KR20200033545A - Composition for Prevention, Treatment or Improvement of Muscular Atrophy comprising DL-Sulforaphane N-acetyl-L-cysteine - Google Patents
Composition for Prevention, Treatment or Improvement of Muscular Atrophy comprising DL-Sulforaphane N-acetyl-L-cysteine Download PDFInfo
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- KR20200033545A KR20200033545A KR1020180112948A KR20180112948A KR20200033545A KR 20200033545 A KR20200033545 A KR 20200033545A KR 1020180112948 A KR1020180112948 A KR 1020180112948A KR 20180112948 A KR20180112948 A KR 20180112948A KR 20200033545 A KR20200033545 A KR 20200033545A
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- Prior art keywords
- cysteine
- acetyl
- sulforapane
- muscle
- treatment
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- A—HUMAN NECESSITIES
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Abstract
Description
본 발명은 DL-설포라판 N-아세틸-L-시스테인을 포함하는 근위축 예방, 치료 또는 개선용 조성물에 관한 것이다.The present invention relates to a composition for preventing, treating or improving muscular dystrophy comprising DL-sulforapane N-acetyl-L-cysteine.
근위축(muscle atrophy)은 호르몬 불균형, 심한 부상, 패혈증, 암 및 노화로 인한 여러 가지 이화 상태(catabolic condition)에서 발생하는 근육세포와 근조직의 크기 및 질량적 손실을 의미한다. 근위축은 근육의 손실을 유발하여 근육 약화 및 피로감을 유발하고 합병증을 악화시킨다. 근위축은 크레아틴 키나아제(Creatine kinase: CK), 근전도검사, 근육생검, 분자생물학적 유전자검사, 세포유전학적 검사 등을 통해 진단이 이루어진다. 현재 근위축을 치료하기 위한 방법으로써, 물리치료가 일반적으로 수행되며, 합병증, 기형 및 기능 장애 예방을 위한 작업치료, 호흡치료 및 지지요법(supportive therapy)등이 병행되고 있으나, 이러한 치료는 대증요법으로써의 한계를 갖는다는 점에서, 근위축에 대한 치료제 개발이 절실한 상황이다.Muscle atrophy refers to the loss of muscle cell and muscle tissue size and mass in various catabolic conditions due to hormonal imbalance, severe injury, sepsis, cancer and aging. Muscular atrophy causes muscle loss, causing muscle weakness and fatigue, and exacerbating complications. Muscle atrophy is diagnosed through creatine kinase (CK), electromyography, muscle biopsy, molecular biological genetic testing, and cytogenetic testing. Currently, as a method for treating muscular dystrophy, physical therapy is generally performed, and occupational therapy, respiratory therapy, and supportive therapy for the prevention of complications, malformations, and functional disorders are combined, but such therapy is symptomatic therapy. In view of its limitations, the development of therapeutic agents for muscular dystrophy is urgent.
근위축의 병인기전은 아직까지 명확히 규명되지 않았으며, 현재까지 근위축 발병의 주 원인으로 보고된 것으로써, 산화물질 증가에 의한 근세포 손상, 스트레스 단백질 발현 감소로 인한 근단백질 생성 및 재생 감소, 프로테아좀-유비퀴틴 활성화에 따른 근단백질 분해 촉진 등이 알려져 있다. 또한, 항염증제로 잘 알려진 합성 글루코코르티코이드인 덱사메타손(DEX)의 투여에 의하여 근육량과 관련된 단백질의 분해가 촉진된다는 사실이 많은 연구에서 보고되었다.The pathogenesis of muscular atrophy has not been clarified so far, and has been reported to be the main cause of the development of muscular atrophy. As a result, muscle cell damage caused by increased oxides, muscle protein production and regeneration due to decreased stress protein expression, pro It is known to promote the degradation of myofoprotein by activating theosomal-ubiquitin. In addition, many studies have reported that the decomposition of proteins related to muscle mass is promoted by administration of dexamethasone (DEX), a synthetic glucocorticoid, well known as an anti-inflammatory agent.
덱사메타손은 암과 같은 여러 질병을 치료하는데 사용되지만, 유비퀴틴-프로 테아좀 시스템을 통해 골격근에서 단백질 합성 속도를 감소시키고, 단백질 분해 속도를 증가시켜 근위축을 유발한다. 2개의 근육 유비퀴틴 리가아제(ubiquitin ligase)는 Atrogin-1 및 MuRF1과 관련이 있는데, 덱사메타손은 Atrogin-1을 통해 MyoD(myogenic differentiation antigen)를 저하시키고, 이와 같은 기전을 통하여 근육량이 감소하게 된다.Dexamethasone is used to treat various diseases such as cancer, but the ubiquitin-proteasome system reduces the rate of protein synthesis in skeletal muscle and increases the rate of proteolysis, causing muscle atrophy. Two muscle ubiquitin ligase are related to Atrogin-1 and MuRF1, and dexamethasone lowers myoD (myogenic differentiation antigen) through Atrogin-1, and the muscle mass decreases through this mechanism.
따라서, 근위축, 특히 덱사메타손에 의해 유도되는 근위축을 치료하기 위한 치료제의 개발이 진행되고 있으나, 현재까지 근위축에 대한 효과적인 치료제는 개발되지 않은 상황이며, 인구의 노령화, 우주개발 및 삶의 질을 추구하는 사회적 인식의 변화로 인하여, 근위축에 대한 치료제의 요구가 점차 증가할 것으로 예상된다.Therefore, although the development of a therapeutic agent for the treatment of muscular dystrophy, especially dexamethasone induced muscular dystrophy, is currently in progress, an effective treatment for muscular dystrophy has not been developed, and the aging of the population, space development and quality of life It is expected that the demand for therapeutic agents for muscular dystrophy will gradually increase due to changes in social perception pursuing.
한편, DL-설포라판 N-아세틸-L-시스테인(DL-Sulforaphane N-acetyl-L-cysteine)은 항암 및 항염증 활성을 나타내는 것으로 알려져 있으나, 근위축 개선 활성에 대해서는 아직까지 보고된 바 없다.On the other hand, DL-Sulforaphane N-acetyl-L-cysteine (DL-Sulforaphane N-acetyl-L-cysteine) is known to exhibit anti-cancer and anti-inflammatory activity, but has not been reported about the muscle atrophy improvement activity.
이에 본 발명자는 근위축을 효과적으로 개선할 수 있는 치료제를 발굴하기 위한 연구를 수행하여 본 발명을 완성하였다.Accordingly, the present inventor completed the present invention by conducting research to find a therapeutic agent that can effectively improve muscular dystrophy.
본 발명의 하나의 목적은 DL-설포라판 N-아세틸-L-시스테인(DL-Sulforaphane N-acetyl-L-cysteine)을 포함하는 근위축(muscle atrophy) 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for preventing or treating muscle atrophy, including DL-Sulforaphane N-acetyl-L-cysteine.
본 발명의 다른 목적은 DL-설포라판 N-아세틸-L-시스테인을 포함하는 근위축 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving muscular dystrophy, comprising DL-sulforapane N-acetyl-L-cysteine.
본 발명의 일 양상은 DL-설포라판 N-아세틸-L-시스테인(DL-Sulforaphane N-acetyl-L-cysteine)을 포함하는 근위축(muscle atrophy) 예방 또는 치료용 약학적 조성물을 제공한다.One aspect of the present invention provides a pharmaceutical composition for preventing or treating muscle atrophy including DL-Sulforaphane N-acetyl-L-cysteine.
본 발명에서 사용되는 용어, "근위축"은 근육세포와 근조직의 크기 및 질량적 손실을 말하며, 이러한 근위축은 노화, 중증질병, 신경손상 등으로 인해 오랫동안 움직일 수 없는 상태에 처하거나, 영양공급장애 등 다양한 원인에 의하여 유발되는 것일 수 있다.As used in the present invention, the term "muscular atrophy" refers to the size and mass loss of muscle cells and muscle tissue, and such muscular atrophy is in a state of inability to move for a long time due to aging, severe disease, nerve damage, etc. It may be caused by various causes such as disability.
본 발명의 약학적 조성물에 포함되는 DL-설포라판 N-아세틸-L-시스테인은 하기 화학식 1로 표시되는 화합물이다.DL-Sulfolapan N-acetyl-L-cysteine included in the pharmaceutical composition of the present invention is a compound represented by the following Chemical Formula 1.
본 발명의 약학적 조성물은 약학적으로 허용되는 담체를 포함할 수 있다. 본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 약제의 제조에 통상적으로 이용되는 것으로써, 락토오스, 덱스트로스, 수크로오스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산칼슘, 알기네이트, 젤라틴, 규산칼슘, 미세결정성 셀룰로오스, 폴리비닐피롤리돈, 셀룰로오스, 물, 시럽, 메틸 셀룰로오스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (22th ed., 2013)에 상세히 기재되어 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention is commonly used in the manufacture of pharmaceuticals, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. It is not limited. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (22th ed., 2013).
본 발명의 일 구체예에 따른 약학적 조성물은 하나 이상의 근위축의 예방 또는 치료에 활성을 나타내는 물질과 함께 투여될 수 있다.The pharmaceutical composition according to an embodiment of the present invention may be administered with a substance that is active in the prevention or treatment of one or more muscular dystrophy.
또한, 본 발명의 일 구체예에 따른 약학적 조성물은 근위축의 치료를 위하여 단독으로, 또는 시술, 호르몬 치료, 약물치료 및/또는 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용될 수 있다.In addition, the pharmaceutical composition according to an embodiment of the present invention may be used alone or in combination with methods using procedures, hormonal therapy, drug therapy and / or biological response modifiers for the treatment of muscular dystrophy.
본 발명의 약학적 조성물은 그 제형의 제제화에 필요하고 적절한 각종 기제 및/또는 첨가물을 포함할 수 있으며, 그 효과를 떨어트리지 않는 범위 내에서 비이온 계면활성제, 실리콘 폴리머, 체질안료, 향료, 방부제, 살균제, 산화 안정화제, 유기 용매, 이온성 또는 비이온성 증점제, 유연화제, 산화방지제, 자유 라디칼 파괴제, 불투명화제, 안정화제, 에몰리언트(emollient), 실리콘, α-히드록시산, 소포제, 보습제, 비타민, 곤충 기피제, 향료, 보존제, 계면활성제, 소염제, 물질 P 길항제, 충전제, 중합체, 추진제, 염기성화 또는 산성화제, 또는 착색제 등 공지의 화합물을 더 포함하여 제조될 수 있다.The pharmaceutical composition of the present invention may include various bases and / or additives necessary and appropriate for the formulation of the formulation, and non-ionic surfactants, silicone polymers, extenders, flavors, and preservatives within a range that does not impair its effectiveness. , Fungicides, oxidation stabilizers, organic solvents, ionic or nonionic thickeners, softeners, antioxidants, free radical destroyers, opacifiers, stabilizers, emollients, silicones, α-hydroxy acids, antifoaming agents, moisturizers , Vitamins, insect repellents, fragrances, preservatives, surfactants, anti-inflammatory agents, substance P antagonists, fillers, polymers, propellants, basicizing or acidifying agents, or coloring agents.
본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약학적 조성물의 투여량은 성인 기준으로 0.001~1000㎎/kg일 수 있다.Suitable dosages of the pharmaceutical compositions of the invention are variously prescribed by factors such as formulation method, mode of administration, patient's age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion, and response sensitivity. Can be. The dosage of the pharmaceutical composition of the present invention may be 0.001 to 1000 mg / kg on an adult basis.
본 발명의 약학적 조성물은 경구 또는 비경구 투여할 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally.
본 발명의 약학적 조성물은 경구 투여 시 다양한 제형으로 투여될 수 있는데, 환제, 분말제, 과립제, 정제 또는 캡슐제 등의 고형제제 형태로 투여될 수 있으며, 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 더 포함할 수 있다. 구체적으로, 본 발명의 조성물을 분말, 과립, 정제 또는 캅셀 형태로 제형화 할 경우, 이의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 예를 들어, 락토오스, 덱스트로스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 인산칼슘, 규산칼슘, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및/또는 광물유가 사용될 수 있으나 이에 한정되지 않는다. 또한, 제제화에 일반적으로 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함하여 조제될 수 있으며, 상기 부형제 이외에 마그네슘 스테아레이트 또는 탈크 같은 윤활제를 더 포함할 수 있다.The pharmaceutical composition of the present invention may be administered in various dosage forms when administered orally, and may be administered in the form of solid preparations such as pills, powders, granules, tablets or capsules, and various excipients, such as wetting agents and sweeteners. , Fragrances, preservatives, and the like. Specifically, when the composition of the present invention is formulated in the form of a powder, granule, tablet or capsule, it may further include suitable carriers, excipients and diluents commonly used in its preparation. The carrier, excipients and diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and / or mineral oil may be used, but is not limited thereto. In addition, diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are generally used for formulation, may be prepared, and in addition to the excipients, lubricants such as magnesium stearate or talc may be further included. .
본 발명의 약학적 조성물은 비경구 투여시 다양한 제형으로 투여될 수 있는데, 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드, 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제 감미제, 방향제, 보존제 등이 포함될 수 있다. 구체적으로, 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제 및 동결건조제제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 또한, 치료제의 효능 증진을 위해 칼슘이나 비타민 D3를 첨가할 수 있다. The pharmaceutical composition of the present invention may be administered in various dosage forms when administered parenterally, and solid preparations include tablets, pills, powders, granules, capsules, etc., and liquid preparations include suspensions, intravenous solutions, emulsions, and syrups. In addition to water, liquid, and paraffin, which are commonly used simple diluents, various excipients may be included, for example, wetting agent sweeteners, fragrances, and preservatives. Specifically, formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions and lyophilized preparations. As a non-aqueous solvent and a suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. In addition, calcium or vitamin D3 may be added to improve the efficacy of the therapeutic agent.
이러한 조성물은 단위-용량(1회분) 또는 다중-용량(수 회분) 용기, 예를 들면, 밀봉된 앰풀 및 바이알에 제시될 수 있고, 사용 직전에 멸균성 액상 담체, 예를 들면, 주사용 수의 부가만을 요구하는 동결-건조 조건하에 저장할 수 있다. 즉석의 사용제 및 현탁제는 멸균성 산제, 과립제 및 정제로부터 제조할 수 있다.Such compositions may be presented in unit-dose (single serving) or multi-dose (several servings) containers, e.g., sealed ampoules and vials, and immediately before use in sterile liquid carriers, e.g. water for injection. Can be stored under freeze-drying conditions requiring only the addition of. Instant use and suspending agents can be prepared from sterile powders, granules and tablets.
본 발명의 일 구체예에 따르면, 상기 근위축은 암성 악액질, 근감소, 노화, 비만, 스테로이드제 장기투여 및 우주비행으로 이루어진 군으로부터 선택되는 어느 하나에 의하여 발생하는 것일 수 있다.According to one embodiment of the present invention, the muscular atrophy may be caused by any one selected from the group consisting of cancerous cachexia, muscle reduction, aging, obesity, long-term administration of steroid drugs, and space flight.
본 발명의 일 구체예에 따르면, 상기 스테로이드제는 덱사메타손일 수 있다.According to one embodiment of the invention, the steroid agent may be dexamethasone.
근위축은 호르몬 불균형, 심한 부상, 패혈증, 암, 비만, 우주비행 및/또는 노화 등 다양한 카타볼릭 상태(catabolic condition)에서 발생한다. 또한, 덱사메타손(dexamethasone)의 투여에 의하여 근육과 관련된 단백질의 분해가 촉진된다는 보고가 있었다. 본 발명의 약학적 조성물에 포함되는 DL-설포라판 N-아세틸-L-시스테인은 이와 같은 근위축, 특히, 덱사메타손에 의하여 유발된 근위축을 억제할 수 있으므로, 근위축의 예방 또는 치료에 유용하게 활용될 수 있다.Atrophy occurs in a variety of catabolic conditions, including hormonal imbalance, severe injury, sepsis, cancer, obesity, space flight and / or aging. In addition, it has been reported that the decomposition of muscle-related proteins is promoted by administration of dexamethasone. DL-sulforapane N-acetyl-L-cysteine included in the pharmaceutical composition of the present invention can effectively suppress such muscular dystrophy, particularly, muscular dystrophy caused by dexamethasone, and thus is useful for prevention or treatment of muscular dystrophy Can be.
본 발명의 다른 양상은 DL-설포라판 N-아세틸-L-시스테인(DL-Sulforaphane N-acetyl-L-cysteine)을 포함하는 근위축(muscle atrophy) 예방 또는 개선용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for preventing or improving muscle atrophy including DL-Sulforaphane N-acetyl-L-cysteine.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로써 DL-설포라판 N-아세틸-L-시스테인 외에, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함할 수 있다. 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 향미제로서 천연 향미제[타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)] 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is prepared as a food composition, in addition to DL-sulforapane N-acetyl-L-cysteine as an active ingredient, it may include a component that is commonly added in food preparation, for example, protein, carbohydrate, Fats, nutrients, seasonings and flavoring agents. Examples of carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose, oligosaccharides, etc .; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents (tauumatin, stevia extract (eg, rebaudioside A, glycyrrhizine, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
예를 들어, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 DL-설포라판 N-아세틸-L-시스테인 외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액 및/또는 감초 추출액 등이 추가로 포함될 수 있다. For example, when the food composition of the present invention is prepared as a drink agent, in addition to DL-sulforapane N-acetyl-L-cysteine of the present invention, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, worm extract, jujube extract And / or licorice extract.
또한, 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. In addition, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and It may contain salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있으며, 이러한 첨가제의 비율은 본 발명의 식품 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택될 수 있으나, 이에 한정되는 것은 아니다.These ingredients may be used independently or in combination, and the proportion of these additives may be selected from 0 to about 20 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 일 구체예에 따르면, 상기 근위축은 암성 악액질, 근감소, 노화, 비만, 스테로이드제 장기투여 및 우주비행으로 이루어진 군으로부터 선택되는 어느 하나에 의하여 발생하는 것일 수 있다.According to one embodiment of the present invention, the muscular atrophy may be caused by any one selected from the group consisting of cancerous cachexia, muscle reduction, aging, obesity, long-term administration of steroid drugs, and space flight.
본 발명의 일 구체예에 따르면, 상기 스테로이드제는 덱사메타손일 수 있다.According to one embodiment of the invention, the steroid agent may be dexamethasone.
DL-설포라판 N-아세틸-L-시스테인을 포함하는 근위축 예방, 치료 또는 개선용 조성물에 따르면, C2C12 세포에 독성이 없으면서도, 근위축을 효과적으로 억제할 수 있으므로, 근위축 예방, 치료 또는 개선에 유용하게 활용할 수 있다.According to the composition for preventing, treating or improving muscular dystrophy comprising DL-sulforapane N-acetyl-L-cysteine, C2C12 cells can effectively inhibit muscle atrophy without being toxic, and thus prevent, treat or improve muscular dystrophy. It can be useful.
도 1은 C2C12 근아세포(myoblast)(A) 및 근관세포(myotube)(B)에 대한 DL-설포라판 N-아세틸-L-시스테인(DL-Sulforaphane N-acetyl-L-cysteine: SFN-NAC)의 농도별(0.01, 0.1, 1, 5 및 10μM) 세포독성을 나타낸 그래프이다.
도 2는 C2C12 근관세포에 1μM DL-설포라판 N-아세틸-L-시스테인(NAC)의 처리에 따른, 4종의 주요 미오신 중쇄(myosin heavy chain: MHC)인 MHCIIb(A), MHCIb(B), MHCIIa(C) 및 MHCIIx(D)의 mRNA 수준을 나타낸 그래프이다.
도 3은 C2C12 근관세포(myotube)에 1μM DL-설포라판 N-아세틸-L-시스테인(NAC)의 처리에 따른, 근육 분화 마커인 MyoD(A), Myogenin(B) 및 근위축 마커인 Atrogin-1(C), MuRF1(D)의 mRNA 수준을 나타낸 그래프이다.
도 4는 C2C12 근관세포(myotube)에 1μM DL-설포라판 N-아세틸-L-시스테인(SFN-NAC) 단독, 또는 DL-설포라판 N-아세틸-L-시스테인(0, 0.1 및 1μM)과 덱사메타손(DEX)(5μM)의 동시 처리에 따른 p-Akt(S473), Atrogin-1, MuRF1 및 MyoD의 수준을 웨스턴 블롯으로 분석하여 나타낸 그림이다.
도 5는 정상대조군(CON)(A), 5μM 덱사메타손 단독 처리군(B), 1μM DL-설포라판 N-아세틸-L-시스테인 단독 처리군(C) 및 5μM 덱사메타손 및 1μM DL-설포라판 N-아세틸-L-시스테인 동시 처리군(D)의 근관세포를 나타낸 현미경 사진이다.1 shows DL-Sulforaphane N-acetyl-L-cysteine (SFN-NAC) for C2C12 myoblast (A) and myotube (B) It is a graph showing cytotoxicity by concentration (0.01, 0.1, 1, 5 and 10 μM).
FIG. 2 shows four major myosin heavy chain (MHC) MHCIIb (A), MHCIb (B), according to treatment of 1 μM DL-sulforapane N-acetyl-L-cysteine (NAC) on C2C12 root canal cells. It is a graph showing the mRNA levels of MHCIIa (C) and MHCIIx (D).
FIG. 3 shows muscle differentiation markers MyoD (A), Myogenin (B) and muscle atrophy markers Atrogin-1 according to treatment of 1 μM DL-sulfolapan N-acetyl-L-cysteine (NAC) on C2C12 myotubes (myotube). (C), It is a graph showing the mRNA level of MuRF1 (D).
FIG. 4 shows
FIG. 5 shows normal control (CON) (A), 5 μM dexamethasone alone treatment group (B), 1 μM DL-sulforapane N-acetyl-L-cysteine alone treatment group (C) and 5 μM dexamethasone and 1 μM DL-sulforapane N-acetyl- It is a micrograph showing the root canal cells of the L-cysteine co-treated group (D).
이하 본 발명을 하나 이상의 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through one or more embodiments. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1. DL-설포라판 N-아세틸-L-시스테인의 근위축 개선 효과 분석 방법Example 1.Method for analyzing the effect of improving muscle atrophy of DL-sulforapane N-acetyl-L-cysteine
1-1. 세포배양 및 시약 처리1-1. Cell culture and reagent treatment
C2C12 근아세포(myoblast)는 American Type Culture Collection(ATCC)에서 구입하였으며, 10% FBS(fetal bovine serum) 및 1% 페니실린-스트렙토마이신(penicillin-streptomycin: P/S)이 보충된 DMEM(Dulbecco's Modified Eagle's Medium)에서, 37℃의 5% CO2 조건으로 배양하였다. 근관세포(myotube)로의 분화를 유도하기 위하여, C2C12 근아세포가 80% 컨플루언트(confluent)가 되었을 때, 2% FBS 및 1% P/S를 포함하는 DMEM으로 4일 동안 매일 배지를 교체하였다. 그 후, 0.1 또는 1μM 농도의 DL-설포라판 N-아세틸-L-시스테인(DL-Sulforaphane N-acetyl-L-cysteine)으로 근관세포를 처리하였다. C2C12 myoblast was purchased from American Type Culture Collection (ATCC), DMEM (Dulbecco's Modified Eagle's) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (P / S) Medium), and cultured at 37 ° C under 5% CO 2 conditions. To induce differentiation into myotubes, when C2C12 myoblasts were 80% confluent, the medium was changed daily for 4 days with DMEM containing 2% FBS and 1% P / S. . Subsequently, the root canal cells were treated with DL-Sulforaphane N-acetyl-L-cysteine at a concentration of 0.1 or 1 μM.
한편, 근위축은 5μM의 덱사메타손을 사용하여 유도하였으며, 덱사메타손은 단독으로 또는 DL-설포라판 N-아세틸-L-시스테인과 동시에 처리되었다.On the other hand, muscular atrophy was induced using 5 μM dexamethasone, and dexamethasone was treated alone or simultaneously with DL-sulforapane N-acetyl-L-cysteine.
1-2. 세포 생존율 분석1-2. Cell viability analysis
96-웰 플레이트에 2×105 cells/㎖의 C2C12 근아세포를 100㎕씩 분주하고, 하루 배양한 후, DL-설포라판 N-아세틸-L-시스테인을 0.01, 0.1, 1, 5 및 10μM로 각 웰에 처리하고, 37℃의 5% CO2의 조건에서 24 및 48시간 동안 배양하였다. 근관세포는 96-웰 플레이트에 2×105 cells/㎖의 C2C12 근아세포를 100㎕씩 분주하고, 분화배지에서 4일간 분화시킨 후 DL-설포라판 N-아세틸-L-시스테인을 0.01, 0.1, 1, 5 및 10μM로 각 웰에 처리하고, 37℃의 5% CO2의 조건에서 24시간 또는 48시간 동안 배양하였다. 그 후, 배지를 제거하고, 최종농도가 2㎎/㎖이 되도록 MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)(Sigma) 용액을 각 웰에 넣은 다음, 배양기에서 4시간 동안 반응시키고, MTT 용액을 제거한 후, DMSO 100㎕를 넣어 교반하였다. 완전히 교반되면, 마이크로플레이트 판독기(microplate reader)(Molecular Device, Sunnyvale, Cam USA)를 이용하여 570㎚에서 UV 흡광도를 측정하였다. 세포 생존율(％)은 DL-설포라판 N-아세틸-L-시스테인을 처리하지 않은 정상대조군의 흡광도값에 대한 백분율로 나타냈다.After dispensing 100 µl of 2 × 10 5 cells / ml C2C12 myoblasts into 96-well plates and incubating for a day, DL-sulforapane N-acetyl-L-cysteine is 0.01, 0.1, 1, 5, and 10 μM, respectively. The wells were treated and incubated for 24 and 48 hours in the condition of 5% CO 2 at 37 ° C. Root canal cells are divided into 100 µl of 2 × 10 5 cells / ml C2C12 myoblasts in 96-well plates, differentiated for 4 days in differentiation medium, and then DL-sulforapane N-acetyl-L-cysteine is 0.01, 0.1, 1 , 5 and 10μM treatment to each well, and incubated for 24 hours or 48 hours at 37
1-3. Real-time PCR 분석1-3. Real-time PCR analysis
TRI 시약(Invitrogen, Grand Island, NY, USA)을 사용하여 실시예 1-1의 C2C12 세포로부터 총 RNA를 분리한 후, Atrogin-1, MuRF1, MyoD, Myogenin, MHCIb, MHCIIa, MHCIIb, MHCIIx 및 18sRNA mRNA의 발현을 LightCycler96 실시간(real-time) PCR 기기(Roche, Basel, Switzerland)를 사용하여 분석하였다. 사용한 forward 및 reverse 프라이머 서열은 하기 표 1과 같다.After total RNA was isolated from C2C12 cells of Example 1-1 using TRI reagent (Invitrogen, Grand Island, NY, USA), Atrogin-1, MuRF1, MyoD, Myogenin, MHCIb, MHCIIa, MHCIIb, MHCIIx and 18sRNA mRNA expression was analyzed using a LightCycler96 real-time PCR instrument (Roche, Basel, Switzerland). The forward and reverse primer sequences used are shown in Table 1 below.
1-4. 웨스턴 블롯 분석1-4. Western blot analysis
실시예 1-1의 근관세포를 PBS로 씻어낸 후, protease inhibitor cocktail(GenDEPOT, Barker, TX, USA)과 phosphatase inhibitor cocktail(GenDEPOT, Barker, TX, USA)을 함유한 RIPA 버퍼(Thermo Scientific, Rockford, IL, USA)에 용해하였다. 용해물을 샘플 버퍼[50 mM Tris-HCl, pH 6.8, 2% sodium dodecyl sulfate (SDS), 0.14 M 2-mercaptoethanol, 10% glycerol, 및 0.001% bromophenol blue]에서 끓인 후, 전기영동으로 분리하였다. 샘플을 SDS-폴리아크릴아마이드 젤 전기영동(SDS-polyacrylamide gel electrophoresis)으로 분석하고, PVDF멤브레인으로 옮긴 후, 5% 탈지분유 중 Tween-20을 함유하는 인산염 완충 식염수(phosphate-buffered saline)로 블로킹하였다. 그 후, Atrogin-1, MyoD, MuRF1, Akt, p-Akt(S473), FOXO1, p-FOXO1, FOXO3a, p-FOXO3a 및 α-tubulin(Cell Signaling, Danvers, MA, USA)에 대한 일차 항체와 4℃에서 밤새 배양한 다음, 실온에서 1시간 동안 2차 항체와 반응시켰다. 항체-항원 복합체는 향상된 화학발광(chemiluminescent) 키트(Pierce, Rockford, IL, USA)를 사용하여 검출하였고, 신호 강도는 Fusion Solo 2 화상이미지 분석기(Vilber Lourmat, Paris, France)를 사용하여 측정하였다.After washing the root canal cells of Example 1-1 with PBS, RIPA buffer containing the protease inhibitor cocktail (GenDEPOT, Barker, TX, USA) and phosphatase inhibitor cocktail (GenDEPOT, Barker, TX, USA) (Thermo Scientific, Rockford , IL, USA). The lysate was boiled in sample buffer [50 mM Tris-HCl, pH 6.8, 2% sodium dodecyl sulfate (SDS), 0.14 M 2-mercaptoethanol, 10% glycerol, and 0.001% bromophenol blue] and then separated by electrophoresis. Samples were analyzed by SDS-polyacrylamide gel electrophoresis, transferred to PVDF membrane, and then blocked with phosphate-buffered saline containing Tween-20 in 5% skim milk powder. . Subsequently, with primary antibodies against Atrogin-1, MyoD, MuRF1, Akt, p-Akt (S473), FOXO1, p-FOXO1, FOXO3a, p-FOXO3a and α-tubulin (Cell Signaling, Danvers, MA, USA) After incubation at 4 ° C overnight, it was reacted with secondary antibody for 1 hour at room temperature. Antibody-antigen complexes were detected using an enhanced chemiluminescent kit (Pierce, Rockford, IL, USA), and signal intensity was measured using a
1-5. 근관세포 현미경 관찰1-5. Root canal cell microscopy
PAS 염색 키트(Merck, Whitehouse Station, NJ, USA)를 사용하여 실시예 1-1의 근관세포를 염색하고, PA(과요오드산) 용액에서 5분 동안 배양한 후, PBS로 3분간 세척하고, Schiff's 시약으로 실온에서 15분간 처리하고, 3분간 PBS로 세척하였다. Gill III 용액으로 핵을 2분 동안 염색하였다. 근관세포는 Neo-Mount 용액에 담근 후, 100배율로 촬영하였다. The root canal cells of Example 1-1 were stained using a PAS staining kit (Merck, Whitehouse Station, NJ, USA), incubated in a PA (periodic acid) solution for 5 minutes, washed with PBS for 3 minutes, Treated with Schiff's reagent at room temperature for 15 minutes and washed with PBS for 3 minutes. Nuclei were stained for 2 minutes with Gill III solution. Root canal cells were immersed in Neo-Mount solution, and photographed at 100 magnification.
1-6. 통계 분석1-6. Statistical analysis
결과는 평균 ± 표준편차(SD)로 나타내었다. GraphPad PRISM(GraphPad Software, San Diego, CA, USA)을 사용하는 t-test 또는 one-way ANOVA를 사용하여 그룹 결과를 분석하였다. < 0.05 및 < 0.01의 P value는 유의한 것으로 간주하였다.Results were expressed as mean ± standard deviation (SD). Group results were analyzed using t-test or one-way ANOVA using GraphPad PRISM (GraphPad Software, San Diego, CA, USA). P values of <0.05 and <0.01 were considered significant.
실시예 2. DL-설포라판 N-아세틸-L-시스테인 처리에 따른 근아세포 및 근관세포의 세포 생존율 확인Example 2. Confirmation of cell viability of myoblasts and myotubes according to DL-sulforapane N-acetyl-L-cysteine treatment
근아세포 및 근관세포에 대하여, DL-설포라판 N-아세틸-L-시스테인 처리에 따른 세포 생존율 확인하기 위하여, 실시예 1-2를 수행하여, DL-설포라판 N-아세틸-L-시스테인이 세포 생존율에 미치는 영향을 분석하였다.For myoblasts and myotubes, in order to confirm the cell viability according to DL-sulforapane N-acetyl-L-cysteine treatment, Example 1-2 was performed, and DL-sulforapane N-acetyl-L-cysteine was used for cell viability. The impact was analyzed.
그 결과, 1μM까지 DL-설포라판 N-아세틸-L-시스테인을 처리하여도 근아세포(도 1A) 및 근관세포(도 1B)에 대한 세포 생존율에 유의적인 감소가 없음을 확인하여, DL-설포라판 N-아세틸-L-시스테인은 1μM 이하의 농도에서 근아세포 및 근관세포에 독성을 나타내지 않음을 확인하였다.As a result, it was confirmed that there was no significant decrease in cell viability for myoblasts (FIG. 1A) and myotubes (FIG. 1B), even after treatment of DL-sulforapane N-acetyl-L-cysteine to 1 μM, DL-sulforapane N -It was confirmed that acetyl-L-cysteine did not show toxicity to myoblasts and myotubes at a concentration of 1 μM or less.
실시예 3. DL-설포라판 N-아세틸-L-시스테인 처리에 따른 주요 미오신 중쇄의 발현 수준 확인Example 3. Confirmation of the expression level of the main myosin heavy chain according to DL-sulforapane N-acetyl-L-cysteine treatment
4종의 주요 미오신 중쇄(myosin heavy chain: MHC)(MHCIb, MHCIIa, MHCIIb 및 MHCIIx)는 근육 유형 및 근육 신진대사를 나타낸다. 따라서, DL-설포라판 N-아세틸-L-시스테인 처리 후, 미오신 중쇄의 발현 변화를 확인하기 위하여, 4종의 주요 미오신 중쇄의 mRNA 수준을 실시예 1-3을 수행하여 분석하였다.The four major myosin heavy chains (MHC) (MHCIb, MHCIIa, MHCIIb and MHCIIx) represent muscle types and muscle metabolism. Therefore, after the DL-sulforapane N-acetyl-L-cysteine treatment, mRNA levels of four major myosin heavy chains were analyzed by performing Examples 1-3 to confirm the expression change of the myosin heavy chain.
그 결과, DL-설포라판 N-아세틸-L-시스테인을 처리하지 않은 경우의 MHCIb, MHCIIa, MHCIIb 및 MHCIIx의 mRNA 수준과 비교하였을 때, DL-설포라판 N-아세틸-L-시스테인을 처리한 후에 측정한 MHCIb, MHCIIa, MHCIIb 및 MHCIIx의 mRNA 수준에서 유의적인 차이는 나타나지 않음을 확인하였다(도 2). 즉, DL-설포라판 N-아세틸-L-시스테인은 정상 근관세포의 주요 미오신 중쇄의 발현에 영향을 주지 않음을 확인하였다. As a result, when compared to the mRNA levels of MHCIb, MHCIIa, MHCIIb and MHCIIx in the absence of treatment with DL-sulforapane N-acetyl-L-cysteine, it was measured after treatment with DL-sulforapane N-acetyl-L-cysteine. It was confirmed that there was no significant difference in mRNA levels of MHCIb, MHCIIa, MHCIIb and MHCIIx (FIG. 2). That is, it was confirmed that DL-sulforapane N-acetyl-L-cysteine does not affect the expression of the main myosin heavy chain of normal myocardial cells.
실시예 4. DL-설포라판 N-아세틸-L-시스테인의 근위축 개선 효과 확인Example 4. Confirmation of the effect of improving the atrophy of DL-sulforapane N-acetyl-L-cysteine
MyoD 및 Myogenin은 근육 분화(muscle differentiation)의 마커이고, Atrogin-1 및 MuRF1은 근위축(muscle atrophy)의 마커이다. 따라서, DL-설포라판 N-아세틸-L-시스테인 처리 후, 근육 분화 및 근위축 여부를 확인하기 위하여, 이들 마커에 대한 mRNA 수준을 실시예 1-3 및 1-4를 수행하여 분석하였다.MyoD and Myogenin are markers of muscle differentiation, and Atrogin-1 and MuRF1 are markers of muscle atrophy. Therefore, after DL-sulforapane N-acetyl-L-cysteine treatment, mRNA levels for these markers were analyzed by performing Examples 1-3 and 1-4 to confirm muscle differentiation and muscular atrophy.
그 결과, DL-설포라판 N-아세틸-L-시스테인을 처리하지 않은 경우의 MyoD, Myogenin, Atrogin-1 및 MuRF1의 mRNA 수준과 비교하였을 때, DL-설포라판 N-아세틸-L-시스테인을 처리한 후에 측정한 MyoD, Myogenin, Atrogin-1 및 MuRF1의 mRNA 수준에서 유의적인 차이는 나타나지 않았다(도 3). 즉, DL-설포라판 N-아세틸-L-시스테인은 정상 근관세포의 근육 분화 및 근위축에 영향을 주지 않음을 확인하였다.As a result, after treatment with DL-sulforapane N-acetyl-L-cysteine compared to mRNA levels of MyoD, Myogenin, Atrogin-1 and MuRF1 when DL-sulforapane N-acetyl-L-cysteine was not treated There was no significant difference in the measured mRNA levels of MyoD, Myogenin, Atrogin-1 and MuRF1 (FIG. 3). That is, it was confirmed that DL-sulforapane N-acetyl-L-cysteine does not affect muscle differentiation and muscular atrophy of normal myocardial cells.
또한, 웨스턴 블롯 결과에 따르면, 5μM의 덱사메타손을 근관세포에 처리한 경우, Atrogin-1 및 MuRF1의 수준이 증가하고, MyoD의 수준은 감소하였으나, 덱사메타손과 DL-설포라판 N-아세틸-L-시스테인을 동시에 처리한 경우, DL-설포라판 N-아세틸-L-시스테인의 농도의존적으로 Atrogin-1과 MuRF1의 수준은 감소하고, MyoD의 수준은 증가하는 것을 확인하였다(도 4). 즉, DL-설포라판 N-아세틸-L-시스테인을 사용하여 근위축을 개선할 수 있음을 확인하였다.In addition, according to Western blot results, when 5 μM of dexamethasone was treated in the root canal cells, the levels of Atrogin-1 and MuRF1 increased and the levels of MyoD decreased, but dexamethasone and DL-sulforapane N-acetyl-L-cysteine When treated at the same time, it was confirmed that the levels of Atrogin-1 and MuRF1 decreased and the levels of MyoD increased, depending on the concentration of DL-sulforapane N-acetyl-L-cysteine (FIG. 4). That is, it was confirmed that the muscular atrophy can be improved by using DL-sulforapane N-acetyl-L-cysteine.
한편, 감소된 Akt 신호 활성은 대부분의 근위축 모델에서 관찰된다. 덱사메타손에 의해 유도된 근위축 모델에서, DL-설포라판 N-아세틸-L-시스테인이 Akt의 발현에 영향을 주는지를 확인하기 위하여, 실시예 1-4를 수행하여 p-Akt(S473)의 수준을 분석하였다.On the other hand, reduced Akt signal activity is observed in most atrophy models. In a muscle atrophy model induced by dexamethasone, to confirm whether DL-sulforapane N-acetyl-L-cysteine affects the expression of Akt, Example 1-4 was performed to increase the level of p-Akt (S473). Analysis.
그 결과, 덱사메타손을 처리할 경우, p-Akt(S473)의 수준이 유의하게 감소하였으나, 덱사메타손과 DL-설포라판 N-아세틸-L-시스테인을 동시에 처리한 경우, p-Akt(S473)의 정상대조군과 유사한 수준으로 회복됨을 확인하였다(도 4). As a result, when dexamethasone was treated, the level of p-Akt (S473) was significantly decreased, but when dexamethasone and DL-sulforapane N-acetyl-L-cysteine were treated simultaneously, the normal control of p-Akt (S473) It was confirmed that the recovery to a level similar to (Fig. 4).
상기 결과를 통하여, 즉, DL-설포라판 N-아세틸-L-시스테인을 사용하여 근위축을 개선할 수 있으며, DL-설포라판 N-아세틸-L-시스테인은 Akt 신호 전달을 활성화시킴으로써 근위축을 개선함을 확인하였다.Through the above results, i.e., DL-sulforaphane N-acetyl-L-cysteine can be used to improve muscle atrophy, and DL-sulforapane N-acetyl-L-cysteine improves muscular atrophy by activating Akt signaling. Was confirmed.
실시예 5. 현미경 사진 분석에 따른 근관세포의 근위축 개선 효과 확인Example 5. Confirmation of the effect of improving muscular atrophy of root canal cells according to micrograph analysis
DL-설포라판 N-아세틸-L-시스테인 처리 후, 근위축의 개선 효과를 확인하기 위하여, 실시예 1-5를 수행하여 근관세포에 대한 현미경 사진을 분석하였다.After treatment with DL-sulforapane N-acetyl-L-cysteine, to confirm the improvement effect of muscular dystrophy, Example 1-5 was performed to analyze micrographs of the root canal cells.
그 결과, 덱사메타손을 처리한 경우, 근관세포의 직경이 감소하여 근위축이 발생한 것을 확인한 반면, 덱사메타손과 DL-설포라판 N-아세틸-L-시스테인을 동시에 처리한 경우, 근관세포의 지름이 대조군 및 DL-설포라판 N-아세틸-L-시스테인 단독 처리군과 유사한 수준으로 회복되었음을 확인하였다(도 5).As a result, when treated with dexamethasone, it was confirmed that muscular atrophy occurred due to a decrease in the diameter of the root canal cells. On the other hand, when dexamethasone and DL-sulforapane N-acetyl-L-cysteine were treated simultaneously, the diameter of the root canal cells was compared to the control group and DL. -It was confirmed that the sulfolapan N-acetyl-L-cysteine treatment group recovered to a similar level (FIG. 5).
상기 결과를 통하여, DL-설포라판 N-아세틸-L-시스테인의 사용에 따른 실질적인 근위축 개선 효과를 확인하였다.Through the above results, it was confirmed that a substantial effect of improving muscular atrophy according to the use of DL-sulforapane N-acetyl-L-cysteine.
이제까지 본 발명에 대하여 그 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been focused on the embodiments. Those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered in terms of explanation, not limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent range should be interpreted as being included in the present invention.
<110> Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation <120> Composition for Prevention, Treatment or Improvement of Muscular Atrophy comprising DL-Sulforaphane N-acetyl-L-cysteine <130> PN180281 <160> 18 <170> KoPatentIn 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Atrogin-1_forward <400> 1 ctctgtacca tgccgttcct 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Atrogin-1_reverse <400> 2 ggctgctgaa cagattctcc 20 <210> 3 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MuRF1_forward <400> 3 tgtctggagg tcgtttccg 19 <210> 4 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MuRF1_reverse <400> 4 tgccggtcca tgatcactt 19 <210> 5 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MyoD_forward <400> 5 actacagtgg cgactcagat gc 22 <210> 6 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> MyoD_reverse <400> 6 ccgctgtaat ccatcatgcc atc 23 <210> 7 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Myogenin_forward <400> 7 tcccaaccca ggagatcatt tgc 23 <210> 8 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Myogenin_reverse <400> 8 acgtaaggga gtgcagattg tgg 23 <210> 9 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> MHCIb_forward <400> 9 gaggaagagt gagcggcg 18 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MHCIb_reverse <400> 10 gccgcagtag gttcttcctg t 21 <210> 11 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MHCIIa_forward <400> 11 tacaacctca aagagcgtta tgca 24 <210> 12 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MHCIIa_reverse <400> 12 aagggttgac ggtgacacag a 21 <210> 13 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> MHCIIb_forward <400> 13 gagatcgatg atctcgctag taacat 26 <210> 14 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> MHCIIb_reverse <400> 14 gggtgcggca catcttc 17 <210> 15 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MHCIIx_forward <400> 15 acagatcggg agaaccagtc tatt 24 <210> 16 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MHCIIx_reverse <400> 16 cgtttcgtgt tcacagtctt cc 22 <210> 17 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> 18sRNA_forward <400> 17 cgatgctctt agctgagtgt 20 <210> 18 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> 18sRNA_reverse <400> 18 ggtccaagaa tttcacctct 20 <110> Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation <120> Composition for Prevention, Treatment or Improvement of Muscular Atrophy comprising DL-Sulforaphane N-acetyl-L-cysteine <130> PN180281 <160> 18 <170> KoPatentIn 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Atrogin-1_forward <400> 1 ctctgtacca tgccgttcct 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Atrogin-1_reverse <400> 2 ggctgctgaa cagattctcc 20 <210> 3 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MuRF1_forward <400> 3 tgtctggagg tcgtttccg 19 <210> 4 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MuRF1_reverse <400> 4 tgccggtcca tgatcactt 19 <210> 5 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MyoD_forward <400> 5 actacagtgg cgactcagat gc 22 <210> 6 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> MyoD_reverse <400> 6 ccgctgtaat ccatcatgcc atc 23 <210> 7 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Myogenin_forward <400> 7 tcccaaccca ggagatcatt tgc 23 <210> 8 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Myogenin_reverse <400> 8 acgtaaggga gtgcagattg tgg 23 <210> 9 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> MHCIb_forward <400> 9 gaggaagagt gagcggcg 18 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MHCIb_reverse <400> 10 gccgcagtag gttcttcctg t 21 <210> 11 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MHCIIa_forward <400> 11 tacaacctca aagagcgtta tgca 24 <210> 12 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MHCIIa_reverse <400> 12 aagggttgac ggtgacacag a 21 <210> 13 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> MHCIIb_forward <400> 13 gagatcgatg atctcgctag taacat 26 <210> 14 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> MHCIIb_reverse <400> 14 gggtgcggca catcttc 17 <210> 15 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MHCIIx_forward <400> 15 acagatcggg agaaccagtc tatt 24 <210> 16 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> MHCIIx_reverse <400> 16 cgtttcgtgt tcacagtctt cc 22 <210> 17 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> 18sRNA_forward <400> 17 cgatgctctt agctgagtgt 20 <210> 18 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> 18sRNA_reverse <400> 18 ggtccaagaa tttcacctct 20
Claims (6)
DL-Sulforaphane N-acetyl-L-cysteine (DL-Sulforaphane N-acetyl-L-cysteine) comprising a pharmaceutical composition for the prevention or treatment of muscle atrophy (muscle atrophy).
The pharmaceutical composition for preventing or treating muscular dystrophy according to claim 1, wherein the muscular dystrophy is caused by any one selected from the group consisting of cancerous cachexia, muscle reduction, aging, obesity, long-term administration of steroid drugs, and space flight. .
The pharmaceutical composition for preventing or treating muscular dystrophy according to claim 2, wherein the steroid agent is dexamethasone.
Food composition for preventing or improving muscle atrophy, including DL-Sulforaphane N-acetyl-L-cysteine.
The food composition for preventing or improving muscle atrophy according to claim 4, wherein the atrophy is caused by any one selected from the group consisting of cancerous cachexia, muscle reduction, aging, obesity, long-term administration of steroid drugs, and space flight.
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| Biomedicine&Pharmacotherapy 95(2017)1486-1492 (2017.11.) * |
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