KR100416650B1 - Extract Polygonatum and composition caontaining the same with hypocholesterolemic and hypoglycemic activities - Google Patents
Extract Polygonatum and composition caontaining the same with hypocholesterolemic and hypoglycemic activities Download PDFInfo
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- KR100416650B1 KR100416650B1 KR10-2000-0061753A KR20000061753A KR100416650B1 KR 100416650 B1 KR100416650 B1 KR 100416650B1 KR 20000061753 A KR20000061753 A KR 20000061753A KR 100416650 B1 KR100416650 B1 KR 100416650B1
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Abstract
본 발명은 둥굴레 추출물과 그를 함유한 혈장 지질 및/또는 혈당 강하용 조성물에 관한 것으로, 잘게 부순 둥굴레-메탄올 용액을 가온추출하고 여과하여 메탄올 추출액을 수득한 후 유기용매인 헥산, 클로로포름, n-부탄올 순으로 추출분리한 둥굴레 추출물은 동물체내의 혈장 지질 및 혈당 강하효과 등의 좋은 생리활성도를 유의적으로 나타내고, 부작용이나 급성독성 등의 면에서 안전하여 심혈관계 질환인 고지혈중 및/또는 당뇨병의 예방 및 치료를 위한 약학적 조성물 또는 기능성 식품등의 유효성분으로 이용할 수 있는 매우 뛰어난 효과가 있다.The present invention relates to a doungle extract and a composition for lowering blood lipids and / or blood sugar containing the same, which is obtained by heating and filtering a finely crushed doungle-methanol solution to obtain a methanol extract, and then using organic solvents hexane, chloroform, and n-butanol. In order to prevent cardiovascular diseases such as hyperlipidemia and / or diabetes, the extract of donggule extract shows significant physiological activities such as plasma lipids and hypoglycemic effect in animals and is safe in terms of side effects and acute toxicity. And there is a very excellent effect that can be used as an active ingredient, such as pharmaceutical compositions or functional food for treatment.
Description
본 발명은 둥굴레 추출물과 그를 함유한 혈장 지질 및 혈당 강하용 조성물에 관한 것으로, 보다 상세하게는 인체와 동물에서 콜레스테롤 흡수와 생합성을 억제함과 동시에 항산화기능을 향상시켜 혈장 지질농도를 현저히 저하시키며 식후 혈중 포도당 농도의 상승을 조절하는 혈당 강하기능을 가져 고지혈증, 당뇨병과 같은 심혈관계 질환 및 합병증 조절에 유효한 약리학적 효과를 갖는 둥굴레 추출물, 그의 제조방법 및 이를 유효성분으로 포함하는 약학적 조성물에 관한 것이다.The present invention relates to a gourd extract and a composition for lowering blood lipids and blood sugar containing the same, and more particularly, to inhibit cholesterol absorption and biosynthesis in humans and animals, and to improve antioxidant function, significantly lowering plasma lipid concentrations, and The present invention relates to a perilla extract, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient, having a hypoglycemic ability to control a rise in blood glucose levels and having a pharmacological effect effective in controlling cardiovascular diseases and complications such as hyperlipidemia and diabetes. .
최근 산업사회의 발달과 식생활 양상의 변화로 고지방 가공식품 및 육류소비가 보편화되면서 고지혈증, 동맥경화, 고혈압, 당뇨병 등과 같은 심혈관계 만성 성인병 환자가 점차 급증하고 있는 추세이다. 특히 45세 이상 고령층에 특히 많은 심혈관질환의 주요원인으로 고혈압, 비만증, 고지혈증, 당뇨등이 지적되고 있으며, 미국에서만 보더라도 연간 90만명이 발병하여 그 중 15만명이 사망하는 것으로 알려져 있다. 이러한 심혈관계 질환은 전체 사망율의 30%를 차지하고 있으며, 현재 일본과 우리나라에서는 콜레스테롤에 의한 여러 가지 성인병이 가장 심각한 문제로 대두되고 있어 혈중 높은 수준의 포도당뿐만 아니라 콜레스테롤 농도도 낮추기 위한 물질 및 기능성 식품 개발이 시급히 요청되는 실정이다.Recently, as high-fat processed foods and meat consumption become more common due to the development of industrial society and changes in eating habits, patients with chronic cardiovascular diseases such as hyperlipidemia, arteriosclerosis, hypertension and diabetes are increasing rapidly. In particular, high blood pressure, obesity, hyperlipidemia, diabetes, etc. have been pointed out as a major cause of many cardiovascular diseases, especially in the elderly over 45 years old, and in the United States alone, 900,000 cases occur and 150,000 of them die. These cardiovascular diseases account for 30% of all mortality rates. Currently, many adult diseases caused by cholesterol are the most serious problems in Japan and Korea, and the development of substances and functional foods to lower cholesterol levels as well as high glucose levels in the blood. This is urgently requested.
고지혈증은 혈액내 콜레스테롤(cholesterol)과 중성지방(triglycerides)치가 정상보다 높은 경우를 뜻하며 동맥경화, 심근경색, 뇌경색과 같은 혈액순환질환을 초래하므로 조기에 치료하고 그로 인한 합병증을 예방하는 것이 중요하다. 고지혈증의 원인 물질인 콜레스테롤은 세포를 구성하는 필수성분으로 세포의 성장, 분화 및 발육에 중요한 역할을 한다. 성인의 경우 하루 콜레스테롤 요구량은 1,300mg 정도이며, 이 중 약 1,000mg이 신체의 거의 모든 세포에서 합성되고, 약 300mg 정도의 콜레스테롤이 음식물로부터 섭취된다. 음식물로부터 과다섭취된 콜레스테롤은 세포 필요량을 만족시키면 남게되어 혈류를 따라 떠돌아 고지혈증을 야기시키며, 단핵세포, 거핵세포 등과 함께 혈관내막에 흡착되어 거품세포로 전환되는 원인이 되고 이는 결국 동맥내벽을 두껍게 하여 혈류를 차단시킴으로써 협심증, 동맥경화 또는 심장마비를 유발하게된다(Johan F, Jan N, Anders H, Hans W, Hidlund M. 1990. Proc. Natl. Acad. Sci. 87:904-908.).Hyperlipidemia refers to a case in which blood cholesterol and triglycerides are higher than normal, and it causes blood circulation diseases such as arteriosclerosis, myocardial infarction, and cerebral infarction. Therefore, it is important to treat early and prevent complications. Cholesterol, the causative agent of hyperlipidemia, is an essential component of cells and plays an important role in cell growth, differentiation and development. In adults, the daily cholesterol requirement is about 1,300 mg, of which about 1,000 mg is synthesized in almost every cell of the body, and about 300 mg of cholesterol is taken from food. Cholesterol ingested from food remains when it meets the cell requirement, causing it to float along the bloodstream, causing hyperlipidemia, which is adsorbed to the vascular lining with monocytes and megakaryocytes, and converts into foam cells, which eventually thickens the arterial wall. Blocking blood flow can cause angina, arteriosclerosis or heart attack (Johan F, Jan N, Anders H, Hans W, Hidlund M. 1990. Proc. Natl. Acad. Sci. 87: 904-908.).
이와 같이 혈중 콜레스테롤은 관상동맥경화증의 발생빈도, 심근경색과 높은 상관관계를 보이는 것으로 보고되고 있으며, 이러한 보고는 콜레스테롤 섭취가 많은 국가에서 관상동맥질환 또는 허혈성 심장질환에 의한 사망율이 높다는 보고와도 일치한다(Keys, A., Circulation, 41(Supp1), 1(1970). 음식물로부터 섭취된 식이 콜레스테롤과 심혈관계 질환과의 관계에 대한 LRC-CPPT(The Lipid Research Clinic Program, J. Am. Med. Assoc., 251, 365 (1984)) 연구결과와 헬싱키 심장연구결과(Helsinki Heart Study; Kannel WB, Dawber TR, Kagan A, Revostski N, Strokes J. 1961. Factors of risk in the development of coronary heart disease-six year follow-up experience: the Framingham study. Ann. Intern. Med. 55:33-50.)에 의하면 콜레스테롤의 섭취를 1% 줄일 경우 심혈관계 질환을 2% 줄일 수 있다고 한다.As such, blood cholesterol is highly correlated with the incidence of coronary atherosclerosis and myocardial infarction. This report is consistent with the high mortality rate from coronary artery disease or ischemic heart disease in countries with high cholesterol intake. (Keys, A., Circulation, 41 (Supp1), 1 (1970). The Lipid Research Clinic Program, J. Am. Med., On the relationship between dietary cholesterol and cardiovascular disease ingested from food). Assoc., 251, 365 (1984)) and Helsinki Heart Study; Kannel WB, Dawber TR, Kagan A, Revostski N, Strokes J. 1961. Factors of risk in the development of coronary heart disease According to the six year follow-up experience: the Framingham study.Annn.Intern.Med. 55: 33-50.), a 1% reduction in cholesterol can reduce cardiovascular disease by 2%.
현재 각국에서는 심현관계 질환 문제를 해결하기 위하여 식이요법과 함께 사용될 각종 기능성 식품 및 고지혈증 치료제의 합성에 주력하고 있는 상황이다. 현재까지 개발된 고지혈증 치료제를 살펴보면 LDL-콜레스테롤을 혈중에서 20∼35%까지 낮출 수 있는 콜레스티라민(cholestyramine)과 콜레스티폴(cholestipol)과 같은 콜레스테롤 유도체들과 콜레스테롤 생합성에 관여하는 HMG-CoA 환원효소(HMG-CoA reductase; 3-Hydroxy-3-methylglutaryl-CoA reductase)의 저해제인 Lovastatin, Simvastatin(Illingworth DR, Bacon S. 1987. American J. Cardiology 60:33G-42G.), Pravastatin (Kajinami K, Toshimura A, Watanabe A. 1986. Proc. IXth International Symposium on Drug Effecting Lipid Metabolism, Florence, 0ct. 27.)등이 개발되어 시중에 판매되고 있다. 이들 약제들은 콜레스테롤농도를 낮출 수 있는 장점은 가지고 있으나 장기간 사용으로 오심, 두통, 피로감, 불면증, 피부발진, 장기능변화 등의 심각한 부작용을 수반하고 있어서 이상적인 약물요법으로는 적합하지 못하다(Illingworth DR. 1988. Drug 36 (suppl.3):63-71.). 또한, 니코틴산(nicotinic acid) 등을 사용하여 간의 LDL이나 VLDL의 생합성을 저하시킴으로서 동맥경화와 같은 심질환의 발생빈도를 낮추려고 시도하고 있지만 이 또한 위장관에 오심, 복부불쾌감 및 설사 등의 부작용이 심각하며, 소화성 궤양이나 과뇨산혈증, 간장질환이 있는 환자에게는 투여가 금지되고 있는 형편이다.At present, countries are focusing on the synthesis of various functional foods and hyperlipidemia treatments to be used with diet to solve the cardiovascular diseases. The hyperlipidemia treatments developed to date show that cholesterol derivatives such as cholestyramine and cholestipol, which can lower LDL-cholesterol by 20-35% in the blood, and HMG-CoA reduction involved in cholesterol biosynthesis. Lovastatin, Simvastatin (Illingworth DR, Bacon S. 1987. American J. Cardiology 60: 33G-42G.), An inhibitor of the enzyme (HMG-CoA reductase; 3-Hydroxy-3-methylglutaryl-CoA reductase), Pravastatin (Kajinami K, Toshimura A, Watanabe A. 1986. Proc. IXth International Symposium on Drug Effecting Lipid Metabolism, Florence, 0ct. 27.), have been developed and sold in the market. These drugs have the advantage of lowering cholesterol levels but are not suitable for ideal drug therapy because of their long-term use and serious side effects such as nausea, headache, fatigue, insomnia, skin rash, and changes in intestinal function (Illingworth DR. 1988. Drug 36 (suppl. 3): 63-71.). In addition, nicotinic acid is used to reduce the biosynthesis of LDL and VLDL in the liver, thereby reducing the incidence of cardiac diseases such as atherosclerosis. However, side effects such as nausea, abdominal discomfort and diarrhea in the gastrointestinal tract are severe. In patients with peptic ulcer, hyperuricemia, or liver disease, administration is prohibited.
한편, 최근의 식생활 변화와 관련하여 현재 국내뿐만 아니라 전세계적으로 성인병인 당뇨병의 발생율이 점차 증가하고 있어 당뇨병 환자의 치료 및 질환조절에 있어서 혈액 내의 포도당 농도를 조절하는 것이 매우 중요한 일이 되고 있다.Meanwhile, in relation to recent dietary changes, the incidence of diabetes mellitus, which is an adult disease, is increasing not only in Korea but also in the world, and controlling glucose concentration in blood is very important in the treatment and control of diseases of diabetics.
음식물 중에 포함된 탄수화물은 소장에서 탄수화물 분해효소의 작용을 받아 포도당으로 소화되어 혈액내로 흡수된다. 음식물을 섭취하면 혈액 내 급격히 포도당 농도는 상승하는데, 당뇨병, 고지혈증과 같은 질환의 경우 인슐린이 부족하거나 인슐린 작용에 결함이 있음으로 인해 상승된 포도당 농도가 계속 높게 유지되어 위험한 상태를 초래할 수 있다. 즉, 인슐린 부족 시에 포도당이 에너지원으로 이용되지 못하고 혈중농도가 증가하게 되면, 근육 내의 단백질 및 지방세포가 분해되어 포도당신생(gluconegenesis)을 통해 에너지원으로 대신 이용된다. 간장에서는 포도당의 신생과 단백질 분해가 증가하게 되고 지방세포의 분해증가도 야기되어 지방산과 글리세롤의 유리가 일어난다. 지방산은 주요 에너지원이기는 하나 활성아세트산(Acetyl-CoA)의 생성을 야기하여 케톤체의 과다 축적을 초래하고 유리된 지방산이 간장 내에서 중성지방으로 전환되기 때문에 합병증으로 지방간이 발생하기도 한다.Carbohydrates contained in food are digested into glucose by the action of carbohydrate degrading enzymes in the small intestine and absorbed into the blood. Ingestion of food rapidly increases glucose levels in the blood. In diseases such as diabetes and hyperlipidemia, elevated glucose levels may be maintained at high levels due to lack of insulin or a lack of insulin action, resulting in dangerous conditions. In other words, when glucose is not used as an energy source and the blood concentration increases when insulin is deficient, proteins and fat cells in muscle are decomposed and used instead as an energy source through gluconegenesis. In the liver, angiogenesis and proteolysis of glucose are increased and fat cells are degraded, leading to the release of fatty acids and glycerol. Fatty acids are a major energy source, but they cause the production of active acetic acid (Acetyl-CoA), which leads to excessive accumulation of ketone bodies, and fatty liver is a complication because free fatty acids are converted into triglycerides in the liver.
그러므로 이와같은 인슐린 부족으로 인한 당뇨병 치료시 정상적인 대사과정을 수행하기 위해 인슐린 투여, 설포닐우레아 제제 투여, 식이요법 등의 국한적인 치료를 하게 된다. 최근에는 당뇨병의 치료를 위해 합성된 약물보다는 천연물에서의 약리 효과가 있는 물질을 탐색하는 연구가 이루어지고 있으며, 약 400여종의 야생식용식물이 당뇨병 치료에 효과가 있다고 보고된 바 있다(Bailey CJ, Day C. 1989. Raditional plant medicines as treatments for diabetes.Diabetic Care12:553-564.). 약용작물 또는 식용작물이 혈당강하에 효과를 나타내었다는 연구가 계속적으로 이루어지고 있으나, 과학적인 증명이 시작된 것은 최근의 일이며 그 대부분은 아직 약리 효능과 생리적 기전 및 유효성분 분석에 대해 임상 및 과학적으로 입증되지 못하고 있는 실정이며, 야생식용식물은 그 성분 및 약리 효과에 대하여 국내·외적으로 많은 관심이 집중되고 있고, 항암성 및 혈당강하 효능에 대하여 발표된 연구 논문이 다수 존재한다. 특히 우리의 고유식품이며 전통적으로 질병 치료에 이용되어 오던 야생식용식물의 효능에 대한 적극적이고 과학적인 연구가 이루어졌으며, 씀바귀 (Ixeris dentataNakai), 산복사(Prunus davidianaFr.) 및 갈대(Phragmites communisTrin)의 메탄올 추출물이 alloxan 당뇨 유발 흰쥐에서 유의적으로 혈당을 낮춘다고 보고(Choi JS, Chung HY, Han SY. 1990.Kor. J. Pharmacogn21(2):153-157.)된 바 있으며, streptozotocin 당뇨 유발 흰쥐에서 닭의장풀(Commeninae Herba) H2O 추출물과 메탄올 추출물이 혈당강하효과를 보였다고 하였고, 닭의장풀 추출물 투여로 allxan에 의해 당뇨가 유발된 쥐에서 혈당치 증가의 유의적인 감소와 함께 간조직내 glucose-6-phosphate dehydrogenase 의 활성도가 회복되었다고 보고하였다(박수영. 1992. Hypoglycemic effects ofCommelina communisL. and characterization of glucose-6-phosphate dehydrogenase in rat liver. 석사학위 논문. 덕성여자대학교대학원.). 그 외에도 두릅나무(Lee MY, Lee JS, Sheo HJ. 1988. Effects of Aralia elata extract on experimentally alloxan induced diabees im rabbits.J. Korean Soc. Food Nutr.17(1):57-61.; 김옥경. 1990. 두릅나무 근피추출물의 혈당강하 효과. 박사학위논문. 서울여자대학교대학원)를 비롯한 여러가지 국내 자생 야생식용식물의 혈당강하효과에 대한 연구가 이루어져 왔다.Therefore, in the treatment of diabetes due to such insulin deficiency, local administration of insulin administration, sulfonylurea preparation administration, and dietary therapy is performed to perform normal metabolic processes. Recently, research has been conducted to search for substances that have pharmacological effects in natural products, rather than drugs synthesized for the treatment of diabetes, and about 400 wild edible plants have been reported to be effective in treating diabetes (Bailey CJ, Day C. 1989. Raditional plant medicines as treatments for diabetes.Diabetic Care 12: 553-564.). Although studies on medicinal crops or edible crops have been shown to have an effect on hypoglycemic activity, scientific proofs have recently been started, and most of them have been clinically and scientifically analyzed for pharmacological efficacy, physiological mechanisms and effective ingredient analysis. Although it is not proven, wild edible plants are attracting much attention both domestically and internationally for their components and pharmacological effects, and there are many published research papers on anticancer and hypoglycemic efficacy. In particular, active and scientific researches have been conducted on the efficacy of wild edible plants, which are our own foods and have traditionally been used to treat diseases, and include Ixeris dentata Nakai, Prunus davidiana Fr. and Phragmites communis. Methanol extract of Trin has been reported to significantly lower blood glucose in alloxan diabetic rats (Choi JS, Chung HY, Han SY. 1990. Kor. J. Pharmacogn 21 (2): 153-157.) Hemoglycemic effect of Commeninae Herba H 2 O extract and methanol extract in streptozotocin-induced diabetic rats was shown to have hypoglycemic effect. It was reported that the activity of -6-phosphate dehydrogenase was recovered (Park Soo Young. 1992. Hypoglycemic effects of Commelina communis L. and characterization of glucose-6-phosphate dehydrogenase i Master's Thesis, Graduate School of Duksung Women's University. Lee MY, Lee JS, Sheo HJ. 1988. Effects of Aralia elata extract on experimentally alloxan induced diabees im rabbits.J. Korean Soc.Food Nutr. 17 (1): 57-61 .; Kim Ok-kyung. 1990 Hypoglycemic Effects of Root Extracts of Aralia elata, Ph.D. Dissertation, Graduate School of Seoul Women's University).
최근 건강식품의 관심 대상이 되고 있는 한국산 야생식용식물 중 민간에서 약용으로 오랫동안 사용되어온 식물로 둥굴레(Polygonatum odoratum)가 있다. 둥굴레는 백합과에 속하는 다년생초본으로 흔히 전국 산야의 그늘이나 고산의 초원에서 30∼60 cm의 높이로 자라고 6∼7월경에 녹색 꽃이 피며 8월에 종자가 익는다. 한방과 민간에서는 자양 및 강장의 목적으로 많이 이용되며, 여러 가지 허약증상, 영양불량, 폐결핵으로 인한 기침, 당뇨로 인한 지갈 등의 약재로 쓰이고 있으나, 과거에는 궁핍을 면할 수 있는 구황 식물이었다(김희선, 김숙희. 1987. 조선시대 기아 만성화와 구황식품 개발의 사회, 경제적 고찰. 한국 식문화학회지 2:82-91). Polygonatum odoratum is a plant that has been used for a long time in medicinal use among Korean wild edible plants that have recently been the focus of health food. Dungole is a perennial herb belonging to the family Liliaceae, often grows in heights of 30-60 cm in the shades of mountainous areas and alpine meadows around the country. Green flowers bloom around June and July, and the seeds ripen in August. It is widely used for the purpose of nourishment and tonic in oriental medicine and private medicine. It is used as a medicine for various weakness symptoms, malnutrition, cough caused by pulmonary tuberculosis, and jigal caused by diabetes. Kim, Sook-Hee 1987. Socio-economic Consideration of Chronic Hunger and Development of Kwangwang Food in the Joseon Dynasty.
둥굴레에 대한 약리효과에 관해서는 한방서 및 최근 동물실험(임숙자, 김수연, 이주원. 1995. 한국영양학회지 28:585-594.; 임숙자, 김계진. 1995. 한국영양학회지 28: 727-736.)에서 혈당강하 작용이 기재되어 있다.On the pharmacological effects of the donggullet, in oriental medicine and recent animal experiments (Sook-Jae Lim, Soo-Yeon Kim, Ju-Won Lee, 1995. Korean Journal of Nutrition, 28: 585-594 .; Sook-Jae Lim, Kye-Jin Kim, 1995. Hypoglycemic action is described.
그러나 혈당강하 이외의 약리작용 및 주성분에 대해서는 잘 알려져 있지 않으며 아직까지 둥굴레의 여러 성분들 중에서 어떠한 성분이 각각의 작용을 나타내는 지에 대한 구체적이고 체계적인 연구결과는 보고된 바가 없고 현재까지는 둥굴레의 특정성분을 추출하여 이용하기보다는 주로 둥굴레를 그대로 물에 넣고 끓여서 차로 먹거나 술에 담구어 먹고 있는 실정이다. 그러나 이러한 방식으로 복용하는 경우에는 목적하는 성분이외의 성분이 포함될 수도 있기 때문에 복용하는 사람에 따라서는 그 목적하는 약리적 효과가 상쇄되거나 원치않는 부작용까지 나타날 수도 있다. 또한 둥굴레의 약리효과에 있어 혈장 지질저하 효과와 관련한 고지혈증 개선효과에 대하여 발표된 특허 및 연구논문은 전혀 발표된 적이 없는 실정이다.However, pharmacological action and main components other than hypoglycemic are not well known, and there are no concrete and systematic researches on which ones among the various components of Dongleul have not been reported. Rather than extracting and using, the donggole is boiled in water as it is, eaten as tea or dipped in alcohol. However, when taken in this way, it may contain ingredients other than the desired ingredient, so the person taking the drug may cancel the desired pharmacological effect or even have an unwanted side effect. Also, no published patents or research papers have been published on the improvement of hyperlipidemia related to plasma lipid-lowering effects on the pharmacological effects of donggule.
이에 본 발명자들은 생체에 대한 부작용이 없으면서 혈장 지질 강하 작용이 우수한 물질을 제공하고자 둥굴레 뿌리를 다양한 용매로 추출하여 수득되는 각종 추출물에 대하여 약리적 효과를 시험하여 보았으며, 그 결과 후술하는 바와 같이 본 발명 방법에 의해 추출하여 수득되는 둥굴레 추출물이 당뇨병 및/또는 그 합병증의 하나인 고지혈증의 두 가지 질환을 동시에 개선 또는 치료할 수 있는 우수한 약리적 효과가 있음을 확인하고 본 발명을 완성하게 되었다.Accordingly, the present inventors have tested the pharmacological effects on various extracts obtained by extracting the roots with various solvents in order to provide a substance having excellent plasma lipid-lowering action without side effects on the living body, and as a result, the present invention will be described later. The present invention was completed by confirming that the extract obtained by the method has an excellent pharmacological effect of simultaneously improving or treating two diseases of diabetes and / or hyperlipidemia, which is one of complications thereof.
즉, 본 발명 방법에 의한 둥굴레 추출물은 혈당 강하 효과뿐만 아니라 콜레스테롤 생합성 및 지질 흡수를 억제함과 동시에 항산화기능을 향상시켜 혈장 지질농도를 현저히 저하시키는 효과가 있음을 확인할 수 있었다.In other words, it was confirmed that the extract of the donggulle according to the method of the present invention not only lowers blood glucose lowering effect, but also inhibits cholesterol biosynthesis and lipid absorption and improves antioxidant function, thereby significantly lowering plasma lipid concentration.
따라서, 본 발명의 목적은 혈장 지질 및 혈당 강하효과를 동시에 갖는 둥굴레 추출물 및 그 제조방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a dongleule extract having a plasma lipid and blood sugar lowering effect at the same time and a method for producing the same.
본 발명의 다른 목적은 상기 둥굴레 추출물을 유효성분으로 하여 약제학적으로 허용가능한 담체를 포함하는 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier using the extract as an active ingredient.
본 발명의 또 다른 목적은 상기 둥굴레 추출물을 유효성분으로 함유하는 기능성 식품을 제공하는 것이다.Still another object of the present invention is to provide a functional food containing the extract as an active ingredient.
이하 본 발명의 구성에 대해서 구체적으로 설명하고자 한다.Hereinafter will be described in detail with respect to the configuration of the present invention.
도 1은 본 발명 혈장 지질 및 혈당 강하효과가 있는 둥굴레 추출물의 분리방법을 나타내는 그림이다.Figure 1 is a diagram showing the separation method of the extract of the extract of the present invention plasma lipid and blood sugar lowering effect.
본 발명은 인체와 동물에서 탄수화물 및 지질 대사를 조절함으로써 식후 혈중 포도당과 지질 농도의 급격한 상승을 조절하여 당뇨병, 비만증 및 고지혈증과 같은 심혈관계 질환의 치료 및 합병증 조절에 유효한 둥굴레 추출물 및 이의 제조방법 그리고 이 추출물을 유효성분으로 하여 약학적으로 허용가능한 담체를 포함하는 약학적 조성물 및 기능성 식품에 관한 것이다.The present invention is to regulate the carbohydrate and lipid metabolism in the human body and animals to control the rapid rise in blood glucose and lipid concentrations after a meal, the extract of the extract and its preparation method effective in the treatment of cardiovascular diseases such as diabetes, obesity and hyperlipidemia and control complications It relates to a pharmaceutical composition and a functional food comprising a pharmaceutically acceptable carrier with the extract as an active ingredient.
본 발명의 혈당 및/또는 혈장 지질 강하용 조성물 또는 기능성(건강보조) 식품에서 주성분으로 사용되는 둥굴레(Polygonatum odoratum)는 통둥굴레, 왕둥굴레, 용둥굴레 등 여러 종류가 있는데 한국에는 16종 2변종의 18종류가 있으며(이창복. 1995. 대한식물도감. 향문사), 모두 식용, 관상용 및 약용으로 사용할 수 있다(최영전. 1991. 산나물재배와 이용법. 오성출판사.). 둥굴레의 다른 이름으로는 위수, 위유, 황정, 옥죽, 황지, 소필관엽, 선인반, 토죽, 죽네풀, 괴물꽃, 죽대, 진황정 등이 있으며, 본 발명 방법에 따라 사용가능한 둥굴레는 상기 둥굴레의 어떤 종류일 수도 있으며 주로 늦가을과 이른봄에 뿌리를 채취하여 깨끗하게 씻어 사용한다. Polygonatum odoratum used as a main ingredient in the blood sugar and / or plasma lipid-lowering composition or functional (health supplement) food of the present invention has various types such as tongle, dongleung, yongdongle, etc. There are 18 varieties (Lee Chang-bok. 1995. Korea Plant Book. Hyangmunsa), all of which can be used for edible, ornamental and medicinal purposes (CHO Young-jeon. 1991. Growing and using wild vegetables. Oh Seong Publishing Co.). Other names of the dungole include Wissu, Yuyu, Hwangjeong, Jade Juk, Hwangji, Sopil Houseplant, Seonban, Sakju, Staghorn, Monster Flower, Bamboo, Qinhuangjeong, etc. It can be of any kind, and the roots are taken in late autumn and early spring and washed thoroughly.
본 발명 둥굴레 추출물의 제조방법으로는 공지의 방법을 사용하는 것이 가능한데 예컨대, 둥굴레 뿌리 등을 채취하여 생뿌리 자체로 또는 햇빛에 의한 자연건조나 기계적인 강제건조의 방법 등으로 건조하여 잘게 자른 후 물, 메탄올, 에탄올, 부탄올 등의 극성용매 및 에테르, 헥산, 클로로포름 등의 비극성 용매들을 가한후 실온에서 침적 추출하거나 가온 추출할 수 있다.As a method of producing the extract of the present invention, it is possible to use a known method, for example, taking the roots, etc., and then cutting them finely by drying them by means of raw roots or by natural drying or mechanical forced drying by sunlight or the like. , Polar solvents such as methanol, ethanol and butanol, and non-polar solvents such as ether, hexane and chloroform may be added, and then extracted or heated extracted at room temperature.
본 발명의 바람직한 한 실시예에 있어서 둥굴레를 메탄올 용매 하에서 80℃로 48시간동안 가온 추출처리하여 부탄올 층에서 얻은 추출물이 혈당강하효과, 혈장 지질(총 콜레스테롤과 중성지질, P<0.01) 저하효과 등의 좋은 생리활성도를 나타내었다. 더욱 구체적으로는, 본 발명자들은 건조 둥굴레와 메탄올을 분쇄기에 넣어 잘게 부순후, 잘게 부순 둥굴레-메탄올 용액을 48시간 동안 80℃ 수욕 상에서 냉각기와 기계적 교반기를 부착하여 1-3회 반복·추출하고 상기 과정에 의한 추출용액을 거름장치로 여과하여 메탄올 층을 얻은 후 메탄올 층에 포함되어 있는 메탄올을 감압장치를 이용하여 제거하고, 상기 과정에 의해 수득된 메탄올 추출물에 대해 메탄올 추출물 : H2O : 메탄올 : 추출용매 = 10 : 9 : 1 : 10의 비율로 섞은 후에 추출용매 헥산, 클로로포름, n-부탄올 순으로 각각 추출하여 최종적으로 약리적 효과를 갖는 부탄올 추출물을 얻을 수 있었다.In a preferred embodiment of the present invention, the extract obtained from the butanol layer was heated for 48 hours at 80 ° C. under methanol solvent, and the extract obtained from the butanol layer lowered blood sugar, lowered plasma lipids (total cholesterol and neutral lipid, P <0.01), and the like. Showed good physiological activity. More specifically, the present inventors crushed finely dried dry gourd and methanol in a pulverizer, and then repeated and extracted 1-3 times by attaching a cooler and a mechanical stirrer in a water bath at 80 ° C. for 48 hours. The extraction solution was filtered through a filter to obtain a methanol layer, and the methanol contained in the methanol layer was removed using a pressure reduction device. The methanol extract obtained by the above process was extracted with methanol extract: H 2 O: methanol. : Solvent Extraction = 10: 9: 1: 10 After mixing in the ratio of extract solvent hexane, chloroform, n-butanol in each order was finally obtained a butanol extract having a pharmacological effect.
고콜레스테롤 식이에 민감하게 반응하는 동물인 토끼를 이용하여 상기 방법에 의해 제조된 둥굴레 부탄올 추출물의 전반적인 지질대사 및 관련 유전자 발현에 미치는 영향을 검색한 결과, 0.5% 고콜레스테롤 식이에 둥굴레 추출물을 급여한 토끼에서 혈장 총콜레스테롤 수준이 유의적으로 감소되었을 뿐만 아니라, 콜레스테롤생합성 관련 효소인 간의 HMG-CoA 환원효소 및 ACAT 활성 역시 유의적으로 감소되었으며, 간조직에서 항산화효소인 SOD 및 카탈라아제 활성을 유의적으로 증가시켰다. 따라서 본 발명 둥굴레 추출물은 식이 콜레스테롤의 체내 흡수를 막음으로써 식이 콜레스테롤에 의한 혈중 콜레스테롤 농도 증가를 방지하여 최종적으로 동맥경화증을 예방하고 치료할 수 있을 뿐만 아니라, 동맥경화증의 치료 외에도 혈중 지질농도를 감소시켜 결국 고지혈증(hyperlipidemia)을 치료하는 효과도 가져 동맥경화증을 비롯한 각종 심혈관계 질환을 예방 또는 치료하기 위하여 식이 콜레스테롤 및 중성지질의 흡수방지제로 이용할 수 있는 것으로 판단되었다.Rabbits, which are sensitive to high cholesterol diets, were used to detect the effects on the total lipid metabolism and related gene expression of the extracts of butoleol extract prepared by the above method, and were supplemented with 0.5% high cholesterol diet. In addition to significantly reduced plasma total cholesterol levels in rabbits, HMG-CoA reductase and ACAT activity, a liver enzyme related to cholesterol biosynthesis, was also significantly reduced, and significantly inhibited antioxidant enzymes SOD and catalase activity in liver tissues. Increased. Therefore, the extract of the present invention can prevent the increase of blood cholesterol concentration by dietary cholesterol, thereby preventing and treating atherosclerosis, and finally reducing blood lipid concentration in addition to the treatment of atherosclerosis. It has also been shown to be effective as an anti-absorption agent of dietary cholesterol and triglycerides in order to prevent or treat various cardiovascular diseases including atherosclerosis due to the effect of treating hyperlipidemia.
또한, 둥굴레로부터 추출한 n-부탄올 추출물을 고콜레스테롤혈증과 동맥경화에 내성이 약한 토끼와 실험적 방법으로 고지혈증-당뇨병을 동시 유도시킨 흰쥐의 식이에 보충하여 급여함으로써, 이들 실험동물의 동맥경화 예방효과와 고지혈증-당뇨질환에 대한 둥굴레 추출물의 치료효과를 분석한 결과, 고콜레스테롤 식이에 둥굴레 추출물의 보충은 혈중 지질(콜레스테롤과 중성지질 수준) 강하외에 혈당강하 작용에도 현저한 효과가 있는 것으로 나타났으며, 본 발명 둥굴레 추출물은 흰쥐에서 아주 많은 양을 경구투여하여도 전혀 급성 독성을 나타내지 않았다. 이와 같이 본 발명 둥굴레 추출물은 부작용이나 독성 등의 문제가 없어 스트레스, 지방과다섭취, 당과다섭취 및 인동부족 등으로 인한 당뇨병의 유발을 예방 또는 치료하는데 안전하게 사용할 수 있는 효과적인 혈당 강하제로 판단되었다.In addition, by supplementing the diet of n-butanol extract extracted from the round gills to the diet of rabbits having high cholesterol and arteriosclerosis resistance and rats inducing hyperlipidemia-diabetes by the experimental method, the effects of preventing the atherosclerosis of these experimental animals and Analysis of the treatment effect of Dongleul extract on hyperlipidemia-diabetes disease showed that supplementation of dietary extract in high cholesterol diet has a significant effect on the hypoglycemic effect in addition to lowering blood lipids (cholesterol and triglyceride levels). The invention of the extract of Donggulle showed no acute toxicity at all even when administered orally in a large amount in rats. As described above, the extract of the present invention has not been found to be an effective blood sugar lowering agent that can be safely used for preventing or treating diabetes due to stress, excessive fat intake, excessive sugar intake and lack of dynamics due to no side effects or toxicity.
상기 설명한 바와 같이 둥굴레 추출물이 동물체내의 혈장 지질(총 콜레스테롤과 중성지질, P<0.01) 저하효과 및 혈당강하효과 (P<0.05) 등의 좋은 생리활성도를 유의적으로 나타내고, 부작용이나 급성독성 등의 면에서 안전한 성분인 것으로 밝혀져 본 발명 둥굴레 추출물은 임상적으로 유효한 고지혈증 및/또는 당뇨병의 예방 및 치료제로 이용될 수 있으며 또한 당뇨합병증의 하나인 고지혈증을 당뇨병과 동시에 개선 또는 치료할 수 있는 기능성 물질로 이용되거나 기능성 식품의 유효성분으로도 이용될 수 있다.As described above, the extract contains significant physiological activities such as plasma lipids (total cholesterol and triglycerides, P <0.01) lowering and hypoglycemic effect (P <0.05) in the animal body. It has been found to be a safe ingredient in the sense of the present invention, the extract of the present invention can be used as a clinically effective prevention and treatment of hyperlipidemia and / or diabetes mellitus and also as a functional substance that can improve or treat hyperlipidemia, one of the diabetic complications at the same time with diabetes It may also be used as an active ingredient of functional foods.
본 발명에 따라 수득되는 둥굴레 추출물을 고지혈증 및/또는 당뇨병을 예방 또는 치료하기 위하여 임상적으로 이용시 투여 용량은 고지혈증 또는 당뇨병의 중증도, 환자의 상태, 연령, 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 이때, 효과적인 약물요법이 이행되기 위해서는 환자의 생활스타일과 같은 환자의 요소와 약제의 요소, 즉 제제학적·약리학적·독성적 요소 등을 분석 종합하여 환자에게 제공되어야 최상의 효과가 얻어진다는 것은 당업계에 공지되어 있다. 본 발명에 따른 둥굴레 추출물은 실질적으로 부작용이나 독성없이 안전하게 투여할 수 있는 약제로 판단된다.When clinically using the gourd extract obtained according to the present invention to prevent or treat hyperlipidemia and / or diabetes, the dosage to be determined by an expert depends on various factors such as the severity of hyperlipidemia or diabetes, the condition, age, and complications of the patient. Can be. In this case, in order for effective drug therapy to be implemented, it is necessary to analyze and synthesize the patient's factors such as the patient's lifestyle and the factors of the drug, that is, the pharmaceutical, pharmacological and toxic factors, so that the best effect is obtained. Known in According to the present invention, the extract is considered to be a drug that can be safely administered without substantially any side effects or toxicity.
본 발명 둥굴레 추출물을 함유하는 약학적 조성물을 임상적으로 이용시 약제학적 분야에서 통상적인 방법에 따라 통상적인 약제학적 제제로 제형화시켜 이용할 수 있으며, 이러한 목적에 바람직한 약제로는 정제, 경질 또는 연질캅셀제, 액제, 현탁제 등과 같은 경구투여용 제제, 주사용 용액 또는 현탁액과 같은 비경구투여용 주사제 등이 있다. 이들 약제학적 제제는 약학적으로 허용되는 담체, 예컨대 경구투여용 제제의 경우에는 부형제, 결합제, 봉해제, 활탁제, 가용화제, 현탁화제, 보존제 또는 중량제, 주사제의 경우에는 안정화제, 보존제, 용해보조제, 완충제, 등장화제 등을 이용하여 제조할 수 있다.The pharmaceutical composition containing the extract of the present invention can be used in the form of a conventional pharmaceutical formulation according to a conventional method in the pharmaceutical field for clinical use, and preferred pharmaceutical agents for this purpose include tablets, hard or soft capsules. Oral preparations such as solutions, suspensions and the like, and parenteral injections such as injectable solutions or suspensions. These pharmaceutical preparations include excipients, binders, sealants, suspending agents, solubilizing agents, suspending agents, preservatives or weight agents in the case of pharmaceutically acceptable carriers such as oral preparations, stabilizers, preservatives in the case of injections, Dissolution aids, buffers, isotonic agents and the like can be prepared.
본 발명에 따른 둥굴레 추출물을 함유하는 혈장 지질 및/또는 혈당 강하제 조성물에는 단위 제형당 둥굴레 추출물의 표준 1일 용량 또는 그의 1/2. 3/1. 1/4. 1/5 또는 1/6의 용량이 함유되도록 하여, 이러한 단위 제형을 1일 1 내지 6회 투여할 수 있다. 또한 둥굴레 추출물의 1일 용량의 수배량을 함유하는 제형, 예컨대 액제 등의 형태로 제조하여 적량으로 분할 투여할 수도 있다.The plasma lipid and / or blood glucose lowering agent composition containing the extract according to the present invention contains a standard daily dose of the extract of the extract, or half thereof. 3/1. 1/4. Such unit dosage forms may be administered 1 to 6 times per day so that a dose of 1/5 or 1/6 is contained. It may also be prepared in the form of a formulation containing several times the daily dose of the extract of Goulle, for example in the form of a liquid or the like and dividedly administered in an appropriate amount.
또한 극성 및/또는 비극성 용매를 사용하여 계통적으로 분획하여 수득한 약리학적 효과를 갖는 추출액을 감압농축(동결건조)하여 분말상으로 제조하여 추출분말을 사용할 수도 있다. 둥굴레 추출물 분말은 음료수, 식품, 가축사료 등에 혼합하여 고상, 액상, 또는 젤리 형태의 혈장 지질 및/또는 혈당을 강하시킬 수 있는 기능성 식품의 제조에 이용할 수도 있으며, 필요에 따라 식용색소, 식용향료, 생약초, 과일, 올리고당, 키토산, 구연산 등의 통상적인 성분을 적량 가하여 좋은 맛과 향을 나타내도록 할 수도 있다. 본 발명자들은 당뇨쥐를 사용하여 고콜레스테롤 첨가 실험식이에 둥굴레 추출물을 0.6% 수준으로 첨가한 것을 2주간 급여한 결과 혈당 강하 작용외 혈중 지질을 저하시키는데도 탁월하게 작용하는 것을 확인할 수 있었다.In addition, extract powder having a pharmacological effect obtained by systematically fractionating using a polar and / or non-polar solvent may be concentrated under reduced pressure (freeze-drying) to be prepared in powder form to use an extract powder. The powder of Donggulle extract may be mixed with beverages, foods, livestock feeds, etc., and used to prepare functional foods capable of lowering plasma lipids and / or blood sugars in solid, liquid, or jelly form. Ordinary ingredients such as herbal medicine, fruits, oligosaccharides, chitosan, citric acid, etc. may be added in an appropriate amount to give a good taste and aroma. The present inventors confirmed that the diabetic rats were fed a high cholesterol diet with 0.6% level of Dongleul extract in the experimental diet for 2 weeks, and it was found to work excellently in lowering blood lipids in addition to hypoglycemic action.
본 발명의 조성물 또는 기능성 식품에는 또한 필요에 따라 인체의 당흡수를 억제하여 당뇨병을 예방 및/또는 치료하거나 콜레스테롤의 생합성 및/또는 흡수를 억제할 수 있는 공지의 물질 또는 추출물을 추가로 포함시킬 수 있다.The compositions or functional foods of the present invention may also further contain known substances or extracts which, if necessary, may inhibit glucose absorption in the human body to prevent and / or treat diabetes or inhibit biosynthesis and / or absorption of cholesterol. have.
이하, 본 발명의 구성 및 작용효과를 실시예를 통하여 보다 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 목적일 뿐 본 발명의 권리범위는 하기 실시예에만 한정되는 것은 아니다.Hereinafter, the configuration and operation of the present invention will be described in more detail with reference to Examples. However, the following examples are only for the purpose of illustrating the present invention and the scope of the present invention is not limited only to the following examples.
실시예 1 : 둥굴레 추출물의 분리Example 1 Isolation of a Roundabout Extract
본 실시예는 (주)산청식품에서 제공된 둥굴레 40 kg(1회 찜)를 사용하였으며, 도 1에 도시한 바와 같이 둥굴레 추출물은 하기와 같은 순서로 추출분리하여 생리적 활성도를 측정하기 위한 다음 단계의 실험에 사용하였다.This example used 40 kg (steamed once) of the dongleul provided by Sancheong Food Co., Ltd., as shown in Figure 1 the extract of the dongleul extract in the following order to measure the physiological activity It was used for the experiment.
활성을 갖는 둥굴레 부탄올 추출물을 수득하기 위해 먼저, 분쇄기에 건조한 둥굴레와 메탄올을 넣어 잘게 부순 후, 분쇄기에서 잘게 부순 둥굴레-메탄올 용액을 48시간 동안 80℃ 수욕상에서 냉각기와 기계적 교반기를 부착하여 2회 반복·추출한 추출용액을 거름장치(감압여과 및 삼베주머니)로 여과하여 메탄올 층을 얻은 후 메탄올 층에 포함되어 있는 메탄올을 감압장치를 이용하여 제거하였다. 상기 과정에 의해 수득된 메탄올 추출액에 메탄올 추출물 : H2O : 메탄올 : 추출용매 = 10 : 9 : 1 : 10의 비율로 섞은 후 도 1과 같이 추출용매인 헥산, 클로로포름, n-부탄올 순으로 각각 추출하고 n-부탄올 층의 추출물을 농축하여 시료, 둥굴레 I 을 얻었으며, 다른 시료는 메탄올 용매 하에서 실온에서 처리하여 둥굴레Ⅱ의 시료를 얻었다.In order to obtain an active butulol butanol extract, first, dry dry gulore and methanol are crushed in a pulverizer, and the pulverized donggulete-methanol solution is repeated twice by attaching a cooler and a mechanical stirrer on a water bath at 80 ° C. for 48 hours. The extracted extract solution was filtered through a strainer (pressure filtration and burlap bag) to obtain a methanol layer, and the methanol contained in the methanol layer was removed using a reduced pressure apparatus. Methanol extract: H 2 O: Methanol: Extraction solvent = 10: 9: 1: 10 in the methanol extract obtained by the above process was mixed in the ratio of hexane, chloroform, n-butanol as shown in FIG. After extracting and concentrating the extract of the n-butanol layer to obtain a sample, the doungle I, the other sample was treated at room temperature in methanol solvent to obtain a sample of the doungle II.
실시예 2 : 둥굴레 추출물의 생리활성측정Example 2: Determination of the biological activity of the extract
본 실시예에서는 둥굴레로부터 분리된 기능성물질을 고콜레스테롤혈증과 동맥경화에 내성이 약한 토끼와 고지혈증-당뇨병을 동시 유도시킨 흰쥐의 식이에 보충하여 급여함으로서, 이들 기능성 물질이 실험동물의 동맥경화 예방효과와 고지혈증-당뇨질환에 대한 치료효과를 분석하고자 하였다.In the present embodiment, the functional substances isolated from the roundworm were supplemented and fed to the diets of rabbits that were hyper-cholesterolemia and arteriosclerosis resistant and hyperlipidemia-diabetes co-induced, so that these functional substances prevented arteriosclerosis in experimental animals. The purpose of this study was to analyze the therapeutic effects of hyperlipidemia and diabetes.
시험예 1 : 혈장 지질저하 효과시험Test Example 1 Plasma Lipid Lowering Effect Test
3주령의 건강한 수컷토끼(New Zealand White(NZW) Rabbit, BW 2.7-2.9 kg)를 대한실험동물센터로(충북, 음성군)부터 구입하여 lab-chow 식이를 제공하면서 1주간 안정시킨 후 무작위로 4그룹으로 나누었다. 정상군(cholesterol-free control)은 normal Lab-chow를, 콜레스테롤 대조군(high-cholesterol(HC) control)은 0.5% 콜레스테롤 식이, 그리고 lovastatin군(high-cholesterol(HC)+lovastatin) 및 둥굴레군(HC+polygonatum)은 0.5% 콜레스테롤 식이에 lovastatin 및 둥굴레 추출물을 각각 0.03% 및 0.15% 첨가하여 제조한 식이를 6주간 공급하였다. 동물들은 항온(20℃)과 항습(50%), 그리고 7:00부터 19:00까지의 light-cycle을 유지하는 동물실험실에 설치된 개개의 스테인레스 캐이지(stainless cage) 안에서 사육하였으며, 모든 식이와 식수들은 자유식(ad libitum)으로 먹게 한다. 체중은 매주 측정하였으며 식이 섭취량은 실험식이 기간 중 매일 측정하였다.Three-week-old healthy male rabbits (New Zealand White (NZW) Rabbit, 2.7-2.9 kg) were purchased from the Korea Experimental Animal Center (Chungbuk, Eumseong) and stabilized for one week while providing a lab-chow diet. Divided into groups. The cholesterol-free control group was normal lab-chow, the high-cholesterol (HC) control group was 0.5% cholesterol diet, and the lovastatin group (high-cholesterol (HC) + lovastatin) and donggulae group (HC). + polygonatum) was fed to the diet prepared by adding 0.03% and 0.15% lovastatin and dongleule extract to 0.5% cholesterol diet for 6 weeks. Animals were housed in individual stainless cages installed in animal laboratories that maintained constant temperature (20 ° C), humidity (50%), and light cycles from 7:00 to 19:00. Drinking water is eaten in ad libitum. Body weight was measured weekly and dietary intake was measured daily during the experimental diet.
실험동물들은 15시간 절식 후 헤파린 처리된 주사기로 heart puncture를 실시하여 혈액을 채취하고, 복부를 절개하여 각 장기조직을 수집하였다. 혈액은 3000 rpm에서 15분간 원심 분리하여 혈장을 분리하고, 혈장 지질분석용으로 -20℃에 보관하였으며, 간 조직은 콜레스테롤 조절효소 및 항산화 효소 활성도 측정을 위해 액체질소에 보관하였다가 필요시 사용하였다. 본 실험에서 나온 모든 결과는 컴퓨터 통계 프로그램 중의 하나인 SPSS 패키지 프로그램을 이용하고, 각 군간의 평균차이에 대한 유의성 검정을 위해 ANOVA를 실시하였다. 다군간의 차이는 던칸의 다중범위 테스트(Duncan's multiple range test)에 의해 P<0.05 이상의 수준에서 검정하였으며 그 결과를 표준오차(standard deviation; S.D)과 함께 표시하여 나타내었다.After fasting for 15 hours, the animals underwent a heart puncture with a heparinized syringe to collect blood, and an incision was taken to collect organ tissues. Blood was centrifuged at 3000 rpm for 15 minutes to separate plasma and stored at −20 ° C. for plasma lipid analysis. Liver tissue was stored in liquid nitrogen for cholesterol cholesterol and antioxidant enzyme activity. . All results from this experiment were performed using SPSS package program, which is one of the computer statistics programs, and ANOVA was performed to test the significance of the mean difference between groups. Multigroup differences were tested at the level of P <0.05 or higher by Duncan's multiple range test, and the results were expressed with standard deviation (S.D).
콜레스테롤 조절효소 및 항산화 효소에 대한 활성도 측정은 하기와 같은 방법으로 실시하였다.Activity measurement for cholesterol regulators and antioxidant enzymes was carried out in the following manner.
(1) 혈장 지질 측정(1) plasma lipid measurement
혈장 총 콜레스테롤(Plasma Total Cholesterol) 측정은 다음과 같이 실시하였다; 혈장 중에 있는 콜레스테롤은 cholesteryl ester와 free cholesterol의 형태로 존재하므로 두 형태를 모두다 정량하기 위하여, cholesteryl ester를 콜레스테롤 옥시다아제(cholesterol oxidase)에 의해 지방산과 유리 콜레스테롤로 바꾸었다. 이렇게 전환된 유리형 콜레스테롤과 혈장중의 유리 콜레스테롤을 콜레스테롤 옥시다아제에 의해 Δ4-콜레스테논(cholestenon)으로 전환하여 퍼옥시다아제와 기질인 H2O2, 페놀 및 4-아미노-안티피린(4-amino-antipyrine)을 섞어서 적색으로 발색시켜 500 nm에서 흡광도를 측정하여 콜레스테롤 표준용액과 비교하여 정량하였다.Plasma Total Cholesterol was measured as follows; Cholesterol in plasma exists in the form of cholesteryl ester and free cholesterol, so to quantify both forms, the cholesteryl ester was converted to fatty acid and free cholesterol by cholesterol oxidase. The converted free cholesterol and free cholesterol in plasma are converted to Δ 4 -cholestenon by cholesterol oxidase to peroxidase and substrates H 2 O 2 , phenol and 4-amino-antipyrine (4-amino -antipyrine) was mixed and colored in red, and absorbance was measured at 500 nm and quantified by comparison with cholesterol standard solution.
혈장중 중성지방(Triglyceride)은 다음과 같은 방법으로 측정하였다; 혈장 중에 있는 중성지질을 리포프로테인 리파아제(lipoprotein lipase)를 이용하여 글리세롤과 지방산으로 분해시킨 후 글리세롤을 글리세롤 키나아제 (glycerol kinase)와 에너지원인 ATP를 첨가하여 반응시켜 L-α-포스포글리세롤로 변형시켰다. 여기에 글리세롤-포스포-옥시다아제(glycerol- phospho-oxidase; GPO)를 첨가하여 반응시키면 H2O2가 발생하는데, 이에 페록시다아제를 처리하여 발색시킨 후 550 nm에서 흡광도를 조사하여 글리세롤 표준과 비교하여 정량하였다.Triglyceride in plasma was measured by the following method; Neutral lipids in plasma were decomposed into glycerol and fatty acids using lipoprotein lipase, and then glycerol was transformed to L-α-phosphoglycerol by adding glycerol kinase and ATP as an energy source. . When glycerol-phospho-oxidase (GPO) is added thereto and reacted, H 2 O 2 is generated. After treatment with peroxidase, the absorbance at 550 nm is examined to determine the glycerol standard. Quantification compared to
상기 방법에 의해 측정한 혈장 총 콜레스테롤 및 중성지방 농도를 하기 표 1에 나타내었다.The plasma total cholesterol and triglyceride concentrations measured by the method are shown in Table 1 below.
실험식이 전 혈장 총 콜레스테롤 농도는 군간 차이가 없었으며, 6주간 실험 식이 후에는 콜레스테롤 대조군이 다른 군에 비해 가장 유의적으로 높은 수준을 나타내었다. 둥굴레군의 경우 정상군에 비해서는 유의적으로 총 콜레스테롤 농도가 상승하였으나 콜레스테롤 대조군에 비해서는 유의적인 감소(50% 감소)를 보였고, 특히 Lovastatin군은 정상군과 유의적인 차이를 보이지 않았다. 따라서 고콜레스테롤 식이에 Lovastatin과 둥굴레 추출물의 보충은 혈장 콜레스테롤의 상승을 상당히 억제하는 것으로 나타났다.There was no difference in the total plasma total cholesterol level in the experimental diet, and after the 6-week diet, the cholesterol control group showed the highest level significantly compared to the other groups. In the case of the group, the total cholesterol level was significantly increased compared to the normal group, but it was significantly decreased (50% reduction) compared to the control group, and the Lovastatin group was not significantly different from the normal group. Therefore, the supplementation of Lovastatin and dongleule extract in the high cholesterol diet significantly suppressed the rise of plasma cholesterol.
한편, 혈장 중성지방 농도를 측정한 결과, 실험식이 전후 모두에서 정상군과 비슷한 수준으로 나타나 고콜레스테롤 식이에 의한 중성지방 농도의 증가는 보이지않았다.On the other hand, as a result of measuring the plasma triglyceride concentration, the experimental formula was similar to the normal group both before and after, there was no increase in the triglyceride concentration by the high cholesterol diet.
(2) 간 조직내 HMG-CoA 환원효소 및 ACAT 활성 측정(2) HMG-CoA reductase and ACAT activity measurement in liver tissue
간조직내 HMG-CoA 환원효소(HMG-CoA reductase) 및 ACAT 활성도를 측정하기 위해 효소원으로 마이크로좀(microsome)을 분리하였으며, Hulcher 등의 분리방법을 약간 변형, 수정하여 간 2 g을 0.1 M 트리에탄올아민(triethanolamine), 0.02 M EDTA(ethylenediamine tetra-acetic acid) (pH 7.4), 2 mM DTT(dithiothritol) 완충용액에 분쇄 후 10,000×g와 12,000×g에서 차례로 원심분리하여 세포찌꺼기를 제거하였다. 상층액을 취하여 100,000×g에서 초원심분리한 후 상층액을 버리고 현탁 및 세척하여 다시 100,000×g에서 초원심분리하였다. 다시 상층액을 버리고 침전물을 1 ㎖ 완충액에 녹여 마이크로좀 단백질(microsomal protein) 량을 브래드포드(Bradford) 방법을 이용하여 정량하였으며, 적당히 나누어 액체질소에 보관하였다가 필요시 녹여 사용하였다.In order to measure HMG-CoA reductase and ACAT activity in liver tissue, microsomes were isolated as enzyme source, and Hulcher's separation method was slightly modified and modified. Cellular debris was removed by triethanolamine (triethanolamine), 0.02 M EDTA (ethylenediamine tetra-acetic acid) (pH 7.4), 2 mM DTT (dithiothritol) buffer and then centrifugation at 10,000 × g and 12,000 × g. The supernatant was taken, ultracentrifuged at 100,000 × g, the supernatant was discarded, suspended and washed, and then ultracentrifuged at 100,000 × g. The supernatant was discarded again, and the precipitate was dissolved in 1 ml of buffer, and the amount of microsomal protein was quantified using the Bradford method. The aliquot was stored in liquid nitrogen, and used as needed.
HMG-CoA 환원효소 활성 측정은 Shapiro 등(1974)이 실시한 방법을 수정 보완하여 실시하였다. 본 실험을 실시하기 전에 효소원의 양, 기질의 양, 보조인자(cofactor)의 양, 그리고 반응 시간에 따른 활성도의 변화를 분석하였다. 이 분석에서 HMG-CoA 환원효소의 활성은 마이크로좀(microsome)과 NADPH를 같이 반응시킬때 전반응 (preincubation) 시간과 본반응(incubation)시간, 그리고 마이크로좀 단백질의 농도에 의존성(dependence)이 매우 강하여 NADPH를 포함한 반응은 전반응 시키지 않았을 때 활성도가 높으며, 반응 시간은 짧을수록 활성도에 미치는 영향이 적어서 5∼15분으로 실시하였다. 마이크로좀 단백질은 1 mg이하에서, 특히300 ㎍이하에서, 그리고, 보조인자의 양은 1∼2 mM의 농도에서 활성도에 미치는 영향이 적다는 타보고와 일치함을 알 수 있었다(Ness et al., 1987). 마이크로좀 100 ~ 300 ㎍을 NADPH 500 nmole 그리고 [14C]HMG-CoA 50 nmole(1,200 cpm or 2,400 cpm/nmole specific activity)과 혼합하여 전체 반응 양을 60 ㎕로 하여 37℃ 항온 수조에서 15분간 반응후 1/5 volume (15 ㎕) 6 N HCl을 혼합하여 30분간 37℃ 항온 수조에서 반응시켰다. 이렇게 메발로네이트(mevalonate)를 락톤 형태(lactone form)로 만든후 Silica Gel 60F254 TLC plate에 점적하여 전개시킨 후 메발로네이트 스탠다드(mevalonate standard, lactone form)와 비교하여 Rf 값이 0.2 부근의 밴드를 잘라 신틸레이션 계수(Scintilation counting) 하였다. 활성도는 1분 반응당 마이크로좀 단백질이 1 ㎎이 생성하는 메발로네이트의 양을 pmole로 나타내었다(pmoles mevalonate formed/min incubation time/mg microsomal proteins).The measurement of HMG-CoA reductase activity was performed by modifying the method performed by Shapiro et al. (1974). Before the experiment, the amount of enzyme source, the amount of substrate, the amount of cofactor, and the change of activity according to reaction time were analyzed. In this assay, HMG-CoA reductase activity was highly dependent on the preincubation time, incubation time, and concentration of microsome protein when microsomes and NADPH were reacted together. The reaction containing NADPH was strong and the activity was high when the reaction was not pre-reacted, and the shorter the reaction time, the less effect on the activity was carried out in 5 to 15 minutes. It was found that the microsomal protein is consistent with other reports that the amount of cofactor is less than 1 mg, in particular less than 300 μg, and the amount of cofactor has little effect on activity (Ness et al., 1987). 100 ~ 300 ㎍ microsomes were mixed with 500 nmole of NADPH and 50 nmole of [14C] HMG-CoA (1,200 cpm or 2,400 cpm / nmole specific activity) to make the total reaction 60 ㎕ for 15 minutes in a 37 ℃ constant temperature water bath. 1/5 volume (15 μl) 6 N HCl was mixed and reacted in a 37 ° C. constant temperature water bath for 30 minutes. After the mevalonate was formed into lactone form, it was instilled on a Silica Gel 60F254 TLC plate and developed, and then a band having an Rf value of about 0.2 was compared with the mevalonate standard (lactone form). Scintilation counting was performed. Activity was expressed as pmole the amount of mevalonate produced by 1 mg of microsomal protein per minute reaction (pmoles mevalonate formed / min incubation time / mg microsomal proteins).
ACAT(acyl CoA:acyltransferase) 활성 측정은 Erickson et. al과 Gillies 등(1986)의 방법을 수정, 보완하여 본 실험에 적용하였다. 트리톤 WR-1339에 녹인 콜레스테롤 6 ㎍ (20 ㎕), 1 M 인산 칼륨(K-phosphate, pH 7.4), 0.6 mM BSA 5 ㎕와 50∼100 ㎍ 마이크로좀을 잘 섞은 후 물로 180 ㎕가 되게 채운 후 37℃에서 30분간 전반응시켰다. [14C]]0leoyl-CoA (specific activity; 15,000 cpm/nmole) 5.62 nmole를 섞어 전체 부피가 200 ㎕가 되게 한 후 37℃에서 30분간 반응시키고 500 ㎕의 이소프로판올:헵탄(4:1) 용액, 300 ㎕의 헵탄 그리고 200 ㎕의 0.1 M 인산 칼륨(pH 7.4)을 넣고 잘 섞은 후 실온에서 2분간 방치하였다. 상등액 중 200 ㎕를 취하여 신틸레이션 계수하여 나온 값을 2배(보정인자)로 곱하여 활성도를 측정하였다. 활성도의 계산은 HMG-CoA 환원효소의 활성도와 비슷하게 1 mg의 마이크로좀 단백질이 1분간 생성하는 Cholesteryl Oleoate의 pmole 수(pmoles Cholesteryl Oleoate formed/min/mg microsomal protein)로 나타내었다(Gillies 등, 1986).ACAT (acyl CoA: acyltransferase) activity measurement was performed by Erickson et. al and Gillies et al. (1986) modified and supplemented the method. 6 μg (20 μl) cholesterol, 1 M potassium phosphate (K-phosphate, pH 7.4), 5 μl of 0.6 mM BSA and 50 to 100 μg microsomes dissolved in Triton WR-1339 were mixed well. The reaction was carried out for 30 minutes at 37 ° C. [14C]] 0leoyl-CoA (specific activity; 15,000 cpm / nmole) 5.62 nmole was mixed to a total volume of 200 μl, followed by reaction for 30 minutes at 37 ° C., and 500 μl of isopropanol: heptane (4: 1) solution, 300 200 μl of heptane and 200 μl of 0.1 M potassium phosphate (pH 7.4) were added, mixed well, and left at room temperature for 2 minutes. 200 μl of the supernatant was taken and the activity obtained by multiplying the value obtained by scintillation counting by 2 times (correction factor) was measured. Calculations of activity are expressed as pmoles of Cholesteryl Oleoate (pmoles Cholesteryl Oleoate formed / min / mg microsomal protein) produced by 1 mg of microsomal protein for 1 minute, similar to HMG-CoA reductase activity (Gillies et al., 1986). .
상기 방법에 의해 간의 콜레스테롤 항상성 유지에 관여하는 효소인 HMG-CoA reductase와 ACAT 활성도를 측정하여 비교한 결과를 하기 표 2에 나타내었다.Table 2 shows the results of comparing HMG-CoA reductase, an enzyme involved in maintaining liver cholesterol homeostasis, and ACAT activity by the above method.
간조직의 콜레스테롤 생합성 조절효소인 HMG-CoA 환원효소 활성도 비교에서, Lovastatin군이 가장 높은 활성을 보였고 둥굴레군의 경우 가장 낮은 활성을 보여, 둥굴레 추출물의 보충이 콜레스테롤 생합성 억제에 기여하는 것으로 나타났다. 한편 간조직에서 유리 콜레스테롤을 저장형태인 콜레스테릴 에스터로 전환시키는 효소인 ACAT 활성도 비교에서, 콜레스테롤 대조군이 다른 군에 비해 유의적으로 높은 활성을 보여, lovastatin 및 둥굴레추출물이 ACAT 효소활성 억제효과가 있는 것으로 나타났다.In the comparison of HMG-CoA reductase activity, a cholesterol biosynthesis regulator of liver tissue, the Lovastatin group showed the highest activity and the lowest activity in the Hungle group, suggesting that supplementation of Hungle extract may contribute to the inhibition of cholesterol biosynthesis. On the other hand, in the comparison of ACAT activity, an enzyme that converts free cholesterol into cholesteryl ester in the liver, the cholesterol control group showed a significantly higher activity than the other groups, and lovastatin and roundworm extracts inhibited ACAT enzyme activity. Appeared to be.
(3) 항산화효소 활성 측정(3) measurement of antioxidant enzyme activity
간조직 2 g을 취하여 10 ㎖의 0.25 M 설탕 완충액을 가하고 균질화 시킨 후 600×g에서 10분간 원심분리하여 상층액을 취하고 10,000×g에서 20분간 원심분리하여 미토콘드리아 분획을 얻고, 상층액은 다시 105,000×g에서 1시간동안 초원심분리하여 세포질(cytosol) 분획을 분리하였다. 미토콘드리아 분획은 카탈라아제(catalase) 활성측정에, 세포질 분획은 GSH-Px 및 SOD 활성도 측정에 사용하였다.Take 2 g of liver tissue, add 10 ml of 0.25 M sugar buffer, homogenize, centrifuge at 600 x g for 10 minutes, take supernatant and centrifuge at 10,000 x g for 20 minutes to obtain mitochondrial fraction. Cytosol fractions were separated by ultracentrifugation at xg for 1 hour. Mitochondrial fraction was used to measure catalase activity, and cytoplasmic fraction was used to measure GSH-Px and SOD activity.
수퍼옥사이드 디스뮤타아제(Superoxide Dismutase; SOD) 활성도는 알칼리 상태에서 피로갈롤(pyrogallol)의 자동산화에 의한 발색을 이용한 Marklund의 방법(1974)으로 측정하였다. 즉, 50 mM Tris-HCl 완충액 2.8 ㎖과 15 mM의 피로갈롤 0.1ml을 혼합하여 5℃에서 5분간 전반응시킨 후 시료 0.1 ㎖를 가하여 25℃에서 10분간 반응시키고, 1 N HCl 0.1 ㎖를 가하여 반응을 종료시킨 후 440 nm에서 흡광도 변화를 측정하였다. 효소활성 단위는 효소액을 넣지 않고 반응시킨 15mM 피로갈롤 용액의 자동산화를 50% 억제하는 단백질의 양으로 정하였다.Superoxide Dismutase (SOD) activity was measured by Marklund's method (1974) using color development by automatic oxidation of pyrogallol in alkaline state. That is, 2.8 ml of 50 mM Tris-HCl buffer and 0.1 ml of 15 mM pyrogallol were mixed and pre-reacted at 5 ° C. for 5 minutes, and then 0.1 ml of the sample was reacted at 25 ° C. for 10 minutes, and 0.1 ml of 1 N HCl was added thereto. After the reaction was completed, the absorbance change was measured at 440 nm. The enzyme activity unit was determined as the amount of protein that inhibits the automatic oxidation of the 15 mM pyrogallol solution reacted without adding the enzyme solution by 50%.
카탈라아제 활성도는 Abei(1974)의 방법으로 측정하였다. 즉, 50mM 인산 칼슘 완충액(pH 7.0) 2.89ml에 기질인 30mM H2O2100㎕를 넣어 25℃에서 5분간 반응시켰다. 여기에 시료 10㎕를 가하여 25℃로 조절된 스펙트로포토메터를 이용하여 240nm에서 5분간 흡광도를 측정하였다. H2O2의 흡광도 변화와 H2O2의 몰흡광계수로 H2O2의 농도를 구한 다음 decreased H2O2nmol/min/mg protein으로 효소활성도를 계산하였다.Catalase activity was measured by the method of Abei (1974). That is, 100 mM of 30mM H 2 O 2 serving as a substrate was added to 2.89ml of 50mM calcium phosphate buffer (pH 7.0) and reacted at 25 ° C for 5 minutes. 10 μl of the sample was added thereto, and the absorbance was measured at 240 nm for 5 minutes using a spectrophotometer adjusted to 25 ° C. The concentration of H 2 O 2 was determined by the change in absorbance of H 2 O 2 and the molar extinction coefficient of H 2 O 2 , and then the enzyme activity was calculated by decreasing H 2 O 2 nmol / min / mg protein.
글루타티온 페록시다아제(Glutathione Peroxidase)-Px 활성도는 산화형 글루타티온이 글루타티온 환원효소(glutathion reductase)와 NADPH에 의하여 환원될 때 NADPH의 흡광도가 340 nm에서 감소하는 정도를 측정하였다. 즉, 0.1 M Tris-HCl(pH 7.2) 완충액 2.6 ㎖과 30 mM 환원형 글루타티온 0.1 ㎖을 넣고 6 mM NADPH 용액 0.1 ㎖에 6.25 μM H2O2를 넣은 뒤 25℃에서 5분간 전반응시키고, 여기에 0.1 ㎖의 시료를 혼합하여 25℃에서 5분간 반응시킨 후 340 nm에서 흡광도를 측정하였다. 효소활성 단위는 1분간 1 nmol의 산화형 NADPH를 생성하는 효소의 양으로 나타내었다.Glutathione Peroxidase-Px activity was measured to reduce the absorbance of NADPH at 340 nm when oxidized glutathione was reduced by glutathione reductase and NADPH. That is, 2.6 ml of 0.1 M Tris-HCl (pH 7.2) buffer and 0.1 ml of 30 mM reduced glutathione were added and 6.25 μM H 2 O 2 was added to 0.1 ml of 6 mM NADPH solution, followed by pre-reaction at 25 ° C. for 5 minutes. 0.1 ml of the sample was mixed and reacted at 25 ° C. for 5 minutes, and the absorbance was measured at 340 nm. Enzyme units were expressed as the amount of enzyme that produced 1 nmol of oxidized NADPH for 1 minute.
상기 방법에 의해 측정한 간조직의 항산화 효소 활성도 측정결과를 하기 표 3에 나타내었다.The antioxidant enzyme activity of the liver tissue measured by the method is shown in Table 3 below.
SOD 활성도 비교에서, lovastatin 및 둥굴레군이 정상군 및 콜레스테롤 대조군에 비해 유의적으로 증가하였다. 카탈라아제 활성도의 경우, 콜레스테롤 대조군만이 다른 군에 비해 유의적으로 낮았으며, GSH-Px 활성도의 경우 정상군이 다른 세 군에 비해 유의적으로 높은 수준을 나타내었다. 따라서 lovastatin 및 둥굴레 추출물 보충이 SOD 및 catalase 활성을 증가시켜 항산화기능을 향상시키는 것으로 나타났다.In comparison of SOD activity, lovastatin and dongleure group increased significantly compared to normal group and cholesterol control group. In the case of catalase activity, only the cholesterol control group was significantly lower than the other groups, and in the GSH-Px activity, the normal group was significantly higher than the other three groups. Therefore, supplementation of lovastatin and dongleule extract increased antioxidant activity by increasing SOD and catalase activity.
따라서, 고콜레스테롤 식이에 민감하게 반응하는 동물인 토끼를 이용하여 둥굴레 부탄올 추출물의 전반적인 지질대사 및 관련 유전자 발현에 미치는 영향을 검색한 결과, 0.5% 고콜레스테롤 식이에 둥굴레 추출물을 급여한 토끼에서 혈장 총콜레스테롤 수준이 유의적으로 감소되었을 뿐만 아니라, 간의 HMG-CoA reductase 및 ACAT 활성 역시 유의적으로 감소되었으며, 간 조직에서 항산화효소인 SOD 및 카탈라아제 활성을 유의적으로 증가시켰다. 따라서 둥굴레 추출물은 콜레스테롤 생합성을 억제함과 동시에 항산화기능을 향상시켜 혈장 지질농도를 현저히 저하시키는 것으로 판단되었다.Therefore, using rabbits, which are animals sensitive to high cholesterol diets, the effects of the oncolipid butanol extracts on the overall lipid metabolism and related gene expression were investigated. In addition to a significant decrease in cholesterol levels, hepatic HMG-CoA reductase and ACAT activities were also significantly reduced and significantly increased antioxidant enzymes SOD and catalase activity in liver tissue. Therefore, the extract was found to significantly reduce plasma lipid concentrations by inhibiting cholesterol biosynthesis and enhancing antioxidant function.
시험예 2 : 혈당강하 효과 시험Test Example 2: hypoglycemic effect test
시험에 사용된 동물은 생후 3주되는 24마리의 Sprague-Dawley 수컷 쥐를 대한동물실험센터(충북 음성군)로부터 구입하였으며, 체중이 280 g에 달할 때까지 Lab. chow pellet 식이로 사육한 후 Streptozotocin 주사에 의한 당뇨유도실험을 통하여 당뇨병을 발병시켰다. 동물들은 항온 (25± 2℃)과 항습 (50±5%), 그리고 자연조명의 일정 환경하의 동물실험에서 상동 실험식이에 의해 5주간 사육되었다. 모든 식이는 자유 식이로 먹게 하고 물은 매일 공급하여주면서 세균번식의 침입이 없도록 청결상태를 유지하였다. 사육기간이 완료된 다음날 아침 12시간 절식시킨후 에테르로 동물들을 마취시키고 마취제인 Ketamine-HCl을 복강에 투여한 후 복부 대정맥(inferior vena cava)으로부터 혈액을 수집하였다. 수집된 피는 원심분리기로 4℃에서 3,000 rpm으로 15분 동안 원심분리 시켜 혈청을 분리하였다. 동물들의 간, 심장, 신장은 적출 후 생리식염수로 여러 번 헹구어 표면의 피를 제거한 다음 측정하고는 -20℃에서 보관하였다. 보관된 혈청은 단백질, 중성지질, 총 혈청콜레스테롤 등의 농도측정에 사용되었다.The animals used for the test were 24 Sprague-Dawley male rats 3 weeks old from the Korean Animal Experiment Center (negative group of Chungbuk), and until the weight reached 280 g, Lab. Diabetes was developed through chow pellet diet and diabetes-induced experiments by Streptozotocin injection. Animals were reared for 5 weeks by homologous diets in animal experiments under constant temperature (25 ± 2 ° C), humidity (50 ± 5%), and natural lighting. All diets were fed on a free diet and water was supplied daily and kept clean to prevent invasion of bacteria. The animals were anesthetized with ether for 12 hours the morning after the breeding period was completed, and the blood was collected from the inferior vena cava after anesthesia Ketamine-HCl was administered to the abdominal cavity. Collected blood was separated by centrifugation at 3,000 rpm for 15 minutes at 4 ℃ centrifuge. Liver, heart and kidney of the animals were removed after rinsing with physiological saline several times to remove the surface blood and stored at -20 ℃. The stored serum was used to measure the concentration of protein, triglyceride, total serum cholesterol, and the like.
혈당농도, 중성지방 농도, 그리고 총 콜레스테롤 농도는 효소법을 적용시킨 아산제약 킷트를 사용하여 측정하였으며, 모든 자료는 SPSS 패키지를 이용하여 처리하였다. 식이군간 비교는 student t-test를 실시하여 그 유의성을 검증하였으며, 모든 측정치의 평균, 표준오차를 계산하였고, 자료 각각에 대해 비모수적 콜모고르프 스미노프 검정으로 정규분포 여부를 검정하였다.Glucose, triglyceride, and total cholesterol levels were measured using the enzyme-assisted Asan Pharmaceutical Kit. All data were processed using the SPSS package. The comparison between the dietary groups was performed by student t-test, and the significance was calculated. The mean and standard error of all measurements were calculated, and the normal distribution was tested by non-parametric Colmomorph Sminov test for each data.
실험동물의 체중이 280 g에 달 할 때까지 Lab. chow pellet 식이로 사육한 후 Streptozotocin 주사에 의한 당뇨유도실험을 통하여 당뇨병을 발병시켰다. Streptozotocin 주사 후 24시간째에 6시간 공복시킨 후 이들 동물의 꼬리정맥혈을 채취하여 고혈당 증세를 확인하였으며 난괴법(randomized block desing)에 의해 3식이군으로 나누었다(표 4).Lab. Until laboratory animals weigh 280 g. Diabetes was developed through chow pellet diet and diabetes-induced experiments by Streptozotocin injection. After fasting for 6 hours at 24 hours after streptozotocin injection, the tail vein blood of these animals was collected to identify the hyperglycemic symptoms and divided into three dietary groups by randomized block desing (Table 4).
상기 3식이군은 상기 표 1에 나타낸 바와 같이 대조구(control), 둥굴레 Ⅰ군(Low 둥굴레군), 둥굴레 Ⅱ군(High 둥굴레군)으로 구성되었고 둥굴레 Ⅰ군은 식이 둥굴레 추출물을 0.6%로, 둥굴레 Ⅱ군은 둥굴레 추출물을 1% 수준으로 하였다. 대조구와 둥굴레Ⅱ군은 5주 동안, 둥굴레 Ⅰ군은 3주 동안 급여하였으며 모든 식이는 기본식이(basal diet, AIN-76 semipurified diet)를 기준으로 제조하였다.As shown in Table 1, the three dietary groups were composed of a control group, a group of dongleul group (Low dongleore group), and a group of dongleore Ⅱ (high donglele group). In Group II, the extract was 1%. The control group and Donggulle II group were fed for 5 weeks and the Donggulle I group for 3 weeks. All diets were prepared based on the basal diet (AIN-76 semipurified diet).
상기 실시예 1과 같이 둥굴레 (1회 찜. 20 kg)를 MeOH용매 하에서 80℃로 48시간동안 처리하여 추출한 추출물을 헥산과 클로로포름층을 거쳐서 n-부탄올층의 추출물을 농축하여 얻은 시료, 둥굴레Ⅰ은 혈당강하효과 (P<0.05), 혈장 지질(총 콜레스테롤과 중성지질, P<0.01) 저하효과가 유의적으로 나타났으며, 둥굴레를 MeOH 용매 하에서 실온에서 처리하여 얻은 시료, 둥굴레Ⅱ를 사용한 동물실험에서는 혈당 및 혈장지질 저하효과가 전혀 관찰되지 않았다. 따라서, 둥굴레를 MeOH용매 하에서 80℃로 48시간동안 처리하여 n-부탄올층에서 얻은 추출물이 혈당강하효과(P<0.05), 혈장 지질(총 콜레스테롤과 중성지질, P<0.01) 저하효과 등의 좋은 생리활성도를 유의적으로 나타냈다(표 5).A sample obtained by concentrating an extract of n-butanol layer through a hexane and chloroform layer by extracting a round gourd (steamed once. 20 kg) at 80 ° C. for 48 hours in a MeOH solvent as in Example 1, Significantly lowered blood glucose (P <0.05), lowered plasma lipids (total cholesterol and triglycerides, P <0.01). In the experiment, no blood glucose and plasma lipid lowering effects were observed. Therefore, the extract obtained from n-butanol layer after treatment of doungle at 80 ° C. under MeOH solvent for 48 hours has good effects such as hypoglycemic effect (P <0.05), plasma lipid (total cholesterol and triglyceride, P <0.01) Physiological activity was significantly shown (Table 5).
시험결과에 의하면, 둥굴레 Ⅰ군은 대조군에 비하여 포도당, 총 콜레스테롤(total cholesterol)과 중성지방(triacylglycerol)이 낮은 반면, 반면 둥굴레 Ⅱ군은 혈당 및 혈장지질 저하효과가 전혀 관찰되지 않았다.According to the test results, the group contained a lower level of glucose, total cholesterol and triacylglycerol than the control group, whereas the group contained no blood glucose and plasma lipid lowering effects.
이상 실시예를 통하여 설명한 바와 같이, 메탄올, 헥산, 클로로포름, n-부탄올 등의 유기용매로 분리한 둥굴레 추출물은 동물체내의 혈장 지질 및 혈당 강하효과 등의 좋은 생리활성도를 유의적으로 나타내고, 부작용이나 급성독성 등의 면에서 안전하여 심혈관계 질환인 고지혈증 및/또는 당뇨병의 예방 및 치료를 위한 약학적 조성물 또는 기능성 식품 등의 유효성분으로 이용할 수 있는 매우 뛰어난 효과가 있어 본 발명은 식품의약산업상 매우 유용한 발명인 것이다.As described through the above examples, the extract of Donggulle separated by organic solvents such as methanol, hexane, chloroform and n-butanol significantly shows good physiological activity such as plasma lipid and hypoglycemic effect in the animal body. It is safe in terms of acute toxicity and can be used as an active ingredient, such as pharmaceutical compositions or functional foods for the prevention and treatment of cardiovascular hyperlipidemia and / or diabetes, the present invention is very effective in the food and pharmaceutical industry It is a useful invention.
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| WO2011062458A2 (en) * | 2009-11-23 | 2011-05-26 | 일동제약주식회사 | Composition containing homoisoflavanone as active ingredient for preventing and treating obesity or metabolic syndrome |
| KR101509066B1 (en) | 2013-03-08 | 2015-04-08 | 대한민국 | Composition comprising extract of polygonatum for inhibiting cell aging |
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| KR102183687B1 (en) * | 2017-10-31 | 2020-11-27 | 안국건강 주식회사 | Extract of Polygonatum odoratum for preventing non-alcoholic fatty liver |
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| US1074350A (en) * | 1912-07-11 | 1913-09-30 | Martin Brunet | Sign. |
| KR950002776A (en) * | 1993-07-23 | 1995-02-16 | 이상화 | Hypoglycemic composition |
| KR100195886B1 (en) * | 1996-11-01 | 1999-06-15 | 김상조 | Pharmaceutical composition for treating diabetes mellitus |
| JP2000139405A (en) * | 1998-11-13 | 2000-05-23 | Shinhan Sha | Food additive and health food |
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| US1074350A (en) * | 1912-07-11 | 1913-09-30 | Martin Brunet | Sign. |
| KR950002776A (en) * | 1993-07-23 | 1995-02-16 | 이상화 | Hypoglycemic composition |
| KR100195886B1 (en) * | 1996-11-01 | 1999-06-15 | 김상조 | Pharmaceutical composition for treating diabetes mellitus |
| JP2000139405A (en) * | 1998-11-13 | 2000-05-23 | Shinhan Sha | Food additive and health food |
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| WO2011062458A2 (en) * | 2009-11-23 | 2011-05-26 | 일동제약주식회사 | Composition containing homoisoflavanone as active ingredient for preventing and treating obesity or metabolic syndrome |
| WO2011062458A3 (en) * | 2009-11-23 | 2011-11-03 | 일동제약주식회사 | Composition containing homoisoflavanone as active ingredient for preventing and treating obesity or metabolic syndrome |
| KR101509066B1 (en) | 2013-03-08 | 2015-04-08 | 대한민국 | Composition comprising extract of polygonatum for inhibiting cell aging |
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