenin derivative, and a composition for preventing or treating heart disease.
- Non-Patent Documents 1 to 4 Studies on the pathogenesis and causes of metabolic diseases such as obesity, diabetes, and hyperlipidemia are gradually increasing in proportion to the incidence rate. It is a disease caused by various and complex actions such as genetic, environmental, and psychological factors. For this reason, it is judged that a new strategy for the treatment of obesity is necessary, and research on brown fat control as a new treatment technique has been very actively conducted (Non-Patent Documents 1 to 4).
- Non-Patent Document 8 published by the Salk Research Institute in the United States in 2015, it was reported that fexaramine, a new drug developed by the group, has developed a new drug that causes fat to be burned by making the person mistakenly eat food. From all over the world, from natural products to various low-molecular compounds, we are immersed in the search for and development of drugs for inducing brown fat.
- Non-Patent Document 9 discloses a method for treating heart disease.
- various adipose tissues and characteristics distributed in the heart have been reported, and studies on various brown fat inducing factors are in progress, but they are in an early stage and the mechanisms of heart disease and brown fat are still unknown.
- Non-Patent Document 1 NFIA co-localizes with PPAR ⁇ and transcriptionally controls the brown fat gene program, Nat Cell Biol. 2017 Sep;19(9):1081-1092. doi: 10.1038/ncb3590
- Non-Patent Document 2 BMP4 Gene Therapy in Mature Mice Reduces BAT Activation but Protects from Obesity by Browning Subcutaneous Adipose Tissue, Cell Rep. 2017 Aug 1:20(5):1038-1049.
- Non-Patent Document 3 Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat, Cell Rep. 2017 Jul 18;20(3):641-654
- Non-Patent Document 4 Integrative analyzes of translatome and transcriptome reveal important translational controls in brown and white adipose regulated by microRNAs, Sci Rep. 2017, 7, 5681
- Non-Patent Document 5 Adult Epicardial Fat Exhibits Beige Features, J Clin Endocrinol Metab. 2013, 98, E1448-E1455
- Non-Patent Document 6 Gene pathway development in human epicardial adipose tissue during early life, JCI insight. 2016, 1(13), e87460
- Non-Patent Document 7 'Browning' the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk
- Non-Patent Document 8 Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance, Nature Medicine. 2015, 21, 159-165
- Non-Patent Document 9 Dietary Isoliquiritigenin at a Low Dose Ameliorates Insulin Resistance and NAFLD in Diet-Induced Obesity in C57BL/6J Mice, Int. J. Mol. Sci. 2018, 19(10), 3281; doi:10.3390/ijms19103281
- the present inventors have completed the present invention by confirming the brown fat-inducing effect of the isoriquiritijenin derivative and then revealing the protective effect of the brown adipocyte secretory induced in this way and the therapeutic efficacy and mechanism for cardiomyocytes.
- An object of the present invention is to provide a novel isolicuritigenin derivative, a method for preparing the same, a composition for inducing brown fat containing the isoliquiritigenin derivative, a pharmaceutical composition for preventing or treating heart disease, and a food composition for preventing or improving heart disease including the same and a method for inducing brown fat.
- the isoliquiritijenin derivatives according to the present invention may be used alone or in combination, and induce brown localization differentiation without significant cytotoxicity, and the induced brown adipocytes have an effect of reducing myocardial damage, thus preventing or treating heart disease. can be usefully used as
- Figure 2 shows the differentiation of human stem cells (human Adipocyte-derived stem cells) into adipocytes and treatment with ILG to induce brown fat, followed by fat staining with Oil Red O staining (A) and expression of UCP1, a brown fat marker (B). ), the degree of differentiation of brown adipocytes was confirmed by confirming the change.
- human stem cells human Adipocyte-derived stem cells
- ILG Oil Red O staining
- UCP1 a brown fat marker
- FIG. 6 shows the changes in brown fat marker proteins after treatment with selected ILG derivatives #1, #2, #10, and #13 by Western blot analysis.
- FIGS. 8 and 9 show a comparative analysis of factors secreted between cells by using a human adipokine array kit for secretions secreted from human stem cells, white adipocytes, and brown adipocytes.
- ASCs stem cell
- WAC white adipocyte
- BAC brown adipocyte
- FIG. 11 is a result showing the cardiac function improvement/recovery effect of the ASCs secretory, WAC secretory, BAC secretory treated group and the control group in an animal model of cardiovascular disease (IR) damaged by myocardial infarction (MI).
- IR cardiovascular disease
- MI myocardial infarction
- the present invention provides a compound represented by the following formula (13) or a pharmaceutically acceptable salt thereof.
- the term "pharmaceutically acceptable salt thereof” may be prepared by a conventional method in the art, for example, hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid
- Drugs with salts with inorganic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin)
- forms pharmaceutically acceptable salts of these acids or reacts with alkali metal ions such as sodium or potassium to form metal salts thereof, or reacts with ammonium ions to form another pharmaceutically acceptable salt thereof means to form
- the present invention relates to a compound represented by the following formula (1), a compound represented by the following formula (2), a compound represented by the following formula (10), a compound represented by the following formula (13), a pharmaceutically acceptable salt thereof, or a mixture thereof.
- a composition for inducing brown fat comprising a compound or mixture selected from the group consisting of as an active ingredient.
- the compound represented by Formula 1 is named as ( E )-1-(2,4-Dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, and represented by Formula 2 the compound is named as 7-Hydroxy-2- (4- hydroxyphenyl) -4 H -chromen-4-one.
- the compound represented by Formula 10 is named as ( E )-1-(2,4-Dihydroxyphenyl)-3-(3,4,5-trihydroxyphenyl)prop-2-en-1-one.
- the compound represented by Formula 13 is named (E)-1-(2,4-difluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, It is a synthetic substance.
- the term “differentiation” refers to the generation of relatively unspecified cells (eg, undifferentiated cells, eg, multilineage-inducing cells) with specific structural and/or functional characteristics characteristic of mature cells. It is the process of acquiring a characteristic. Typically, during differentiation, cellular structure is altered and tissue-specific proteins are revealed. "Adipogenic differentiation” is the process by which undifferentiated cells acquire one or more properties (eg, morphological, biochemical or functional properties) characteristic of an adipocyte, eg, a brown adipocyte. Those skilled in the art will appreciate that "brown adipocyte-like cells” include brown adipocytes derived from MSCs, adipocyte progenitor cells, preadipocytes, and arterial-derived cells.
- composition of the present invention is characterized in that it increases the activity of brown adipocytes or increases the expression of UCP-1 or PRDM16.
- Brown adipose tissue refers to a function of maintaining body temperature by generating heat in a hypothermia situation. can be further reduced.
- Brown adipocytes have a relatively large number of mitochondria compared to white adipocytes, and have a brown color due to the cytochrome pigment present in the mitochondria.
- UCP1 uncoupling protein 1 protein exists in the inner mitochondrial membrane of brown adipocytes, and UCP1 uncouples the H + electrochemical concentration gradient formed during oxidative phosphorylation of mitochondria and the ATP synthesis process by ATP polymerase. Releases chemical energy in the form of heat.
- brown adipocyteization refers to the process of metastasis or differentiation of fat-storing white fat into fat-burning brown fat and including cells having characteristics of the obtained brown fat.
- Transition is a phenomenon in which a substance changes from one state to another, and includes white adipocytes acquiring the characteristics of brown adipocytes and becoming brown adipocytes.
- differentiation inducing composition refers to a composition capable of inducing a process in which cells in the initial stage have characteristics as individual tissues, and for the purpose of the present invention, white adipocytes are differentiated into brown adipocytes. inducible composition.
- the composition for inducing differentiation into brown adipocytes of the present invention relates to a compound represented by Formula 1 below, a compound represented by Formula 2 below, a compound represented by Formula 10 below, a compound represented by Formula 13 below, and pharmaceutically
- the compound or mixture selected from the group consisting of acceptable salts or mixtures thereof may be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition, but is not limited thereto.
- derivatives of isoliquiritigenin are prepared, and four derivatives of isoliquiritigenin (ILG) are selected by brown fat markers UCP1, PPAR ⁇ , and PGC1A, It was confirmed that the expression of UCP-1 and PRDM16, which are markers of brown adipocytes, increased by the treatment of these fluids (see Example 1). In particular, a remarkable effect on the expression of UCP-1 and PRDM16 by the compound represented by Formula 13 (hereinafter referred to as compound 13) among other ILG derivatives was confirmed (see Example 2), and in an animal model of ischemic heart disease It was confirmed that it exhibited excellent cardioprotective action against ischemia/reperfusion (see Example 4).
- composition of the present invention may include a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier may include, but is not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate.
- it may further include a conventionally known medium for culturing stem cells, a differentiation inducing agent, and the like.
- composition of the present invention may be prepared as an aqueous solution for parenteral administration, and preferably a buffer solution such as Hank's solution, Ringer's solution or physically buffered saline may be used. .
- Aqueous injection suspensions may contain a substrate capable of increasing the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or detrans.
- composition of the present invention may be in the form of a sterile injectable preparation of a sterile injectable aqueous or oleaginous suspension.
- the suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg Tween 80) and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension (eg, a solution in 1,3-butanediol) in a non-toxic parenterally acceptable diluent or solvent.
- Vehicles and solvents that can be used in the present invention include mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, non-volatile oils are conventionally employed as the solvent or suspending medium. Any non-volatile, non-irritating oil may be used for this purpose, including synthetic mono or diglycerides.
- the present invention provides a pharmaceutical composition for preventing or treating heart disease, comprising the composition for inducing brown fat.
- Heart disease which is a disease to be prevented or treated by the pharmaceutical composition of the present invention, refers to a disease in which adequate blood supply to the heart is not provided due to coronary blood flow disorder, preferably ischemic heart disease such as angina pectoris, myocardial infarction or heart failure.
- ischemic heart disease such as angina pectoris, myocardial infarction or heart failure.
- the pharmaceutical composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceuticals.
- Carriers, excipients and diluents that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- the pharmaceutical composition of the present invention When formulating the pharmaceutical composition of the present invention, it is prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant usually used.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition of the present invention, for example, starch, calcium carbonate, sucrose (sucrose) or lactose (lactose), gelatin, etc. are mixed and prepared.
- lubricants such as magnesium stearate and talc are also used.
- Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
- various excipients for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
- Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- the pharmaceutical composition of the present invention may be administered orally or parenterally, preferably oral administration.
- the preferred dosage of the composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. Administration may be administered once a day or may be administered in several divided doses, and the dosage is not intended to limit the scope of the present invention in any way.
- the present invention provides a food composition for preventing or improving heart disease comprising the composition for inducing brown fat.
- the food composition uses the same ingredients as the pharmaceutical composition for preventing or treating heart disease, overlapping content between the two is omitted to avoid excessive description of the specification.
- the food composition may be provided in the form of powder, granule, tablet, capsule, syrup, beverage or pill, and is used with other foods or food additives in addition to the compound represented by Formula 1 or Formula 2 as an active ingredient, It can be used suitably according to a conventional method.
- the mixing amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.
- the effective dose of the active ingredient contained in the food composition may be used in accordance with the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene or health control, it may be less than the above range, It is certain that the active ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.
- the food composition includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
- examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- flavoring agents natural flavoring agents and synthetic flavoring agents can be used.
- citric acid, high fructose, sugar, glucose, acetic acid, malic acid, fruit juice, etc. may be additionally included in addition to the active ingredient of the present invention.
- the present invention also provides a method for inducing differentiation from white adipocytes into brown adipocytes, comprising the step of treating the white adipocytes with the composition for inducing differentiation of brown adipocytes.
- the present invention relates to a compound represented by the following formula (1), a compound represented by the following formula (2), a compound represented by the following formula (10), a compound represented by the following formula (13), a pharmaceutically acceptable salt thereof, or a mixture thereof.
- a method for inducing brown localization differentiation in stem cells comprising culturing the stem cells in a medium containing a compound or mixture selected from the group consisting of:
- the stem cells are subject to those isolated by a natural or artificial method from an individual.
- the cells isolated from the subject may be cultured for several days to several weeks under appropriate culture conditions, and in some cases may be stored frozen.
- derivative 1 (2E)-1-(2,4-Dihydroxyphenyl)-3-(4-fluorophenyl)-2-propen-1-one (hereinafter, referred to as derivative 1) and robtein 2 among ILG derivatives
- derivative 2 The effects of ',3,4,4',5-pentahydroxychalcone (hereinafter referred to as derivative 2) were confirmed in Examples 1 to 5 below.
- Brown adipocyte-induced differentiation of white adipocytes was performed using adipose-derived stem cells (ASCs) purchased from the American Cell Line Bank (ATCC). ⁇ 10 4 cells/cm 2 , 60mm dish: 2 ⁇ 10 5 cells/cm 2 , 100mm dish: 1 ⁇ 10 6 cells/cm 2 ) 12 Insulin (Sigma, I9278; 5 ug/ml), 3,3',5-Triiodo-L-thyronine (T3, Sigma, T2877; 1 nM), Indomethasone (Sigma, I7378; 125 uM), Dexamethasone (Sigma) in 12 medium , D1756; 2 ug/ml), 3-Isobutyl-1-methylxanthine (IBMX, Sigma, I5879; 0.5 mM) and Rosiglitazone (Sigma, R2408; 0.5 uM) were added and cultured for 4 days.
- ASCs adipose
- Oil Red O staining was performed to visually confirm the amount of fat accumulation in differentiated adipocytes. After removing the medium and washing twice with 1 x PBS, the cells were fixed with 4% formalin at room temperature for 1 hour. Formalin was removed, washed with tertiary distilled water, and stained with Oil red O solution (0.5 g oil red O/100 mL propylene glycol, Sigma) for 20 minutes. After washing with tertiary distilled water, intracellular fat was observed using an optical microscope. A round bubble-shaped fat mass was observed in all visually differentiated experimental groups except for the undifferentiated control group, confirming that the adipocytes were differentiated (FIG. 2).
- Propylen Gycol (Duksan, Ansan, Korea) was added to the stained cells to elute and recover the pigment, and then absorbance was measured at 450 nm with a microplate reader (Molecular Devices, USA).
- RNA was isolated with TRIzol Reagent solution (Live Technologies, Frderick, Maryland, USA), and Oligo dT-primed cDNA was prepared using Maxime RT PreMix kit (iNtRON Biotechnology, Seongnam, Korea) was used for synthesis.
- Maxime RT PreMix kit iNtRON Biotechnology, Seongnam, Korea
- the expression of each gene was investigated with the SYBR Green Dye system (SYBR Premix Ex Taq (Tli RNase Plus) and ROX reference dye (Takara Bio Inc. Foster City, CA, USA). The amount of each transcript was corrected to the level of the GAPDH transcript.
- the primers used for PCR are shown in Table 1 below.
- PCR conditions are as follows.
- ILG derivatives synthesized by the present inventor (FIG. 1) and purchased ILG (Tokyo Chemical Industry Co., Ltd. product number: I0822) [Formula 14] were used in ASCs at three different concentrations (0.025, 0.05 and 0.1 uM) for 24 hours, respectively, and the expression level of brown fat differentiation-specific markers (UCP1, PPARG, PPARGC(PGC1A)) was investigated using qRT-PCR ( FIGS. 3 to 5 ).
- the protein expression change of brown fat markers (UCP1, PRDM16, PPARG) according to the treatment of ILG derivatives #1, #2, #10, and #13, which had excellent increase in UCP1 expression was further verified by Western blot analysis (Fig. 6). ).
- ILG and ILG derivatives #1 and #13 were each added to each concentration (0, 0.25, 0.5, 1uM), and after 48 hours, 10 ul of EZ-Cytox per well was added, and after reaction for 1 to 4 hours, cell viability was measured at absorbance at 450 nm.
- Adipose-derived stem cells purchased from the American Cell Line Bank (ATCC) were used for the production of stem cell secretions, and the number of cells was measured in a plate (6 well plate: 1 ⁇ 10 4 cells/cm 2 , 60mm dish: 2 ⁇ 10 5 cells/cm 2 , 100mm dish: 1 ⁇ 10 6 cells/cm 2 ) and add 10% serum to DMEM/F-12 (serum free DMEM/F-12) medium 100,0000 uinit/L penicillin was added and cultured. After removing the culture medium and washing the stem cells with 1X PBS, the secretory stem cells were exchanged with a serum-free DMEM/F-12 (serum free DMEM/F-12) medium and cultured at 37° C. for 2 hours. After 2 hours, the cell culture medium (conditioned medium) was collected and concentrated about 50 times using an ultrafree 15 centrifuge filter unit (Millipore, Braford, MA, USA).
- Differentiation of white adipose tissue is a fat-derived purchased from bank (ATCC) American cell lines Stem Cells: The number of cells to differentiate was conducted using the (adipose-derived stem cells ASCs) are plate (6 well plate: 1 ⁇ 10 4 cells /cm 2 , 60mm dish: 2 ⁇ 10 5 cells/cm 2 , 100mm dish: 1 ⁇ 10 6 cells/cm 2 ) (Sigma, I9278; 5 ug/ml), 3,3',5-Triiodo-L-thyronine (T3, Sigma, T2877; 1 nM), Indomethasone (Sigma, I7378; 125 uM), Dexamethasone (Sigma, D1756; 2 ug/ml), 3-Isobutyl-1-methylxanthine (IBMX, Sigma, I5879; 0.5 mM) and Rosiglitazone (Sigma, R2408; 0.5 uM) were added and cultured for 4
- the culture medium was removed and the white adipocytes were washed with 1X PBS, and then exchanged with a serum-free DMEM/F-12 (serum free DMEM/F-12) medium. and incubated at 37°C for 2 hours. After 2 hours, the cell culture medium (conditioned medium) was collected and concentrated about 50 times using an ultrafree 15 centrifuge filter unit (Millipore, Braford, MA, USA).
- Example 1 using the brown adipocytes differentiated by the ILG derivative 13, a secretory body of brown adipocytes was prepared as follows.
- Brown adipocyte differentiation is a fat-derived stem cells purchased from banks (ATCC) US cell: cells to differentiate was conducted using (adipose-derived stem cells ASCs) is plate (6 well plate: 1 ⁇ 10 4 cells / cm 2 , 60mm dish: 2 ⁇ 10 5 cells/cm 2 , 100mm dish: 1 ⁇ 10 6 cells/cm 2 ) Sigma, I9278; 5 ug/ml), 3,3',5-Triiodo-L-thyronine (T3, Sigma, T2877; 1 nM), Indomethasone (Sigma, I7378; 125 uM), Dexamethasone (Sigma, D1756; 2 ug) /ml), 3-Isobutyl-1-methylxanthine (IBMX, Sigma, I5879; 0.5 mM) and Rosiglitazone (Sigma, R2408; 0.5 uM) were added and cultured for 4 days.
- ASCs adipose-
- the medium contained insulin (Sigma, I9278; 5 ug/ml), 3,3',5-Triiodo-L-thyronine (T3, Sigma, T2877; 1 nM) in MEM/F-12 medium; Then, Rosiglitazone (Sigma, R2408; 1 uM) was added and the maturation medium was exchanged 3 times by replacing it once every 2 days.
- the secreted body of the differentiated brown adipocytes was removed from the culture medium, washed with 1X PBS, and then exchanged with serum-free DMEM/F-12 (serum free DMEM/F-12) medium. Incubated at °C for 2 hours. After 2 hours, the cell culture medium (conditioned medium) was collected and concentrated about 50 times using an ultrafree 15 centrifuge filter unit (Millipore, Braford, MA, USA).
- adipocyte secretion factors related to 58 diseases were analyzed, and secretion factors with high or low expression specifically in white fat or brown fat compared to stem cells were analyzed (FIG. 8).
- the changed proteins are indicated by a red box (FIG. 9).
- Example 4 ILG derivative-induced differentiation-induced brown adipocyte secretory effect on heart disease treatment
- the end of the conduit passed through the aortic valve and was fixed between the time point when the left ventricular pressure wave appeared and the point when the spike wave which appeared when the conduit stimulated the left ventricle wall disappeared.
- EF left ventricular ejection fraction
- Ves end-systolic volume
- V@dP/dt min systolic Minimum left ventricular pressure instantaneous rate of change
- EF left ventricular ejection fraction
- End-systolic Volume end-systolic volume
- left ventricular systolic function indicators. Ves
- V@dP/dt min systolic minimum left ventricular volume instantaneous rate of change
- Vmin Minimum Volume, Vmin
- heart rate per minute were measured.
- the left ventricular ejection fraction (EF) was significantly decreased in the group injected with the IR group, stem cell secretory, and white adipocyte secretion compared to the Sham group, but different in the group injected with the brown adipocyte secretion body. decreased less than in the group.
- the instantaneous rate of change in the systolic minimum left ventricular volume (V@dP/dt min), the IR group, the stem cell secretory body, and the white adipocytes in the minimum systolic volume (Vmin) It increased in the group to which the non-body was injected, but did not increase in the group to which the brown adipocyte secretory body was injected (FIG. 10).
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Food Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention concerne des dérivés d'isoliquiritigénine et une utilisation de ces derniers. Les dérivés d'isoliquiritigénine induisent une différenciation de graisse brune et ne présentent pas de cytotoxicité significative. Une composition, qui est destinée à induire des cellules adipeuses brunes et comprend les dérivés d'isoliquiritigénine, a pour effet de réduire les lésions myocardiques et peut donc être utilisée efficacement pour prévenir ou traiter une maladie cardiaque.
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KR1020200030293A KR102414532B1 (ko) | 2020-03-11 | 2020-03-11 | 이소리퀴리티제닌 유도체를 포함하는 갈색 지방 유도화 분화 조성물 |
KR10-2020-0030293 | 2020-03-11 |
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WO2021182896A1 true WO2021182896A1 (fr) | 2021-09-16 |
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PCT/KR2021/003043 WO2021182896A1 (fr) | 2020-03-11 | 2021-03-11 | Composition de différenciation de graisse brune induite comprenant un dérivé d'isoliquiritigénine |
Country Status (2)
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KR (1) | KR102414532B1 (fr) |
WO (1) | WO2021182896A1 (fr) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070092551A1 (en) * | 2003-05-02 | 2007-04-26 | Takara Bio Inc. | Therapeutic agent |
WO2013149258A2 (fr) * | 2012-03-30 | 2013-10-03 | Charles Drew University of Medicine and Science | Compositions et procédés de traitement ou de prévention de troubles du syndrome métabolique |
KR20160000840A (ko) * | 2014-06-25 | 2016-01-05 | 성균관대학교산학협력단 | 베이지 및 갈색 지방세포 분화 유도용 조성물 및 이의 방법 |
-
2020
- 2020-03-11 KR KR1020200030293A patent/KR102414532B1/ko active IP Right Grant
-
2021
- 2021-03-11 WO PCT/KR2021/003043 patent/WO2021182896A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070092551A1 (en) * | 2003-05-02 | 2007-04-26 | Takara Bio Inc. | Therapeutic agent |
WO2013149258A2 (fr) * | 2012-03-30 | 2013-10-03 | Charles Drew University of Medicine and Science | Compositions et procédés de traitement ou de prévention de troubles du syndrome métabolique |
KR20160000840A (ko) * | 2014-06-25 | 2016-01-05 | 성균관대학교산학협력단 | 베이지 및 갈색 지방세포 분화 유도용 조성물 및 이의 방법 |
Non-Patent Citations (1)
Title |
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REN BING-ZHAO; ABLISE MOURBOUL; YANG XU-CHAO; LIAO BO-ER; YANG ZHENG: "Synthesis and biological evaluation of α-methyl-chalcone for anti-cervical cancer activity", MEDICINAL CHEMISTRY RESEARCH, vol. 26, no. 9, 22 April 2017 (2017-04-22), US, pages 1871 - 1883, XP036287793, ISSN: 1054-2523, DOI: 10.1007/s00044-017-1891-0 * |
Also Published As
Publication number | Publication date |
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KR20210115115A (ko) | 2021-09-27 |
KR102414532B1 (ko) | 2022-06-30 |
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