KR102276122B1 - Quercetin-3-O-rhamnoside as a potential pharmaceutical component for the prevention and treatment of Type 2 diabetes - Google Patents
Quercetin-3-O-rhamnoside as a potential pharmaceutical component for the prevention and treatment of Type 2 diabetes Download PDFInfo
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- KR102276122B1 KR102276122B1 KR1020190137317A KR20190137317A KR102276122B1 KR 102276122 B1 KR102276122 B1 KR 102276122B1 KR 1020190137317 A KR1020190137317 A KR 1020190137317A KR 20190137317 A KR20190137317 A KR 20190137317A KR 102276122 B1 KR102276122 B1 KR 102276122B1
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- quercetin
- rhamnoside
- diabetes
- preventing
- pharmaceutical composition
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- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
본 발명은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 유효 성분으로 포함하는 2형 당뇨 예방 및 치료용 약학적 조성물에 관한 것으로서, 보다 상세하게는 인슐린 저항성이 유도된 근육세포에서 포도당 운반체 막 단백질인 GLUT-4 인자의 발현을 증가시켜 포도당 흡수를 촉진시키고, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)가 항당뇨 과정에 중요한 전사 인자 (AKT, IRS-1) 들을 효과적으로 조절하고, 현재 2형 당뇨 치료 약물인 아카보즈 (Acarbose) 보다 알파-글루코시다제 (α-Glucosidase)를 저해하는 활성이 더 우수하여 항당뇨 활성이 우수함을 밝혔고, 나아가 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)와 퀘르세틴 (Quercetin)의 복합물이 퀘르세틴-3-O-람노시드를 단독으로 처리했을 때 보다 인슐린 저항성이 유도된 근육세포에서 포도당 흡수율을 더욱 증가시키는 상승효과를 나타내어 항당뇨 효능이 증가한다는 사실을 밝히고, 이에 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside) 또는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)와 퀘르세틴 (Quercetin)의 복합물을 포함하는 2형 당뇨 예방 및 치료용 약학적 조성물을 발명한 것이다. The present invention relates to a pharmaceutical composition for preventing and treating type 2 diabetes comprising quercetin-3-O-rhamnoside as an active ingredient, and more particularly, to a muscle in which insulin resistance is induced. It promotes glucose uptake by increasing the expression of GLUT-4, a glucose transporter membrane protein, in cells, and Quercetin-3-O-rhamnoside is an important transcription factor for the antidiabetic process (AKT, IRS-1), it was found that the antidiabetic activity was superior to that of the current type 2 diabetes treatment drug, Acarbose, thereby inhibiting α-glucosidase, and furthermore, quercetin The combination of -3-O-rhamnoside (Quercetin-3-O-rhamnoside) and quercetin improved the glucose uptake rate in muscle cells induced by insulin resistance than when quercetin-3-O-rhamnoside was treated alone. It was revealed that the antidiabetic effect was increased by showing a synergistic effect that increased further, and thus, quercetin-3-O-rhamnoside or Quercetin-3-O-rhamnoside (Quercetin-3-O) -rhamnoside) and quercetin (Quercetin) to the invention of a pharmaceutical composition for preventing and treating type 2 diabetes comprising a complex.
Description
본 발명은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 유효 성분으로 포함하는 2형 당뇨 예방 및 치료용 약학적 조성물에 관한 것으로서, 보다 상세하게는 인슐린 저항성이 유도된 근육세포에서 포도당 운반체 막 단백질인 GLUT-4 인자의 발현을 증가시켜 포도당 흡수를 촉진시키고, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)가 항당뇨 과정에 중요한 전사 인자 (AKT, IRS-1) 들을 효과적으로 조절하고, 현재 2형 당뇨 치료 약물인 아카보즈 (Acarbose) 보다 알파-글루코시다제 (α-Glucosidase)를 저해하는 활성이 더 우수하여 항당뇨 활성이 우수함을 밝혔고, 나아가 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)와 퀘르세틴 (Quercetin)의 복합물이 퀘르세틴-3-O-람노시드를 단독으로 처리했을 때 보다 인슐린 저항성이 유도된 근육세포에서 포도당 흡수율을 더욱 증가시키는 상승효과를 나타내어 항당뇨 효능이 증가한다는 사실을 밝히고, 이에 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside) 또는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)와 퀘르세틴 (Quercetin)의 복합물을 포함하는 2형 당뇨 예방 및 치료용 약학적 조성물을 발명한 것이다. The present invention relates to a pharmaceutical composition for preventing and treating
당뇨병은 현재 전세계적으로 사망률의 주요 원인 질병으로 부상하는 대사성질환의 하나이다. 국제당뇨병연맹 (IDF)의 보고서에 따르면 2017년 약 4억2500만 명 (20-79세)이 당뇨병으로 겪고 있으며 2045년에는 6억3500만 명으로 증가할 것으로 예상된다 (IDF, 2017년). 또한 UN의 보고에 따르면, 전 세계적으로 당뇨병으로 인한 사망이 매년 증가하고 있다. 보고에 따르면 사망자 수가 국내에서만 2010년 11,575명에서 2016년 11986명으로 증가했다고 밝히고 있다 (Statistics Korea, 2018-12-20). 이처럼 문제가 되고 있는 당뇨병 환자 증가의 주된 이유는 어린이와 청소년들과 같은 젊은 층의 발병율 증가이다. 선천적으로 인슐린 분비가 되지 않는 제 1형 당뇨와 달리 후천적으로 발병하는 제 2형 당뇨의 경우 환경적인 요인과 유전적인 요인으로 발병하게 되는데 이 중 환경적인 요인은 생활습관을 의미한다. 서구화된 식단, 식생활의 증가를 비롯하여 적은 신체활동량 즉 운동부족 등이 주요 환경적인 요인으로 알려져있다. 따라서 제 2형 당뇨병은 생활양식의 변화 (조절식, 규칙적인 운동 등)에 의해 잘 관리되거나 억제 또는 지연될 수 있는 것으로 알려졌다. 그러나 생활습관 변경 후에도 정상적인 포도당 수준을 유지하지 못할 경우, 치료의 유일한 선택사항으로 의약품을 사용하고 있다 (Tabish, S.A, International journal of health sciences , 2007).Diabetes mellitus is one of the metabolic diseases that are currently emerging as a major cause of mortality worldwide. According to a report by the International Diabetes Federation (IDF), approximately 425 million people (ages 20-79) suffered from diabetes in 2017 and it is expected to increase to 635 million by 2045 (IDF, 2017). Also, according to the UN report, the number of deaths due to diabetes is increasing every year worldwide. According to the report, the number of deaths increased from 11,575 in 2010 to 11986 in 2016 in Korea alone (Statistics Korea, 2018-12-20). The main reason for this problematic increase in the number of diabetic patients is the increase in the incidence of young people such as children and adolescents. Unlike
앞서 설명하였듯이 당뇨병은 인체가 충분한 인슐린을 생성하지 못하는 인슐린 결핍, 제 1형 당뇨와 인슐린이 제대로 기능하지 못하는 인슐린 저항성, 제 2형 당뇨로 나뉘는 대사 장애의 일종이다. 제 2형 당뇨의 발병은 여러 가지 기작으로 인해 발생한다. 먼저 췌장의 베타 세포 (β-Cell)의 감소, 또는 기능 저하로 인한 인슐린의 생성 감소, 간 또는 지방조직에서의 지속적인 염증 반응으로 인한 인슐린 저항성(Insulin-Resistance)과 과도한 지방산 대사로 인한 당 대사 장애, 마지막으로 근육조직에서의 인슐린 저항성(Insulin-Resistance)과 인슐린 부족으로 인해 포도당 흡수가 제한되면서 발병한다. 이러한 발병 기작 중에 췌장의 베타세포를 비롯한 췌장의 문제가 아닌 간, 지방 조직, 그리고 근육 조직에서 나타나는 인슐린 저항성 (Insulin-Resistance)을 세포가 띄게 되면 세포가 인슐린에 의해 포도당 (Glucose) 을 세포가 흡수하여야 하는데 그러지 못 하게 되어 혈중에 포도당 (Glucose)가 과도하게 많아지고 이로 인해 다른 합병증 또한 유발하게 된다.As described above, diabetes is a type of metabolic disorder that is divided into insulin deficiency, in which the body does not produce enough insulin,
이와 같은 당뇨병을 치료하기 위해 현재까지 개발된 주요 약물들은 인슐린 저항성을 완화하거나 췌장으로부터 더 많은 인슐린을 향상시키는 것을 목표로 하고 있다. 대표적으로 메트포르민(Metformin)이 있으며 인슐린 의존성 (Insulin dependent) 또는 인슐린 독립 포도당 섭취 (Insulin independent glucose uptake) 경로에 관여하는 다양한 단백질을 통해 다른 근육 세포에서 포도당 이동을 가속화하고 조직을 적응시킨다. 이와 유사하게 알파-글루코시다제 (α-gltcosidase) 효소 또한 항당뇨제로 알려져 있으며 대표적으로 아카보즈 (Acarbose)가 알려져 있다. 또한 다양한 유형의 DPP-4 억제제는 항당뇨 약물로 이용되고 있으며 대표적으로 시타글립틴 (Sitagliptin)이 있다 (Miyazaki 그 외, 2012). 그러나 현재까지 나온 치료제들은 체중 증가, 흉부 기능 상실, 메스꺼움 등과 같은 심각한 부작용을 가지고 있다. 이와 같은 여러 부작용들로 인해 최근에 약용식물 (medicinal herb)의 치료효과에 대한 관심이 높아지면서 천연물에 대한 수요가 증대되고 있으며 최근에는 약용식물을 이용한 항 당뇨제의 연구에 대한 관심이 집중되어 왔다. 당뇨치료제의 다양한 부작용으로 인해 최근에는 인체에 최소한의 부작용을 가지는 식물로부터 분리한 화합물, 미생물 유래 천연물질, 플라보노이드 등 천연물을 이용한 당뇨치료제 개발을 위한 연구가 이루어지고 있다. 그 중 항산화, 항암, 면역 등 다양한 방면에 플라보노이드 계열의 퀘르세틴 (Quercetin)은 효능이 있다고 알려져 있다. 하지만 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 경우 퀘르세틴 (Quercetin)과 마찬가지로 항산화를 비롯하여 다양한 방면에 연구 되고 알려졌지만 항당뇨 효능에 대해서는 아직 잘 알려진 바가 없다. 본 발명은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 유효 성분으로 포함하는 2형 당뇨 예방 및 치료용 약학적 조성물에 관한 것으로서, 보다 상세하게는 인슐린 저항성이 유도된 근육세포에서 포도당 운반체 막 단백질인 GLUT-4 인자의 발현을 증가시켜 포도당 흡수를 촉진시키고, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)가 항당뇨 과정에 중요한 전사 인자 (AKT, IRS-1) 들을 효과적으로 조절하고, 현재 2형 당뇨 치료 약물인 아카보즈 (Acarbose) 보다 알파-글루코시다제 (α-Glucosidase)를 저해하는 활성이 더 우수하여 항당뇨 활성이 우수함을 밝혔고, 나아가 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)와 퀘르세틴 (Quercetin)의 복합물이 퀘르세틴-3-O-람노시드를 단독으로 처리했을 때 보다 인슐린 저항성이 유도된 근육세포에서 포도당 흡수율을 더욱 증가시키는 상승효과를 나타내어 항당뇨 효능이 증가한다는 사실을 밝히고, 이에 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside) 또는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)와 퀘르세틴 (Quercetin)의 복합물을 포함하는 2형 당뇨 예방 및 치료용 약학적 조성물을 발명한 것이다. The main drugs developed so far to treat diabetes like this are aimed at alleviating insulin resistance or improving more insulin from the pancreas. A representative example is metformin, which accelerates glucose transport in other muscle cells and adapts tissues through various proteins involved in insulin-dependent or insulin-independent glucose uptake pathways. Similarly, alpha-glucosidase (α-gltcosidase) enzyme is also known as an antidiabetic agent, and acarbose is typically known. In addition, various types of DPP-4 inhibitors are used as antidiabetic drugs, and a representative example is Sitagliptin (Miyazaki et al., 2012). However, treatments available so far have serious side effects such as weight gain, chest loss, and nausea. Due to these side effects, as interest in the therapeutic effect of medicinal herbs has recently increased, the demand for natural products is increasing, and interest in research on antidiabetic agents using medicinal plants has recently been focused. Due to the various side effects of diabetic drugs, recently, research is being conducted for the development of diabetic drugs using natural substances such as compounds isolated from plants, microorganism-derived natural substances, and flavonoids, which have minimal side effects to the human body. Among them, quercetin, a flavonoid type, is known to be effective in various fields such as antioxidant, anticancer, and immunity. However, in the case of quercetin-3-O-rhamnoside, like quercetin, it has been studied and known in various fields including antioxidant, but its antidiabetic effect is not yet well known. The present invention relates to a pharmaceutical composition for preventing and treating
본 발명은 상술한 문제를 해결하기 위해 안출된 것으로, 본 발명은 천연 플라보노이드 배당체인 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 항당뇨 활성을 규명하여 본 물질을 포함하는 신규의 당뇨 예방 및 치료용 조성물과 제조방법 및 이를 이용한 건강기능성 식품을 제공하는 것이다.The present invention has been devised to solve the above-mentioned problems, and the present invention is a natural flavonoid glycoside, quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) by identifying the antidiabetic activity of the substance It is to provide a novel composition for preventing and treating diabetes, a manufacturing method, and a health functional food using the same.
본 발명은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)을 포함하는, 당뇨병의 예방 또는 치료용 약학적 조성물을 제공할 수 있다. The present invention may provide a pharmaceutical composition for preventing or treating diabetes, including quercetin-3-O-rhamnoside.
본 발명의 바람직한 일실시예에 따르면, 상기 약학적 조성물은 알파-글리코시다제 억제 (α-Glycosidase inhibition) 활성을 가질 수 있다. According to a preferred embodiment of the present invention, the pharmaceutical composition may have α-glycosidase inhibition activity.
본 발명의 바람직한 일실시예에 따르면, 상기 약학적 조성물은 GLUT, AKT 및 IRS-1 (Insulin receptor substrate)으로 이루어진 군 중 1종 이상의 단백질 발현을 감소 또는 증가시킬 수 있다.According to a preferred embodiment of the present invention, the pharmaceutical composition can decrease or increase the expression of one or more proteins from the group consisting of GLUT, AKT, and IRS-1 (Insulin receptor substrate).
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)을 10 내지 30 μM의 농도로 포함할 수 있다.According to another preferred embodiment of the present invention, the pharmaceutical composition may include quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM.
또한 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)을 포함하는 2형 당뇨 예방 또는 치료용 약학적 조성물을 제공할 수 있다. In addition, it is possible to provide a pharmaceutical composition for preventing or treating
본 발명의 바람직한 또 다른 일실시예에 따르면, 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 몰비는 1:10 (mole : mole) 내지 10:1 (mole : mole)일 수 있다. According to another preferred embodiment of the present invention, the molar ratio of quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) is 1:10 (mole: mole) to 10:1 ( mole: mole).
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 1 내지 100 μM의 농도로 포함할 수 있다. According to another preferred embodiment of the present invention, the quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) may include a concentration of 1 to 100 μM.
또한, 본 발명은 Quercetin-3-O-rhamnoside를 포함하는 당뇨 예방 또는 개선용 건강기능성 식품을 제공한다.In addition, the present invention provides a functional health food for preventing or improving diabetes containing Quercetin-3-O-rhamnoside.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 건강기능성 식품 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내재 30 μM 의 농도로 포함할 수 있다. According to another preferred embodiment of the present invention, the functional health food composition may include quercetin-3-O-rhamnoside at a concentration of 10 intrinsic 30 μM.
본 발명은 또한 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)을 포함하는 2형 당뇨병의 예방 또는 개선용 건강기능성 식품 조성물을 제공할 수 있다. The present invention may also provide a functional health food composition for preventing or improving
본 발명은 종래 합성 약제 조성물과 달리 유발하는 부작용들이 적으며, 근육세포의 인슐린 저항에 의한 포도당 흡수 저해를 개선시켜, 항당뇨 활성을 가지는 Quercetin-3-O-rhamnoside 또는 Quercetin과 Quercetin-3-O-rhamnoside를 각각 10 μM의 농도로 함유한 1:1 (mole : mole) 복합물을 포함하는 당뇨 예방 및 치료용 약학적 조성물 또는 항당뇨 예방 및 개선용 건강기능성 식품을 제공한다.The present invention has fewer side effects, unlike conventional synthetic pharmaceutical compositions, and improves glucose absorption inhibition by insulin resistance in muscle cells, so that Quercetin-3-O-rhamnoside or Quercetin and Quercetin-3-O has antidiabetic activity It provides a pharmaceutical composition for preventing and treating diabetes or a health functional food for preventing and improving anti-diabetes, including a 1:1 (mole: mole) complex containing -rhamnoside at a concentration of 10 μM, respectively.
도 1은 Quercetin 및 Quercetin-3-O-rhamnoside의 화학적 구조이다.
도 2는 실시예 1에서 확인한 Quercetin-3-O-rhamnoside의 처리에 따른 α-Glucosidase 저해 활성을 현재 2형 당뇨 치료 약물인 아카보즈 (Acarbose)를 양성대조군으로 하여 알파-글루코시다제 (α-Glucosidase)를 저해하는 활성을 측정한 결과이다.
도 3은 실시예 2에서 확인한 Quercetin-3-O-rhamnoside의 Hep G2 세포 내 생존력 측정 결과이다.
도 4는 실시예 3에서 확인한 Quercetin-3-O-rhamnoside 처리에 의한 Hep G2 세포에서의 DPP-4 억제 활성 측정 결과이다.
도 5는 실시예 2에서 확인한 Quercetin-3-O-rhamnoside의 근육세포 내 생존력 측정 결과이다.
도 6은 실시예 5에서 확인 한 Quercetin-3-O-rhamnoside의 근육세포 내 포도당 흡수율 측정 결과이다.
도 7은 실시예 5에서 확인한 근육세포에서의 IRS-1, AKT, GLUT-4 단백질 발현량 측정 결과이다.
도 8은 실시예 6에서 확인한 Quercetin-3-O-rhamnoside와 Quercetin 두 물질의 1:1 (mole : mole) 복합물 처리에 의한 인슐린 저항성 근육세포에서의 포도당 흡수 상승효과에 대한 결과이다. 1 is the chemical structure of Quercetin and Quercetin-3-O-rhamnoside.
Figure 2 shows the α-Glucosidase inhibitory activity according to the treatment of Quercetin-3-O-rhamnoside confirmed in Example 1 using alpha-glucosidase (α-) using Acarbose, a drug for treating
3 is a result of measuring the viability of Quercetin-3-O-rhamnoside in Hep G2 cells confirmed in Example 2.
4 is a measurement result of DPP-4 inhibitory activity in Hep G2 cells by Quercetin-3-O-rhamnoside treatment confirmed in Example 3.
5 is a measurement result of intramuscular viability of Quercetin-3-O-rhamnoside confirmed in Example 2.
6 is a measurement result of the glucose uptake rate in muscle cells of Quercetin-3-O-rhamnoside confirmed in Example 5.
7 is a measurement result of IRS-1, AKT, GLUT-4 protein expression levels in muscle cells confirmed in Example 5.
8 is a result of the synergistic effect of glucose uptake in insulin-resistant muscle cells by treatment with a 1:1 (mole: mole) complex of Quercetin-3-O-rhamnoside and Quercetin confirmed in Example 6.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
상술한 바와 같이 종래 합성 약제는 체중 증가, 흉부 기능 상실, 메스꺼움 등 여러 부작용이 나타났으며, 매해마다 세계적으로 증가하는 당뇨로 인한 사망자 수에 따라 이에 대한 새로운 대안이 필요한 실정이었다.As described above, conventional synthetic drugs have several side effects such as weight gain, loss of chest function, and nausea, and a new alternative is needed according to the number of deaths due to diabetes, which is increasing worldwide every year.
이에 본 발명은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하는 당뇨 예방 및 치료용 약학적 조성물 및 당뇨 예방 및 개선용 건강기능성 식품을 제공함으로써 상술한 문제의 해결을 모색하였으며 이를 통해 종래 약학적 조성물에서 나타났던 부작용인 체중 증가, 흉부 기능 상실, 메스꺼움 등 여러 부작용이 없으면서, 종래 생약제 추출물에서는 확인이 힘들었던 근육세포의 인슐린 저항성을 저해하고 근육세포 내 포도당의 흡수율을 상승시키는 효과가 있는 당뇨 예방 및 치료용 약학적 조성물 및 당뇨 예방 및 개선용 건강기능성 식품을 제공하는 효과가 있다. Accordingly, the present invention provides a pharmaceutical composition for preventing and treating diabetes containing quercetin-3-O-rhamnoside and a health functional food for preventing and improving diabetes, thereby solving the above problems Through this, there are no side effects such as weight gain, loss of chest function, and nausea, which are side effects seen in conventional pharmaceutical compositions, while inhibiting insulin resistance of muscle cells, which was difficult to identify in conventional herbal extracts, and increasing the absorption rate of glucose in muscle cells There is an effect of providing a pharmaceutical composition for preventing and treating diabetes and a functional food for preventing and improving diabetes.
상기 Quercetin-3-O-rhamnoside는 플라보노이드 (flavonoid) 계열의 물질로서 항산화작용뿐만 아니라 항바이러스 및 항염증 등의 활성이 있다고 알려져 있다. 그러나 본 발명에서는 Quercetin-3-O-rhamnoside의 제 2형 당뇨에 대한 예방 및 치료 효과를 확인하였다. 본 발명의 Quercetin-3-O-rhamnoside는 통상적으로 제조 및/또는 구매할 수 있는 것이라면 특별히 제한하지 않으나, 바람직하게는 Quercetin으로부터 유래한 것일 수 있다. Quercetin에서 유래된 Quercetin-3-O-rhamnoside의 신규한 생리활성인 당뇨 예방 및/또는 치료 활성을 발견하였다. 구체적으로 실시예 1에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 퀘르세틴 (Quercetin)에 당 유도체 중 하나인 Rhamnoside를 붙여 생성되었다.The Quercetin-3-O-rhamnoside is a flavonoid-based material and is known to have anti-inflammatory and anti-inflammatory activities as well as antioxidant activity. However, in the present invention, the preventive and therapeutic effects of Quercetin-3-O-rhamnoside for
또한, 실시예 2에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 알파-글루코시다제 (α-Glucosidase) 저해 활성이 현재 2형 당뇨 치료 약물인 아카보즈 (Acarbose) 보다 더 우수함을 확인하였다. 실시예 3에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 Hep G2 세포의 세포 생존력에는 영향을 미치지 않는 것을 확인하였다. 또한, 실시예 4에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 Hep G2 세포에서 DPP-4 효소를 저해하여 당뇨를 예방 및 치료하는 활성을 확인하였다. 또한, 실시예 5에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 근육세포의 세포 생존력에는 영향을 미치지 않는 것을 확인하였다. 또한, 실시예 6에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 근육세포 내의 포도당 축적을 증가 시켜 당뇨를 예방 및 치료하는 활성을 확인하였다. 또한, 실시예 6에서 확인되는 바와 같이, 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 근육세포 내 인슐린 저항성을 감소시켜 당뇨를 예방 및 치료하는 활성을 확인하였다. 나아가, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 AKT 및 IRS-1 (Insulin receptor substrate)로 이루어진 군 중 1종 이상의 단백질 발현을 감소 또는 증가시켜 항당뇨 활성을 나타낼 수 있다. 구체적으로, 실시예 7에서 확인되는 바와 같이, 본 발명의 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 p-AKT 및 p-IRS-1 (ser), GLUT4의 발현을 감소 또는 증가시켜 항당뇨 활성을 나타내는 것을 확인할 수 있었다. 나아가, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 또한, 실시예 8에서 확인되는 바와 같이, 상기 퀘르세틴 (Quercetin)와 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 1:1 (mole : mole) 복합물이 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside) 단일 물질에 비하여 포도당 흡수율을 더욱 증가시키는 상승효과를 통해 항당뇨 효능이 증가한다는 사실을 확인하였다. 또한, 실시예 8에서 확인되는 바와 같이, 상기 Quercetin과 Quercetin-3-O-rhamnoside를 유효성분으로 포함한 1:1 (mole : mole) 복합물이 근육세포 내 인슐린 저항성을 감소시켜 포도당 흡수율을 더욱 증가시키는 상승효과를 통해 당뇨를 예방 및 치료하는 활성을 확인하였다.In addition, as confirmed in Example 2, the quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) is an alpha-glucosidase (α-Glucosidase) inhibitory activity is currently a
더불어, 상기 당뇨 예방 및 치료용 약학적 조성물은 Quercetin-3-O-rhamnoside를 포함하는 것이라면 그 함량을 특별히 제한하지 않으나, 바람직하게는 5 내지 30 μM의 농도로 포함할 수 있다. 만약, 10 μM의 농도 이하의 Quercetin-3-O-rhamnoside를 포함할 경우, 충분한 항당뇨 활성 효과를 볼 수 없을 수 있으며, 30 μM의 농도를 초과하는 양의 Quercetin-3-O-rhamnoside를 포함할 경우, 세포독성 증가에 대한 문제가 발생할 수 있다. 좀 더 구체적으로 설명하면, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 Quercetin-3-O-rhamnoside를 포함하는 것이라면 그 함량을 특별히 제한하지 않으나, 바람직하게는 10 내지 30 μM의 농도로 포함할 수 있다. 만약, 10 μM 의 농도 이하의 Quercetin-3-O-rhamnoside를 포함할 경우, 충분한 항당뇨 활성 효과를 볼 수 없을 수 있으며, 30 μg/mL의 농도를 초과하는 양의 Quercetin-3-O-rhamnoside를 포함할 경우, 세포독성 증가에 대한 문제가 발생할 수 있다.In addition, the pharmaceutical composition for preventing and treating diabetes is not particularly limited in its content as long as it contains Quercetin-3-O-rhamnoside, but may preferably contain a concentration of 5 to 30 μM. If Quercetin-3-O-rhamnoside at a concentration of 10 μM or less is included, sufficient antidiabetic activity may not be seen, and Quercetin-3-O-rhamnoside in an amount exceeding 30 μM is included. If so, the problem of increased cytotoxicity may occur. More specifically, if the pharmaceutical composition for preventing and treating diabetes of the present invention contains Quercetin-3-O-rhamnoside, the content is not particularly limited, but preferably at a concentration of 10 to 30 μM. can If Quercetin-3-O-rhamnoside at a concentration of 10 μM or less is included, sufficient antidiabetic activity may not be seen, and Quercetin-3-O-rhamnoside in an amount exceeding the concentration of 30 μg/mL When including, the problem of increased cytotoxicity may occur.
퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60 μM의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 Hep G2 세포와 비교하여, Hep G2 세포의 생존율을 0 내지 20%로 저해시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60μM 의 농도로 포함할 때, 근육세포의 성장을 0 내지 21%로 억제시킬 수 있다. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60 μM의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 근육세포와 비교하여, 근육세포의 생존율을 0 내지 20%로 저해시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60μM 의 농도로 포함할 때, 근육세포의 성장을 0 내지 22 %로 억제시킬 수 있다.When Quercetin-3-O-rhamnoside is included in a concentration of 10 to 60 μM, Quercetin-3-O-rhamnoside is not included Compared to Hep G2 cells, it is possible to inhibit the survival rate of Hep G2 cells to 0 to 20%, preferably quercetin-3-O-rhamnoside at a concentration of 10 to 60 μM. When included, the growth of muscle cells can be inhibited by 0 to 21%. When Quercetin-3-O-rhamnoside is included in a concentration of 10 to 60 μM, Quercetin-3-O-rhamnoside is not included Compared to muscle cells, the survival rate of muscle cells can be inhibited to 0 to 20%, and preferably, quercetin-3-O-rhamnoside is included at a concentration of 10 to 60 μM. In this case, it is possible to inhibit the growth of muscle cells by 0 to 22%.
또한 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 0 내지 200 μM의 농도로 포함할 때 알파-글리코시다제 (α-Glycosidase) 저해 활성 측정 결과 IC50 0.397mM을 나타낼 수 있다.In addition, when the pharmaceutical composition for preventing and treating diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 0 to 200 μM, alpha-glycosidase (α-Glycosidase) ) Inhibitory activity measurement result may indicate an IC50 of 0.397mM.
또한 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 0 내지 30 μM의 농도로 포함할 때 DPP-4 효소 저해 활성 측정 결과 0 내지22%로 DPP-4 효소활성을 저해 할 수 있다.In addition, when the pharmaceutical composition for preventing and treating diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 0 to 30 μM, the measurement result of DPP-4 enzyme inhibitory activity is 0 DPP-4 enzyme activity can be inhibited by to 22%.
나아가, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM 의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 근육세포와 비교하여, 근육세포의 세포 내 포도당 흡수율을 20 내지 100%로 증가시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 20 내지 40 μM 의 농도로 포함할 때, 근육세포의 세포 내 포도당 흡수율을 23 내지 101%로 증가시킬 수 있다.Furthermore, when the pharmaceutical composition for preventing and treating diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM, quercetin-3-O-rhamnoside Compared to muscle cells not containing Quercetin-3-O-rhamnoside, it is possible to increase the intracellular glucose uptake rate of muscle cells by 20 to 100%, preferably quercetin-3-O-rhamnoside ( When Quercetin-3-O-rhamnoside) is included at a concentration of 20 to 40 μM, the intracellular glucose uptake rate of muscle cells can be increased to 23 to 101%.
또한, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM 의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 인슐린 저항성을 유도한 근육세포와 비교하여, 근육세포의 세포 내 포도당 흡수율을 30내지 80%로 증가시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM 의 농도로 포함할 때, 근육세포의 세포 내 포도당 흡수율을 39 내지 83%까지 증가시킬 수 있다.In addition, when the pharmaceutical composition for preventing and treating diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM, quercetin-3-O-rhamnoside Compared with muscle cells induced to insulin resistance that do not contain seed (Quercetin-3-O-rhamnoside), the intracellular glucose uptake rate of muscle cells can be increased to 30 to 80%, preferably quercetin-3- When O-rhamnoside (Quercetin-3-O-rhamnoside) is included in a concentration of 10 to 30 μM, it is possible to increase the intracellular glucose uptake rate of muscle cells by 39 to 83%.
게다가, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM의 농도로 포함할 때, Quercetin-3-O-rhamnoside를 포함하지 않는 근육세포와 비교하여, 근육세포 내 p-AKT 발현을 201%까지 증가시킬 수 있다.In addition, when the pharmaceutical composition for preventing and treating diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM, Quercetin-3-O-rhamnoside Compared to muscle cells that do not contain , p-AKT expression in muscle cells can be increased by 201%.
또한, 본 발명의 당뇨 예방 및 치료용 약학적 조성물은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 20 내지 40μM의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 근육세포와 비교하여, 근육세포 내 p-IRS-1 (ser) 발현을 9%로 감소시킬 수 있다. In addition, when the pharmaceutical composition for preventing and treating diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 20 to 40 μM, quercetin-3-O-rhamnoside As compared to muscle cells not containing (Quercetin-3-O-rhamnoside), p-IRS-1 (ser) expression in muscle cells can be reduced by 9%.
또한 본 발명의 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)을 포함하는 당뇨 예방 및 치료용 약학적 조성물을 제공할 수 있다. In addition, it is possible to provide a pharmaceutical composition for preventing and treating diabetes comprising quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) of the present invention.
상기 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 몰비는 1:10 (mole : mole) 내지 10:1 (mole : mole)일 수 있다. The molar ratio of quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) may be 1:10 (mole: mole) to 10:1 (mole: mole).
상기 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 1 내지 100 μM의 농도로 포함할 수 있다. The quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) may be included in a concentration of 1 to 100 μM.
Quercetin과 Quercetin-3-O-rhamnoside를 각각 10 μM의 농도로 함유한 1:1 (mole : mole) 복합물을 포함할 때, Quercetin-3-O-rhamnoside와 비교하여, 근육세포의 세포 내 포도당 흡수율을 1내지 31%로 상승시키는 효과를 보였으며, 바람직하게는 Quercetin-3-O-rhamnoside 단일물질을 10 μM의 농도로 포함할 때와 비교하여 근육세포의 세포 내 포도당 흡수율을 0 내지 31.6%로 증가시킬 수 있다.When a 1:1 (mole: mole) complex containing Quercetin and Quercetin-3-O-rhamnoside at a concentration of 10 μM is included, the intracellular glucose uptake rate of muscle cells compared to Quercetin-3-O-
본 발명에 따른 Quercetin-3-O-rhamnoside를 포함하는 당뇨 예방 및 치료용 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 Quercetin-3-O-rhamnoside에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 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 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween)61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition for preventing and treating diabetes containing Quercetin-3-O-rhamnoside according to the present invention is an oral form such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc., according to a conventional method, respectively. It can be used in the form of formulations, external preparations, suppositories, or sterile injection solutions. Specifically, in the case of formulation, it can be prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the Quercetin-3-O-rhamnoside, for example, starch, calcium carbonate ), sucrose, lactose, gelatin, etc. can be mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명에 따른 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하는 당뇨 예방 및 치료용 약학적 조성물은 환자의 나이, 성별, 체중에 따라 달라질 수 있으나, 일반적으로 0.01 내지 50 mg/kg의 양, 바람직하게는 0.1 내지 10 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 또한 Quercetin-3-O-rhamnoside를 포함하는 조성물의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 따라서 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 더불어, 상기 당뇨 예방 및 개선용 건강기능성 식품은 Quercetin-3-O-rhamnoside를 포함하는 것이라면 그 함량을 특별히 제한하지 않으나, 바람직하게는 10 내지 30 μM의 농도로 포함할 수 있다. 만약, 10 μM 의 농도 이하의 Quercetin-3-O-rhamnoside를 포함할 경우, 충분한 항당뇨 활성 효과를 볼 수 없을 수 있으며, 30 μg/mL의 농도를 초과하는 양의 Quercetin-3-O-rhamnoside를 포함할 경우, 세포독성 증가에 대한 문제가 발생할 수 있다. The pharmaceutical composition for preventing and treating diabetes comprising quercetin-3-O-rhamnoside according to the present invention may vary depending on the age, sex, and weight of the patient, but generally 0.01 to An amount of 50 mg/kg, preferably 0.1 to 10 mg/kg, may be administered once to several times a day. In addition, the dosage of the composition containing Quercetin-3-O-rhamnoside may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any way. In addition, the content of the functional health food for preventing and improving diabetes is not particularly limited as long as it contains Quercetin-3-O-rhamnoside, but may preferably be included in a concentration of 10 to 30 μM. If Quercetin-3-O-rhamnoside at a concentration of 10 μM or less is included, sufficient antidiabetic activity may not be seen, and Quercetin-3-O-rhamnoside in an amount exceeding the concentration of 30 μg/mL When including, the problem of increased cytotoxicity may occur.
퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60 μM의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 Hep G2 세포와 비교하여, Hep G2 세포의 생존율을 0 내지 20%로 저해시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60μM 의 농도로 포함할 때, 근육세포의 성장을 0 내지 21%로 억제시킬 수 있다. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60 μM의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 근육세포와 비교하여, 근육세포의 생존율을 0 내지 20%로 저해시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 60μM 의 농도로 포함할 때, 근육세포의 성장을 0 내지 22 %로 억제시킬 수 있다. 또한 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 0 내지 200 μM의 농도로 포함할 때 알파-글리코시다제 (α-Glycosidase) 저해 활성 측정 결과 IC 50 0.397mM을 나타낼 수 있다. 또한 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 0 내지 30 μM의 농도로 포함할 때 DPP-4 효소 저해 활성 측정 결과 0 내지22%로 DPP-4 효소활성을 저해 할 수 있다.When Quercetin-3-O-rhamnoside is included in a concentration of 10 to 60 μM, Quercetin-3-O-rhamnoside is not included Compared to Hep G2 cells, it is possible to inhibit the survival rate of Hep G2 cells to 0 to 20%, preferably quercetin-3-O-rhamnoside at a concentration of 10 to 60 μM. When included, the growth of muscle cells can be inhibited by 0 to 21%. When Quercetin-3-O-rhamnoside is included in a concentration of 10 to 60 μM, Quercetin-3-O-rhamnoside is not included Compared to muscle cells, the survival rate of muscle cells can be inhibited to 0 to 20%, and preferably, quercetin-3-O-rhamnoside is included at a concentration of 10 to 60 μM. In this case, it is possible to inhibit the growth of muscle cells by 0 to 22%. In addition, the health functional food for preventing and improving diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 0 to 200 μM, alpha-glycosidase (α-Glycosidase). ) As a result of measuring the inhibitory activity, the
나아가, 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM 의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 근육세포와 비교하여, 근육세포의 세포 내 포도당 흡수율을 20 내지 100%로 증가시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 20 내지 40 μM 의 농도로 포함할 때, 근육세포의 세포 내 포도당 흡수율을 23 내지 101%로 증가시킬 수 있다. Furthermore, when the health functional food for preventing and improving diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM, quercetin-3-O-rhamnoside Compared to muscle cells not containing Quercetin-3-O-rhamnoside, it is possible to increase the intracellular glucose uptake rate of muscle cells by 20 to 100%, preferably quercetin-3-O-rhamnoside ( When Quercetin-3-O-rhamnoside) is included at a concentration of 20 to 40 μM, the intracellular glucose uptake rate of muscle cells can be increased to 23 to 101%.
또한, 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM 의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 인슐린 저항성을 유도한 근육세포와 비교하여, 근육세포의 세포 내 포도당 흡수율을 30내지 80%로 증가시킬 수 있으며, 바람직하게는 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM 의 농도로 포함할 때, 근육세포의 세포 내 포도당 흡수율을 39 내지 83%로 증가시킬 수 있다.In addition, when the health functional food for preventing and improving diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM, quercetin-3-O-rhamnoside Compared with muscle cells induced to insulin resistance that do not contain seed (Quercetin-3-O-rhamnoside), the intracellular glucose uptake rate of muscle cells can be increased to 30 to 80%, preferably quercetin-3- When O-rhamnoside (Quercetin-3-O-rhamnoside) is included at a concentration of 10 to 30 μM, the intracellular glucose uptake rate of muscle cells can be increased to 39 to 83%.
게다가, 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 10 내지 30 μM의 농도로 포함할 때, Quercetin-3-O-rhamnoside를 포함하지 않는 근육세포와 비교하여, 근육세포 내 p-AKT 발현을 201%로 증가시킬 수 있다.In addition, the health functional food for preventing and improving diabetes of the present invention contains Quercetin-3-O-rhamnoside at a concentration of 10 to 30 μM, Quercetin-3-O-rhamnoside Compared to muscle cells that do not contain , p-AKT expression in muscle cells can be increased to 201%.
또한, 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 20 내지 40 μM의 농도로 포함할 때, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 포함하지 않는 근육세포와 비교하여, 근육세포 내 p-IRS-1 (ser) 발현을 9%로 감소시킬 수 있다. In addition, when the health functional food for preventing and improving diabetes of the present invention contains quercetin-3-O-rhamnoside at a concentration of 20 to 40 μM, quercetin-3-O-rhamnoside Compared to myocytes not containing Quercetin-3-O-rhamnoside, the expression of p-IRS-1 (ser) in myocytes can be reduced by 9%.
또한 본 발명은 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)을 포함하는 2형 당뇨병의 예방 또는 개선용 건강기능성 식품 조성물을 제공할 수 있다. 상기 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 몰비는 1:10 (mole : mole) 내지 10:1 (mole : mole)일 수 있다. 상 기 퀘르세틴 (Quercetin) 및 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 1 내지 100 μM의 농도로 포함할 수 있다. In addition, the present invention can provide a functional health food composition for preventing or improving
또한, 본 발명의 당뇨 예방 및 개선용 건강기능성 식품은 Quercetin과Quercetin-3-O-rhamnoside를 각각 10 μM의 농도로 함유한 1:1 (mole : mole) 복합물을 포함할 때, Quercetin-3-O-rhamnoside와 비교하여, 근육세포의 세포 내 포도당 흡수율을 1내지 31%로 상승시키는 효과를 보였으며, 바람직하게는 Quercetin-3-O-rhamnoside 단일물질을 10 μM의 농도로 포함할 때와 비교하여 근육세포의 세포 내 포도당 흡수율을 0 내지 31.6%로 증가시킬 수 있다.In addition, the health functional food for preventing and improving diabetes of the present invention contains a 1:1 (mole: mole) complex containing Quercetin and Quercetin-3-O-rhamnoside at a concentration of 10 μM, respectively, Quercetin-3- Compared to O-rhamnoside, it showed the effect of increasing the intracellular glucose uptake rate of muscle cells by 1 to 31%, preferably compared to when Quercetin-3-O-rhamnoside was included at a concentration of 10 μM. Thus, the intracellular glucose uptake rate of muscle cells can be increased to 0 to 31.6%.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 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, 슈크로스 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. 상기 외에 본 발명의 건강 기능성 식품은 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, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 건강 기능성 식품들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.The health beverage composition of the present invention is not particularly limited in the liquid component except for containing the quercetin-3-O-rhamnoside as an essential ingredient in the indicated ratio, and various Flavoring agents or natural carbohydrates may be contained as additional ingredients. 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 dextrins, cyclodextrins; and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (eg rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have. In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health functional foods of the present invention may contain natural fruit juice and pulp for the production of 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 by way of Examples. However, these Examples are for explaining the present invention in more detail, and the scope of the present invention is not limited to these Examples.
실시예 1. Quercetin 및 Quercetin-3-O-rhamnoside의 화학적 구조Example 1. Chemical structures of Quercetin and Quercetin-3-O-rhamnoside
퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 Flavone 기본 골격을 가지며 3번 탄소 자리에 O 원소와 함께 람노시드 (Rhamnoside)를 가진 구조를 띄고 있다.Quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside) has a flavone basic skeleton and has a structure having a rhamnoside with an O element at the 3rd carbon position.
실시예 2. α-Glucosidase inhibitor assayExample 2. α-Glucosidase inhibitor assay
알파-글루코시다아제 (α-Glucosidase) 저해 활성 측정을 위해 알파-글루코시다아제 (α-Glucosidase/Sharomyces, Sigma, USA)는 0.2 M 인산염 완충제 (pH 7.0)를 사용하여 0.3 U/mL로 희석하였다. 기질 파라-니트로페닐 글루코피라노사이드 (pNPG, Sigma, USA)는 같은 완충용액을 사용하여 0.3 mM 농도로 희석하였다. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)는 0.2 M 인산염 완충제(pH 7.0)에 0, 6.25, 12.5, 25, 50, 100 또는 200 μM 농도까지 희석하였다. Positive control로 α-Glucosidase 억제 활성이 있다고 알려진 아카보즈 (Acarbose, WAKO, Japan) 또한 0.2 M 인산염 완충제 (pH 7.0)에 0, 125, 250, 500 , 1000, 2000, 3000, 4000 또는 8000 μM의 농도로 희석 하였다. For the measurement of alpha-glucosidase inhibitory activity, alpha-glucosidase (α-Glucosidase/Sharomyces, Sigma, USA) was diluted to 0.3 U/mL using 0.2 M phosphate buffer (pH 7.0). . The substrate para-nitrophenyl glucopyranoside (pNPG, Sigma, USA) was diluted to a concentration of 0.3 mM using the same buffer. Quercetin-3-O-rhamnoside was diluted in 0.2 M phosphate buffer (pH 7.0) to concentrations of 0, 6.25, 12.5, 25, 50, 100 or 200 μM. Acarbose (Acarbose, WAKO, Japan), which is known to have α-Glucosidase inhibitory activity as a positive control, is also added at a concentration of 0, 125, 250, 500, 1000, 2000, 3000, 4000 or 8000 μM in 0.2 M phosphate buffer (pH 7.0). was diluted with
그 후 96-웰 플레이트 (96-well plate)에 완충용액 10 μL, Quercetin-3-O-rhamnoside 또는 아카보즈 시료 20 μL와 20 μL의 α-Glucosidase 효소액을 혼합하여 5% CO2, 37℃ 인큐베이터(incubator)에서 15분간 배양하였다. 또한 pNPG와 α-Glucosidase 효소액이 반응하여 흡광도의 차이가 발생할 수 있기에 정확도를 높이고자 Control 군으로 설정하였다. 그리고 시료 자체의 발색으로 인해 흡광도에 차이가 날 수 있으므로 Blank 군을 설정하였다.After that, in a 96-well plate, mix 10 μL of buffer, 20 μL of Quercetin-3-O-rhamnoside or acarbose sample, and 20 μL of α-Glucosidase enzyme solution in a 5% CO2, 37°C incubator ( incubator) for 15 minutes. In addition, since the difference in absorbance may occur due to the reaction between pNPG and α-Glucosidase enzyme solution, the control group was set to increase the accuracy. And since the absorbance may differ due to the color development of the sample itself, a blank group was set.
그 후 20 μL의 pNPG 용액을 각 샘플과 혼합, Control 및 Blank에 첨가한 후 5% CO2, 37℃ 인큐베이터 (incubator)에서 15분 동안 다시 배양했다. 이 반응은 0.2 M 탄산나트륨용액 130 μL를 첨가하여 종료하였다. Blank에서 α-Glucosidase 효소 용액은 완충 용액으로 대체하였다. Control에서 시료는 완충 용액으로 대체되었다. 그 후 ELISA reader로 405 nm에서 흡광도를 측정하였다. 측정 결과는 하기 도 2와 같다.Then, 20 μL of pNPG solution was mixed with each sample, added to Control and Blank, and incubated again for 15 minutes in an incubator at 37° C. under 5
실시예 3. HepG2 세포에서의 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 세포독성 측정 Example 3. Measurement of Cytotoxicity of Quercetin-3-O-rhamnoside in HepG2 Cells
HepG2 ( human liver cancer cell line )세포에 대한 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 세포 생존률을 측정하기 위해 MTT 어세이 (methylthiazolyldiphenyl tetrazolium bromide assay)를 실시하였다. HepG2 세포를 96-웰 플레이트 (96-well plate)에 0.5*104 cells/well로 분주하여 24시간 동안 5% CO2, 37℃ 인큐베이터 (incubator)에서 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Welgene, USA)에 10% FBS (Welgene, USA), 1% 페니실린 스트렙토마이신 (penicillin streptomysin)을 첨가한 배지에서 배양하였다. 배양 후 배양액을 제거하고 DMEM HG medium과 Quercetin-3-O-rhamnoside를 농도별로(0, 20, 30, 40, 또는 60 μM) 24시간 동안 처리하였다. 이후 용매 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 5 mg/mL로 용해한 MTT (3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide)용액을 각 웰 (well) 마다 120 μL씩 처리하여 20분 동안 5% CO2, 37℃ 인큐베이터 (incubator)에서 배양하였다. 배양 이후 배양액을 제거한 뒤 각 웰마다 디메틸 설폭사이드 (DMSO; dimethyl sulfoxide) 200 μL/well로 넣으면서 피펫을 이용해 잘 교반하였다. 그 후 ELISA reader로 570 nm에서 흡광도를 측정하였다. 도 3에서 확인되는 바와 같이, Quercetin-3-O-rhamnoside를 0, 20, 30, 40, 또는 60 μM 의 농도로 처리하였을 때, 세포 생존력에는 큰 변화가 없는 것으로 보아 퀘르세틴-3-O-람노시드는 60 μM 농도까지는 세포 독성은 없는 것으로 나타났다.To measure the cell viability of quercetin-3-O-rhamnoside on HepG2 (human liver cancer cell line) cells, MTT assay (methylthiazolyldiphenyl tetrazolium bromide assay) was performed. HepG2 cells were seeded in a 96-well plate at 0.5*10 4 cells/well, and Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; 5% CO 2 , 37°C incubator) for 24 hours; Welgene, USA) was cultured in a medium containing 10% FBS (Welgene, USA) and 1% penicillin streptomycin. After culture, the culture medium was removed, and DMEM HG medium and Quercetin-3-O-rhamnoside were treated for 24 hours by concentration (0, 20, 30, 40, or 60 μM). After that, a solution of MTT (3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide) dissolved in the solvent DPBS (Dulbecco's Phosphate-Buffered Saline, 1X) at 5 mg/mL was added to each well. Treated with 120 μL of 5% CO 2 for 20 minutes, 37 ℃ incubator (incubator) incubated. After incubation, the culture solution was removed, and 200 μL/well of dimethyl sulfoxide (DMSO) was added to each well and stirred well using a pipette. Then, absorbance was measured at 570 nm with an ELISA reader. As confirmed in FIG. 3, when Quercetin-3-O-rhamnoside was treated at a concentration of 0, 20, 30, 40, or 60 μM, there was no significant change in cell viability. Noside was not shown to be cytotoxic up to a concentration of 60 μM.
실시예 4. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 DPP-4 효소 억제력 측정Example 4. Measurement of DPP-4 Enzyme Inhibition of Quercetin-3-O-rhamnoside
HepG2 (human liver cancer cell line )세포에 대한 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 DPP-4 효소 억제력을 측정하기 위해 DPP-4 inhibition 어세이(DPP-4 inhibition assay) 를 실시하였다. HepG2 세포를 6-웰 플레이트 (6-well plate)에 1*105 cells/well로 분주하여 24시간 동안 5% CO2, 37℃ 인큐베이터 (incubator)에서 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Welgene, USA)에 10% FBS (Welgene, USA), 1% 페니실린 스트렙토마이신 (penicillin streptomysin)을 첨가한 배지에서 배양하였다. 배양 후 배양액을 제거하고 DMEM HG medium과 Quercetin-3-O-rhamnoside를 농도별로(0, 10, 20, 또는 30 μM) 24시간 동안 처리하였다. 이후 배지를 제거하고 인산완충식염수 (phosphate buffered saline; PBS buffer)로 세척하였다. 세척 후 웰 당 100 μL의 용해 버퍼 (lysis buffer)를 첨가 후 스크래퍼로 세포를 긁어 E.p. tube에 모은 후, 30분 동안 얼음 상에서 반응시키고, 13,000 rpm에서 15분 동안 원심분리 하여 단백질을 수득하였다. 수득한 단백질 30 μL와 20 μL의 50 mM Tris-HCl,pH 8.0 ( biosesang, Republic of Korea), 50μL의 5 mM Gly-pro-pNA solution (Sigma aldrich, USA)을 섞어 준 후 실온에서 30분 동안 반응 시켰다. 이 후 피펫을 이용해 잘 교반한 후 ELISA reader로 405 nm에서 흡광도를 1차 측정, 30분 후 2차 측정하였다. 그 후 수득한 단백질을 브래드퍼드 분석법 (Bradford 분석법)을 이용하여 단백질을 정량하여 측정값을 보정하였다. 도 4에서 확인되는 바와 같이, Quercetin-3-O-rhamnoside를 0 μM, 10 μM, 20 μM, 또는 30 μM의 농도로 처리하였을 때, 퀘르세틴-3-O-람노시드가 DPP-4 효소를 30 μM의 농도에서 22%까지 억제하는 것으로 나타났다. DPP-4 inhibition assay to measure the DPP-4 enzyme inhibition of quercetin-3-O-rhamnoside on HepG2 (human liver cancer cell line) cells ) was carried out. HepG2 cells were seeded in a 6-well plate at 1*10 5 cells/well for 24 hours in 5% CO 2 , 37° C. in an incubator, Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Welgene, USA) was cultured in a medium containing 10% FBS (Welgene, USA) and 1% penicillin streptomycin. After incubation, the culture medium was removed and treated with DMEM HG medium and Quercetin-3-O-rhamnoside at different concentrations (0, 10, 20, or 30 μM) for 24 hours. Thereafter, the medium was removed and washed with phosphate buffered saline (PBS buffer). After washing, 100 μL of lysis buffer was added per well, scraped cells with a scraper, collected in an Ep tube, reacted on ice for 30 minutes, and centrifuged at 13,000 rpm for 15 minutes to obtain proteins. After mixing 30 μL of the obtained protein with 20 μL of 50 mM Tris-HCl, pH 8.0 (biosesang, Republic of Korea), and 50 μL of 5 mM Gly-pro-pNA solution (Sigma aldrich, USA), at room temperature for 30 minutes reacted After stirring well using a pipette, the absorbance was first measured at 405 nm with an ELISA reader, followed by a second measurement after 30 minutes. Thereafter, the obtained protein was quantified using a Bradford assay (Bradford assay), and the measured values were corrected. As can be seen in Figure 4, when Quercetin-3-O-rhamnoside was treated at a concentration of 0 μM, 10 μM, 20 μM, or 30 μM, quercetin-3-O-rhamnoside inhibited the DPP-4 enzyme by 30 It was shown to inhibit up to 22% at a concentration of μM.
실시예 5. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 C2C12 근육세포에미치는 세포독성 여부 측정 Example 5. Measurement of cytotoxicity of quercetin-3-O-rhamnoside on C2C12 muscle cells
퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 C2C12 (Mouse myoblast cell line) 근육세포에 미치는 세포 독성 여부를 측정하기 위해 시료 처리 후 MTT 어세이로 세포 생존률 (cell viability)을 측정하였다. MTT 어세이 (methylthiazolyldiphenyl tetrazolium bromide assay)의 경우 근육세포를 분화유도 전과 분화유도 후로 나누어 실시하였다. 분화 유도 전의 경우 C2C12 근육세포를 96-웰 플레이트 (96-well plate)에 0.5*104 cells/well로 분주하여 24시간 동안 5% CO2, 37℃인큐베이터 (incubator)에서 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA)에 10% FBS (Welgene, USA), 1% 페니실린 스트렙토마이신 (penicillin streptomysin)을 첨가한 배지에서 배양하였다. 배양 후 배양액을 제거하고 DMEM HG medium과 Quercetin-3-O-rhamnoside를 농도별로(0, 10, 20, 30, 40, 또는 60 μM) 24시간 동안 처리하였다. 이후 용매 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 5 mg/mL로 용해한 MTT (3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide)용액을 각 웰 (well) 마다 120 μL씩 처리하여 20분 동안 5% CO2, 37℃ 인큐베이터에서 배양하였다. 배양 이후 배양액을 제거한 뒤 각 웰마다 디메틸 설폭사이드 (DMSO; dimethyl sulfoxide) 200 μL/well로 넣으면서 피펫을 이용해 잘 교반하였다. 그 후 ELISA reader로 570 nm에서 흡광도를 측정하였다. 분화 유도후의 세포생존률 확인은 앞선 분화 유도 전의 경우와 마찬가지로 C2C12 근육세포를 96-웰 플레이트 (96-well plate)에 0.5*104 cells/well로 분주하여 24시간 동안 5% CO2, 37℃인큐베이터 (incubator)에서 배양하였다. 배양 후 배양액을 제거하고 배지를 1% 페니실린 스트렙토마이신 (penicillin streptomysin), 2% Horse serum (Gibco, USA) 이 함유된 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA)으로 바꾸어 7일 동안 분화 유도 하였다. 그 후에 DMEM HG medium과 Quercetin-3-O-rhamnoside를 농도별로(0, 10, 20, 30, 40, 또는 50 μM) 24시간 동안 처리하였다. 이후 용매 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 5 mg/mL로 용해한 MTT (3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide)용액을 각 웰 (well) 마다 120 μL씩 처리하여 20분 동안 5% CO2, 37℃ 인큐베이터에서 배양하였다. 배양 이후 배양액을 제거한 뒤 각 웰마다 디메틸 설폭사이드 (DMSO; dimethyl sulfoxide) 200 μL/well로 넣으면서 피펫을 이용해 잘 교반하였다. 그 후 ELISA reader로 570 nm에서 흡광도를 측정하였다. 도 5 a에서 확인되는 바와 같이, Quercetin-3-O-rhamnoside를 0, 10, 20, 30, 40, 또는 60 μM의 농도로 처리하였을 때, 30 μM 까지는 세포 생존력에 큰 변화가 없으며 도 5 b에서 확인 되는 바와 같이, Quercetin-3-O-rhamnoside를 7일 분화 후 0, 10, 20, 30, 40, 또는 50 μM 의 농도로 처리하였을 때, 세포 생존력에 변화가 거의 없는 것으로 보아 퀘르세틴-3-O-람노시드는 30 μM 농도까지는 세포 독성은 없는 것으로 나타났다.To measure the cytotoxicity of quercetin-3-O-rhamnoside on C2C12 (Mouse myoblast cell line) muscle cells, the cell viability was evaluated by MTT assay after sample treatment. measured. In the case of the MTT assay (methylthiazolyldiphenyl tetrazolium bromide assay), the muscle cells were divided into before and after differentiation induction. Before differentiation induction, C2C12 myocytes were aliquoted in 96-well plate at 0.5*10 4 cells/well and Dulbecco's Modified Eagle's Medium High glucose in 5% CO 2 , 37°C incubator for 24 hours. (DMEM HG medium; Hyclone, USA) 10% FBS (Welgene, USA), 1% penicillin streptomycin (penicillin streptomysin) was added to the culture medium. After incubation, the culture medium was removed, and DMEM HG medium and Quercetin-3-O-rhamnoside were treated for 24 hours by concentration (0, 10, 20, 30, 40, or 60 μM). After that, a solution of MTT (3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide) dissolved in the solvent DPBS (Dulbecco's Phosphate-Buffered Saline, 1X) at 5 mg/mL was added to each well. 120 μL of each treatment was carried out for 20 minutes in 5% CO 2 , and incubated in an incubator at 37° C. After incubation, the culture solution was removed, and 200 μL/well of dimethyl sulfoxide (DMSO) was added to each well and stirred well using a pipette. Then, absorbance was measured at 570 nm with an ELISA reader. To check the cell viability after differentiation induction, as in the case before differentiation induction, C2C12 myocytes were dispensed in a 96-well plate at 0.5*10 4 cells/well, 5% CO 2 , 37° C. incubator for 24 hours. (incubator). After incubation, the culture medium was removed and the medium was replaced with Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA) containing 1% penicillin streptomysin and 2% Horse serum (Gibco, USA) for 7 days. differentiation was induced. After that, DMEM HG medium and Quercetin-3-O-rhamnoside were treated for 24 hours by concentration (0, 10, 20, 30, 40, or 50 μM). After that, a solution of MTT (3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide) dissolved in the solvent DPBS (Dulbecco's Phosphate-Buffered Saline, 1X) at 5 mg/mL was added to each well. 120 μL of each treatment was carried out for 20 minutes in 5% CO 2 , and incubated in an incubator at 37° C. After incubation, the culture solution was removed, and 200 μL/well of dimethyl sulfoxide (DMSO) was added to each well and stirred well using a pipette. Then, absorbance was measured at 570 nm with an ELISA reader. As can be seen in Figure 5a, when Quercetin-3-O-rhamnoside was treated at a concentration of 0, 10, 20, 30, 40, or 60 μM, there was no significant change in cell viability up to 30 μM, and Fig. 5b As confirmed in , when Quercetin-3-O-rhamnoside was treated at a concentration of 0, 10, 20, 30, 40, or 50 μM after differentiation for 7 days, there was little change in cell viability. -O-rhamnoside was not shown to be cytotoxic up to a concentration of 30 μM.
실시예 6. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)가 근육세포에서 포도당 흡수 (Glucose uptake)에 미치는 영향 조사Example 6. Investigation of the effect of quercetin-3-O-rhamnoside on glucose uptake in muscle cells
C2C12 근육세포를 96-웰 블랙 플레이트 (96-well black plate)에 0.5 ×104 cells/well 밀도로 분주하고 1% 페니실린 스트렙토마이신 (penicillin streptomysin), 2% Horse serum (Gibco, USA) 이 함유된 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA)으로 배지를 갈아서 7일 동안 근육세포를 분화시키고 Dexamethasone (Sigma aldrich, USA)을 Dulbecco's Modified Eagle's Medium Low Glucose (DMEM LG medium; Welgene, USA)에 1 μM의 농도로 16시간 처리하여 인슐린 저항성 (Insulin-resistance)을 유도 하였다. 유도 후 배양액을 제거 한 뒤 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 1시간 Starvation 시켰다. DPBS를 제거 한 후 Dexamethasone (Sigma aldrich, USA)을 Dulbecco's Modified Eagle's Medium Glucose Free (DMEM GF medium; Welgene, USA)에 1 μM의 농도로 만들고 Quercetin-3-O-rhamnoside를 0, 10, 20, 또는 30 μM 의 농도로 3시간 30분 처리하였다. Quercetin-3-O-rhamnoside 처리 이후 insulin (Sigma aldrich, USA)을 1 μM 농도로 30분 처리하였다. 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG : Invitrogen, USA) 을 50 μM 농도로 2시간 처리하였다. 인산완충식염수로 세척한 후 형광분광광도계(기기 제조사)로 485 nm (exitation), 535 nm (emission) 에서 세포 내 2-NBDG 함량을 측정하였다. 측정 결과는 하기 도면 6에 나타내었다. 도 6a에서 확인 되는 것처럼 분화 전 근육세포에서의 세포 내 포도당 흡수율과 도 6b에서 확인되는 인슐린 저항성이 유도 된 근육세포에서의 세포 내 포도당 흡수율 두 가지 모두 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)가 포도당 흡수율을 촉진하며 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 항당뇨 활성을 나타낸다.C2C12 myocytes were aliquoted in a 96-well black plate at a density of 0.5 × 10 4 cells/well, and 1% penicillin streptomysin and 2% Horse serum (Gibco, USA) were added. Myocytes were differentiated for 7 days by grinding the medium with Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA), and Dulbecco's Modified Eagle's Medium Low Glucose (DMEM LG medium; Welgene, USA) was used to differentiate the muscle cells. Insulin resistance was induced by treatment at a concentration of 1 μM for 16 hours. After induction, the culture medium was removed and then starvated in DPBS (Dulbecco's Phosphate-Buffered Saline, 1X) for 1 hour. After removing DPBS, Dexamethasone (Sigma aldrich, USA) was prepared in Dulbecco's Modified Eagle's Medium Glucose Free (DMEM GF medium; Welgene, USA) at a concentration of 1 μM and Quercetin-3-O-rhamnoside was added to 0, 10, 20, It was treated for 3 hours and 30 minutes at a concentration of 30 μM. After Quercetin-3-O-rhamnoside treatment, insulin (Sigma aldrich, USA) was treated at a concentration of 1 μM for 30 minutes. 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG: Invitrogen, USA) was treated with 50 μM concentration for 2 hours. After washing with phosphate-buffered saline, intracellular 2-NBDG content was measured at 485 nm (exitation) and 535 nm (emission) with a fluorescence spectrophotometer (device manufacturer). The measurement results are shown in Figure 6 below. As confirmed in Figure 6a, both the intracellular glucose uptake rate in the muscle cells before differentiation and the intracellular glucose uptake rate in the insulin resistance-induced myocytes confirmed in Figure 6b are both quercetin-3-O-rhamnoside (Quercetin-3 -O-rhamnoside) promotes glucose absorption and exhibits antidiabetic activity of quercetin-3-O-rhamnoside.
실시예 7. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)처리가 근육세포 신호전달 단백질 발현에 미치는 영향조사Example 7. Investigation of the effect of Quercetin-3-O-rhamnoside treatment on muscle cell signaling protein expression
퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)의 항당뇨 관련 기전을 조사하기 위해 C2C12 근육세포에 대해 AKT, IRS-1 (Insulin receptor substrate), GLUT-4 (Glucose transporter type 4 )의 신호 전달에 의한 근육세포의 단백질 발현 감소 또는 증가를 웨스턴 블렛 (Western blot) 방법으로 조사하였다. 구체적으로, C2C12 근육세포를 6-웰 플레이트 (6-well plate)에 1 ×105 cells/well의 농도로 시딩 (seeding) 후 1% 페니실린 스트렙토마이신 (penicillin streptomysin), 2% Horse serum (Gibco, USA) 이 함유된 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA)으로 배지를 갈아서 7일 동안 근육세포를 분화시켰다. 그 후Dexamethasone (Sigma aldrich, USA)을 Dulbecco's Modified Eagle's Medium Low Glucose (DMEM LG medium; Welgene, USA)에 1μM의 농도로 16시간 처리하여 인슐린 저항성(Insulin-resistance)을 유도 하였다. 유도 후 배양액을 제거 한 뒤 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 1시간 Starvation 시켰다. DPBS를 제거 한 후 Dexamethasone (Sigma aldrich, USA)을 Dulbecco's Modified Eagle's Medium Glucose Free (DMEM GF medium; Welgene, USA)에 1 μM의 농도로 만들고 Quercetin-3-O-rhamnoside를 0, 10, 20, 또는 30 μM 의 농도로 3시간 30분 처리하였다. Quercetin-3-O-rhamnoside 처리 이후 insulin (Sigma aldrich, USA)을 1 μM 농도로 30분 처리하였다. 처리 후 인산완충식염수 (phosphate buffered saline; PBS buffer)로 세척하고 각 웰에 50 μL의 용해 버퍼 (lysis buffer)를 첨가 후, 스크래퍼로 세포를 긁어 모은 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 폴리 비닐 다이플루오라이드 막 (poly-vinyl difluoride membrane)에 옮긴 후, 1차 항-phospho AKT, 항-phospho IRS-1 (Ser), 항-total AKT, 항-total IRS-1, 항-total GLUT-4, 항-베타 액틴 항체 (CST, USA) (1:1000, v/v)를 5% 탈지분유 (skim milk)에 희석하여 폴리 비닐 다이플루오라이드 막에 넣고 4℃에서 24시간 반응시켰다. 이후 TBST (Tris-Buffered Saline와 Tween 20의 혼합액, 0.1% Tween 20)로 10분마다 3번 세척하고 HRP (horeseradish peroxidase)-conjugated 2차 항체를 5% 탈지분유에 1:2000(v/v)으로 희석하여 5 μL 첨가한 후 25 ℃에서 2시간 동안 반응시켰다. 위와 같은 방법으로 TBST를 이용하여 3차례 세척한 후 ECL (enchanced chemiluminescence) 기질 용액을 막아 1분 동안 반응시킨 후에 X-ray 필름에 현상하였다. 얻어진 결과를 이미지 J 프로그램을 이용하여 수치화하였다. 측정 결과는 도면 7에 나타내었다. 도 7a, b에서 확인되는 것과 같이, 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnoside)를 처리한 후 Dexamethason에 Insulin 처리 군과 비교했을 때, Quercetin-3-O-rhamnoside를 처리한 근육세포에서의 p-IRS-1 (Ser)의 발현량이 감소하는 것을 볼 수 있으며 이로 인해 인슐린 저항성을 퀘르세틴-3-O-람노시드가 억제 하는 효능이 있음을 알 수 있다. 또한 도 7a, c에서 확인 되는 것과 같이 p-AKT의 발현량이 증가하는 것을 보아 퀘르세틴-3-O-람노시드가 근육세포에서 포도당 흡수율 증가에 효능이 있음을 알 수 있는 결과를 보여준다. 결과적으로 도 7을 통해 퀘르세틴-3-O-람노시드가 항당뇨 활성이 있음을 나타낸다.To investigate the antidiabetic mechanism of quercetin-3-O-rhamnoside, AKT, IRS-1 (Insulin receptor substrate), GLUT-4 (Glucose transporter type 4) for C2C12 muscle cells ), the decrease or increase in protein expression in muscle cells by signal transduction was investigated by Western blot method. Specifically, after seeding C2C12 myocytes in a 6-well plate at a concentration of 1 × 10 5 cells/well, 1% penicillin streptomysin, 2% Horse serum (Gibco, USA) containing Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA) was ground and myocytes were differentiated for 7 days. After that, Dexamethasone (Sigma aldrich, USA) was treated in Dulbecco's Modified Eagle's Medium Low Glucose (DMEM LG medium; Welgene, USA) at a concentration of 1 μM for 16 hours to induce insulin-resistance. After induction, the culture medium was removed and then starvated in DPBS (Dulbecco's Phosphate-Buffered Saline, 1X) for 1 hour. After removing DPBS, Dexamethasone (Sigma aldrich, USA) was prepared in Dulbecco's Modified Eagle's Medium Glucose Free (DMEM GF medium; Welgene, USA) at a concentration of 1 μM and Quercetin-3-O-rhamnoside was added to 0, 10, 20, It was treated for 3 hours and 30 minutes at a concentration of 30 μM. After Quercetin-3-O-rhamnoside treatment, insulin (Sigma aldrich, USA) was treated at a concentration of 1 μM for 30 minutes. After treatment, wash with phosphate buffered saline (PBS buffer), add 50 μL of lysis buffer to each well, scrape cells with a scraper, and react on ice for 30 minutes, at 12,000 rpm The protein was obtained by centrifugation for 10 minutes. After quantifying the protein using the Bradford analysis method (Bradford method), a sample buffer was added and denatured at 95°C for 5 minutes, followed by SDS-PAGE (Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis) gel. was used for electrophoresis. After electrophoresis, transfer to a polyvinyl difluoride membrane, primary anti-phospho AKT, anti-phospho IRS-1 (Ser), anti-total AKT, anti-total IRS-1, anti -Total GLUT-4, anti-beta actin antibody (CST, USA) (1:1000, v/v) was diluted in 5% skim milk and put in a polyvinyl difluoride membrane at 4°C for 24 hours. reacted. Then, TBST (a mixture of Tris-Buffered Saline and
실시예 8. 퀘르세틴-3-O-람노시드 (Quercetin-3-O-rhamnloside)와 퀘르세틴 (Quercetin)의 1:1 (mole : mole) 복합물이 인슐린 저항성이 유도된 근육세포에서 포도당 흡수 (Glucose uptake) 상승에 미치는 영향 조사Example 8. Quercetin-3-O-rhamnloside and a 1:1 (mole: mole) complex of quercetin-3-O-rhamnloside and glucose uptake in insulin resistance-induced muscle cells ) to investigate the effect on the rise
C2C12 근육세포를 96-웰 블랙 플레이트 (96-well black plate)에 0.5 ×104 cells/well 밀도로 분주하고 1% 페니실린 스트렙토마이신 (penicillin streptomysin), 2% Horse serum (Gibco, USA) 이 함유된 Dulbecco's Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA)으로 배지를 갈아서 7일 동안 근육세포를 분화시키고 Dexamethasone (Sigma aldrich, USA)을 Dulbecco's Modified Eagle's Medium Low Glucose (DMEM LG medium; Welgene, USA)에 1μM의 농도로 16시간 처리하여 인슐린 저항성 (Insulin-resistance)을 유도 하였다. 유도 후 배양액을 제거 한 뒤 DPBS (Dulbecco's Phosphate-Buffered Saline, 1X)에 1시간 Starvation 시켰다. DPBS를 제거 한 후 Dexamethasone (Sigma aldrich, USA)을 Dulbecco's Modified Eagle's Medium Glucose Free (DMEM GF medium; Welgene, USA)에 1 μM의 농도로 만들고 Quercetin-3-O-rhamnoside, Quercetin을 10 μM 농도로 3시간 30분 처리하였다. 또한 Quercetin-3-O-rhamnoside와 Quercetin-3-O-xyloside를 각각 10 μM 농도로 1:1 (mole : mole) Mixture를 제조하여 3시간 30분 처리하였다. Quercetin-3-O-rhamnoside, Quercetin, Mixture 처리 이후 insulin (Sigma aldrich, USA)을 1 μM 농도로 30분 처리하였다. 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG : Invitrogen, USA) 을 50 μM 농도로 2시간 처리하였다. 인산완충식염수로 세척한 후 형광분광광도계(기기 제조사)로 485 nm (exitation), 535 nm (emission) 에서 세포 내 2-NBDG 함량을 측정하였다. 측정한 2-NBDG 의 함량은 도면 8에 나타냈다. Dulbecco's C2C12 myocytes were aliquoted in 96-well black plate at a density of 0.5 × 104 cells/well and contained 1% penicillin streptomysin and 2% Horse serum (Gibco, USA). The medium was ground with Modified Eagle's Medium High glucose (DMEM HG medium; Hyclone, USA) to differentiate muscle cells for 7 days, and Dexamethasone (Sigma aldrich, USA) was added to Dulbecco's Modified Eagle's Medium Low Glucose (DMEM LG medium; Welgene, USA). Insulin-resistance was induced by treatment at a concentration of 1 μM for 16 hours. After induction, the culture medium was removed and then starvated in DPBS (Dulbecco's Phosphate-Buffered Saline, 1X) for 1 hour. After removing DPBS, Dexamethasone (Sigma aldrich, USA) was prepared in Dulbecco's Modified Eagle's Medium Glucose Free (DMEM GF medium; Welgene, USA) at a concentration of 1 μM, and Quercetin-3-O-rhamnoside and Quercetin were added at a concentration of 10
Claims (10)
상기 약학적 조성물은 알파-글리코시다제 억제 (α-Glycosidase inhibition) 활성을 가지는, 제 2형 당뇨병의 예방 또는 치료용 약학적 조성물.
As a pharmaceutical composition for the prevention or treatment of type 2 diabetes comprising quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside)
The pharmaceutical composition has an alpha-glycosidase inhibition (α-Glycosidase inhibition) activity, a pharmaceutical composition for preventing or treating type 2 diabetes.
The pharmaceutical composition for preventing or treating type 2 diabetes according to claim 1, wherein the pharmaceutical composition reduces or increases the expression of one or more proteins from the group consisting of GLUT, AKT and IRS-1 (Insulin receptor substrate). .
The pharmaceutical composition for preventing or treating type 2 diabetes according to claim 1, wherein the pharmaceutical composition contains quercetin-3-O-rhamnoside at a concentration of 10 internal 30 μM. composition.
상기 약학적 조성물은 알파-글리코시다제 억제 (α-Glycosidase inhibition) 활성을 가지는, 제 2형 당뇨병의 예방 또는 치료용 약학적 조성물.
As a pharmaceutical composition for preventing or treating type 2 diabetes comprising quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside),
The pharmaceutical composition has an alpha-glycosidase inhibition (α-Glycosidase inhibition) activity, a pharmaceutical composition for preventing or treating type 2 diabetes.
상기 건강기능성 식품 조성물은 알파-글리코시다제 억제 (α-Glycosidase inhibition) 활성을 가지는, 제 2형 당뇨병의 예방 또는 개선용 건강기능성 식품 조성물.
As a health functional food composition for the prevention or improvement of type 2 diabetes comprising quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside)
The functional health food composition has an alpha-glycosidase inhibition (α-Glycosidase inhibition) activity, a health functional food composition for preventing or improving type 2 diabetes.
상기 건강기능성 식품 조성물은 알파-글리코시다제 억제 (α-Glycosidase inhibition) 활성을 가지는, 제 2형 당뇨병의 예방 또는 개선용 건강기능성 식품 조성물. As a health functional food composition for the prevention or improvement of type 2 diabetes comprising quercetin (Quercetin) and quercetin-3-O-rhamnoside (Quercetin-3-O-rhamnoside),
The functional health food composition has an alpha-glycosidase inhibition (α-Glycosidase inhibition) activity, a health functional food composition for preventing or improving type 2 diabetes.
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