KR101903150B1 - Composition comprising quinizarin for preventing or treating of obesity - Google Patents
Composition comprising quinizarin for preventing or treating of obesity Download PDFInfo
- Publication number
- KR101903150B1 KR101903150B1 KR1020160117532A KR20160117532A KR101903150B1 KR 101903150 B1 KR101903150 B1 KR 101903150B1 KR 1020160117532 A KR1020160117532 A KR 1020160117532A KR 20160117532 A KR20160117532 A KR 20160117532A KR 101903150 B1 KR101903150 B1 KR 101903150B1
- Authority
- KR
- South Korea
- Prior art keywords
- quinizarin
- preventing
- obesity
- adipocytes
- composition
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- A61K31/00—Medicinal preparations containing organic active ingredients
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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
- A23V2200/332—Promoters of weight control and weight loss
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- Y10S514/909—
Abstract
본 발명은 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 치료용 약학적 조성물 및 비만 예방 또는 개선용 건강기능성 식품 조성물에 관한 것으로, 보다 상세하게는 상기 조성물이 지방세포의 지질 축적을 감소 시키고, 지방세포 내 중성지방의 함량을 감소시킴으로써 항비만 활성이 우수한 조성물을 제공한다. The present invention relates to a pharmaceutical composition for preventing or treating obesity comprising quinizarin as an active ingredient and a health functional food composition for preventing or ameliorating obesity. More particularly, the present invention relates to a composition for preventing or treating obesity, The present invention provides a composition having excellent anti-obesity activity by reducing the content of intracellular triglycerides.
Description
본 발명은 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 치료용 약학적 조성물 및 비만 예방 또는 개선용 건강기능성 식품 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for preventing or treating obesity comprising quinizarin as an active ingredient, and a health functional food composition for preventing or ameliorating obesity.
비만은 체지방이 증가된 형태로 에너지의 섭취와 소비의 불균형에 의해 발생하며(Spiegelman & Flier 2001), 체중의 과잉증가가 아니라 체내 지방조직의 과잉증가를 의미한다. 식생활의 서구화와 생활의 편리화로 인한 활동량 감소로 인한 비만 인구의 급격한 증가는 전 세계적인 보건 문제가 있다. 현재 우리나라의 경우에도 급속한 경제 성장과 의학발달, 생활수준의 향상, 생활의 편리화, 식활 형태의 변화와 활동량 감소에 의하여 비만인구가 증가하고 있다(Choi 등 2005). 2010국민건강통계에 의하면 우리나라 성인의 비만(체질량지수 25 kg/㎡)유병률은 1998년 25.65%에서 2010년 30.55%로 지속적으로 증가하고 있으며, 이는 미국(NHANES, 2005-2008년, 만20세 이상, 체질량지수 30.0 kg/㎡이상)의 비만 유병률 34.25%에 근접한 수준이다(Ministry of Health, Welfare and Family Affairs (MOHWFA); Korea Center for Disease Control and Prevention (KCDCP) 2010).Obesity is caused by the imbalance of energy intake and consumption (Spiegelman & Flier 2001), which is an increase in body fat, which means an excess increase in the body fat tissue rather than an increase in body weight. The rapid increase in the obesity population due to the decrease in activity due to the westernization of diet and the convenience of life has a global health problem. In Korea, too, obesity is increasing due to rapid economic growth, medical development, improvement of living standards, convenience of living, change of dietary patterns and decrease of activity (Choi et al. 2005). According to the 2010 National Health Statistics, the prevalence of obesity (body mass index 25 kg / ㎡) in Korean adults is steadily increasing from 25.65% in 1998 to 30.55% in 2010, which is the highest in the United States (NHANES, 2005-2008, , And body mass index (BMI) of 30.0 kg / ㎡) is close to 34.25% (Ministry of Health, Welfare and Family Affairs (MOHWFA); Korea Center for Disease Control and Prevention (KCDCP) 2010).
비만은 대부분 섭취한 열량 중에서 소모되고 남는 부분이 지방세포(adipocyte)에서 지방으로 전환되어 체내의 피하조직과 복강 내에 축적되는 현상이다. 이러한, 지방세포의 크기에는 한계가 있으므로 과잉 에너지를 섭취할 때 에너지를 빨리 저장하기 위해서는 지방세포 수의 증가가 필요하게 되어 인체에서는 새로운 지방세포를 만든다. 새로운 지방세포는 전구지방세포(pro-adipocyte)로부터 분화되는데, 전구지방세포는 줄기세포(stem cell)로부터 분화되어 형성되고, 줄기세포가 전구지방세포를 거쳐 지방세포로 분화되는 과정에는 호르몬, 성장요소, 사이토카인 등의 생체조절자(regulator)들이 영향을 미친다.Obesity is a phenomenon in which most of the consumed calories are consumed and the remaining part is converted from fat cells (adipocyte) to fat and accumulated in the subcutaneous tissue and abdominal cavity of the body. Since there is a limit to the size of the adipocytes, it is necessary to increase the number of adipocytes in order to store the energy quickly when consuming the excess energy, and thus, a new adipocyte is produced in the human body. The new adipocytes differentiate from pro-adipocytes, which are formed by differentiation from stem cells. The process of differentiation of stem cells into adipocytes through adipocytes is called hormone, growth Factors such as urea, cytokine, and the like regulators are affected.
지질 저하효과가 있는 성분으로는 사포닌, 필수 아미노산, 비타민 E, 비타민 C 등이 있으며. 최근에 약용식물(medicinal herb)의 치료효과에 대한 관심이 높아지면서 천연물에 대한 수요가 증대되고 있다. 최근에는 약용식물을 이용한 항비만제의 연구가 활발하다. 이 중 등록특허 10-0903970(공개일자: 2009년03월18일)에는 신선목, 옥수수 수염, 목통, 백출, 갈근, 호박, 생강, 세신, 인진쑥 및 두충 추출물을 포함하는 지방분해용 식품의 제조방법을 기재하고 있다.Saponins, essential amino acids, vitamin E, and vitamin C are the components that have lipid lowering effect. Recently, as the interest in the therapeutic effect of medicinal herbs has increased, the demand for natural products is increasing. Recently, research on anti-obesity agents using medicinal plants has been actively conducted. Among them, a method for producing a fat-soluble food product comprising a fresh neck, a corn mustache, a lycopene, a lycopodium, a squid, an amber, a ginger, a sesin, an arthaxis and a squid extract is disclosed in a registered patent 10-0903970 (public date: Mar. 18, 2009) .
이러한 이유로 비만을 치료하거나 예방하는 다양한 항비만 약물을 개발하기 위한 연구에 대한 관심이 집중되어 왔다. 항비만 약물은 식이 섭취 감소, 대사 작용을 변형 또는 에너지 소비 증가를 통해 체중 감소를 유도하지만, 이러한 효과와 함께 안전성의 문제가 지속적으로 지적되고 있다(Mark 2009). 이로 인하여 지금까지 다양한 항비만 약물들이 생산되어 왔지만 심각한 부작용들로 인해 시판이 중단되기도 하였다(Vivero 등 1998). 현재 미국 식품의약국에서 승인되어 장기간 사용이 가능한 항비만제는 시상하부 신경절에서 세로토닌 및 노르에피네프린의 재흡수를 억제함으로써 식욕억제와 포만감을 증가시키는 Sibutramine(Ryan 등 1995; Hansen 등 1998)과 췌장 리파아제(Pancreatic lipase)의 억제를 통한 장간막 지방흡수를 감소시키는 Orlistat 2종이다(Greenway & Caruso 2005). 그러나 이 약물들 또한 혈압 증가, 구갈, 변비, 두통, 불면증의 부작용이 보고되었다(Thurairajah 등 2005; Simone & D'Addeo 2008; Slovacek 등 2008; Karamadoukis 등 2009). 2002년 10월부터 2006년 10월까지 4년간 18세 이상의 비만 성인을 대상으로 Sibutramine과 Orlistat의 항비만 효능과 부작용에 대해 실험한 결과 Sibutramine의 경우에는 수축기혈압과 확장기혈압이 각각 1.7 mm Hg와 2.4 mm Hg 증가와 불면증, 메스꺼움, 구갈, 변비의 발생률이 7%에서 20%로 증가하였으며, Orlistat의 경우에도 위장병에 따른 부작용의 발생률이 15%에서 30%까지 증가한 것으로 나타났다(Padwal & Majumdar 2007).For this reason, interest has been focused on the development of various anti-obesity drugs that treat or prevent obesity. Anti-obesity drugs induce weight loss through reduced dietary intake, altered metabolism, or increased energy expenditure, but with this effect safety issues are constantly being pointed out (Mark 2009). Because of this, various anti-obesity drugs have been produced so far, but they have been discontinued due to serious side effects (Vivero et al. 1998). Currently, the US Food and Drug Administration approved long-term antiobesity agent, Sibutramine (Ryan et al. 1995; Hansen et al. 1998), which increases appetite suppression and satiety by inhibiting the reuptake of serotonin and norepinephrine in the hypothalamus, and pancreatic lipase (Greenway & Caruso 2005), which reduces mesenteric fat absorption through inhibition of pancreatic lipase. However, these drugs have also been reported to increase blood pressure, gag, constipation, headache, and insomnia (Thurairajah et al., 2005; Simone & D'Addeo 2008; Slovacek et al. 2008; Karamadoukis et al. Sibutramine and Orlistat were tested for antiobesity and adverse effects in obese adults aged 18 years and older over the period from October 2002 to October 2006. Sibutramine had a systolic and diastolic blood pressure of 1.7 mm Hg and 2.4 mm Hg and the incidence of insomnia, nausea, oozing, constipation increased from 7% to 20%, and the incidence of gastrointestinal side effects increased from 15% to 30% in Orlistat (Padwal & Majumdar 2007).
이러한 비만치료제의 다양한 부작용으로 인해 최근에는 인체에 최소한의 부작용을 가지는 조추출물을 포함한 천연물, 식물로부터 분리한 화합물, 미생물 유래 천연물질, 플라보노이드, 안트라퀴논 등을 이용한 비만치료제 개발을 위한 연구가 이루어지고 있다.Due to various side effects of such a therapeutic agent for obesity, studies for the development of a therapeutic agent for obesity using natural products including crude extracts, a compound isolated from plants, natural substances derived from microorganisms, flavonoids and anthraquinones, etc., have.
이에 본 발명자들은 종래 합성 약제 조성물이 유발하는 심혈관작용, 중추작용, 간장장애 및 신장장애 등 여러 부작용이 없는 퀴니자린의 신규한 활성을 밝혀내고자 노력하였다. 그 결과, 상기 퀴니자린이 지방세포의 지질축적 감소 및 지방세포 내 중성지방의 함량을 감소시킴으로써 항비만 활성에 효과가 있음을 규명하였다.Accordingly, the present inventors have sought to discover a novel activity of quinizarin without adverse effects such as cardiovascular action, central action, hepatic disorder and kidney disorder induced by the conventional synthetic pharmaceutical composition. As a result, it was confirmed that quiznizarin is effective for anti-obesity activity by reducing lipid accumulation of fat cells and reducing the content of triglyceride in adipocytes.
따라서, 본 발명의 목적은 상기와 같은 문제점을 해결하기 위해 안출된 것으로, 하기 화학식 1의 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 치료용 약학적 조성물을 제공하는 것이다. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating obesity comprising quinizarin as an active ingredient of the following formula (1).
[화학식 1][Chemical Formula 1]
본 발명의 또 다른 목적은 상기 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 개선용 건강기능성 식품 조성물을 제공하는 것이다. Yet another object of the present invention is to provide a health functional food composition for preventing or improving obesity comprising quinizarin as an active ingredient.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다. However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
따라서, 본 발명은 하기 화학식 1의 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of obesity comprising quinizarin as an active ingredient.
[화학식1][Chemical Formula 1]
상기 본 발명의 바람직한 일실시예에 따르면, 상기 조성물은 지방세포의 지질 축적을 감소시키는 것일 수 있다.According to a preferred embodiment of the present invention, the composition may reduce lipid accumulation of adipocytes.
상기 본 발명의 바람직한 다른 일실시예에 따르면, 상기 조성물은 지방세포 내 중성지방의 함량을 감소시키는 것일 수 있다.According to another preferred embodiment of the present invention, the composition may reduce the content of triglyceride in adipocytes.
상기 본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 조성물은 C/EBP-α(CCAAT/enhancer binding protein peroxisome-α), C/EBP-β(CCAAT/enhancer binding protein peroxisome-β), PPAR-γ(Peroxisome proliferator-activated receptor-γ) 및 aP2(adipocyte protein 2)로 이루어진 군 중 선택되는 하나 이상의 mRNA 또는 단백질 발현량을 감소시키는 것일 수 있다.According to another preferred embodiment of the present invention, the composition is selected from the group consisting of C / EBP-α (CCAAT / enhancer binding protein peroxisome-α), C / EBP- (mRNA or protein) selected from the group consisting of Peroxisome proliferator-activated receptor-gamma (gamma), and aP2 (adipocyte protein 2).
상기 본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 조성물은 퀴니자린을 0.1~100 μM의 농도로 포함하는 것일 수 있다.According to another preferred embodiment of the present invention, the composition may contain quinizarin at a concentration of 0.1 to 100 μM.
또한, 본 발명은 상기 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 개선용 건강기능성 식품 조성물을 제공한다. The present invention also provides a health functional food composition for preventing or improving obesity comprising quinizarin as an active ingredient.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로, 지방세포의 성장억제, 지방세포의 지질축적 및 중성지방의 함량을 감소시킴으로써 항비만 활성이 우수한 퀴니자린을 포함하는 비만 예방 또는 치료용 약학적 조성물을 제공하고자 한다.Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made in order to solve the above-mentioned problems, and it is an object of the present invention to provide a pharmaceutical composition for prevention or treatment of obesity including quinizarin, which has excellent antiobesity activity by reducing fat cell growth, To provide an effective composition.
본 발명은 종래 합성 조성물이 유발하는 심혈관작용, 중추작용, 간장장애 및 신장장애 등 여러 부작용이 없어 인체에 무해하며, 정상세포에는 부작용을 유발하지 않아 장기간 사용하는데 인체에 무리가 없는 조성물을 제공하는데 효과가 있다. The present invention provides a composition which is harmless to the human body due to no adverse effects such as cardiovascular action, central action, hepatic disorder and kidney disorder caused by the conventional synthetic composition, and which does not cause side effects to the normal cells, It is effective.
도 1은 Quinizarin의 물질 구조이다.
도 2는 실시예 1에서 확인한 Quinizarin의 지방전구세포 생존력 측정결과이다.
도 3은 실시예 2에서 확인한 Quinizarin의 지방세포에서의 지질축적 저해 활성 결과이다. 이 때, UC(Undifferentiated control)는 미분화된 대조군 세포이고, Con(Differentiated control)은 분화된 대조군 세포를 나타낸다.
도 4는 실시예 3에서 확인한 Quinizarin 지방세포 내 중성지방 함량 분석 결과이다.
도 5는 실시예 4에서 확인한 지방세포에서의 C/EBP-β의 protein 농도변화이다.
도 6은 실시예 5에서 확인한 지방세포에서의 C/EBP-α의 protein 농도변화이다.
도 7은 실시예 6에서 확인한 지방세포에서 PPAR-γ의 mRAN 발현량 측정 결과이다.
도 8은 실시예 7에서 확인한 지방세포에서 aP2의 mRNA 발현량 측정 결과이다.Figure 1 is the material structure of Quinizarin.
FIG. 2 shows the results of measurement of the lipid precursor cell viability of Quinizarin as confirmed in Example 1. FIG.
FIG. 3 shows the lipid-accumulating inhibitory activity of quinizarin in adipocytes as confirmed in Example 2. FIG. At this time, undifferentiated control (UC) is an undifferentiated control cell, and Con (Differentiated control) represents a differentiated control cell.
FIG. 4 shows the results of analysis of the triglyceride content in quinizarin adipocytes as confirmed in Example 3. FIG.
Fig. 5 is the change in protein concentration of C / EBP-β in adipocytes as confirmed in Example 4. Fig.
6 is a graph showing changes in protein concentration of C / EBP-? In adipocytes as observed in Example 5. Fig.
FIG. 7 shows the results of measurement of mRAN expression level of PPAR-y in adipocytes as confirmed in Example 6. FIG.
Fig. 8 shows the results of measurement of the amount of aP2 mRNA expression in the adipocyte identified in Example 7. Fig.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
상술한 바와 같이, 종래 합성 약제는 심혈관작용, 중추작용, 간장장애 및 신장장애 등 여러 부작용이 나타났으며, 이에 대한 부작용 감소를 위해 제안된 종래 통상적으로 사용되는 열수추출법을 이용하여 제조된 생약제 추출물은 지방세포의 지질축적을 저해하고 지방세포 내 중성지방의 함량을 감소 효과가 없어 이에 대한 새로운 대안이 필요한 실정이었다.As described above, the conventional synthetic medicines have various adverse effects such as cardiovascular action, central action, hepatic disorder and kidney disorder. In order to reduce adverse effects, conventional medicinal herbal extracts Was not effective in inhibiting lipid accumulation of adipocytes and reducing the content of triglyceride in adipocytes. Therefore, a new alternative was needed.
이에 본 발명자들은 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 치료용 조성물을 제공함으로써 상술한 문제의 해결을 모색하였다. 이를 통해 종래 약학적 조성물에서 나타났던 부작용인 심혈관작용, 중추작용, 간장장애 및 신장장애 등 여러 부작용이 없으면서, 종래 생약제 추출물에서는 확인이 힘들었던 지방세포의 지질축적을 저해하고 지방세포 내 중성지방의 함량을 감소시키는 효과가 있는 비만 예방 또는 치료용 약학적 조성물 및 비만 예방 또는 개선용 건강기능성 식품을 제공하는 효과가 있다.Accordingly, the present inventors sought to solve the above-mentioned problems by providing a composition for preventing or treating obesity comprising quinizarin as an active ingredient. Thus, without adverse effects such as cardiovascular action, central action, hepatic disorder and kidney disorder, which were the side effects of the conventional pharmaceutical composition, it was found that the lipid accumulation in the adipocyte, And a health functional food for preventing or ameliorating obesity can be provided.
본 발명은 퀴니자린을 유효성분으로 포함하는 비만 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating obesity comprising quinizarin as an active ingredient.
상기 퀴니자린(quinizarin)은 안트라퀴논(anthraquinone) 계열의 물질로서 종양 억제 작용이 있다고 알려져 있으나, 본 발명에서는 이러한 퀴니자린이 비만 예방 및 치료 효과가 있음을 확인하였다.The quinizarin is an anthraquinone type substance and is known to have a tumor suppressive action. In the present invention, however, it has been confirmed that quinizarin has an effect of preventing and treating obesity.
본 발명의 퀴니자린은 통상적으로 제조 및/또는 구매할 수 있는 것이라면 특별히 제한하지 않는다.The quinizurin of the present invention is not particularly limited as long as it can be conventionally prepared and / or purchased.
상기 퀴니자린의 신규한 생리확성인 비만 예방 및/또는 치료 효과를 발견하였다. 상기 퀴니자린은 지방세포의 지질축적 감소 및 지방세포 내 중성지방 함량을 감소시킴으로써 항비만 활성을 나타낼 수 있다. 구체적으로 본 발명의 실시예 3에서 나타난 바와 같이, 상기 퀴니자린이 지방세포의 지질축적 저해 활성을 나타냄으로써 비만 예방 및/또는 치료 효과를 나타낼 수 있다(실시예 3 및 도 3 참조). 또한 본 발명의 실시예 4에서 나타난 바와 같이, 상기 퀴니자린이 지방세포 내의 중성지방 함량을 감소시킴으로써 비만 예방 및/또는 치료 효과를 나타낼 수 있다(실시예 4 및 도 4 참조).And found the novel physiological properties of quinizarin, which is an effect of preventing and / or treating obesity. The quinizarin may exhibit anti-obesity activity by decreasing lipid accumulation of adipocytes and decreasing triglyceride content in adipocytes. Specifically, as shown in Example 3 of the present invention, the quinizarin exhibits lipid-accumulating inhibitory activity of adipocytes, thereby exhibiting an effect of preventing and / or treating obesity (see Example 3 and FIG. 3). Also, as shown in Example 4 of the present invention, the quinizarin can exhibit an effect of preventing and / or treating obesity by reducing the content of triglycerides in adipocytes (see Example 4 and Fig. 4).
한편, 본 발명의 용어 "비만(obesity)"이란 열량의 섭취와 소비의 불균형으로 발생하는 대사성 질환을 의미하며, 과잉된 열량으로 인해 지방 조직이 비정상적으로 증가된 상태를 말한다. 남자는 체지방이 체중의 25%, 여자는 체중의 30% 이상일 때 비만으로 보며, 임상적으로는 BMI(Body Mass Index: 체질량지수)가 25.0~30.0인 상태를 과체중으로 정의하고 30.0 이상의 경우를 비만으로 정의한다. Meanwhile, the term " obesity " of the present invention means a metabolic disease caused by an unbalance between consumption and consumption of calorie, and refers to a state in which the fat tissue is abnormally increased due to excessive calories. Men are considered to be obese when their body fat is 25% or more and 30% or more of their body weight. Clinically, a body mass index (BMI) of 25.0 to 30.0 is defined as overweight, .
또한, 본 발명의 조성물은 C/EBP-α(CCAAT/enhancer binding protein peroxisome-α), C/EBP-β(CCAAT/enhancer binding protein peroxisome-β), PPAR-γ(Peroxisome proliferator-activated receptor-γ) 및 aP2(adipocyte protein 2)로 이루어진 군 중 선택되는 하나 이상의 mRNA 또는 단백질 발현량을 감소시키는 것일 수 있다. 구체적으로 유효성분인 퀴니자린은 농도 의존적으로 C/EBP-α, C/EBP-β, PPAR-γ 및 aP2의 단백질 발현량을 감소시켜 항비만 활성을 나타낼 수 있다. 본 발명의 실시예 5 내지 8에서 나타난 바와 같이, 지방세포의 단백질 발현이 퀴니자린을 처리함으로써 억제됨을 확인할 수 있었다. 이를 통해 퀴니자린의 비만 치료제로서 사용될 수 있음을 알 수 있다(실시예 5 내지 8 및 도 5 내지 8 참조).In addition, the composition of the present invention can be used in combination with C-EBP-alpha (CCAAT / enhancer binding protein peroxisome-alpha), C / EBP-beta (CCAAT / enhancer binding protein peroxisome- ) And aP2 (adipocyte protein 2). Specifically, quinizarin, which is an active ingredient, can exhibit anti-obesity activity by decreasing protein expression amount of C / EBP-α, C / EBP-β, PPAR-γ and aP2 in a concentration-dependent manner. As shown in Examples 5 to 8 of the present invention, it was confirmed that protein expression of adipocytes was suppressed by treatment with quiznizarin. It can be used as an agent for treating obesity of quinizarin (see Examples 5 to 8 and Figs. 5 to 8).
더불어, 상기 비만 예방 또는 치료용 약학적 조성물은 퀴니자린을 포함하는 것이라면 그 함량을 특별히 제한하지는 않으나, 바람직하게는 0.1 ~ 100 μM 의 농도를 포함할 수 있고, 보다 바람직하게는 0.5 ~ 50 μM 의 농도를 포함할 수 있으며, 더욱 바람직하게는 1.0 ~ 10 μM 의 농도를 포함할 수 있다. In addition, the pharmaceutical composition for preventing or treating obesity may contain a concentration of 0.1 to 100 μM, more preferably 0.5 to 50 μM, although the content thereof is not particularly limited as far as it contains quinizarin. Concentration, and more preferably a concentration of 1.0 to 10 [mu] M.
상기 퀴니자린을 0.1 μM 농도 미만으로 포함할 경우 항비만 활성 효과가 충분하지 않다는 문제점이 있으며, 100 μM 농도를 초과해서 포함할 경우 세포독성 증가에 대한 문제가 발생할 수 있다. 상기 조성물은 농도 의존적으로 활성을 보였는바 구체적으로, 상기 퀴니자린이 1.0 ~ 10 μM 의 농도에서 지방세포의 세포 생존력에 변화가 없음을 확인할 수 있었고, 6 ~ 61%까지 지방세포의 지질축적 감소효과 및 1 ~ 68%까지 지방세포 내 중성지방 함량 감소효과를 나타냈음을 알 수 있었다. When the quinizarin is contained at a concentration of less than 0.1 μM, there is a problem that the effect of anti-obesity activity is not sufficient. If it exceeds the concentration of 100 μM, a problem of increased cytotoxicity may occur. Specifically, it was confirmed that the quinizarin did not change the cell viability of the adipocyte at a concentration of 1.0 to 10 μM, and the lipid accumulation of the adipocyte was decreased by 6 to 61% And 1 ~ 68%, respectively.
또한, 상기 퀴니자린이 1.0 ~ 10 μM 의 농도에서 지방세포 내 C/EBP-α 및 C/EBP-β 발현이 각각 5 ~ 58%, 27 ~ 64% 감소되었음을 확인할 수 있고, PPAR-γ 및 aP2 발현이 각각 16 ~ 52%, 7 ~ 47% 감소되었음을 확인할 수 있었다. Also, it was confirmed that the expression of quinizarin in the adipocytes was decreased by 5 to 58% and 27 to 64%, respectively, at a concentration of 1.0 to 10 μM, and the expression of PPAR-γ and aP2 Expression was decreased by 16 ~ 52% and 7 ~ 47%, respectively.
본 발명에 따른 퀴니자린을 유효성분으로 함유하는 약학적 조성물에는 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽 등의 경구형 제형, 외용제, 크림제, 로션제, 오일제, 보습제, 겔제, 에어로졸, 비강 흡입제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition containing quinizarin as an active ingredient according to the present invention may be administered orally or parenterally in the form of powders, granules, tablets, capsules, suspensions, emulsions and syrups, oral preparations, And may be formulated in the form of an oil, a moisturizer, a gel, an aerosol, a nasal inhaler, a suppository, and a sterilized injection solution.
퀴니자린을 포함하는 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토오즈, 덱스트로오즈, 수크로오즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출액에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트 (calcium carbonate), 수크로오즈 (sucrose) 또는 락토오즈 (lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 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. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Examples of carriers, excipients and diluents that can be contained in the pharmaceutical composition containing quinizarin include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ( sucrose), lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명의 퀴니자린을 유효성분으로 함유하는 약학적 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경 구, 직장 또는 정맥, 근육, 피하, 설하, 골수내, 비강내, 경막내 또는 경피투여일 수 있다. 상기에서 '경피투여'란 본 발명의 약학적 조성물을 세포 또는 피부에 투여하여 약학적 조성물에 함유된 활성성분이 피부 내로 전달되도록 하는 것을 말한다.The pharmaceutical composition containing quinizarin of the present invention as an active ingredient can be administered to mammals such as rats, mice, livestock, and humans in various routes. All modes of administration may be expected, for example, in the tarsal, rectal or intravenous, muscular, subcutaneous, sublingual, intramedullary, intranasal, intrathecal or transdermal administration. The term " transdermal administration " as used herein refers to administration of the pharmaceutical composition of the present invention to cells or skin to allow the active ingredient contained in the pharmaceutical composition to be delivered into the skin.
또한, 본 발명은 퀴니자린을 포함하는 비만 예방 또는 개선용 건강기능성 식품 조성물을 제공한다. 상기 퀴니자린의 구체적인 내용은 전술한 바와 같다.The present invention also provides a health functional food composition for preventing or improving obesity comprising quinizarin. The specific contents of the quinizarin are as described above.
상기 건강 기능성 식품의 종류에는 특별한 제한은 없다. 상기 퀴니자린을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 등이 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료인 형태로 사용할 수 있고 통상적인 의미에서의 건강 기능성 식품을 모두 포함한다.There is no particular limitation on the kind of health functional food. Examples of the food to which quinizarine can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums and ice cream, soups, drinks, tea, , An alcoholic beverage and a vitamin complex, and can be used in the form of pills, powders, granules, infusions, tablets, capsules or beverages, and includes health functional foods in a conventional sense.
이 때, 식품 또는 음료 중 퀴니자린 첨가량은, 일반적으로 본 발명의 건강 기능성 식품 조성물의 경우 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물의 경우 100㎖를 기준으로 0.02 내지 500㎍, 바람직하게는 1 내지 200㎍의 비율로 첨가할 수 있다.In this case, the amount of quinizarin in the food or beverage may generally be from 0.01 to 15% by weight of the total food weight of the health functional food composition of the present invention, and from 0.02 to 500 Mu] g, preferably 1 to 200 [mu] g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 퀴니자린을 함유하는 외에는 액체성분에는 특별한 제한은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예로는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 수크로오즈 등; 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린; 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.The health beverage composition of the present invention is not particularly limited to liquid ingredients other than the quinizarin as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrins; And sugar alcohols such as xylitol, sorbitol, and erythritol. As natural flavors other than those described above, natural flavors (such as tau martin, stevia extract (e.g., rebaudioside A, glycyrrhizin)) and synthetic flavors (saccharin, aspartame, etc.) have.
상기 외에 본 발명의 건강 기능성 식품은 여러가지 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 중점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition to the above, the health functional food of the present invention can be used in various foods such as various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and heavy stabilizers (cheese, chocolate etc.), pectic acid and its salts, A salt thereof, an organic acid, a protective colloid concentrating agent, a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated beverage.
그 밖에 본 발명의 건강 기능성 식품들은 천연 과일 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.In addition, the health functional foods of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination.
이하, 본 발명을 실시예에 의해 상세히 설명하기로 한다. 그러나 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.
<< 실시예Example >>
실시예Example 1. One. Quinizarin의Quinizarin's 물질 구조 Material structure
본 실험에 사용한 Quinizarin은 시그마 (Sigma)사로부터 구입하여 사용하였다.The quinizarin used in this experiment was purchased from Sigma.
실시예Example 2. 지방세포 성장 억제 활성 측정 2. Measurement of adipocyte growth inhibitory activity
3T3-L1(Mouse embryonic fibroblast - adipose like cell line) 지방세포에 대한 Quinizarin의 세포 생존률을 측정하기 위해 MTT assay (methylthiazolyldiphenyl tetrazolium bromide assay)를 실시하였다. MTT assay (methylthiazolyldiphenyl tetrazolium bromide assay) was performed to measure the cell viability of Quinizarin on 3T3-L1 (mouse embryonic fibroblast-adipose like cell line) adipocytes.
3T3-L1 지방세포를 96-웰 플레이트(96-well plate)에 4×104cells/㎖로 분주하여 24시간 동안 5% CO2, 37 인큐베이터(CCL-170B-8, ESCO, USA) 에서 배양하였다. 배양 후 배양액을 제거하고 배지를 1% 페니실린 스트렙토마이신(penicillin streptomysin)이 함유된 Dulbecco's Modified Eagle's Medium(DMEM medium; Thermo Scientific, USA)으로 바꾸어 2시간 동안 배양하였다. 그 후에 DMEM medium과 Quinizarin을 농도별로(1, 5, 10 μM) 24시간 동안 처리하였다. 3T3-L1 adipocytes were plated in 96-well plates at 4 x 104 cells / ml and cultured in 5% CO2 and 37 incubator (CCL-170B-8, ESCO, USA) for 24 hours. After the culture, the culture medium was removed, and the medium was replaced with Dulbecco's Modified Eagle's Medium (DMEM medium; Thermo Scientific, USA) containing 1% penicillin streptomycin and cultured for 2 hours. DMEM medium and quinizarin were then treated for 24 hours at concentrations of 1, 5 and 10 μM.
이후 용매 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 5 ㎎/㎖로 용해한 MTT(3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide)용액을 각 웰(well) 마다 120 ㎕씩 처리하여 4시간 동안 5 % CO2, 37 인큐베이터에서 배양하였다. 배양 이후 배양액을 제거한 뒤 각 웰마다 디메틸 설폭사이드(DMSO; dimethyl sulfoxide) 200 ㎕/well로 넣으면서 피펫을 이용해 잘 교반하였다. 그 후 ELISA reader (BN 02514, Molecular Devices, Korea)로 570 ㎚에서 흡광도를 측정하였다. 측정 결과는 하기 도 1에 나타냈다.Then, a solution of MTT (3- [4,5-dimethyl-thiazole] -2,5-diphenyl-tetrazolium bromide) dissolved in 5 mg / ml of DBS in a solvent DPBS (Dulbecco's Phosphate-Buffered Saline, And incubated for 4 hours in 5% CO2, 37 incubator. After the culture, the culture solution was removed, and 200 μl / well of dimethyl sulfoxide (DMSO) was added to each well, followed by well stirring using a pipette. The absorbance was then measured at 570 nm using an ELISA reader (BN 02514, Molecular Devices, Korea). The measurement results are shown in Fig.
도 2에서 확인되는 바와 같이, Quinizarin을 1, 5, 10 μM 의 농도로 처리하였을 때, 세포 생존력에는 변화가 없는 것으로 보아 세포 독성은 없는 것으로 나타났다.As can be seen in FIG. 2, when quinizarin was treated at the concentrations of 1, 5, and 10 μM, there was no change in cell viability, indicating no cytotoxicity.
실시예Example 3. 3. QuinizarinQuinizarin 처리에 지방세포의 지질축적 저해활성 측정 Measurement of lipid accumulation inhibitory activity of adipocytes in treatment
상기 실시예 1에서와 동일한 방법으로 Quinizarin을 농도별로(1, 5, 10 μM) 처리하면서 분화시킨 세포의 배양액을 버리고 인산완충식염수(PBS; phosphate buffered saline)로 씻어주었다. 이후 세포를 고정시키기 위해 10 % 포름알데하이드(formaldehyde)를 500 ㎕씩 각 웰에 넣고 4 에서 1시간 동안 배양하였다. 그 후에 포름알데하이드를 제거하고 인산완충식염수로 3번 씻어낸 후 CO2인큐베이터에서 건조하였다. In the same manner as in Example 1, quinizarin was treated at different concentrations (1, 5, and 10 μM), and cells were differentiated and washed with phosphate buffered saline (PBS). Then, 500 μl of 10% formaldehyde was added to each well to immobilize the cells, followed by incubation at 4 for 1 hour. After that, formaldehyde was removed, washed three times with phosphate-buffered saline, and then dried in a CO 2 incubator.
이후 플레이트(plate)가 다 마르면 오일 레드 오 염색약을 500 ㎕씩 넣고 상온에서 어두운 상태로 30분간 염색한 후 인산완충식염수로 3번 씻어내었다. 염색이 된 세포는 현미경으로 관찰하였으며, 관찰 후 웰당 300 ㎕의 2-프로판올로 지방세포 내 염색된 염색약을 추출하여 ELISA reader로 500 ㎚에서 광학밀도값(OD값; optical density)을 측정하였다. 측정결과는 도 3에 나타냈다.After the plates were dried, 500 μl of Oil Red Dye was added, and the mixture was stained for 30 minutes at room temperature in a dark state, and washed three times with phosphate-buffered saline. The stained cells were observed under a microscope. After observation, the stained dye in the adipocyte was extracted with 300 μl of 2-propanol per well and the optical density value (OD value) was measured at 500 nm with an ELISA reader. The measurement results are shown in Fig.
상기 오일 레드 오 염색약은 Oil Red O 염색약 500 ㎎을 2-프로파놀(2-propanol) 100 ㎖에 녹인 용액을 증류수와 6:4의 비율로 섞은 후 0.45 ㎛ 필터(DISMIC-25cs ,ADVANTEC, Tokyo)로 여과한 용액이다.The oil red ophthalmic solution was prepared by mixing a solution of 500 mg of Oil Red O dye in 100 ml of 2-propanol in a ratio of 6: 4 with distilled water, followed by a 0.45 占 퐉 filter (DISMIC-25cs, ADVANTEC, Tokyo) Lt; / RTI >
실시예Example 4. 4. QuinizarinQuinizarin 처리에 의한 지방세포 내 중성지방 함량 분석 Analysis of Neutral Fat Content in Adipocytes by Treatment
3T3-L1 지방세포를 6-웰 플레이트(6-well plate)에 7 × 104cells/㎖ 밀도로 분주하고 8일 동안 지방세포를 분화시키면서 Quinizarin을 1, 5, 10 μM 의 농도로 처리하였다. Quinizarin 처리 이후 인산완충식염수로 세척한 후 스크라퍼(scraper)를 이용하여 세포를 모은 후 초음파 분쇄기(Sonifier 450 sonicator, Branson, USA)를 이용하여 세포 내 중성지방을 추출하여 트리글리세리드 키트(Triglyceride Kit, Sigma)를 이용하여 중성지방의 함량을 측정하였다. 측정한 중성지방의 함량은 도 4에 나타냈다.3T3-L1 adipocytes were seeded in 6-well plates at a density of 7 × 10 4 cells / ml and treated with quinizarin at a concentration of 1, 5 and 10 μM for 8 days. After quinizarin treatment, the cells were washed with phosphate-buffered saline, collected using a scraper and extracted with triglyceride kit (Sigma) using an ultrasonic disintegrator (Sonifier 450 sonicator, Branson, USA) ) Was used to measure the content of triglycerides. The measured content of triglyceride is shown in Fig.
도 4에서 나타난 바와 같이, Quinizarin을 1, 5, 10 μM 의 농도로 처리한 후 지방세포와 지방세포만 분화시킨 대조군을 비교했을 때, Quinizarin을 10 μM 농도로 처리한 지방세포의 중성지방이 68% 감소시키는 것을 확인할 수 있었다.As shown in FIG. 4, when the quinizarin was treated at a concentration of 1, 5, and 10 μM and the control group in which the adipocyte and adipocyte were differentiated, the concentration of the triglyceride in the adipocyte treated with 10 μM of quinizarin was 68 % Of the total amount of water.
실시예Example 5. 지방세포에서의 단백질 발현 기전 5. Mechanism of protein expression in adipocytes
Quinizarin의 항비만 관련 기전을 조사하기 위해 3T3-L1 지방세포에 대해 C/EBP-β (CCAAT/enhancer-binding protein-β), C/EBP-α (CCAAT/enhancer-binding protein-α)의 신호 전달에 의한 지방세포 발현 감소를 웨스턴 블렛(wstern blot)방법으로 조사하였다. In order to investigate the anti-obesity mechanism of quinizarin, the signal of C / EBP-β (CCAAT / enhancer-binding protein-β) and C / EBP-α (CCAAT / enhancer-binding protein-α) The decrease of adipocyte expression by transfer was investigated by western blot method.
구체적으로, 3T3-L1 지방세포를 6-웰 플레이트(6-well plate)에 7 × 104cells/㎖의 농도로 시딩(seeding) 후 37에서 8일 동안 분화시키면서 Quinizarin을 1, 5, 10 μM 의 농도로 처리하였다. 8일 후 인산완충식염수(phosphate buffered saline; PBS buffer)로 세척하고, 1,400 rpm에서 5분 동안 원심분리 하여 세포를 획득하였다. Specifically, 3T3-L1 adipocytes were seeded in a 6-well plate at a concentration of 7 × 10 4 cells / ml, and then quinizarin was added at a concentration of 1, 5, and 10 μM Lt; / RTI > After 8 days, the cells were washed with phosphate buffered saline (PBS buffer) and centrifuged at 1,400 rpm for 5 minutes to obtain cells.
획득한 세포에 50 ㎕의 용해 버퍼 (lysis buffer)를 첨가 후, 30분 동안 얼음 상에서 반응시키고, 12,000 rpm에서 10분 동안 원심분리 하여 단백질을 수득하였다. 이후 수득한 단백질을 브래드퍼드 분석법(Bradford 분석법)을 이용하여 단백질을 정량 후 샘플 버퍼(sample buffer)를 넣고 95 에서 5분 동안 변성시킨 뒤에 SDS-PAGE(Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis) 겔을 이용하여 전기영동 하였다. 전기영동 후 니트로셀룰로오스 막(Nitrocellulose membrane)에 옮긴 후, 1차 항체(C/EBP-β, C/EBP-α, Cell signaling, USA)를 5% 탈지분유 (skim milk)에 1:1000, (v/v)으로 희석하여 니트로셀룰로오스 막에 넣고 4에서 24시간 반응시켰다. 이후 TBST(Tris-Buffered Saline와 Tween 20의 혼합액, 0.1% Tween 20)로 10분마다 3번 세척하고 HRP(horeseradish peroxidase)-conjugated 2차 항체 (Anti-rabbit, Cell signaling, USA)를 5% 탈지분유에 1:2000(v/v)으로 희석하여 5 ㎕ 첨가한 후 25 에서 2시간 동안 반응시켰다. The obtained cells were added with 50 占 퐇 of lysis buffer, reacted on ice for 30 minutes, and centrifuged at 12,000 rpm for 10 minutes to obtain proteins. The proteins were then quantitated using Bradford assay (Bradford assay), denatured at 95 for 5 minutes in a sample buffer, and then subjected to SDS-PAGE (Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis) And electrophoresed. After electrophoresis, the cells were transferred to a nitrocellulose membrane, and the primary antibody (C / EBP-β, C / EBP-α, Cell signaling, USA) was added to 5% skim milk at a ratio of 1: 1000 v / v), placed in a nitrocellulose membrane, and reacted for 4 to 24 hours. After that, the cells were washed 3 times every 10 minutes with TBST (mixture of Tris-Buffered Saline and
위와 같은 방법으로 TBST를 이용하여 3차례 세척한 후 ECL(enchanced chemiluminescence) 기질 용액을 처리하여 1분 동안 반응시킨 후에 X-ray 필름에 현상하였다. 얻어진 결과를 이미지 J 프로그램 (National Institutes of Health, Bethesda, MD, USA)을 이용하여 수치화하였고, 도 5 내지 6에 나타냈다.After washing three times with TBST in the same manner as above, ECL (enchanced chemiluminescence) substrate solution was treated and reacted for 1 minute and developed on X-ray film. The results were digitized using the Image J program (National Institutes of Health, Bethesda, Md., USA) and shown in Figures 5 to 6.
도 5에 나타난 바와 같이, Quinizarin을 1, 5, 10 μM 의 농도로 처리한 지방세포와 지방세포만 분화시킨 대조군을 비교했을 때, Quinizarin을 10 μM 의 농도로 처리한 경우 C/EBP-β가 64%까지 감소되 것을 확인할 수 있었다. As shown in FIG. 5, when quinizinin was treated at a concentration of 1, 5 and 10 μM, fat cells and adipocytes were differentiated, and when quinizarin was treated at a concentration of 10 μM, C / EBP-β 64%.
도 6에 나타난 바와 같이, Quinizarin을 1, 5, 10 μM 의 농도로 처리한 지방세포와 지방세포만 분화시킨 대조군을 비교했을 때, Quinizarin을 10 μM 의 농도로 처리한 경우 C/EBP-α가 58%까지 감소되는 것을 확인할 수 있었다.As shown in FIG. 6, when quinizarin was treated at a concentration of 1, 5 and 10 μM, fat cells and adipocytes were differentiated, and when quinizarin was treated at a concentration of 10 μM, C / EBP-α And 58%, respectively.
이를 통해, 본 발명의 Quinizarin은 C/EBP-β 및 C/EBP-α 농도를 감소시키는 것을 확인할 수 있었다.As a result, it was confirmed that the quinizarin of the present invention decreases the concentrations of C / EBP-β and C / EBP-α.
실시예Example 6. 지방세포의 6. Adipocyte mRNAmRNA 발현기전Mechanism of expression
6-1. 지방세포에서의 RNA 분리6-1. Isolation of RNA from adipocytes
3T3-L1 세포를 60 ㎜ 디쉬(dish)에 분화시키면서 Quinizarin을 농도별(1, 5, 10 μM)로 처리하였다. 이후 인산완충식염수로 씻어낸 후 트리졸(Trizol)을 1 ㎖씩 처리하여 세포를 잘 모아서 에펜도르프 튜브(eppendorf tube)에 옮겼다. 3T3-L1 cells were treated with quinizarin at different concentrations (1, 5, and 10 μM) while differentiating into 60 mm dishes. Then, the cells were washed with phosphate-buffered saline and treated with 1 ml of Trizol to transfer the cells to an eppendorf tube.
이후 RNA 추출용(Korea, Intron biotechnology, Total RNA Extraction Kit)인 클로로포름(chloroform)을 트리졸 1 ㎖당 200 ㎕씩 넣고 섞은 후 원심분리(13,000 rpm, 10 분, 4 )하여 제일 윗부분의 상등액에서 RNA을 회수하였다. 회수한 RNA에 바인딩 버퍼(Binding Buffer) 400 ㎕씩 넣고 약 1분간 손으로 섞어주었다. 이후 RNA만 회수하기 위해 RNA 전용 컬럼(column)과 워싱 버퍼(Washing Buffer) 1(700 ㎕) 및 2(700 ㎕)를 사용해 클로로포름을 제거한 후 RNA만 남은 컬럼을 빼서 새로운 EP tube(Eppendorf tube) 옮기고 일루션 버퍼(Elution Buffer)로 RNA을 녹여 컬럼 밑으로 빠지게 해서 RNA만 회수하였다.After that, 200 μl of chloroform per 1 ml of trisole was added to RNA extraction kit (Korea, Intron biotechnology, Total RNA Extraction Kit), followed by centrifugation (13,000 rpm, 10 min, 4). RNA was extracted from the supernatant Respectively. 400 μl of Binding Buffer was added to the recovered RNA and mixed by hand for about 1 minute. After removing the chloroform using a dedicated RNA column and Washing Buffer 1 (700 μl) and 2 (700 μl), the RNA-only column was removed and the new EP tube (Eppendorf tube) was transferred RNA was eluted with an Elution Buffer to be pulled down under the column to recover only the RNA.
6-2. 지방세포에서의 cDNA 합성6-2. CDNA synthesis in adipocytes
상기 실시예 6-1에서 회수한 RNA를 microplate reader (Bio-Tek, USA)기로 정량하여 정량한 RNA를 준비하고, 디에틸 피로칼보네이트 워터(DEPC water; diethyl pyrocarbonate water)를 준비하였다. The RNA recovered in Example 6-1 was quantitatively determined with a microplate reader (Bio-Tek, USA) and RNA was prepared and DEPC water (diethyl pyrocarbonate water) was prepared.
PCR 전용 튜브에 상기 정량한 RNA와 DEPC water를 넣어준 후 역전사효소인 Oligo(dT)15를 1 ㎕씩 넣어주었다. 이후 PCR 기계를 이용하여 75에서 5분 동안 반응시키고 cDNA 합성 kit (Intronbio, Korea)를 잘 혼합하여 넣어주었다. 이후 스핀다운 하여 침전시킨 후 42에서 1시간 반응시킨다. 이후 75에서 5분간 반응시켜 획득한 cDNA에 DEPC water를 50 ㎕씩 넣어서 합성하여 최종적으로 RT-PCR에 사용하였다.The quantified RNA and DEPC water were added to the tubes for PCR and 1 μl of reverse transcriptase Oligo (dT) 15 was added. Then, the PCR reaction was carried out at 75 for 5 minutes, and the cDNA synthesis kit (Intronbio, Korea) was mixed well. After spin-down to precipitate, react at 42 for 1 hour. After that, reaction was performed at 75 for 5 minutes, and 50 μl of DEPC water was added to the obtained cDNA. Finally, the reaction mixture was used for RT-PCR.
6-3. cDNA를 이용한 지방세포의 6-3. of adipocytes using cDNA mRNAmRNA 발현 기전 Mechanism of expression
상기 실시예 6-2에서 합성한 cDNA 1 ㎕, 하기 표 1에 나타낸 프라이머 2 ㎕를 마스터 믹스 솔루션(Master Mix Solutionl; iNtRON, i-StatTaq, Korea)에 넣은 후 DEPC water 17 ㎕를 넣고 PCR 방법으로 증폭시켰다. 구체적인 PCR 방법은 표 1에 나타냈다.1 μl of the cDNA synthesized in Example 6-2 and 2 μl of the primer shown in Table 1 were placed in a Master Mix Solution (iNtRON, i-StatTaq, Korea), 17 μl of DEPC water was added thereto, . The specific PCR method is shown in Table 1.
이후 PCR 반응 산물은 2% 아가로 겔(agarose gel)에서 전기영동 후 브롬화에티듐(ethidium bromide)으로 염색하여, UV 램프에서 확인하였다. 상기 PCR 이후 PPAR-γ(peroxisome proliferator-activated receptors-γ) 및 aP2(adipocyte protein 2)의 농도를 image station (Kodak, USA) 장치를 이용하여 값을 도출한 후 엑셀 파일로 옮겨 계산하여 도 7 내지 8에 나타냈다.The PCR product was then electrophoresed on 2% agarose gel, stained with ethidium bromide, and checked on a UV lamp. After the PCR, the concentration of PPAR-gamma (peroxisome proliferator-activated receptors-y) and aP2 (adipocyte protein 2) was calculated using an image station (Kodak, USA) Respectively.
도 7에 나타난 바와 같이, Quinizarin을 1, 5, 10 μM 의 농도로 처리한 후 지방세포와 지방세포만 분화시킨 대조군을 비교했을 때, Quinizarin을 10 μM 의 농도로 처리한 지방세포에서 PPAR-γ의 mRNA 발현량이 52%까지 감소되는 것을 확인할 수 있었다.As shown in FIG. 7, when quinizarin was treated at a concentration of 1, 5, and 10 μM and the control group in which adipocytes and adipocytes were only differentiated, the adipocyte treated with quinizarin at a concentration of 10 μM showed PPAR-γ Of mRNA expression was reduced by 52%.
도 8에 나타난 바와 같이, Quinizarin을 1, 5, 10 μM 의 농도로 처리한 후 지방세포와 지방세포만 분화시킨 대조군을 비교했을 때, Quinizarin을 10 μM 의 농도로 처리한 지방세포에서 aP2의 mRNA 발현량이 47%까지 감소되는 것을 확인할 수 있었다.As shown in FIG. 8, when quinizarin was treated at a concentration of 1, 5, and 10 μM and the control group in which only adipocytes and adipocytes were differentiated, the adipocytes treated with quinizarin at a concentration of 10 μM showed aP2 mRNA And the expression level was reduced to 47%.
Claims (10)
[화학식1]
The quinizarin has a concentration of 5 to 10 μM. The quinizarin reduces lipid accumulation in the adipocyte and the content of triglycerides, thereby preventing or preventing obesity due to triglycerides. Therapeutic pharmaceutical composition:
[Chemical Formula 1]
상기 조성물은 C/EBP-α(CCAAT/enhancer binding protein peroxisome-α), C/EBP-β(CCAAT/enhancer binding protein peroxisome-β), PPAR-γ(Peroxisome proliferator-activated receptor-γ) 및 aP2(adipocyte protein 2)로 이루어진 군 중 선택되는 하나 이상의 mRNA 또는 단백질 발현량을 감소시키는 것을 특징으로 하는
중성 지방으로 인한 비만 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
The composition comprises at least one of C / EBP-alpha (CCAAT / enhancer binding protein peroxisome-alpha), C / EBP-beta (CCAAT / enhancer binding protein peroxisome- beta), PPAR- adipocyte protein < RTI ID = 0.0 > 2) < / RTI >
A pharmaceutical composition for preventing or treating obesity due to triglycerides.
[화학식1]
The quinizarin has a concentration of 5 to 10 μM. The quinizarin reduces lipid accumulation in the adipocyte and the content of triglycerides, thereby preventing or preventing obesity due to triglycerides. Health functional food composition for improvement:
[Chemical Formula 1]
상기 조성물은 C/EBP-α(CCAAT/enhancer binding protein peroxisome-α), C/EBP-β(CCAAT/enhancer binding protein peroxisome-β), PPAR-γ(Peroxisome proliferator-activated receptor-γ) 및 aP2(adipocyte protein 2)로 이루어진 군 중 선택되는 하나 이상의 mRNA 또는 단백질 발현량을 감소시키는 것을 특징으로 하는
중성 지방으로 인한 비만 예방 또는 개선용 건강기능성 식품 조성물.
The method according to claim 6,
The composition comprises at least one of C / EBP-alpha (CCAAT / enhancer binding protein peroxisome-alpha), C / EBP-beta (CCAAT / enhancer binding protein peroxisome- beta), PPAR- adipocyte protein < RTI ID = 0.0 > 2) < / RTI >
A health functional food composition for preventing or ameliorating obesity caused by triglycerides.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0638317A1 (en) | 1993-08-05 | 1995-02-15 | F. Hoffmann-La Roche Ag | Pharmaceutical composition |
| WO2001082916A2 (en) | 2000-05-03 | 2001-11-08 | Tularik Inc. | Combination therapeutic compositions and methods of use |
| WO2004110368A2 (en) | 2003-06-06 | 2004-12-23 | Merck & Co., Inc. | Combination therapy for the treatment of hypertension |
| WO2005000217A2 (en) | 2003-06-06 | 2005-01-06 | Merck & Co., Inc. | Combination therapy for the treatment of dyslipidemia |
| US20050228038A1 (en) | 2004-04-08 | 2005-10-13 | Vander Jagt David L | 11-Beta hydroxysteroid dehydrogenase type 1 inhibitors as anti-obesity/anti-diabetes compounds and 17-beta hydrosteroid dehydrogenase type I inhibitors as useful agents for the treatment of cancers, especially breast cancer |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0638317A1 (en) | 1993-08-05 | 1995-02-15 | F. Hoffmann-La Roche Ag | Pharmaceutical composition |
| WO2001082916A2 (en) | 2000-05-03 | 2001-11-08 | Tularik Inc. | Combination therapeutic compositions and methods of use |
| WO2004110368A2 (en) | 2003-06-06 | 2004-12-23 | Merck & Co., Inc. | Combination therapy for the treatment of hypertension |
| WO2005000217A2 (en) | 2003-06-06 | 2005-01-06 | Merck & Co., Inc. | Combination therapy for the treatment of dyslipidemia |
| US20050228038A1 (en) | 2004-04-08 | 2005-10-13 | Vander Jagt David L | 11-Beta hydroxysteroid dehydrogenase type 1 inhibitors as anti-obesity/anti-diabetes compounds and 17-beta hydrosteroid dehydrogenase type I inhibitors as useful agents for the treatment of cancers, especially breast cancer |
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