KR101793138B1 - Pharmaceutical composition for preventing or treating muscle weakness diseases comprising Aleuritic Acid or pharmaceutical acceptable salts thereof - Google Patents
Pharmaceutical composition for preventing or treating muscle weakness diseases comprising Aleuritic Acid or pharmaceutical acceptable salts thereof Download PDFInfo
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- KR101793138B1 KR101793138B1 KR1020160014949A KR20160014949A KR101793138B1 KR 101793138 B1 KR101793138 B1 KR 101793138B1 KR 1020160014949 A KR1020160014949 A KR 1020160014949A KR 20160014949 A KR20160014949 A KR 20160014949A KR 101793138 B1 KR101793138 B1 KR 101793138B1
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- acid
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- pharmaceutically acceptable
- acceptable salt
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
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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
- 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
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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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
- A23V2200/316—Foods, ingredients or supplements having a functional effect on health having an effect on regeneration or building of ligaments or muscles
Abstract
The present invention relates to a composition for promoting the differentiation of myoblasts comprising aloylic acid or a pharmaceutically acceptable salt thereof, a method for promoting differentiation of myoblast cells using the above-mentioned alloylic acid, a method for producing differentiated myoblasts, And a food composition for preventing or ameliorating muscular weakness related to muscle weakness. Alloy acid according to the present invention promotes differentiation of myoblasts to form a root canal, thereby preventing muscle weakness and effectively improving muscle function. Accordingly, the pharmaceutical composition containing the same can be usefully used for the prevention or treatment of muscular weakening-related diseases.
Description
The present invention relates to a composition for promoting the differentiation of myoblasts comprising aloylic acid or a pharmaceutically acceptable salt thereof, a method for promoting differentiation of myoblast cells using the above-mentioned alloylic acid, a method for producing differentiated myoblasts, And a food composition for preventing or ameliorating muscular weakness related to muscle weakness.
Diseases that cause weakness of muscle strength include sarcopenia with aging, muscle atrophy caused by imbalance of protein metabolism or muscle use, starvation, wasting disease (such as cancer), aging Cardiotrophy and the like.
Sarcopenia refers to a decrease in muscle strength with a decrease in skeletal muscle mass during aging. In addition to the decrease in muscle mass, which is the most important feature of myopenia, changes in the type of muscle fiber are also observed.
Although myopenia is caused by various factors, research on each factor is still insignificant. The balance of growth hormone reduction or neurological change, changes in physical activity, changes in metabolism, sex hormone levels or fat or catabolic cytokines, and the synthesis and differentiation of proteins (Roubenoff R. and Hughes VA, J. Gerontol . A. Biol . Sci . Med. Sci . 55, M716-M724, 2000). One of the most important features of myopenia is the decrease in satellite cell activation. Satellite cells are small mononuclear cells located between the basement membrane and the sarcolemma of the myofiber. They are activated by stimulation, such as injury or exercise, and proliferate into myoblasts. When differentiation proceeds, they fuse with other cells to form multinuclear muscle fibers. Thus, as the activity of satellite cells decreases, the ability to regenerate damaged muscle or response to differentiation signals is reduced, resulting in decreased muscle formation.
Muscle atrophy is caused by lack of nutrient deficiency or long-term muscle, which is caused by the breakdown of the normal balance of protein synthesis and degradation.
On the other hand, cardiotrophy is caused when starvation, consuming disease (cancer, etc.), and senescence occurs. Myocardial fibers are thin and thin, and the nucleus is concentrated and floating. Therefore, the muscle fascicle is also reduced in volume and the entire heart is smaller, the adipocyte adipose tissue is markedly decreased, and the coronary arteries are curved. A consumable pigment (lipofuscin) appears as a brown pigment on both sides of the core of the myocardial fiber and the whole heart is brownish with decreasing adipose tissue.
There are three main treatment methods for myopenia. The first is exercise. Exercise has been reported to increase skeletal muscle protein synthesis in the short term and to increase muscular strength and motility of the elderly. However, it is inappropriate for long-term treatment (Timothy J. Doherty, J. Appl . Physiol . 95, 1717-1727, 2003). The second is the use of testosterone or anabolic steroid as a medication, but it induces menstruation in women and side effects such as prostate symptoms in men. Other approved therapies include DHEA (dehydroepiandrosterone) and growth hormone, which have been reported to be therapeutically feasible at sites that include SARMs (DD Thompson, J. Musculoskelet Neuronal Interact 7, 344-345 , 2007). Diet therapy is also known as a treatment, but nutritional assessment shows malnutrition and modern eating habits are inadequate to maintain a reasonable total body mass.
Recently, stem cell therapy (stem cell therapy) which separates satellite cells and introduces them into the body after in vitro differentiation and activates satellite cells directly in the body and promotes myogenesis, (Shihuan Kuang and Michael A. Rudnicki, Trends in Molecular Medicine 14, 82-31, 2008).
Therefore, in order to treat muscular weakness related to muscular weakness, it is necessary to develop a material that can promote the differentiation of myoblast cells.
Under these circumstances, the present inventors have made intensive efforts to develop a therapeutic agent for muscular weakness related to muscles that increases muscle mass by promoting differentiation of myoblasts and effectively restores muscle function, and as a result, And thus can be used for the prevention or treatment of diseases associated with weakness in muscle strength, thereby completing the present invention.
It is an object of the present invention to provide a composition for promoting the differentiation of myoblasts.
Another object of the present invention is to provide a method of promoting differentiation of myoblast cells.
It is yet another object of the present invention to provide a method for producing differentiated myocytes.
It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating muscle weakness-related diseases.
It is still another object of the present invention to provide a method for preventing or treating muscular weakness related to muscular weakness.
It is still another object of the present invention to provide a food composition for preventing or ameliorating muscular weakness-related diseases.
It is still another object of the present invention to provide a composition for strengthening muscular strength.
Yet another object of the present invention is to provide a feedstuff for enhancing strength or a feed additive.
In order to achieve the above object, one aspect of the present invention provides a composition for promoting the differentiation of myoblasts, which comprises an Aleuritic Acid or a pharmaceutically acceptable salt thereof.
The term "Aleuritic Acid" in the present invention refers to (9 R , 10 S ) -rel-9,10,16- Trihydroxyhexadecanoic acid, the formula being C 16 H 32 O 5 and a molecular weight of 304.43. In general, aloe vermiculite is known to be used in cosmetics, raw materials for perfume production, and skin conditioning agents, but its association with myoblast differentiation is unknown. The inventors of the present invention completed the present invention by first screening a Korean Chemical Bank library for the purpose of differentiating a source cell with aloylic acid or a pharmaceutically acceptable salt thereof. The structure of the allylic acid of the present invention is as shown in the following formula (1).
[Chemical Formula 1]
The term "pharmaceutically acceptable salt " as used herein means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The pharmaceutical salts may be formed with acids which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, Organic carboxylic acids such as acetic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicinic acid and the like; organic carboxylic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acid, and the like. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine and guanidine, dicyclohexylamine, N Organic salts such as methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like.
In the present invention, the term "myoblast differentiation" is a process in which monocyte myoblasts form myotubes through fusion. Myocyte precursor cells can be identified by Pax7 + marker when they self-renew, and by Pax7 + / MyoD + when proliferating. In addition, cells in the differentiation stage that form canals can be distinguished by using Pax7 - MyoD + MyoG + marker. The cells at the early stage of differentiation to form the canal increase the expression of myogenic transcription factors such as MyoD (D), and increase myosin G (MyoG) in the middle stage. The expression of Myosin heavy chain is increased in the late stage of differentiation
The promoter of the source cell differentiation of the present invention can be, but not limited to, a medium in which a serum-containing DMEM differentiation medium is treated with an Aleuritic Acid or a pharmaceutically acceptable salt thereof. Alloietic acid or a pharmaceutically acceptable salt thereof may be included, and the medium capable of promoting source cell differentiation may be included without limitation. Specifically, 0.01 to 2.0 μM of alloyric acid may be used for the above differentiation medium, more specifically, 0.1 to 1.0 μM of alloyric acid may be used.
In one embodiment of the present invention, the allylic acid was treated at a concentration of 0.2 μM in the source cells, and the promotion of differentiation was examined using an in-cell ELISA. As a result, myosin heavy chain 3 (MHC3) The change was higher than that of the negative control (DMSO) and was similar to that of the positive control (insulin 0.6 μg / ml), confirming that allooid acid promoted myoblast differentiation (FIG. 1).
In addition, in one embodiment of the present invention, when the above-mentioned alloyric acid was treated to the differentiation medium of 0.0001, 0.001, 0.01, 0.1, 0.2, and 1.0 μM at the concentration of 0.2 μM, I could confirm. In addition, it was confirmed that the concentration of insulin could promote myocardial differentiation at a lower concentration than the positive control group (Fig. 2).
Therefore, the inventive alloyric acid or a pharmaceutically acceptable salt thereof can be usefully used for promoting differentiation of a source cell. In addition, the composition may contain an additional substance necessary for promoting differentiation of myoblast, and may include additional components as long as it does not hinder the promotion of differentiation.
Another aspect of the present invention provides a method for promoting differentiation of myoblast cells comprising treating the extracorporeal cells with the above-mentioned alloyric acid or a pharmaceutically acceptable salt thereof.
Alloyric acid or a pharmaceutically acceptable salt thereof is as described above.
The method of promoting the differentiation of the source cells of the present invention can promote the differentiation by treating the aloe vermic acid or its pharmaceutically acceptable salt to the extracorporeal or intracorporeal source cells.
Another aspect of the present invention provides a method of producing differentiated parental cells comprising treating parental cells with an alloital acid or a pharmaceutically acceptable salt thereof to differentiate the parental cells.
The concentrations of the alloyric acid or its pharmaceutically acceptable salts and salts are as described above.
The production method of the present invention is characterized by producing the differentiated source cells comprising the step of treating the extracellular or intracorporeal source cells with aloe vermic acid or a pharmaceutically acceptable salt thereof to differentiate the source cells.
In one embodiment of the present invention, 0.5 μM of alloyric acid was treated in the differentiation culture of myocytes and differentiated for 3 days, and subjected to phase contrast microscopy and immunocytochemistry. As a result, many root canals differentiated from the myocytes myotube) was observed and the expression of myosin heavy chain 3 protein was found to be very high (FIGS. 4 and 5). In addition, the composition for promoting differentiation was treated with myofibers and the amount of myosin heavy chain 3 protein expression was confirmed by Western blotting. As a result, it was confirmed that the expression level of myosin heavy chain 3 protein was much higher than that of negative control (FIG. 6).
Thus, the present invention is able to produce differentiated myocytes capable of forming root canals and expressing myosin heavy chain 3 protein in vitro or in vivo.
Another aspect of the present invention provides a pharmaceutical composition for preventing or treating muscular weakness related to muscular weakness comprising the above-mentioned allic acid or a pharmaceutically acceptable salt thereof.
The concentrations of the alloyric acid or its pharmaceutically acceptable salts and salts are as described above.
As used herein, the term "muscle weakness " means a state in which the force of one or more muscles is reduced. The muscle weakness may be limited to one muscle, one side, upper or lower side of the body, or may appear throughout the body. In addition, subjective muscle weakness symptoms including myopia and myalgia can be quantified in an objective way through physical examination.
In the present invention, muscle weakness related to muscular weakness refers to all diseases that may occur due to weakness of muscle strength, including, for example, muscular dystrophy, muscular dystrophy or cardiotrophy.
Thus, the composition of the present invention can be used for the prevention or treatment of myopenia, muscular dystrophy or cardiac atrophy through promotion of differentiation of myoblast cells.
Specifically, the myopenia of the present invention means a gradual decrease in skeletal muscle mass due to aging, which directly leads to a decrease in muscle strength, resulting in a decrease in various bodily functions and a disorder.
In addition, muscular dystrophy of the limbs is progressively symmetrically progressive, resulting in the progressive denaturation of motor nerve fibers and cells in the spinal cord, leading to the development of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy Spinal progressive muscular atrophy (SPMA).
Myocardial dysfunction of the present invention is a condition in which the heart is contracted by external or internal factors such as starvation, consumable disease, and when the cardiac muscle becomes thinner and thinner, it may cause a brown atrophy of the heart, have.
As used herein, the term "prevention" means any action that inhibits or slows down the onset of muscular weakening by administration of the composition.
In the present invention, the term "treatment" means any action that improves or alleviates symptoms caused by muscle weakness related diseases by administration of the composition.
The pharmaceutical composition of the present invention may contain, for administration, a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-mentioned allic acid or its pharmaceutically acceptable salt. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
The pharmaceutical compositions of the present invention may be formulated into pharmaceutical formulations using methods well known in the art so as to provide rapid, sustained or delayed release of the allo-acid or its pharmaceutically acceptable salts. In the preparation of the formulations, the active ingredient may be mixed with or diluted with the carrier, or enclosed in a carrier in the form of a container.
In addition, the pharmaceutical composition of the present invention can be applied to any formulation, but can be prepared for parenteral use. As the parenteral formulation, it may be of the spray type such as injection, application, aerosol, etc.
Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.
In order to formulate into a spray-type formulation, the aloe vermic acid or its pharmaceutically acceptable salt may be formulated into a solution or suspension by mixing in water with a stabilizer or a buffer to prepare a unit dose of ampoule or vial.
The composition comprising the aloe vermic acid or a pharmaceutically acceptable salt thereof of the present invention can be directly injected into a site where a muscle weakening-related disease has occurred or a site where a potentially susceptible individual is required to be strengthened. Or aloe vermic acid or a pharmaceutically acceptable salt thereof may be applied to in vitro or in vivo endogenous cells to produce differentiated endogenous cells and then the differentiated endothelial cells may be administered to a subject suffering from a weakness of the muscular weakness Can be injected into the site where muscle strengthening is required.
The composition of the present invention is also known as a therapeutic agent for an additive component, for example, a muscle weakening-related disease, so long as the alcoholic acid or its pharmaceutically acceptable salt does not interfere with the prevention or treatment of muscle weakness- Substances may be included.
In the composition of the present invention, the alcoholic acid may be used in a concentration of 0.01 to 2.0 μM of alloyric acid or a pharmaceutically acceptable salt thereof, more specifically 0.1 to 1.0 μM of alloyric acid or a pharmaceutically acceptable salt thereof .
Specifically, the pharmaceutical composition of the present invention is characterized by promoting the differentiation of the source cells.
In one embodiment of the present invention, the allylic acid was treated at a concentration of 0.2 μM in myoblasts, and the promotion of differentiation was investigated using an in-cell ELISA. As a result, the myosin heavy chain 3-fold change in the number of myosin heavy chain (DMSO) And insulin was similar to the positive control (insulin 0.6 μg / ml), confirming that allooid acid promoted myoblast differentiation (FIG. 1).
In one embodiment of the present invention, the aloe vermic acid or its pharmaceutically acceptable salt, aloe vermic acid, was treated with different concentrations of 0.0001, 0.001, 0.01, 0.1, 0.2, At 0.2 μM concentration, rapid differentiation promoting effect was confirmed. In addition, it was confirmed that the concentration of insulin could promote myocardial differentiation at a lower concentration than the positive control group (Fig. 2).
From these results, it has been confirmed that the abovementioned allloitic acid or its pharmaceutically acceptable salt has an effect of promoting muscle cell differentiation at a level equal to or higher than that of insulin, which is known as an accelerator for differentiation of muscle cells, It is effective in promoting differentiation of cells and may be useful for preventive treatment of muscular weakening related diseases.
Another aspect of the present invention provides a method of treating muscular weakness-related diseases by administering to the subject an alleric acid or a pharmaceutically acceptable salt thereof.
The muscle weakness-related disease refers to all diseases that may occur due to weakness in muscle strength, such as, for example, muscular dystrophy, muscular dystrophy, or heart atrophy.
As used herein, the term "individual" means all animals, including humans, who have already developed or are capable of developing a weakness related to muscle weakness, and administering to the individual a composition comprising allloitic acid or a pharmaceutically acceptable salt thereof, The disease can be effectively prevented and treated. The term refers to whole mammals including dogs, cows, horses, rabbits, mice, rats, chickens or humans, but the mammal of the present invention is not limited by these examples. Specifically, the object may be an object other than a human.
The optimal amount and dosage interval of the individual doses of the compositions of the present invention will be determined by the nature and extent of the disease being treated, the dosage form, route and site of administration, and the age and health status of the particular patient being treated, It will be apparent to those skilled in the art that the appropriate dosage will be determined. Such dosing can be repeated as often as is appropriate. If side effects occur, dosage and frequency can be altered or decreased depending on the usual clinical practice.
The route of administration of the composition may be administered via any conventional route so long as it can reach the target tissue. The composition of the present invention may be administered intraperitoneally, intravenously, subcutaneously, intradermally, or orally, but is not limited thereto. The composition may also be administered by any device capable of transferring the active agent to the target cell.
Another aspect of the present invention provides a food composition for preventing or ameliorating muscular weakness related to muscular weakness comprising aloylic acid or a pharmaceutically acceptable salt thereof.
That is, the composition of the present invention can be used either simultaneously with or separately from the agent for treating a disease before or after the onset of the muscle weakening-related disease to prevent or ameliorate the muscle weakening-related disease.
The concentrations of salts and salts which are acceptable as aloe vermic acid or food thereof are as described above.
The concentration of the alcoholic acid or its pharmaceutically acceptable salt in the food composition of the present invention may be 0.01 to 2.0 μM, more specifically 0.1 to 1.0 μM.
Specifically, the composition of the present invention can be used for the prevention or amelioration of myopenia, muscular atrophy or cardiac atrophy.
Specifically, the food composition is characterized by promoting the differentiation of myoblasts.
The term "improvement" in the present invention means all actions that at least reduce the degree of symptom associated with the condition being treated.
In addition, when the food composition of the present invention is used as a food additive, the composition may be added as it is, or may be used together with other food or food ingredients, and suitably used according to a conventional method. Generally, the composition of the present invention is added in an amount of not more than 15% by weight, specifically not more than 10% by weight based on the raw material in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of controlling health, it may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include healthy foods in a conventional sense.
The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharine and aspartame, and the like . The ratio of the natural carbohydrate can be appropriately determined by a person skilled in the art.
In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, A carbonating agent used in a carbonated beverage, and the like. In addition, the composition of the present invention may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The ratios of these additives can also be appropriately selected by those skilled in the art.
Another aspect of the present invention provides a composition for strengthening muscle strength comprising aloe vermic acid or a pharmaceutically acceptable salt thereof.
In the present invention, the term "muscle strengthening" refers to strengthening body performance, strengthening maximum endurance, increasing muscle mass, strengthening muscle recovery, reducing muscle fatigue, improving energy balance, or a combination thereof.
The composition for muscle strengthening comprising the aloe vermic acid or its pharmaceutically acceptable salt of the present invention can increase the total muscle mass by increasing the muscle mass through the ability to differentiate the source cells into muscle cells, , Thereby enhancing body performance and reducing muscle fatigue. In addition, muscle cells can be quickly replaced because muscle cells can be replaced quickly.
The composition for muscle strengthening of the present invention may contain a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-mentioned alluvic acid or a pharmaceutically or pharmacologically acceptable salt thereof for administration. The pharmaceutically acceptable carrier, excipient or diluent is as described above.
In addition, the composition for improving muscle strength of the present invention can be manufactured in the form of a food composition or a food additive, and in particular, can be manufactured in the form of a health food composition. The food composition is as described above. Therefore, the composition for muscle strengthening of the present invention can be used not only as a muscle for aging, but also as an adjuvant for general muscle building and muscle strengthening.
Another aspect of the present invention provides a muscle strengthening feed or feed additive comprising an alloitalic acid or a pharmaceutically acceptable salt thereof.
The term "feed" in the present invention means a substance which supplies organic or inorganic nutrients necessary for maintaining the life of an animal. The feed includes nutrients such as energy, protein, lipid, vitamins, and minerals required by animals such as livestock, and includes nutrients such as cereals, muscle roots, food processing busines logistics, algae, fibrous materials, But are not limited to, animal feeds such as vegetable feeds such as cereal crops and cereal crops, or protein feeds, inorganic feeds, oils, fats, oils, fats, and single cell proteins.
The term "feed additive " in the present invention means a substance added to feed to improve animal productivity or health and includes, but not limited to, amino acids, vitamins, enzymes, A flavoring agent, a silicate agent, a buffering agent, an extracting agent, and an oligosaccharide.
The content of the alloeic acid or the pharmaceutically acceptable salt thereof in the feed or feed additive of the present invention is not particularly limited, but may be 0.001 to 1% (w / w), specifically 0.005 To 0.9% (w / w), and most specifically from 0.01 to 0.5% (w / w).
Aleuritic Acid or a pharmaceutically acceptable salt thereof according to the present invention can promote root differentiation and root canal formation, thereby preventing muscle weakness and effectively improving muscle function. Accordingly, the pharmaceutical composition containing the same can be usefully used for the prevention or treatment of muscular weakening-related diseases.
1 is a graph showing the effect of accelerating the differentiation of myocytes in primary myoblasts of Aleuritic Acid.
Fig. 2 is a graph showing the effect of accelerating the differentiation of myocytes according to the concentration of Aleuritic Acid.
3 is a graph showing the results of measurement of cytotoxicity in a differentiation medium (DM) of Aleuritic Acid.
Fig. 4 is a diagram showing the effect of accelerating the differentiation of the myocardial cells of aleuritic acid by a phase contrast microscope.
FIG. 5 is a graph showing the effect of accelerating the differentiation of Aleuritic Acid into myocytes by Immunocytochemistry. FIG.
FIG. 6 is a graph comparing the expression levels of myosin heavy chain 3 (MHC3) in primary myoblasts. FIG.
Hereinafter, the present invention will be described in more detail with reference to examples. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the present invention.
Example 1: myocyte ( myoblast ) Culture
Example 1-1. Primary myoblast cell separation and culture
To isolate the primary stem cells, the mice that were 1-5 days old were washed with 70% ethanol and choked using CO 2 . The upper part of the hind leg ankle and the knee were cut and immersed in 1 X phosphate-buffered saline (PBS) to remove skin and bones with sterilized tweezers, and muscle tissue was collected. The collected muscle tissue was washed 3 times with 1 X PBS and finely chopped. An enzyme solution containing 1 ml of collagenase (1.5 U / ml), 1 ml of dispase (2.4 U / ml) and 5 μl of CaCl 2 (1 M) was added to the fragmented muscle tissue and incubated at 37 ° C. for 30 minutes Lt; / RTI > The muscle tissues that had been subjected to the enzymatic reaction were filtered using a nylon mesh (80 μm) to filter out bones, etc., and centrifuged at 800 rpm for 5 minutes to obtain cells.
The cells obtained above (primary source cells) were re-dissolved in 2 ml of F10 medium (Invitrogen) and transferred to a 100-mm general culture vessel, which was designated as P1 and transferred to a culture vessel coated with 0.1% gelatin at intervals of 1 hour P5. The cells were cultured in an incubator containing 5% CO 2 at 37 ° C and replaced with fresh F10 medium every 2 days. For cell passage, the cells were separated in a culture vessel using 0.005% trypsin. To induce differentiation into muscle cells, DMEM (Dulbecco's Modified Eagle Medium, Invitrogen) supplemented with 5% horse serum was used .
Example 1-2. Source cell main C2Cl2 culture
C2Cl2 is a parental cell line obtained from mice of C3H species and is widely used for studying myoblast differentiation.
The C2C12 cells were cultured in a general cell culture medium and a differentiation medium, respectively. DMEM supplemented with 10% fetal bovine serum was used as a normal cell culture medium (DM), and DMEM containing 2% horse serum was used as a differentiation medium Respectively.
Example 2: source cell ( myoblast ) Induction of differentiation induction
Example 2-1. Promotion of Differentiation by In-Cell ELISA
In-Cell ELISA was performed to compare the amount of myosin heavy chain 3 (MHC3) protein expressed in primary myoblasts. 5 x 10 < 3 > primary myeloma cells were cultured in a 96-well plate coated with 0.1% gelatin, and after 24 hours, differentiation was induced by DMEM supplemented with 5% horse serum. Was replaced with fresh medium supplemented with DMSO (5%) or treatment concentration of chemicals, or DMSO (5%) with insulin every 24 hours. On the third day after the differentiation, the medium was removed and 100 쨉 l paraformaldehyde (3.7%) was treated at room temperature for 15 minutes to fix the cells. After washing with phosphate buffer (1 × PBS), 100 μl of a permeabilization buffer (pH 7.0) containing 0.1% saponin, 3% tiriton X-100 and 0.009% sodium azide ) Was treated at room temperature for 15 minutes to pierce the cell membrane. The cells were washed with 1X PBS and treated with blocking buffer (100 μl) containing 0.1% albumin (bovine serum albumin) for 1 hour at room temperature. The cells were washed three times with 1 × PBS, and then 100 μl of a primary antibody diluted 1: 500 (SC-20641, Santa Cruz Biotechnology) was added and reacted at 37 ° C. for 2 hours. The cells were washed three times with 1 × PBS, and then 100 μl of a secondary antibody (Goat anti-Rabbit IgG-HRP) diluted 1: 10,000 was added and reacted at 37 ° C. for 1 hour. The cells were washed three times with 1 × PBS and then reacted for 20 minutes with 50 μl TMB solution (Gen Depot # T3551), and 50 μl stop solution (Gen Depot # T3552) Stop. To analyze the amount of myosin heavy chain 3 protein expression in the cells, absorbance was measured at 485 nm wavelength and the results were analyzed.
Specifically, the differentiation process specifically induced the differentiation into muscle cells by replacing the primary myocytes with the differentiation medium and then changing the medium with fresh differentiation medium for 3 days each day. After 3 days, the expression level of myosin heavy chain 3 protein was compared by in-cell ELISA. As a result, the differentiation promoting effect of 0.2 μM Aleuritic Acid was similar to that of 0.6 μg / ml insulin (positive control) when compared with DMSO (negative control), and the myosin heavy chain 3-fold change fold change value of 1.240 (n = 2) (Fig. 1).
As a result of the in-cell ELISA analysis, aloylic acid promoted differentiation by high fold change value of myosin heavy chain than DMSO, which is a drug carrier, and its degree of promotion was higher than that of insulin Which is similar to the degree of promotion.
Example 2-2. Alloy acid Induced differentiation induction
After confirming that alloyric acid promotes differentiation in Example 2-1, aloylic acid was treated with primary myocytes at concentrations of 0.0001, 0.001, 0.01, 0.1, 0.2, and 1.0 μM, and myosin heavy chain 3 was measured (n = 2). The allylic acid reducing method was carried out in the same manner as described in Example 2-1. As a result, it was confirmed that alloite acid showed an effect of promoting rapid differentiation at a concentration of 0.2 μM and an effect of promoting differentiation to 1.0 μM (FIG. 2).
Example 3: Alroic acid Myocytes myoblast ) For cytotoxicity measurement
Cytotox 96 Non-Radioactive Cytotoxicity Assay (Promega) kit for measuring LDH (lactate dehydrogenase), an enzyme secreted during apoptosis, was used to measure the cytotoxicity against insulin and alloylic acid.
5 × 10 3 primary stem cells were cultured on a 96-well plate using a cell culture medium (GM). After 24 hours, the cell culture medium and the differentiation medium (DM) were used for insulin and alluric acid Were treated with concentrations (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1.0, and 2.0 μM). 50 μl of the medium containing each sample was transferred to a 96-well flat bottom plate, and a 50 μl reconstituted substrate mix was added thereto, followed by reaction at room temperature for 30 minutes. 50 μM H 2 O 2 was treated as a control for complete cell death. After 30 minutes of the reaction, 50 ㎕ of stop solution was added to the cells, and the absorbance at 490 nm was measured and expressed as a ratio with respect to the LDH value at the time of cell death by lysis buffer.
As a result, there was no significant difference in the cytotoxicity of Alloy acid according to the concentrations measured in the differentiation medium (DM) of the primary myocyte cell, and even when 2.0 μM of Alloy acid was treated, complete cell death The ratio of apoptotic cells was less than 6% as compared with the value of lysic buffer treated with 50 μM H 2 O 2 , indicating that the toxicity of myocardial differentiation was very small (FIG. 3).
Example 4: Alroic acid Myocytes myoblast ) Identification Promotion of Differentiation
Example 4-1. Phase difference microscope (Phase contrast microscopy)
In order to confirm the formation of large amount of myotubes in myoblasts by aloietic acid (0.5 μM), C2Cl2 cells were incubated in 0.1% gelatin-coated cover glass for 3 days while being treated with Vehicle DMSO and Alloy acid And observed with a phase contrast microscope.
As a result of this experiment, when compared with the control group, DMSO, when myroitic acid (0.5 μM) was treated, many myotubes were formed, and thus the differentiation promoting effect was confirmed (X100) (FIG.
Example 4-2. Immunocytochemistry Immunocytochemistry )
C2Cl2 cells were differentiated for 3 days in a cover glass coated with 0.1% gelatin. The cells were washed with 1 × PBS, fixed with 3.7% paraformaldehyde at room temperature for 15 minutes, washed 3 times with 1 × PBS, permeabilized with permeabilization buffer, and incubated at room temperature for 15 minutes Lt; / RTI > After washing 3 times with 1X PBS, the cells were reacted with PBST containing 1% BSA (blocking buffer, PBS containing 0.5% Tween 20) for 30 minutes to inhibit unspecific antibody binding. The primary antibody (SC-20641, Santa Cruz Biotechnology) for myosin heavy chain 3 was diluted 1: 500 in blocking buffer and reacted at room temperature for 1 hour. After washing three times with 1 × PBS, secondary antibody (Goat anti-Rabbit IgG-HRP) diluted 1: 5000 in blocking buffer was added and reacted at room temperature for 1 hour. 3 times. The cover glass was placed on a slide glass and photographed with a fluorescence microscope to analyze the results.
In the present invention, differentiation of C2Cl2 cell line was induced while treating DMSO (negative control) and alloyric acid, respectively. On the third day, the expression of protein was confirmed by staining with myosin heavy chain 3 antibody to compare the degree of myocyte differentiation . As a result, it was confirmed that the expression of myosin heavy chain 3 (MHC3) was remarkably high when Alloy acid (0.5 μM) was treated as compared with DMSO (FIG. 5).
Example 4-3. Western Blat (Western blot)
After the cells were cultured for 24 hours in a culture medium, differentiation was induced by treating DMSO and 0.5 μM aloe vermiculite daily in the differentiation medium. On the third day of differentiation induction, cells were obtained and centrifuged at 1200 rpm for 3 minutes. After adding 100 μL of lysis buffer to the cells, sonication was performed and centrifuged at 3000 rpm for 10 minutes to obtain a water-soluble protein. A 4 × sample buffer was added to the cells, The reaction was carried out for 5 minutes. 10 [mu] g of protein was loaded on a 12% SDS-PAGE gel and developed and transferred to a Watman membrane. The membrane was blocked with 5% skim milk for 1 hour at room temperature and then washed five times for 5 minutes with TTBS (0.03
As a result of the above experiment, it was confirmed that the expression level of the myosin heavy chain 3 protein contained in the same amount of protein was significantly increased as compared with the control group of DMSO treatment (Fig. 6).
These results show that the amount of myosin protein expressed in the same amount of protein is rapidly increased by allylic acid. Thus, the effect of aloylic acid on promoting differentiation of muscle cells is very high.
From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
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| KR20190009084A (en) * | 2017-07-18 | 2019-01-28 | 연세대학교 산학협력단 | Composition comprising furaneol or as active ingredients for muscle strengthening, development, differentiation, regeneration or inhibiting muscle atrophy |
| KR20210065518A (en) | 2019-11-27 | 2021-06-04 | 재단법인대구경북과학기술원 | Composition comprising liranaftate and use thereof |
| KR20210065519A (en) | 2019-11-27 | 2021-06-04 | 재단법인대구경북과학기술원 | Composition comprising primaquine and use thereof |
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| KR20190009084A (en) * | 2017-07-18 | 2019-01-28 | 연세대학교 산학협력단 | Composition comprising furaneol or as active ingredients for muscle strengthening, development, differentiation, regeneration or inhibiting muscle atrophy |
| KR101997334B1 (en) | 2017-07-18 | 2019-07-08 | 연세대학교 산학협력단 | Composition comprising furaneol or as active ingredients for muscle strengthening, development, differentiation, regeneration or inhibiting muscle atrophy |
| KR20210065518A (en) | 2019-11-27 | 2021-06-04 | 재단법인대구경북과학기술원 | Composition comprising liranaftate and use thereof |
| KR20210065519A (en) | 2019-11-27 | 2021-06-04 | 재단법인대구경북과학기술원 | Composition comprising primaquine and use thereof |
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