KR20140131263A - Compositions for Preventing or Treating Obesity and Fatty Liver Containing Ariginase Inhibitors - Google Patents
Compositions for Preventing or Treating Obesity and Fatty Liver Containing Ariginase Inhibitors Download PDFInfo
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- KR20140131263A KR20140131263A KR20140044234A KR20140044234A KR20140131263A KR 20140131263 A KR20140131263 A KR 20140131263A KR 20140044234 A KR20140044234 A KR 20140044234A KR 20140044234 A KR20140044234 A KR 20140044234A KR 20140131263 A KR20140131263 A KR 20140131263A
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- arginase inhibitor
- composition according
- pharmaceutical composition
- health functional
- functional food
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Abstract
Description
본 발명은 아르기나아제 억제제를 함유하는 비만 또는 지방간 예방 또는 치료용 조성물에 관한 것으로, 보다 구체적으로는 아르기나아제 억제제를 유효성분으로 함유하는 비만 또는 지방간 예방 또는 치료용 약학 조성물 및 건강기능식품 조성물에 관한 것이다.
The present invention relates to a composition for preventing or treating obesity or fatty liver containing arginase inhibitor and more particularly to a pharmaceutical composition and health functional food composition for preventing or treating obesity or fatty liver comprising arginase inhibitor as an active ingredient .
비만은 에너지의 축적과 방출에 대한 조절의 불균형으로 인하여 과도한 에너지가 축적되어 발생하는 것으로, 지방세포의 수가 증가하고 증가된 지방세포에 에너지와 중성지방이 과도하게 발생되어 지방세포의 크기가 증가하는데 기인하고 있는 것으로 보고되고 있다. 즉, 비만은 섭취 열량과 소비 열량의 차이로 인해 발생하는 지방 세포의 과증식과 성장을 의미하는 것으로, 운동부족과 탐식을 강요하는 현대생활 방식에 의해 갈수록 심화되고 있다. 비만으로 인해 고지혈증, 당뇨, 동맥경화, 고혈압 등과 같은 심혈관계질환 등의 심각한 질환이 발생될 수 있다는 사실에 비추어 비만은 단순한 대사 장애나 질병의 위험 인자를 넘어 하나의 질환으로 여겨지고 있다(Mantzoros et al., J Clin Endocrinol Metab, 85, 4000-2, 2000).Obesity is caused by the accumulation of excessive energy due to the imbalance of energy accumulation and regulation, resulting in an increase in the number of adipocytes, an increase in the amount of energy and triglycerides in the increased adipocytes, and an increase in the size of adipocytes Is reported to be caused. In other words, obesity means the hyperplasia and growth of fat cells caused by the difference between calorie intake and calorie consumption, and it is getting worse by the modern lifestyle which insists on lack of exercise and phagocytosis. Obesity is considered to be a disease not just a metabolic disorder or disease but a serious disease such as cardiovascular diseases such as hyperlipemia, diabetes, atherosclerosis and hypertension due to obesity (Mantzoros et al ., J Clin Endocrinol Metab , 85, 4000-2, 2000).
비만을 치료하기 위한 노력이 그간 계속되어 운동요법, 식이요법 외에 비만치료제, 지방흡입술과 같은 수술요법까지 등장하게 되었다. 현재 비만치료제는 크게 중추신경계에 작용하여 식욕에 영향을 주는 약제와 위장관에 작용하여 흡수를 저해하는 약제로 나눌 수 있다. 전자로는 세로토닌 신경계를 저해하는 펜플루라민, 세로토닌 및 노르아드레날린 신경계에 동시 작용하여 비만을 저해하는 시부트라민 등의 약물이 시판되고 있으며, 후자로는 췌장에서 생성되는 리파아제를 저해하여 지방의 흡수를 감소시키는 오를리스타트 등이 시판되고 있다. 그러나 기존의 비만치료제는 혈압감소, 소화장애, 변비, 피부탄력 감소 등 부작용이 나타날 수 있다는 문제점이 있다. 따라서, 부작용이 작으며 보다 나은 비만 예방 및 치료 방법을 찾기 위한 노력이 현재 계속되고 있다.Efforts to treat obesity have continued until the end of exercise therapy, diet therapy, obesity treatment, and liposuction. Currently, obesity treatment drugs mainly affect the central nervous system, drugs affecting the appetite and gastrointestinal tract can be divided into drugs to inhibit absorption. In the former, medications such as sibutramine, which inhibits the serotonin nervous system, and sibutramine, which simultaneously acts on the nervous system and the noradrenergic nervous system, are commercially available. The latter include Orly, which inhibits the lipase produced by the pancreas, Start and the like are commercially available. However, existing therapeutic agents for obesity have problems such as decreased blood pressure, digestive disorders, constipation, and reduced skin elasticity. Therefore, there is a continuing effort to find a better method of preventing and treating obesity with small side effects.
또한, 지방간은 의학적으로 지방이 전체 간 무게의 5% 이상을 초과하는 병적 상태를 의미하는데, 이를 함유하는 간질환은 선진국 40-50대 성인 인구의 사망원인에서 암 다음으로 심각한 질환으로 알려져 있다. 지방간과 같은 간경변증 환자의 약 절반은 진단 후 10년 이내에 간질환으로 사망한다. 지방간의 원인은 과음, 비만, 당뇨병, 고지혈증 등이며, 지방간은 간염, 간경변 및 간암으로 악화될 위험성이 매우 높다.In addition, fatty liver disease refers to a disease state in which the fat exceeds 5% or more of the total liver weight, and the liver disease, which contains it, is known to be the second most serious disease next to cancer in the 40-50 adult population. About half of patients with liver cirrhosis such as fatty liver die from liver disease within 10 years of diagnosis. The causes of fatty liver are overeating, obesity, diabetes, hyperlipidemia, and fatty liver is very likely to be exacerbated by hepatitis, cirrhosis and liver cancer.
현재 지방간을 약물학적으로 치료하는데 유용한 약제는 거의 없는 상태이므로 운동요법과 식이요법이 권장되고 있으나, 이러한 방법에 의한 지방간의 치료율은 매우 낮아 유효한 치료제 개발에 대한 요구가 절실한 상황이다. 지방간이 당뇨병 및 비만상태에서 관찰되는 세포의 인슐린 저항성과 관련이 있는 것으로 확인되면서 메트포르민(Metformin)과 같은 혈당강하제의 지방간 치료에 대한 효과가 보고되었으나(Hui Zhi Lin et al., Nature Medicine, 6, 998-1003, 2000), 간독성 또는 젖산증과 같은 부작용을 유발한다는 문제점이 있는바, 효과가 탁월하면서도 부작용을 유발하지 않는 안전한 지방간 치료제의 개발이 필요하다.Currently, there are few medicines useful for the pharmacological treatment of fatty liver. Therefore, exercise therapy and diet therapy are recommended, but the treatment rate of fatty liver by this method is very low, so there is an urgent need to develop effective therapeutic agents. The effect of a hypoglycemic agent such as metformin on the treatment of fatty liver has been reported as being confirmed to be related to the insulin resistance of cells observed in diabetes and obesity (Hui Zhi Lin et al., Nature Medicine, 6, 998-1003, 2000) , there is a problem that it causes side effects such as liver toxicity or increased lactate bar, is effective but requires excellent liver side effects, the development of a safe drug that does not cause.
아르기나아제(Arginase)는 요소회로(Urea cycle)에서 아르기닌으로부터 요소를 방출해 오르니틴을 생성할 때에 작용하는 효소로써, L-아르기닌을 오르니틴 및 요소로 가수분해한다. 아르기나아제는 당뇨병, 심혈관질환 발병에 중요한 역할을 하는 것으로 알려져 있다.Arginase is an enzyme that acts to produce ornithine by releasing an element from arginine in the urea cycle, which hydrolyzes L-arginine into ornithine and urea. Arginine is known to play an important role in the pathogenesis of diabetes and cardiovascular disease.
아르기나아제 억제가 심혈관질환에 효과가 있다는 것이 알려져 있고(T. Bagnost et al., Cardiovascular Research, 87(3), 569-577, 2010), 미국 공개특허공보 제2010-0189644호에는 아르기나아제 억제제가 당뇨병, 위장질환, 폐렴, 면역장애, 암, 건선, 류마티스성 관절염 등에 효과가 있을 수 있다는 것이 개시되어 있으나, 아르기나아제 억제제를 비만 또는 지방간 치료에 이용할 수 있다는 사실은 밝혀진바 없었다.Arginase inhibition is known to be effective in cardiovascular disease (T. Bagnost et al., Cardiovascular Research , 87 (3), 569-577, 2010), U.S. Published Patent Application No. 2010-0189644 discloses that argininease inhibitors are effective for diabetes, gastrointestinal diseases, pneumonia, immune disorders, cancer, psoriasis and rheumatoid arthritis However, it has not been found that arginase inhibitors can be used for the treatment of obesity or fatty liver disease.
오히려 대한민국 공개특허공보 제10-2007-0100875호는 간염 치료용 약학 조성물에 관한 발명으로써, 아르기나아제를 이용하여 환자의 아르기닌 수준을 선택적으로 감소시킴으로써 간질환 치료 효과를 얻는 것인바, 본 발명은 아르기나아제의 활성을 억제하여 지방간 예방 또는 치료 효과를 얻을 수 있다는 점에서 큰 차이가 있다고 할 것입니다.Korean Patent Laid-Open Publication No. 10-2007-0100875 discloses a pharmaceutical composition for treating hepatitis. In the present invention, the arginine level is selectively reduced by using arginase as an antineoplastic agent, There is a big difference in that the activity of arginine or azine is inhibited and the effect of preventing or treating fatty liver can be obtained.
이에, 본 발명자들은 상기 문제점을 해결하기 위하여 예의 노력한 결과, 아르기나아제 억제제가 비만 또는 지방간 치료에 효과가 있는 것을 확인하고 본 발명을 완성하게 되었다.
Accordingly, the present inventors have made intensive efforts to solve the above problems, and as a result, they have found that arginase inhibitors are effective for the treatment of obesity or fatty liver, and have completed the present invention.
본 발명의 목적은 아르기나아제 억제제의 비만 또는 지방간 예방 또는 치료 용도를 제공하는데 있다.
It is an object of the present invention to provide an obesity or fatty liver preventive or therapeutic use of an arginase inhibitor.
상기 목적을 달성하기 위하여, 본 발명은 아르기나아제 억제제를 유효성분으로 함유하는 비만 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating obesity, which comprises an arginase inhibitor as an active ingredient.
본 발명은 또한, 아르기나아제 억제제를 유효성분으로 함유하는 비만 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing or improving obesity containing an arginase inhibitor as an active ingredient.
본 발명은 또한, 아르기나아제 억제제를 유효성분으로 함유하는 지방간 예방 또는 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for prevention or treatment of fatty liver comprising arginase inhibitor as an active ingredient.
본 발명은 또한, 아르기나아제 억제제를 유효성분으로 함유하는 지방간 예방 또는 개선용 건강기능식품 조성물을 제공한다.
The present invention also provides a health functional food composition for prevention or improvement of fatty liver comprising arginase inhibitor as an active ingredient.
본 발명에 따르면, 아르기나아제 억제제는 체중 증가량, 체지방량, 간 내 중성지방량 감소 효과가 있어, 비만 또는 지방간의 예방 또는 치료에 유용하다.
According to the present invention, arginase inhibitors have an effect of reducing body weight gain, fat saturation and hepatic triglyceride level, and are thus useful for prevention or treatment of obesity or fatty liver.
도 1은 실시예 2-2의 아르기나아제 억제제의 효과를 나타낸 것으로, 13주간 세 그룹의 체중증가량을 비교하여 나타낸 것이다.
도 2는 실시예 2-2의 아르기나아제 억제제의 효과를 나타낸 것으로, 예비사육 기간을 포함한 총 13주 후 세 그룹의 (A)는 간무게, (B)는 부고환 지방무게, (C)는 간 형태, (D)는 부고환 지방형태, (E)는 신장주위 지방무게, (F)는 복막후방 지방무게, (G)는 장간막 지방무게를 비교하여 나타낸 것이다. 또한, (C) 및 (D)는 헤마톡실린(hematoxylin) 및 에오신(eosin)으로 염색한 간 및 부고환 지방 파라핀 절편을 400배 확대한 것으로, (ⅰ)은 ND그룹을, (ⅱ)는 HFD 그룹을, (ⅲ)은 HFD+AI 그룹을 나타낸 것이다.
도 3은 실시예 2-2의 13주간 세 그룹의 간 중성지방(triglyceride) 농도를 비교하여 나타낸 것이다.
도 4는 실시예 3-2의 간 조직 내 mRNA 수치에 대한 아르기나아제 억제제의 효과를 세 그룹간 비교하여 나타낸 것으로, 전체 RNA는 간으로부터 추출하였고, (A)는 PPAR-γ, (B)는 PPAR-α, (C)는 PGC-1β에 대한 특정 프라이머를 사용한 실시간 PCR 분석 결과이다.
도 5는 실시예 4의 세포의 현미경 촬영 결과를 나타낸 것이다.
도 6은 실시예 4의 TG 측정 결과를 나타낸 것이다.
도 7은 실시예 4의 Oil Red O 측정 결과를 나타낸 것이다.Figure 1 shows the effect of the arginase inhibitor of Example 2-2, comparing the weight gain of the three groups over 13 weeks.
Figure 2 shows the effect of the arginase inhibitor of Example 2-2. After a total of 13 weeks including the preliminary feeding period, (A), (B) and (C) (D) is the epididymal fat type, (E) is the peripheral fat weight, (F) is the posterior peritoneal fat weight, and (G) is the mesenteric fat weight. In addition, (C) and (D) show 400-fold magnification of liver and epididymal fat paraffin sections stained with hematoxylin and eosin, (i) ND group, (ii) HFD (Iii) represents the HFD + AI group.
Figure 3 compares the triglyceride concentrations of the three week-old groups of Example 2-2.
Fig. 4 shows the effect of arginase inhibitor on the mRNA level in liver tissues of Example 3-2 by comparing three groups. Total RNA was extracted from liver, (A) was PPAR-gamma, (B) (C) is the result of real-time PCR analysis using PGC-1? Specific primers.
5 shows microscopic photographs of cells of Example 4. Fig.
6 shows the TG measurement result of Example 4. Fig.
Fig. 7 shows the results of Oil Red O measurement in Example 4. Fig.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 가진다. 일반적으로, 본 명세서에서 사용된 명명법은 본 기술 분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.
본 발명에서는, 고지방·고콜레스테롤 식이 공급과 함께 아르기나아제 억제제를 투여하는 비교실험을 수행한 결과, 아르기나아제 억제제가 체중증가량, 체지방량, 간 내 중성지방량 감소 효과가 있음을 확인하였다. In the present invention, a comparative experiment in which an arginase inhibitor was administered in combination with a high fat / high cholesterol diet supplement showed that the arginase inhibitor had an effect of reducing body weight gain, fat saturation and hepatic triglyceride.
본 발명의 일 실시예에서는 아르기나아제 억제제가 체중 증가량 및 체지방량 감소 효과가 있다는 것을 확인할 수 있었다.In one embodiment of the present invention, it has been confirmed that the arginase inhibitor has an effect of reducing body weight gain and body fat mass.
본 발명의 다른 실시예에서는 아르기나아제 억제제가 간 내 중성지방 농도 감소 효과가 있다는 것을 확인할 수 있었다.In another embodiment of the present invention, it has been confirmed that the arginase inhibitor has an effect of reducing hepatic triglyceride concentration.
본 발명의 또 다른 실시예에서는 올레산으로 유도된 지방간세포에 아르기나아제 억제제를 처리한 결과, 간세포 내 지방축적도가 현저하게 감소하는 것을 확인할 수 있었다.In another embodiment of the present invention, it was confirmed that the fat accumulation in the hepatocyte was remarkably reduced by treating the oleic acid-induced lipid hepatocyte with the arginase inhibitor.
따라서, 본 발명은 일 관점에서, 아르기나아제 억제제를 유효성분으로 함유하는 비만의 예방 또는 치료용 약학 조성물에 관한 것이다.Accordingly, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating obesity containing an arginase inhibitor as an active ingredient.
본 발명은 다른 관점에서, 아르기나아제 억제제를 유효성분으로 함유하는 비만의 예방 또는 개선용 건강기능식품 조성물에 관한 것이다.In another aspect, the present invention relates to a health functional food composition for preventing or ameliorating obesity containing an arginase inhibitor as an active ingredient.
본 발명은 또 다른 관점에서, 아르기나아제 억제제를 유효성분으로 함유하는 지방간 예방 또는 치료용 약학 조성물에 관한 것이다.In another aspect, the present invention relates to a pharmaceutical composition for prevention or treatment of fatty liver comprising arginase inhibitor as an active ingredient.
본 발명은 다른 관점에서, 아르기나아제 억제제를 유효성분으로 함유하는 지방간 예방 또는 개선용 약학 조성물에 관한 것이다.In another aspect, the present invention relates to a pharmaceutical composition for prevention or improvement of fatty liver comprising arginase inhibitor as an active ingredient.
본 발명에 있어서, 아르기나아제 억제제는 N-w-하이드록시-노르-L-아르기닌(N-w-hydroxy-nor-L-arginine)인 것을 특징으로 하나, 이에 한정되는 것은 아니다.In the present invention, the arginase inhibitor is N-w-hydroxy-nor-L-arginine, but is not limited thereto.
본 발명에 있어서, 아르기나아제 억제제는 화합물(chemicals), 천연물(natural compounds), 천연소재 유래 추출물, siRNA, micro RNA 또는 recombinant DNA 등의 핵산(nucleic acids), 펩타이드 및 단백질로 구성된 군에서 선택된 하나 이상인 것을 특징으로 하나, 이에 한정되는 것은 아니다.In the present invention, the arginase inhibitor is selected from the group consisting of chemicals, natural compounds, extracts derived from natural materials, nucleic acids such as siRNA, microRNA or recombinant DNA, peptides and proteins Or more, but is not limited thereto.
본 발명에 있어서, 아르기나아제 억제제가 PPAR -γ의 발현을 감소시키고, PPAR-α의 발현을 증가시키며, PGC -1β의 발현을 증가시키는 것을 특징으로 할 수 있다. 그 결과, 간 지질대사와 미토콘드리아 기능에 긍정적인 영향을 미침으로써, 결과적으로 지방간 양상을 호전시킨다는 것을 확인할 수 있었다.In the present invention, the arginase inhibitor is to decrease the expression of PPAR -γ, increases the expression of PPAR-α, it can be characterized by increasing the expression of PGC -1β. As a result, it was confirmed that hepatic lipid metabolism and mitochondrial function were positively influenced, resulting in improvement of fatty liver pattern.
본 발명의 명세서에서 사용된 용어 "조성물"은 특정 성분을 포함하는 산물 뿐만 아니라, 특정 성분의 배합에 의해 직접 또는 간접적으로 만들어지는 임의의 산물을 포함하는 것으로 간주된다.The term "composition" as used herein in the context of the present invention is intended to encompass the products containing the specified ingredients, as well as any products made directly or indirectly by the combination of the specified ingredients.
본 발명의 약학 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여의 경우에는 복강주입, 정맥내 주입, 피하주입, 근육주입 등으로 투여할 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intraperitoneal injection, intravenous injection, subcutaneous injection, muscle injection, or the like.
본 발명의 약학 조성물의 적합한 투여량은 증상의 경중도, 환자의 체중, 연령, 성, 투여 방식 및 투여시간 등과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정할 수 있다.The appropriate dosage of the pharmaceutical composition of the present invention will vary depending on factors such as severity of symptoms, body weight, age, sex, mode of administration and time of administration, etc. Usually, the skilled physician will administer effective doses Can be easily determined.
본 발명의 약학 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약학으로 허용되는 담체 또는 부형제를 이용하여 제제화함으로써 단위용량의 형태로 제조되거나 또는 다용량 용기내에 내입시켜 제조될 수 있다. 상기의 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로오스, 솔비톨, 아카시아 고무, 인산칼슘, 젤라틴, 셀룰로오스, 물, 시럽, 메틸하이드록시벤조에이트, 활석, 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 상기 조성물은 파라옥시안식향산메틸, 솔빈산칼륨 등과 같은 방부제, 안정화제, 매실향, 레몬향 등의 천연향료, 클로로필린 등의 천연색소, 과당, 벌꿀, 설탕 등과 같은 감미료, 염료, 항-산화제 등을 추가로 함유할 수 있다.The pharmaceutical composition of the present invention may be prepared in the form of a unit dose by formulating it using a pharmaceutically acceptable carrier or excipient according to a method which can be easily carried out by a person skilled in the art to which the present invention belongs Into a capacity container. The above carriers include lactose, dextrose, sucrose, sorbitol, acacia, calcium phosphate, gelatin, cellulose, water, syrup, methylhydroxybenzoate, talc, mineral oil and the like which are conventionally used in the formulation , But is not limited thereto. The composition can be used as a preservative such as methyl parahydroxybenzoate or potassium sorbate, a stabilizer, a natural flavor such as a plum flavor or a lemon flavor, a natural coloring matter such as chlorophyllin, a sweetener such as fructose, honey or sugar, May be further contained.
본 발명의 약학 조성물의 비경구투여를 위한 제제로는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제 등이 있으며, 비수성용제 또는 현탁제의 제로를 위해 프로필렌글리콜, 올리브오일과 같은 식물성기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있으며, 좌제의 기제로 위텝솔, 마크로골, 카카오지, 글리세로젤라틴 등이 사용될 수 있으나, 이에 한정되는 것은 아니다.Examples of the agent for parenteral administration of the pharmaceutical composition of the present invention include a sterilized aqueous solution, a non-aqueous solvent, a suspending agent, an emulsion, a freeze-dried preparation and a suppository. Examples thereof include propylene glycol, And injectable esters such as vegetable oil and ethyl oleate may be used. As a suppository, suppositories, macrogol, cacao butter, glycerogelatin and the like may be used, but the present invention is not limited thereto.
본 발명의 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다.The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent.
본 발명의 건강기능식품은 건강기능식품에 관한 법률 제6722호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 식품을 의미한다.The health functional food of the present invention refers to a food prepared and processed by using raw materials or ingredients having useful functions in accordance with Law No. 6722 on Health Functional Foods, Physiological function, etc., for the purpose of obtaining a beneficial effect for health food.
본 발명의 건강기능식품 조성물은 당해 기술분야에 공지되어 있는 통상적인 건강기능식품의 제형으로 제제화될 수 있고, 상기 건강기능식품은 과립제, 정제, 환제, 현탁액, 에멀젼, 시럽제, 껌, 차, 젤리, 각종 음료수, 드링크제, 알코올 음료 등으로 제조될 수 있으며, 상기 건강기능식품의 종류에는 특별한 제한이 없다.The health functional food composition of the present invention can be formulated into a conventional health functional food formulation known in the art, and the health functional food can be a granular preparation, a tablet, a pill, a suspension, an emulsion, a syrup, , Various beverages, drinks, alcoholic beverages and the like, and there is no particular limitation on the kind of the health functional food.
본 발명의 건강기능식품 조성물은 인체를 비롯한 동물 신체에 투여하기 적합한 임의의 생약 형태, 더욱 구체적으로는 경구 투여에 통상적인 임의의 형태, 예를 들어 식품 또는 사료, 식품 또는 사료의 첨가제 및 보조제, 강화된 식품 또는 사료, 정제, 환제, 과립, 캡슐 및 발포 배합물 등과 같은 고체 형태 또는 용액, 현탁액, 유화액, 음료, 페이스트 등과 같은 액체형태 일 수 있다. 상기 조성물은 영양제, 비타민, 전해질, 감미제, 착색제, 유기산, 방부제 등을 함유할 수 있으며, 이러한 성분들을 독립적으로 또는 조합하여 사용할 수 있다.
The health functional food composition of the present invention may be in any form suitable for administration to an animal body including the human body, more specifically any form usual for oral administration, for example additives and adjuvants of food or feed, food or feed, Solid forms such as fortified foods or feeds, tablets, pills, granules, capsules, and foamed formulations or liquid forms such as solutions, suspensions, emulsions, drinks, pastes and the like. The composition may contain nutrients, vitamins, electrolytes, sweeteners, colorants, organic acids, preservatives and the like, and these components may be used independently or in combination.
[실시예][Example]
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
실시예 1:Example 1: 마우스의 사육 및 식이Breeding and diet of mice
실험동물은 무특이병원체(Specific pathogen-free; SPF) 환경에서 사육된 4주령의 C57BL/6 마우스를 구입하여 사용하였다. 난괴법(randomized complete block design)에 의해 8마리씩 3그룹으로 분류하여 사육하였다: 정상식이 대조군(ND 그룹); 고지방·고콜레스테롤 식이 공급군(HFD 그룹); 고지방·고콜레스테롤 식이 공급 및 아르기나아제 억제제 경구투여군(HFD+AI 그룹). 환경에 적응시키기 위해 실험 시작 전 1주일간 예비사육한 후 체중 20±1g 내외로 실험을 시작하였고, 하기 표 1의 식이를 공급하며 실험동물 사육실의 온도는 18~24℃, 습도는 50~60%를 유지하여 12주간 사육하였다. 다만, HFD+AI 그룹의 경우, 사육 7주간은 고지방·고콜레스테롤 식이만을 공급하였고, 그 후 5주간은 고지방·고콜레스테롤 식이와 함께 0.9% NaCl 용액에 용해된 아르기나아제 억제제(N-w-hydroxy-nor-L-arginine; nor-NOHA) 40 mg/kg diet를 존데(sonde)를 이용하여 경구투여하였다.Experimental animals were purchased with 4-week-old C57BL / 6 mice raised in a specific pathogen-free (SPF) environment. Groups of 8 rats were randomly divided into three groups according to the randomized complete block design: the control group (ND group); High fat and high cholesterol diet (HFD group); High-fat, high-cholesterol diet and oral arginase inhibitor (HFD + AI group). In order to adapt to the environment, the experiment was started at a weight of 20 ± 1 g after preliminary breeding for 1 week before the start of the experiment. The temperature of the experimental animal breeding room was 18-24 ° C. and the humidity was 50-60% And maintained for 12 weeks. In the HFD + AI group, only high-fat and high-cholesterol diet was fed for 7 weeks, followed by high-fat and high-cholesterol diet for 5 weeks, and Nw-hydroxy- nor-L-arginine; nor-NOHA) was orally administered using 40 mg / kg diet using a sonde.
(미네랄믹스: AIN-76 미네랄믹스, 비타민믹스: AIN-76 비타민믹스)
(Mineral Mix: AIN-76 Mineral Mix, Vitamin Mix: AIN-76 Vitamin Mix)
실시예Example 2: 비만 및 지방간 치료 효과 확인 및 분석 2: Identification and Analysis of Obesity and Fatty Liver Therapeutic Effect
2-1: 마우스의 혈액 채취, 조직 적출 및 지질추출2-1: Blood collection, tissue extraction and lipid extraction of mouse
사육기간이 종료된 후 희생시키기 전 12시간 동안 절식시킨 후, 마우스를 고정시키고, 30mg/kg 졸레틸 및 10mg/kg 럼푼을 섞어 복강 내 투입하여 마취시켰다. 마취 후 개복한 뒤 주사기를 이용하여 복부 하대정맥에서 혈액을 채취하였다. 채취한 혈액은 EDTA가 들어있는 폴리스티렌(polystylene) 원심분리관에 담아 분석에 이용하였다. After the end of the rearing period, the mice were fasted for 12 hours before the sacrifice, and the mouse was fixed and anesthetized by intraperitoneal injection of 30 mg / kg of zoletil and 10 mg / kg of rumon. After laparotomy, anesthesia was performed and blood was collected from the abdominal cavity using a syringe. The collected blood was collected in a polystyrene centrifuge tube containing EDTA and used for analysis.
또한, 간조직과 부위별 내장 지방(epididymal, perirenal, mesenteric fat, retroperitoneal fat pad)을 부위별로 적출하였다. 적출한 부고환지방과 간 조직을 1 M 인산완충식염수(phosphate buffered saline)로 세척한 후, 그 일부를 0.1 mm3 크기로 잘게 조각내어, 10 % 포르말린(formalin) 용액에서 고정시켰다. 간세포는 HE 염색(헤마톡실린 및 에오신 염색; HE staining)을 통해 핵과 세포질을 염색하여 지방축적의 정도를 관찰하고, 부고환지방 세포는 그 크기변화를 관찰하여, 체지방 감량 효과를 평가하였다.In addition, intestinal fat (epididymal, perirenal, mesenteric fat, retroperitoneal fat pad) was extracted by site. The epididymal fat and hepatic tissues were washed with 1 M phosphate buffered saline, and a portion of the epididymal fat and liver was minced to a size of 0.1 mm 3 and fixed in 10% formalin solution. Hepatocytes were stained with hematoxylin and eosin staining (HE staining) to observe the extent of fat accumulation by staining nuclei and cytoplasm, and observed the change in size of epididymal adipocytes, and evaluated the effect of body fat loss.
간조직의 지질성분을 추출하기 위해, 폴츠법에 준해, 0.25g의 간조직에 1 ml의 증류수를 가한 후, 조직파쇄장치(tissue lyser)를 사용하여 균질화시켰다(Folch et al., J Biol Chem, 226, 497, 1957). 상기 균질액에 클로로포름:메탄올(chloroform:methanol) 용액(2:1, v/v) 2.5 ml을 가하고, 볼텍싱한(vortexing) 후, 1000xg에서 10분간 원심분리하여 하층액만을 분리하였다. 상기 하층액을 취하여 질소가스로 완전히 건조시킨 후, 총 지질량을 측정하였다. 건조된 지질은 0.5 ml의 이소프로판올(isopropanol)에 녹여 지질분석에 사용하였다. 간조직 지질추출액의 중성지방은 상업용 지질분석 키트(아산제약, 서울, 한국)를 사용하여 측정하였다.
To extract the lipid component of the liver tissue, 1 ml of distilled water was added to 0.25 g of liver tissue according to the Pauls' method and homogenized using a tissue lyser (Folch et al., J Biol Chem. , 226, 497, 1957). 2.5 ml of a chloroform: methanol solution (2: 1, v / v) was added to the homogenate, vortexed and centrifuged at 1000 xg for 10 minutes to separate only the bottom layer. The lower layer liquid was taken out and completely dried with nitrogen gas, and then the total lipid amount was measured. The dried lipids were dissolved in 0.5 ml of isopropanol and used for lipid analysis. The triglyceride of hepatic lipid extract was measured using a commercial lipid analysis kit (Asan Pharm, Seoul, Korea).
2-2: 아르기나아제 억제제의 체중 및 2-2: body weight of arginase inhibitor and 체지방량에In body fat 대한 효과 분석 Effect analysis
사육을 시작할 당시, 그룹간 체중에 유의적인 차이가 없었고, 고지방·고콜레스테롤 식이를 공급한 두 그룹(HFD 그룹 및 HFD+AI 그룹)은 사육 2주차부터 식이를 통해 체중을 대조군(ND 그룹)에 비해 유의하게 상승시켰다. 7주간의 비만 유도(obesity induction) 후 5주간 추가적으로 고지방·고콜레스테롤 식이 공급과 더불어 아르기나아제 억제제를 투여하였을 때, 체중 증가(도 1)및 체지방량(도 2)이 현저하게 감소되었다는 것을 확인하였다. HFD+AI 그룹의 경우, ND 그룹 및 HFD 그룹에 비해 음식 섭취량(food intake)이 더 많음에도 불구하고 체중 증가폭이 더 적은 것으로 나타나 사료효율비(Feed Efficiency Ratio; FER) 감소측면에서 의미가 있음을 알 수 있었다(표 2). 또한, 고지방 식이 비만 유도시 간 내 지방이 축적되는 지방간 양상이 나타나게 되는데, HFD+AI 그룹의 경우 간 중량, 간 내 지방축적량 및 간 중성지방 농도가 유의하게 감소한 것을 알 수 있었다(도 2 및 도 3).Two groups (HFD group and HFD + AI group) that fed high fat and high cholesterol diet were divided into two groups by feeding diets to control group (ND group) Respectively. (Fig. 1) and body fat mass (Fig. 2) were significantly reduced when an arginine or azide inhibitor was administered in addition to a high fat / high cholesterol diet for 5 weeks after 7 weeks of obesity induction . In the HFD + AI group, weight gain was smaller than that of the ND group and the HFD group in spite of more food intake, which is significant in terms of decreasing the feed efficiency ratio (FER) (Table 2). In addition, it was found that the liver weight, the amount of accumulated fat in the liver, and the concentration of hepatic triglyceride were significantly decreased in the HFD + AI group when the high fat diet induces obesity (FIG. 2 and FIG. 3).
그룹
group
(n=8)ND Group
(n = 8)
(n=8)HFD Group
(n = 8)
(n=8)HFD + AI group
(n = 8)
실시예Example 3: 유전자 발현 조절을 통한 비만 및 지방간 치료 효과 확인 및 분석 3: Identification and Analysis of Obesity and Fatty Liver Therapy by Gene Expression Control
3-1: 3-1: RNARNA 추출 및 실시간 Extract and Real Time RTRT -PCR(-PCR ( RealReal -- TimeTime RTRT -- PCRPCR ))
조직 내 RNA를 QIAzol Lysis reagent RNeasy Lipid Tissue Mini Kit (Qiagen, 미국)을 이용하여 추출하고, 1 μg RNA를 올리고-dT(oligo-dT)와 superscript Ⅱ 역전사효소(Invitrogen, 미국)로 cDNA 합성하였다. 그 후, 상기 cDNA(1000 ng)의 유전자발현을 실시간 정량 PCR 증폭(quantitative real-time PCR amplification)을 통해 비교하였다. 데이터는 비교-사이클 역치법(comparative-cycle threshold method)을 이용하여 확보하여 배수변화(fold change)로 나타내었다. 분석 대상 유전자는 PPAR-gamma, PPAR-alpha, PGC-1 beta 등의 관련 유전자를 함유한다. PCR조건은 95 ℃에서 15분, 94 ℃에서 30초, 58 ℃에서 20초, 72 ℃에서 30초이었고, 두 번째 단계에서부터 40 회(cycle) 반복하였다(Step One Plus, Applied Biosystems, Foster City, 캘리포니아, 미국). 글리세르알데히드-3-인산 탈수소효소(glyseraldehyde-3-phosphate dehydrogenase; GAPDH)는 비교 CT법(Comparative CT method)에서 대조군으로 사용하였다.
RNA was extracted with oligo-dT (oligo-dT) and superscript II reverse transcriptase (Invitrogen, USA). The gene expression of the cDNA (1000 ng) was then compared by quantitative real-time PCR amplification. Data were obtained using the comparative-cycle threshold method and expressed as a fold change. The genes to be analyzed contain related genes such as PPAR-gamma, PPAR-alpha and PGC-1 beta. The PCR conditions were 15 min at 95 ° C, 30 sec at 94 ° C, 20 sec at 58 ° C, and 30 sec at 72 ° C, and repeated 40 cycles from the second step (Step One Plus, Applied Biosystems, Foster City, California, USA). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a control in the comparative CT method.
3-2: 간 조직 내 3-2: In the liver mRNAmRNA 수치에 대한 아르기나아제 억제제의 효과 분석 Analysis of the effects of arginase inhibitors on levels
유전자 발현도를 분석해본 결과, 대조군(ND 그룹)을 1로 나타내었을때, PPAR-γ의 경우 HFD 그룹은 2.22배 증가하였고, HFD+AI 그룹은 1.26배로 HFD에 비해 감소하는 것으로 나타났다. PPAR-α의 경우 HFD 그룹은 0.78배로 감소하였으나, HFD+AI 그룹은 1.42배로 대조군보다 높게 발현되었다. 또한 PGC-1β의 경우 HFD 그룹은 0.58배로 감소되었는데, HFD+AI 그룹은 0.91배로 대조군과 근접하게 상승되는 것으로 나타났다(도 4).In the analysis of gene expression, when the control group (ND group) was represented as 1, the HFD group was increased by 2.22-fold in PPAR-γ and the HFD + AI group was decreased by 1.26-fold compared to HFD. In the case of PPAR-α, the HFD group was reduced to 0.78-fold, while the HFD + AI group was 1.42-fold higher than that of the control group. In the case of PGC-1β, the HFD group was reduced to 0.58-fold, and the HFD + AI group was 0.91-fold, which was close to that of the control group (FIG.
따라서, 아르기나아제 억제제가 간 조직 내 PPAR-γ, PPAR-α 및 PGC-1β 유전자 발현도를 조절함으로써, 간 지질대사와 미토콘드리아 기능에 긍정적인 영향을 끼치고, 결과적으로 지방간 양상을 호전시키며, 체중 및 체지방의 감소로 이어진 것으로 확인되었다.
Thus, arginase inhibitors have a positive effect on hepatic lipid metabolism and mitochondrial function by modulating the expression of PPAR-γ, PPAR-α and PGC-1β genes in liver tissues, resulting in improved fatty liver morphology, And decreased body fat.
실시예Example 4: 올레산으로 유도된 지방간세포 내 아르기나아제 억제제의 지방간 치료 효과 확인 및 분석 4: Identification and Analysis of Fatty Liver Therapeutic Effect of Arginine and Agase Inhibitors in Oleic Acid Induced Fatty Liver Cells
고당 둘베코 변형 이글 배지(high-glucose Dulbecco's modified Eagle medium; DMEM; Gibco, 에겐스타인, 독일)에 1% ABS와 열에 의해 비활성화시킨 FBS 10%를 첨가하여 간암세포(HepG2)를 배양하였고, 배지를 2일 마다 교체하였다. Liver cancer cells (HepG2) were cultured by adding 1% ABS and heat-inactivated
2 X 105 개의 세포를 48-웰 배양 플레이트에 깔고, 24시간 후 무혈청배지(serum-starved)로 교체하였다. 다음날, 절식시킨 세포에 1.5 mM 농도의 올레산(OLA; Sigma-Aldrich)과 함께, 아르기나아제 억제제(N-w-hydroxy-nor-L-arginine; nor-NOHA)를 농도를 달리하여 24시간 동안 처리하였다(10 및 50 μM). 정상대조세포의 경우에는, 올레산의 용매인 에탄올과 nor-NOHA의 용매인 증류수(DW)를 함께 처리하였다.2
24시간 후 세포를 1 X PBS로 2번 세척하고, 10% 포르말린 용액으로 1시간 동안 실온에서 고정시켰다. 고정된 세포를 60%의 이소프로판올로 세척하고, 오일 레드 오(Oil Red O; ORO) 용액을 10분 동안 실온에서 방치시켰다. 염색된 세포를 증류수로 4번씩 조심스럽게 세척하여, 현미경을 이용하여 사진을 촬영하였다(도 5). 그 후, 이소프로판올(100%)을 세포에 첨가하여 10분간 방치시키고, 수차례 파이페팅 후 500 nm에서 흡광도를 측정하였다. After 24 hours, the cells were washed twice with 1X PBS and fixed with 10% formalin solution for 1 hour at room temperature. The fixed cells were washed with 60% isopropanol and the Oil Red O (ORO) solution was left at room temperature for 10 minutes. The stained cells were carefully washed four times with distilled water and photographed using a microscope (Fig. 5). After that, isopropanol (100%) was added to the cells and allowed to stand for 10 minutes. After several times of pipetting, the absorbance was measured at 500 nm.
아디포레드 측정 시약(AdipoRed assay reagent; Lonza, Walkersville, MD, 미국)을 이용하여, 세포 내 중성지방(triglyceride; TG) 측정을 수행하였다. 오일 레드 오 처리 실험과 동일한 방법으로, 1 X PBS로 세척 후, 프로토콜에 제시되어 있는 적절한 양의 시약을 1 X PBS와 섞은 후 15분 동안 실온에서 방치하였다. 빛을 차단시키기 위하여 호일로 감싸주었다. 형광강도측정기(Fluorimeter)를 이용하여 형광 흡광도를 측정하였다(여기(excitation) 485 nm 및 방출(emission) 572 nm).Intracellular triglyceride (TG) measurements were performed using the AdipoRed assay reagent (Lonza, Walkersville, MD, USA). After washing with 1 X PBS, the appropriate amount of reagent as given in the protocol was mixed with 1 X PBS and left at room temperature for 15 minutes in the same manner as the oil red osmotic treatment experiment. It was wrapped with foil to block the light. Fluorescence absorbance was measured using fluorescent intensity meter (Fluorimeter) (excitation 485 nm and emission 572 nm).
그 결과, 1.5 mM의 올레산을 처리한 지방간 유도 세포는 정상대조세포와 비교하였을 때, TG와 ORO를 통한 지방축적도가 유의적으로 증가하였음을 확인할 수 있었다. 아울러, 아르기나아제 억제제인 nor-NOHA(10 및 50 μM)를 처리한 세포는 TG와 ORO를 통한 지방축적도가 현저히 감소된 것을 확인할 수 있었다(도 6 및 7).
As a result, it was confirmed that the fatty accumulation degree of TG and ORO was significantly increased in the fatty liver induction cells treated with 1.5 mM oleic acid compared with the normal control cells. In addition, it was confirmed that the cells treated with arginase inhibitor nor-NOHA (10 and 50 [mu] M) significantly decreased fat accumulation through TG and ORO (FIGS. 6 and 7).
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시태양일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (18)
A pharmaceutical composition for preventing or treating obesity, comprising an arginase inhibitor as an active ingredient.
The pharmaceutical composition for preventing or treating obesity according to claim 1, wherein the arginase inhibitor is Nw-hydroxy-nor-L-arginine.
The pharmaceutical composition for preventing or treating obesity according to claim 1, wherein the arginase inhibitor is at least one selected from the group consisting of compounds, natural products, extracts derived from natural materials, nucleic acids, peptides and proteins.
A health functional food composition for preventing or ameliorating obesity containing arginase inhibitor as an active ingredient.
The health functional food composition according to claim 4, wherein the arginase inhibitor is Nw-hydroxy-nor-L-arginine.
The health functional food composition according to claim 4, wherein the arginase inhibitor is at least one selected from the group consisting of a compound, a natural product, a natural extract, a nucleic acid, a peptide and a protein.
A pharmaceutical composition for the prevention or treatment of fatty liver comprising arginase inhibitor as an active ingredient.
The pharmaceutical composition according to claim 7, wherein the arginase inhibitor is Nw-hydroxy-nor-L-arginine.
[Claim 7] The pharmaceutical composition according to claim 7, wherein the arginase inhibitor is at least one selected from the group consisting of compounds, natural products, extracts derived from natural materials, nucleic acids, peptides and proteins.
8. The pharmaceutical composition according to claim 7, wherein said arginase inhibitor reduces the expression of PPAR- gamma .
The pharmaceutical composition according to claim 7, wherein the arginase inhibitor increases the expression of PPAR- alpha .
8. The pharmaceutical composition according to claim 7, wherein said arginase inhibitor increases the expression of PGC-1 beta .
A health functional food composition for prevention or improvement of fatty liver comprising arginase inhibitor as an active ingredient.
14. The health functional food composition according to claim 13, wherein the arginase inhibitor is Nw-hydroxy-nor-L-arginine.
14. The health functional food composition according to claim 13, wherein the arginase inhibitor is at least one selected from the group consisting of compounds, natural products, extracts derived from natural materials, nucleic acids, peptides and proteins.
14. The health functional food composition according to claim 13, wherein said arginase inhibitor reduces the expression of PPAR- gamma .
14. The health functional food composition according to claim 13, wherein said arginase inhibitor increases the expression of PPAR- alpha .
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