KR101297726B1 - Composition for treating diabete-induced complication containing an extract from Ligularia fischeri - Google Patents
Composition for treating diabete-induced complication containing an extract from Ligularia fischeri Download PDFInfo
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- KR101297726B1 KR101297726B1 KR1020110029151A KR20110029151A KR101297726B1 KR 101297726 B1 KR101297726 B1 KR 101297726B1 KR 1020110029151 A KR1020110029151 A KR 1020110029151A KR 20110029151 A KR20110029151 A KR 20110029151A KR 101297726 B1 KR101297726 B1 KR 101297726B1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
Abstract
곰취(Ligularia fischeri)추출물 또는 상기 추출물의 분획물을 유효성분으로 함유하는 당뇨합병증의 예방 및/또는 개선용 조성물이 제공된다.Provided is a composition for preventing and / or improving diabetic complications comprising Ligularia fischeri extract or a fraction of the extract as an active ingredient.
Description
본 발명은 곰취(Ligularia fischeri) 추출물 또는 상기 추출물의 분획물을 유효성분으로 함유하는 당뇨합병증의 예방 및/또는 개선용 조성물에 관한 것이다.The present invention bear ( Ligularia fischeri ) extract or a composition for the prevention and / or improvement of diabetic complications containing the extract as an active ingredient.
최근 현대인들의 생활수준의 향상과 인간수명의 증가로 인하여 건강에 대한 인식도가 증가함에 따라 급속도로 증가하고 있는 당뇨병은 전 세계적으로 주목 받고 있는 만성질환이다.Diabetes mellitus is a chronic disease that has been attracting attention worldwide because of the recent increase in the level of living standards of modern people and the increase in the longevity of human life.
당뇨병은 췌장의 베타세포에서 생성되는 인슐린 호르몬 부족 또는 인슐린 저항성의 이상과 나아가 이러한 두 가지 모두의 결함으로 발생하는 고혈당을 특징으로 하는 대사장애증후군이다. 이러한 당뇨병은 인슐린 의존형 당뇨병 (IDDM; Type I) 과 인슐린 저항 및 인슐린 분비 손상에 의해 발생하는 인슐린 비의존형 당뇨병(NIDDM; Type II)으로 나눌 수 있다.Diabetes mellitus is a metabolic syndrome characterized by a deficiency of insulin hormone or insulin resistance in the beta cells of the pancreas, as well as hyperglycemia resulting from both of these defects. Such diabetes can be divided into insulin-dependent diabetes mellitus (IDDM) and insulin-dependent diabetes mellitus (NIDDM) (Type II) caused by insulin resistance and insulin secretory damage.
당뇨병은 고혈당이 만성으로 지속되면서 당질대사뿐만 아니라 지질 및 단백질 대사장애도 함께 일으킨다. 그 병태는 다양하며 직접 고혈당에 기인하는 것으로 망막, 신장, 신경, 심혈관계 등에서 당뇨병성 말초신경장해, 당뇨병성 망막증, 당뇨병성 신증, 당뇨병성 백내장, 각막증, 당뇨병성 동맥경화증 등이 있다. 당뇨병 환자수는 과식, 운동부족, 서구화된 식생활, 스트레스, 음주, 흡연 등 생활습관의 변화로 인해 꾸준히 증가하는 추세이다. Diabetes mellitus, chronic hyperglycemia, as well as lipid metabolism, lipid and protein metabolic disorders are also caused. The condition is diverse and is directly caused by hyperglycemia, and includes diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cataract, keratosis, and diabetic atherosclerosis in the retina, the kidney, the nervous system, and the cardiovascular system. The number of diabetic patients is steadily increasing due to changes in lifestyle such as overeating, lack of exercise, westernized eating habits, stress, drinking and smoking.
제I형과 제II형 당뇨병 모두에서 심장 질환, 장 질환, 안과 질환, 신경 질환, 뇌졸증 등과 같은 다양한 합병증이 발생하게 되는데 이는 장시간 동안 혈당과 인슐린 수준이 상승하여 만성신경질환과 심혈관질환이 발생하게 되고 단시간의 저혈당과 고혈당반응으로 급성 합병증을 야기시키게 되는 것이다.In Type I and Type II diabetes, diverse complications such as heart disease, bowel disease, ophthalmic disease, neurological disease, and stroke occur, which can lead to chronic neuropathy and cardiovascular disease due to elevated blood glucose and insulin levels over a long period of time And short-term hypoglycemia and hyperglycemia reaction cause acute complications.
당뇨의 치료법은 약물요법, 운동요법 및 식이요법이 있으며 환자의 증상에 따라 인슐린 약재와 각종 혈당제가 사용되고 있다. 그러나 당뇨병은 간에서의 당 생성 과다, 인슐린 저항성, 근육과 지방 세포 등에서 당 처리 능력 감소 등의 특징을 나타내는 복합적인 질병이므로 특정 치료법만으로는 여러 가지 부작용의 유발을 막을 수 없다. 이 중 약물요법은 인슐린 및 화학물질을 사용하고 있어 약물 복용에 따란 부작용과 환자의 내성에 끊임없는 문제가 되고 있기 때문에, 최근에는 당뇨병 치료에 있어 식이가 가능하며 부작용이 적은 천연물을 이용하여 당뇨병을 치료하고, 더 나아가 당뇨병합병증의 예방 및 치료하기 위한 연구가 필요한 실정이다.Diabetes mellitus is medication, exercise and diet, and insulin medicines and various blood glucose drugs are used depending on the patient's symptoms. However, diabetes is a complex disease characterized by overgrowth of glucose in the liver, insulin resistance, and decreased glucose tolerance in muscle and adipocytes. Therefore, specific treatment alone can not prevent the occurrence of various side effects. Among them, pharmacotherapy uses insulin and chemicals, which is a constant problem for side effects and patient resistance due to taking medications. Recently, it is possible to treat diabetes by using natural products with low side effects. There is a need for research to treat and further prevent and treat diabetic complications.
이에, 본 발명자들은 곰취가 항산화 효과와 더불어 당뇨합병증 치료에 우수한 효과가 있음을 발견하여 본 발명을 완성하였다.Thus, the present inventors have found that bear odor has an excellent effect on the treatment of diabetic complications in addition to the antioxidant effect has been completed the present invention.
따라서, 본 발명의 일례는 곰취의 추출물 및 분획물로 이루어진 군에서 선택된 1종 이상을 유효성분으로 함유하는 당뇨합병증 예방 및/또는 개선용 조성물을 제공한다.Accordingly, one embodiment of the present invention provides a composition for preventing and / or improving diabetic complications containing at least one selected from the group consisting of extracts and fractions of bear odor as an active ingredient.
또 다른 예는 곰취의 추출물 및 분획물로 이루어진 군에서 선택된 1종 이상을 포함하는 당뇨합병증 예방 및/또는 개선용 조성물을 제공한다.Another example provides a composition for preventing and / or improving diabetic complications comprising at least one selected from the group consisting of extracts and fractions of bear odor.
또 다른 예는 곰취의 추출물 및 분획물로 이루어진 군에서 선택된 1종 이상을 유효성분으로 함유하는 항산화용 조성물을 제공한다.Another example provides an antioxidant composition containing at least one selected from the group consisting of extracts and fractions of bear odor as an active ingredient.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
곰취 추출물 및/또는 상기 추출물의 분획물을 유효성분으로 포함하는 당뇨합병증 예방 및/또는 개선용 조성물이 제공된다.Provided is a composition for preventing and / or improving diabetic complications comprising an extract of bear and / or a fraction of the extract as an active ingredient.
현재 강원도에서 많이 자생하고 있는 대표적 산채류인 곰취(Ligularia fischeri)는 넓은 잎을 특징으로 하는 취의 일종으로 우리나라에서는 주로 나물, 생채, 쌈의 형태로 섭취되고 있으며(Cho SD와 Kim GH 2005), chamomile, jacobine, ameleme 등의 약리성분과 polyphenol 화합물과 flavonoids가 확인됨에 따라(Cho SD와 Kim GH 2005, Chang SK 등 2008) 동물 실험 및 분자 생물학적 수준에서 곰취의 생리활성에 관한 연구가 많이 진행되고 있다. 대표적으로, 폐암, 경부암, 간압세포를 대상으로 한 곰취의 세포독성 효과(Ham SS 등 1998b), 항돌연변이성 및 유전독성 억제효과(Ham SS 등 1998a, Jeong SW 등 1998), 곰취의 높은 폴리페놀 함량으로부터 기인되었을 항산화 효과(Jeong SW 등1998, Park JA와 Kim MK 1999, Kwon YJ 등 2002, Kim EY 등 2004, Chang SK 등 2008) 및 혈압상승을 주도하는 효소인 ACE(angiotensin converting enzyme)의 저해 효과(Choi GP 등 2002) 등은 이미 과학적으로 충분히 입증되고 있다. 영양적인 측면에서도 곰취는 특히 비타민 A, B1, B2, B3, C와 β-carotene 등이 고루 함유되어 있고, 이 중 비타민 A(780 RE/100 g), β-carotene(4681 μg/100 g), 칼슘(241 mg/100 g), 섬유소(1.7 g/100 g), 철분(5.7 mg/100 g)의 함량은 다른 채소류에 비해 비교적 높은 것으로 알려져 있어, 기능성 식품 소재로 활용가치가 높은 것으로 평가되고 있다. Ligularia , a representative wild vegetable that grows a lot in Gangwon-do fischeri ) is a type of odor characterized by broad leaves. It is mainly consumed in the form of herbs, raw vegetables and Ssam in Korea (Cho SD and Kim GH 2005), pharmacological components such as chamomile, jacobine, ameleme, polyphenol compounds and flavonoids. As is confirmed (Cho SD and Kim GH 2005, Chang SK et al. 2008), a lot of researches on the biological activity of bear odor at the animal experiment and molecular biological level. Representatively, the cytotoxic effect of bear odor (Ham SS 1998b), the antimutagenic and genotoxic effect (Ham SS 1998a, Jeong SW et al. 1998), and the high polyphenols of bear odor Inhibition of antioxidant effects (Jeong SW et al. 1998, Park JA and Kim MK 1999, Kwon YJ et al. 2002, Kim EY et al. 2004, Chang SK et al. 2008) and blood pressure elevation-enhancing enzyme ACE (angiotensin converting enzyme) The effectiveness (Choi GP et al. 2002) is already well proven scientifically. In terms of nutrition, bear odor is particularly rich in vitamins A, B 1 , B 2 , B 3 , C and β-carotene. Among them, vitamin A (780 RE / 100 g) and β-carotene (4681 μg / 100 g), calcium (241 mg / 100 g), fiber (1.7 g / 100 g) and iron (5.7 mg / 100 g) are known to be relatively high compared to other vegetables. It is estimated to be high.
본 발명에서는 곰취(Ligularia fischeri)를 사용하여 당뇨합병증 예방을 위한 단기검색방법으로 최종당화산물(advanced glycation endproducts)의 형성 억제와 알도오스 환원효소(aldose reductase) 억제 활성을 확인하였다.
In the present invention bear ( Ligularia) fischeri ) was used as a short-term screening method for the prevention of diabetic complications. Inhibition of the formation of advanced glycation endproducts and aldose reductase inhibitory activity was confirmed.
본 발명에서 사용된 곰취는, 그 형태에 특별한 제한이 없으며, 발명의 조성물은 곰취로부터 얻어진 추출물 및/또는 분획물을 유효성분으로 포함하는 것을 특징으로 한다. The bear odor used in the present invention is not particularly limited in its form, and the composition of the present invention is characterized by including extracts and / or fractions obtained from the bear odor as an active ingredient.
상기 곰취 추출물은 물 및 C1 내지 C4의 직쇄 또는 분지형 알코올 또는 혼합물로 이루어진 군에서 선택된 1종 이상의 용매를 이용하여 통상의 곰취 추출방법으로 얻어진 것일 수 있다. The bear odor extract may be obtained by a common bear odor extraction method using at least one solvent selected from the group consisting of water and C 1 to C 4 straight or branched alcohol or mixture.
본 발명의 한 구체예에 있어서, 보다 우수한 항당뇨합병증 효과를 달성하기 위하여, 상기 추출물은 곰취를 60 내지 80%(v/v) 에탄올로 추출하여 얻어진 에탄올 추출물일 수 있으며, In one embodiment of the present invention, in order to achieve a better anti-diabetic complication effect, the extract may be an ethanol extract obtained by extracting the bear odor with 60 to 80% (v / v) ethanol,
상기 분획물은 상기 추출물을 헥산, 메틸렌클로라이드, 에틸아세테이트 및 부탄올로 이루어진 군에서 선택된 1종 이상으로 분획하여 얻어진 것일 수 있다. 보다 바람직하게는, 상기 분획물은 상기 얻어진 추출물을 상기 헥산, 메틸렌클로라이드, 에틸아세테이트 및 부탄올로 이루어진 군에서 선택된 1종 이상을 극성 순으로 적용하여 각 적용시마다 얻어지는 분획물들로 이루어진 군에서 선택된 것일 수 있다. 예컨대, 상기 에탄올 추출물을 헥산으로 분획하여 얻어진 헥산 분획물 상기 헥산 분획물을 분리하고 남은 수성층을 메틸렌클로라이드로 분획하여 얻어진 메틸렌클로라이드 분획물 상기 메틸렌클로라이드 분획물을 분리하고 남은 수성층을 에틸아세테이트로 분획하여 얻어진 에틸아세테이트 분획물 상기 에틸아세테이트 분획물을 분리하고 남은 수성층을 부탄올로 분획하여 얻어진 부탄올 분획물 및 상기 부탄올 분획물을 분리하고 남은 물 분획물로 이루어진 군에서 선택된 1종 이상의 것일 수 있다. The fraction may be obtained by fractionating the extract into at least one selected from the group consisting of hexane, methylene chloride, ethyl acetate and butanol. More preferably, the fraction may be selected from the group consisting of fractions obtained by applying at least one selected from the group consisting of hexane, methylene chloride, ethyl acetate and butanol in the order of polarity, . For example, the hexane fraction obtained by fractionating the ethanol extract with hexane, the methylene chloride fraction obtained by fractionating the hexane fraction, and the remaining aqueous layer fractionated with methylene chloride. The methylene chloride fraction is separated and the remaining aqueous layer is fractionated with ethyl acetate to obtain the ethyl acetate fraction The butanol fraction obtained by separating the ethyl acetate fraction and the remaining aqueous layer with butanol, and the water fraction remaining after separating the butanol fraction.
곰취 추출물은 통상의 식물 추출물의 제조방법에 따라 제조된 것일 수 있으며, 바람직하게는 가압추출법, 환류추출법, 온침 추출법, 초음파분쇄 추출법 등에 의할 수 있고, 바람직하게는 가압추출법에 의할 수 있으나, 이에 제한되는 것은 아니다. Bear extract may be prepared according to the conventional method for producing a plant extract, preferably by pressure extraction method, reflux extraction method, hot needle extraction method, ultrasonic grinding extraction method, etc., preferably by pressure extraction method, It is not limited to this.
또한, 상기한 바와 같이 제조된 추출물은 이후 감압 여과과정을 수행하거나 추가로 농축 및/또는 동결건조를 수행하여 농축하거나 용매를 제거할 수 있다. 따라서, 본 발명에서의 곰취 추출물은 통상적 방법으로 건조된 건조물과 통상적 방법으로 농축된 농축물을 포함하는 의미로 사용된다.In addition, the extract prepared as described above can be concentrated or removed by concentration filtration and / or lyophilization in a subsequent vacuum filtration step. Thus, the bear extract in the present invention is used in the sense including a dried product dried in a conventional manner and a concentrate concentrated in a conventional method.
본 발명에서는 곰취 추출물 및 분획물 조성물의 당뇨합병증 치료 효과를 제공한다. 당뇨합병증은 당뇨병으로 인한 고혈당과 단백질의 반응이 비가역적으로 진행되어 최종당화산물(Advanced glycation endproducts, AGEs) 이 생성되어 혈중이나 조직의 다른 단백질과 교차결합하여 유발시키는 여러 가지 합병증을 의미한다. 구체적으로, 본 발명에서 곰취 추출물 및/또는 분획물이 치료 효과를 갖는 당뇨합병증은 당뇨병성 혈관장애, 당뇨병성 신경장애 또는 당뇨병성 감염증 등일 수 있으며, 바람직하게는 당뇨성 망막증(diabetic retinopathy), 당뇨성 백내장(diabetic cataract), 당뇨성 신증(diabetic nephropathy), 당뇨성 신경병증(diabetic neuropathy), 당뇨성 혈관합병증 등일 수 있으며, 더욱 바람직하게는 당뇨성 망막증, 당뇨성 백내장 또는 당뇨성 신증일 수 있다.The present invention provides a diabetic complication treatment effect of bear extract and fraction composition. Diabetic complications are diabetic complications that lead to hyperglycemia and protein reactions that irreversibly progress to produce advanced glycation endproducts (AGEs) that cross-link with other proteins in the blood or tissue. Specifically, the diabetic complication of the bear extract and / or fractions in the present invention may have a diabetic vascular disorder, diabetic neuropathy or diabetic infection, and the like, preferably diabetic retinopathy, diabetic Cataract, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy, and the like, more preferably diabetic retinopathy, diabetic cataract or diabetic nephropathy.
본 발명의 당뇨합병증 치료 활성은 최종당화산물(Advanced Glycation Endproducts, AGEs)의 형성 억제능 및 알도오스 환원효소(Aldose reductase) 억제능을 통하여 시험하였다. Diabetic complication treatment of the present invention was tested through the ability to inhibit the formation of advanced glycation end products (AGEs) and aldose reductase (Aldose reductase).
최종당화산물은 비효소적 당화반응에 의해 당이 단백질과 결합하여 schiff base와 아마도리 산물(amadori product)을 거쳐서 생성된다. 그러나 만성적인 고혈당 상태에서는 아마도리 산물이 가역적으로 최종당화산물을 생성하는 비가역적인 반응으로 가속화되어 조직과 혈청 중에 대량 생성되어 축적된다. 따라서, 최종당화산물의 생성은 심각한 당뇨합병증을 일으키는 주요원인 중 하나로 된다. The final glycation products are formed by non - enzymatic glycation through sugar - protein binding and schiff base and amadori product. However, in a chronic hyperglycemic state, perhaps a lipid product is reversibly accelerated by a irreversible reaction that produces a final glycation product and is mass-produced and accumulated in tissues and serum. Thus, the production of the final glycated product is one of the major causes of severe diabetic complications.
제2형 당뇨병 환자의 혈액 내 최종당화산물의 농도와 심혈관계질환의 유무 및 중증도와 연관이 뚜렷하고 여러 동물 모델 연구에서도 상관관계가 있는 것으로 알려져 있다. 만성적인 고혈당과 생체 단백질과의 비효소적 당화 반응에 의해 생성되는 최종당화산물은 당뇨합병증의 주요 원인중 하나이다. 당뇨합병증은 혈당이 정상적으로 회복되었음에도 불구하고 발병하는 경우가 많다. 최종당화산물은 고혈당의 농도에 비례하여 조직에 축적되는 단백질 당화산물로 특이한 흡광도 및 형광을 나타내고, 특히 단백질의 아미노기가 서로 cross-link 반응을 일으키는 성질을 가지고 있다. 최종당화산물은 한번 생성되면 혈당이 정상적으로 조절되어도 분해되지 않고 조직에 축적되어 조직의 구조와 기능을 비정상적으로변화시키며, atheroma성 동맥경화증, DNA의 돌연변이, 노화, 알츠하이머병, 당뇨합병증등에 관여한다고 알려져 있다. It is known that the concentration of the final glycated product in the blood of patients with type 2 diabetes is highly correlated with the presence or severity of cardiovascular disease and also correlates with various animal model studies. The end glycation products produced by non-enzymatic glycation of chronic hyperglycemia and biologic proteins are one of the major causes of diabetic complications. Diabetic complications often occur despite the normal recovery of blood sugar. The final glycation product is a protein glycosylation product accumulated in tissues in proportion to the concentration of hyperglycemia, and exhibits a specific absorbance and fluorescence. Especially, amino groups of proteins cause cross-link reaction with each other. Once the final glycation products are produced, they are not degraded even when blood glucose is normally regulated, and accumulate in the tissues, abnormally changing the structure and function of the tissue, and are known to be involved in atherosclerosis, DNA mutation, senescence, Alzheimer's disease and diabetic complications have.
기존에 최종 당화산물의 억제제로서 알려진 아미노구아니딘(aminogua- nidine)의 독성이 증가하는 것으로 나타남에 따라, 이를 대체할 수 있는 독성이 없는 안전한 천연물의 개발이 필요한 실정이다.As the toxicity of aminoguanidine, which is known as an inhibitor of the final glycation endogenous product, has been shown to increase, there is a need for the development of a safe natural product with no toxicity to replace it.
본 발명에 따른 곰취 추출물 및 분획물의 최종당화산물에 대한 억제 활성을 시험한 결과, 최종당화산물 생성 억제 효과를 갖는 것으로 나타났다(표 1 및 표 2 참조).As a result of testing the inhibitory activity on the final glycated product of the bear extract and fractions according to the present invention, it was found to have the effect of inhibiting the production of the final glycated product (see Table 1 and Table 2).
또한, 당뇨합병증의 유발기전 중 하나인 폴리올 경로(polyol pathway)의 증가는 세포손상을 일으키는 기전이다. 알도오스 환원효소(Aldose In addition, an increase in the polyol pathway, which is one of the trigger mechanisms of diabetic complications, is a mechanism causing cell damage. Aldose Reductase
reductase)는 폴리올 경로에서 글루코오스를 소르비톨에서 프룩토오스로 전환하는 과정에 관여하는 효소이다. 고혈당 상태가 되면 세포내 포도당 대사의 변화가 일어나는데, 과잉의 포도당이 세포내로 들어오면 알도오스 환원효소에 의해 소르비톨로 전환되며, 소르비톨 탈수소효소(sorbitol dehydrogenase)에 의해 프룩토오스(fructose)로 전환된다. 정상혈당 상태에서는 포도당에 대한 알도오스 환원효소의 Km값(70 mM)이 높아 세포 내 소르비톨 농도는 매우 낮다. 그러나 고혈당에 의해 세포 내 포도당 농도가 올라가면 세포 내 소르비톨 농도가 증가될 뿐만 아니라 소르비톨 탈수소효소의반응속도가 느려 소르비톨이 세포내에 축적하게 된다. 결국 세포내에 축적된 소르비톨의 높은 삼투압으로 세포가 팽창하게 되고 세포가 손상을 입게 되며 결국 백내장, 당뇨성 신경증, 망막증 등의 합병증을 야기하게 된다. reductase) is an enzyme involved in the process of converting glucose from sorbitol to fructose in the polyol pathway. In hyperglycemic conditions, changes in glucose metabolism occur in the cell. When excess glucose enters the cell, it is converted to sorbitol by aldose reductase and converted to fructose by sorbitol dehydrogenase . In the normal glucose state, the Km value (70 mM) of aldose reductase to glucose is high and the concentration of sorbitol in the cell is very low. However, if the intracellular glucose concentration is increased by hyperglycemia, not only the intracellular sorbitol concentration is increased but also the sorbitol dehydrogenase slows down the reaction so that sorbitol accumulates in the cell. Eventually, the high osmotic pressure of sorbitol accumulated in the cells expands the cells and damages the cells, resulting in complications such as cataracts, diabetic neurosis and retinopathy.
따라서 본 발명에서는 부작용이 없으며 효과적으로 당뇨합병증을 예방할 수 있는 새로운 천연물을 개발하기 위하여, 곰취 추출물 및 분획물의 알도오스 환원효소 활성 억제능을 시험하였다. 그 결과 곰취 추출물 및 분획물이 알도오스 환원효소 활성 억제능을 갖는 것으로 나타났다 (표 3 및 표 4 참조).Therefore, in the present invention, in order to develop a new natural product that can effectively prevent diabetic complications, we tested the ability to inhibit the aldose reductase activity of the extract and fractions of bear odor. As a result, bear extract and fractions were found to have the ability to inhibit aldose reductase activity (see Table 3 and Table 4).
본 발명에 따른 곰취 추출물 및/또는 분획물은 우수한 항산화 활성을 갖는 것으로 나타났다. 본 발명의 조성물의 항산화 효과를 시험하기 위하여 DPPH(1,1-diphenyl-2-picrylhydrazyl) 소거효과를 시험하였다. DPPH는 화학적으로 안정한 자유 가디칼을 지니고 있는 화합물로 항산화 활성을 가진 물질을 만나면 환원되어 항산화 능력을 확인하는데 널리 사용되는 물질이다. DPPH를 이용한 전자공여작용은 자유 라디칼에 전자를 공여하여 식품 중의 지방 산화를 억제하는 목적으로 사용되고 인체 내에서는 자유 라디칼에 의한 노화를 억제시키는 작용으로 이용되고 있다.Bear extract and / or fractions according to the present invention have been shown to have good antioxidant activity. DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging effect was tested to test the antioxidant effect of the composition of the present invention. DPPH is a compound with chemically stable free cardial and is widely used to check the antioxidant capacity when it meets a substance with antioxidant activity. The electron donating action using DPPH is used for the purpose of inhibiting lipid oxidation in foods by donating electrons to free radicals and is being used in the body to suppress aging by free radicals.
곰취 추출물 및/또는 분획물의 DPPH 라디칼 소거능을 시험하여 항산화능을 평가한 결과, 곰취 추출물 및/또는 분획물은 우수한 항산화능을 갖는 것으로 나타났다 (표 5 및 표 6 참조). As a result of evaluating the antioxidant activity by testing DPPH radical scavenging ability of the bear extract and / or fractions, it was found that the bear extract and / or fractions had excellent antioxidant ability (see Table 5 and Table 6).
본 발명의 조성물은 유효성분인 곰취 추출물 및/또는 분획물 외에, 영양제, 비타민, 전해질, 풍미제, 착색제, 중진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 추가로 함유할 수 있다. 상기 성분들은 독립적으로 또는 조합하여 추가될 수 있다. 상기 추가성분의 함량은 바람직하게는 상기 곰취의 추출물 또는 분획물 100 중량부 당 0.1 내지 20 중량부 범위 또는 리코리시딘 100 중량부 당 100 내지 10,000,000 중량부 범위에서 추가할 수 있으나, 이에 제한되는 것은 아니다.The composition of the present invention is a nutrient, vitamins, electrolytes, flavoring agents, coloring agents, neutralizing agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, in addition to the bear extract and / or fractions as an active ingredient , Stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. The components can be added independently or in combination. The content of the additional component is preferably added in the range of 0.1 to 20 parts by weight or 100 to 10,000,000 parts by weight per 100 parts by weight of licoridine, but is not limited thereto. .
상기 조성물 내의 상기 곰취 추출물 및/또는 분획물의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 바람직하게는 0.001 내지 50중량%인 것이 좋으나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다. The content of the bear extract and / or fractions in the composition can be appropriately adjusted according to the symptoms of the disease, the progress of the symptoms, the condition of the patient, for example, 0.0001 to 99.9% by weight, preferably 0.001 based on the total weight of the composition It is preferably from 50% by weight, but is not limited thereto. The content ratio is a value based on the drying amount from which the solvent is removed.
상기 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있으며, 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액 등의 형태로 제형화하여 사용될 수 있다. The composition may further contain an appropriate carrier, excipient and diluent conventionally used in the production of a pharmaceutical composition. The composition may be administered orally or parenterally in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, An external preparation, a suppository or a sterilized injection solution, and the like.
상기 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 적어도 한 가지 이상의 부형제 및/또는 윤활제 등을 포함할 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. When the composition is formulated, it is prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may include at least one excipient and / or lubricant. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
상기 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 보다 바람직한 효과를 위해서, 본 발명의 조성물의 투여량은 유효성분을 기준으로 1일 0.1 mg/kg 내지 20 mg/kg으로 하는 것이 좋으나 이에 제한되는 것은 아니다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수 있다. 본 발명의 조성물은 동물, 바람직하게는 인간을 포함하는 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 정맥, 근육, 피하주사 등에 의해 투여될 수 있다. 본 발명의 조성물의 약학적 투여 형태는 유효성분의 약학적 허용 가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. The preferred dosage of the composition varies depending on the condition and the weight of the patient, the degree of the disease, the drug form, the administration route and the period, but can be appropriately selected by those skilled in the art. For a more preferable effect, the dose of the composition of the present invention is preferably 0.1 mg / kg to 20 mg / kg per day based on the active ingredient, but is not limited thereto. The administration may be carried out once a day or divided into several doses. The compositions of the present invention may be administered to a mammal, including a human, in various ways. All modes of administration may be expected, for example, by oral, intravenous, intramuscular, subcutaneous injection, and the like. The pharmaceutical dosage form of the composition of the present invention may be used in the form of a pharmaceutically acceptable salt of the active ingredient, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable combination.
또 다른 예에서, 상기한 바와 같은 곰취 추출물 및/또는 분획물을 포함하는 당뇨합병증의 예방 및/또는 개선용 조성물이 제공된다. 본 발명에서 식품은 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하며, 바람직하게는 어느 정도의 가공 공정을 거쳐 직접 먹을 수 있는 상태가 된 것을 의미하며, 통상적인 의미로서, 각종 식품, 건강기능 식품, 음료, 식품 첨가제 및 음료 첨가제를 모두 포함하는 의미로 사용된다. 상기 식품의 예로서 각종 식품류, 음료, 껌, 차, 비타민 복합제, 기능성 식품 등이 있다. 추가로, 본 발명에서 식품에는 특수영양식품(예, 조제유류, 영,유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류(예, 라면류, 국수류 등), 건강보조식품, 조미식품(예, 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류(예, 스넥류), 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 김치, 절임식품(각종 김치류, 장아찌 등), 음료(예, 과실,채소류 음료, 두유류, 발효음료류, 아이스크림류 등), 천연조미료(예, 라면 스프 등), 비타민 복합제, 알코올 음료, 주류 및 그 밖의 건강보조식품류를 포함하나 이에 한정되지 않는다. 상기 건강기능식품, 음료, 식품첨가제 또는 음료첨가제는 통상의 제조방법으로 제조될 수 있다.In another example, there is provided a composition for the prevention and / or improvement of diabetic complications comprising the bear odor extract and / or fraction as described above. In the present invention, the term " food " means a natural product or a processed product containing one or more nutrients, preferably a state of being able to be directly eaten through a certain processing step, , Health functional foods, beverages, food additives and beverage additives. Examples of the food include various foods, beverages, gums, tea, vitamin complex, and functional foods. In addition, in the present invention, the food may contain special nutritional foods (e.g., crude oil, spirits, infant food, etc.), meat products, fish products, tofu, jelly, noodles (Such as soy sauce, soybean paste, hot pepper paste, mixed sauce), sauces, confectionery (eg snacks), dairy products (eg fermented milk, cheese), other processed foods, kimchi, pickled foods But are not limited to, natural flavors (eg, ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic beverages and other health supplement foods. The health functional food, beverage, food additive or beverage additive can be produced by a usual production method.
상기 식품 조성물은 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 기능성 식품의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.The food composition may comprise a pharmaceutically acceptable food-aid additive and may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of a functional food.
또한, 상기 식품에 있어서, 상기 곰취 추출물 및/또는 분획물의 양은 전체 식품 중량의 0.00001 중량% 내지 50 중량%로 포함될 수 있으며, 상기 식품이 음료인 경우에는 식품 전체의 부피 100 ml 를 기준으로 0.001 g 내지 50 g, 바람직하게는 0.01 g 내지 10 g의 비율로 포함될 수 있으나, 이에 한정되는 것은 아니다.In addition, in the food, the amount of the bear extract and / or fraction may be included in 0.00001% to 50% by weight of the total weight of the food, if the food is a beverage 0.001 g based on 100 ml of the total volume of food To 50 g, preferably 0.01 g to 10 g, but is not limited thereto.
본 발명에 따른 곰취 추출물 및/또는 분획물을 포함하는 조성물은 당뇨합병증 치료 효과가 우수하면서도 독성과 부작용이 없는 천연물 유래의 조성물이므로, 당뇨합병증의 치료에 보다 안전하게 적용될 수 있다.Since the composition comprising bear extract and / or fractions according to the present invention is a composition derived from natural products which is excellent in treating diabetic complications but does not have toxicity and side effects, it can be more safely applied to the treatment of diabetic complications.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하도록 한다. 그러나, 이들 실시예는 본 발명을 대표적으로 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 제한되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are merely illustrative of the present invention, and the scope of the present invention is not limited by these examples.
재료준비Material preparation
곰취(Ligularia fischeri)는 강원도,양구군 약업사를 운영하시는 분으로부터 구입하였으며, DPPH(1,1-diphenyl-2-picrylhydrazyl), DMSO(dimethyl sulfoxide), BSA(Albumin from bovin serum), 메틸글리옥살(Methylglyoxal), 아미노구아니딘(Aminoguanidine), NADPH, DL-글리세르알데하이드(DL-glyceraldehyde), 퀘르세틴(Quercetin), NaCO3은 Sigma(USA)로부터 구입하여 사용하였고, 그 외 분석에 사용된 모든 시약은 특급을 사용하였다. Ligularia fischeri ) was purchased from Gangwon-do, Yanggu-gun pharmacist, DPPH (1,1-diphenyl-2-picrylhydrazyl), DMSO (dimethyl sulfoxide), BSA (Albumin from bovin serum), methylglyoxal, amino Guanidine (Aminoguanidine), NADPH, DL-glyceraldehyde, Quercetin (Quercetin), NaCO 3 was purchased from Sigma (USA), and all other reagents used in the analysis were express.
시료 sample 제조예1Preparation Example 1
본 발명의 곰취 추출물 및 분획물은, 건조된 곰취 무게 1000 g의 10배의 70% 에탄올을 가하고 수용액상에서 65℃에서 3시간 추출한 다음 이를 여과하여 추출액을 얻는다. 추출하는 과정을 3회 반복한다. 얻어진 추출액을 40℃ 이하에서 감압 농축한 후 이를 동결 건조하여 분말상의 추출물을 얻는다. Bear extract and fractions of the present invention is added to 10 times 70% ethanol of 1000 g of dried bear odor weight and extracted at 65 ℃ in an aqueous solution for 3 hours and then filtered to obtain an extract. The extraction process is repeated three times. The obtained extract was concentrated under reduced pressure at 40 ° C. or lower, and then freeze-dried to obtain a powdery extract.
시료 sample 제조예2Production Example 2
상기 시료제조예1에서 얻은 곰취 추출물 100 g에 증류수 500 L를 가하여 현탁하고 헥산 500 L 를 가하여 혼합한 후 헥산 가용성 분획부 및 수가용성 분획부로 분리하였다. 동일과정을 3회 반복하여 헥산 가용성 분획부만을 모은 후 이를 감압건조하여 헥산 가용추출물 분말을 얻었으며, 이와 동일하게 메틸렌클로라이드, 에틸아세테이트, 부탄올 가용성 분획부와 수가용성 분획부도 따로 모아 이를 감압건조하여 분말을 얻었다.
Bear odor obtained in Sample Preparation Example 1 To 100 g of the extract, 500 L of distilled water was added, suspended, 500 L of hexane was added thereto, and the mixture was separated into a hexane-soluble fraction and a water-soluble fraction. The same procedure was repeated three times to collect only the hexane soluble fraction, followed by drying under reduced pressure to obtain hexane soluble extract powder. The methylene chloride, ethyl acetate, butanol soluble fraction and water soluble fraction were collected and dried under reduced pressure Powder was obtained.
실시예Example 1. One. 최종당화산물(AGEs)의Of final glycation end products (AGEs) 억제 효과 시험 Inhibitory effect test
본 실시예에서는 당뇨합병증의 치료 효과를 시험하기 위하여, 메틸글리옥살을 이용한 24시간 단기 검색법으로 곰취 추출물 및 분획물의 최종당화산물(AGEs) 억제 효과를 Blank와 대조군을 기준으로 형광의 증가 정도를 측정하였다.In this example, to examine the therapeutic effect of diabetic complications, the 24-hour short-term screening method using methylglyoxal was used to determine the effect of suppressing the final glycosylated product (AGEs) of the extracts and fractions of the bear odor on the basis of the blank and the control. Measured.
BSA(5mg/mL)와 메틸글리옥살(2mg/mL)에 DMSO(dimethyl sulfoxide)로 녹인 시료 (상기 실시예 1에서 얻어진 곰취의 추출물 및 분획물) (11 mg/mL)를 넣고 50 mM 포스페이트 버퍼(pH 7.4)를 사용하여 총 부피를 5 mL로 맞추었다. 36℃에서 24시간동안 반응시킨 후, spectrofluorometer (Fluoroskan Ascent FL, Thermo Scientific, USA)를 이용하여 반응 전후의 시료의 흡광도(Excitation: 355 nm, Emission: 460 nm)를 측정하였다. 흡광도의 억제율은 대조군의 흡광도 증가값을 기준으로 시료의 흡광도 증가값을 비교하여 계산하였다. A sample dissolved in DMSO (dimethyl sulfoxide) in BSA (5 mg / mL) and methylglyoxal (2 mg / mL) (extract and fraction of the odor obtained in Example 1) (11 mg / mL) was added thereto, and 50 mM phosphate buffer ( pH 7.4) was used to adjust the total volume to 5 mL. After reacting at 36 ° C. for 24 hours, the absorbance (Excitation: 355 nm, Emission: 460 nm) of the sample before and after the reaction was measured using a spectrofluorometer (Fluoroskan Ascent FL, Thermo Scientific, USA). The inhibition rate of the absorbance was calculated by comparing the absorbance increase value of the sample based on the absorbance increase value of the control group.
계산식={1-(S1-S0)/(C1-C0)}*100 Calculation = {1- (S 1 -S 0 ) / (C 1 -C 0 )} * 100
(S0: sample 0hr 흡광도반응값, S1: sample 24hr 흡광도반응값, C0: control 0hr 흡광도반응값, C1: control 24hr 흡광도반응값)을 사용하였다. 또한, 최종당화산물에 억제효과가 있다고 알려진 표준물질로 아미노구아니딘 (aminoguanidine, Sigma Chemical Co.(St Louis, MO, USA))을 사용하여 위와 같은 방법으로 형광억제율을 비교하였다. 대조군에 대한 50% 흡광도의 감소를 나타내는 시료의 농도 (IC50)으로 표시하였고, 각 시료를 3회 반복 실시하여 평균하였다. (S 0 : sample 0hr absorbance response value, S 1 : sample 24hr absorbance response value, C 0 : control 0hr absorbance response value, and C 1 : control 24hr absorbance response value). In addition, fluorescence inhibition rates were compared using aminoguanidine (Sigma Chemical Co., St. Louis, Mo., USA) as a standard substance known to have an inhibitory effect on the final glycation end product. The concentrations (IC 50 ) of the samples show a 50% reduction in absorbance relative to the control, and each sample was run three times and averaged.
상기 얻어진 결과를 표 1 및 표 2에 나타내었다. Blank와 대조군을 기준으로 형광의 증가 정도를 측정한 결과, 곰취 추출물의 경우 70% 에탄올 추출물이 5.5 mg/mL의 농도에서 71.9%로 추출물 중 가장 형광 억제가 높은 것으로 나타내었다.The obtained results are shown in Table 1 and Table 2. As a result of measuring the increase of fluorescence based on the blank and the control group, the 70% ethanol extract was 71.9% at the concentration of 5.5 mg / mL for the bear extract, showing the highest fluorescence inhibition among the extracts.
또한, 곰취 분획물의 농도별 억제율 및 IC50을 각각 아래의 표 2에 나타내었다.
In addition, the inhibitory rate and IC 50 of each concentration of the bear odor fraction are shown in Table 2 below.
표 1. 곰취 추출물의 AGEs 형성 억제 효과Table 1. Inhibitory Effect of Bear Extract on AGEs Formation
표 2. 곰취 분획물의 AGEs 형성 억제 효과Table 2. Effect of Inhibitory Formation on AGEs Formation
1)IC50값은 AGEs 형성의 50% 억제를 보이는 농도를 나타내는 것으로, %억제율 vs. 3 가지 농도의 로그 곡선에서 최소제곱 회귀 방정식(least-square regression equation)으로 계산된 값. 1) IC 50 values represent concentrations showing 50% inhibition of AGEs formation. The calculated value is the least-square regression equation for a log curve of three concentrations.
2) 양성대조 물질(통상적인AGEs 형성 억제제). 2) Positive Control (Typical AGEs Formation Inhibitors).
상기 표 1,2에서 알 수 있는 바와 같이, 곰취 70% 에탄올 추출물에서 높은 활성이 나타났으며, 그에 따른 에틸아세트와 부탄올 분획물에서 각각 0.795, 0.621 μg/mL의 농도에서 50%의 억제율을 갖는 것으로 나타났다.
As can be seen in Table 1, 2, 70% ethanol extract of Goji odor was shown to have high activity, and the ethyl acetate and butanol fractions had a inhibition rate of 50% at concentrations of 0.795 and 0.621 μg / mL, respectively. appear.
실시예Example 5. 5. 알도오스Aldos 환원효소( Reductase ( AldoseAldose reductasereductase ) 억제 효능 시험Inhibitory efficacy test
당뇨성합병증 발생에 중요한 역할을 한다고 알려져 있는 글루코오스 대사경로인 폴리올 경로의 촉매 효소인 알도오스 환원효소(aldose reductase) 활성에 대한 곰취 추출물의 효과를 확인하였다. 알도오스 환원효소 억제제는 글루코오스를 소르비톨로 변환하는 알도오스 환원효소를 억제하는 효소 억제제이며 소르비톨의 생산을 저하시키는 것이 목적이다. 많은 연구에서 폴리올 대사 이상이 당뇨병성 합병증을 유발하는 것으로 알려져 있으므로, 알도오스 환원효소 억제제는 당뇨병성 합병증의 치료제로서 유용할 수 있다. The effect of bear extract on aldose reductase activity, a catalytic enzyme of the polyol pathway, a glucose metabolism known to play an important role in the development of diabetic complications, was confirmed. An aldose reductase inhibitor is an enzyme inhibitor that inhibits aldose reductase, which converts glucose into sorbitol, and aims to reduce the production of sorbitol. Since many studies have shown that polyol metabolic abnormalities cause diabetic complications, aldose reductase inhibitors may be useful as treatments for diabetic complications.
이에, 본 실시예에서는 당뇨합병증 치료 효과를 입증하기 위하여, 곰취 추출물 및 분획물의 알도오스 환원효소 활성 억제능을 시험하였다.Thus, in this embodiment, in order to prove the effect of treating diabetic complications, the ability of inhibiting the aldose reductase activity of the extract and fractions of bear odor.
무게가 200g이 넘는 래트(Sprague-Dawly(SD) rats; 250~280g)의 수정체(lens)를 적출하여 그 안의 수정체의 습중량에 따라 0.05M의 소듐 버퍼(pH 6.8)를 수정체 1개당 250 μL을 넣어 얼음 안에서 균질화시켰다. 이를 4℃, 7500rpm에서 30분간 원심분리(centrifuge UNION 55 R Hanil, Korea) 후, 그 상등액을 취하여 알도오스 환원효소 시험의 효소원으로 사용하였다.Lenses weighing more than 200 g (Sprague-Dawly (SD) rats; 250-280 g) were extracted and 0.05 μL sodium buffer (pH 6.8) was added to the lens, depending on the wet weight of the lens therein. Was added to homogenize in ice. After centrifugation (centrifuge UNION 55 R Hanil, Korea) for 30 minutes at 4 ℃, 7500rpm, the supernatant was taken and used as the enzyme source of the aldose reductase test.
알도오스 환원효소(Aldose reductase) 활성 억제능은 Haymanh와 Kinoshita가 사용한 방법을 변형하여 실험을 수행하였다(Hayman S, Kinoshita JH. 1965. Isolation and properties of lens aldose reductase. J. Biol. Chem. 240(2): 877-882). 0.05M 포타슘 포스페이트 버퍼(pH 7.0) 530μL에 상기 준비한 효소원 160μL와 1.6mM NADPH(Applichem, Germany) 100μL, 시료 (시료제조예 1,2에서 얻어진 곰취 추출물 또는 분획물, 1mg/mL) 10 μL를 넣어주고, 마지막으로 0.1M DL-글리세르알데하이드(DL-Glyceraldehyde, Sigma, USA) 100μL를 넣어주었다. 큐벳내부에서 4.4 분 동안 반응시켜 340nm에서 NADPH 흡광도의 감소율을 측정하였다. 반응은 큐벳내부에서 4.4분동안 반응시켜 0s와 280s의 흡광값으로 sample의 흡광도값을 계산하였다. 계산식 1={0s에서의 흡광도 값-280s에서의 흡광도값)/반응시킨 시간}을 사용하였다. 억제율은 아래와 같은 계산식을 사용하였다. The ability to inhibit aldose reductase activity was tested by modifying the method used by Haymanh and Kinoshita (Hayman S, Kinoshita JH. 1965. Isolation and properties of lens aldose reductase. J. Biol. Chem. 240 (2) ): 877-882). Into 530 μL of 0.05M potassium phosphate buffer (pH 7.0), put 160 μL of the above prepared enzyme source, 100 μL of 1.6 mM NADPH (Applichem, Germany), and 10 μL of the sample (Gear extract or fraction obtained in Sample Preparation Example 1, 1 mg / mL). Finally, 100 μL of 0.1M DL-glyceraldehyde (DL-Glyceraldehyde, Sigma, USA) was added. The reaction was allowed to proceed for 4.4 minutes inside the cuvette to measure the decrease rate of NADPH absorbance at 340 nm. The reaction was carried out for 4.4 minutes in the cuvette, and the absorbance values of the samples were calculated with absorbance values of 0s and 280s. Formula 1 = (absorbance value at 0 s-absorbance value at 280 s) / time of reaction} was used. Inhibition rate was used as the following formula.
계산식={(control-sample)-(control-blank)}Calculation = {(control-sample)-(control-blank)}
또한 알도오스 환원효소 억제효과가 있다고 알려진 대조 물질로 퀘르세틴 (Quercetin, Sigma Chemical Co.(St Louis, MO, USA))을 사용하여 상기와 같은 방법으로 처리하여 흡광도의 감소율을 측정하여 시료제조예 1,2에서 제조된 시료들에서의 결과와 비교하였다. 대조물질에 대한 50% 흡광도의 감소를 나타내는 시료의 농도 (IC50)으로 표시하였고, 각 시료를 3회 반복 실시하여 평균하였다 In addition, using a quercetin (Quercetin, Sigma Chemical Co. (St Louis, MO, USA)) as a control substance known to have an aldose reductase inhibitory effect was measured in the same manner as described above to measure the rate of decrease in absorbance sample Preparation Example 1 It was compared with the results in the samples prepared in, 2. The concentration of the sample (IC 50 ), indicating a 50% reduction in absorbance for the control material, was expressed, and each sample was repeated three times and averaged.
표3. 곰취 추출물의 알도오스 환원효소 활성 억제 효과Table 3. Inhibitory Effects of Bear Extracts on Aldose Reductase Activity
표4. 곰취 분획물의 알도오스 환원효소 활성 억제 효과Table 4. Inhibitory Effect of Aldose Reductase Activity on the Bear Fraction
1)IC50값은 알도오스 환원효소 활성의 50% 억제를 보이는 농도를 나타내는 것으로, %억제율 vs. 3 가지 농도의 로그 곡선에서 최소제곱 회귀 방정식(least-square regression equation)으로 계산된 값. 1) IC 50 value represents the concentration showing 50% inhibition of aldose reductase activity,% inhibition vs. The calculated value is the least-square regression equation for a log curve of three concentrations.
2) 양성대조 물질(통상적인 알도오스 환원효소 활성 억제제). 2) positive control substance (typical aldose reductase activity inhibitor).
상기 표 3,4에서 알 수 있는 바와 같이, 곰취 70% 에탄올 추출물에서 높은 활성이 나타났으며, 그에 따른 에틸아세트와 부탄올 분획물에서 각각 0.003, 0.013 μg/mL의 농도에서 50%의 억제율을 갖는 것으로 나타났다. 곰취 에틸아세테이트와 부탄올 분획물의 경우 대조 물질인 퀘르세틴의 IC50값보다 훨씬 낮은 농도를 나타내었다.
As can be seen in Tables 3 and 4, high activity was observed in the 70% ethanol extract of Goji odor, and accordingly, the ethyl acetate and butanol fractions had 50% inhibition rate at concentrations of 0.003 and 0.013 μg / mL, respectively. appear. The fractions of the odor ethyl acetate and butanol fractions showed much lower concentrations than the IC 50 values of quercetin.
실시예Example 3. 3. DPPHDPPH 를 이용한 항산화효과 시험Antioxidant Effect Test
DPPH는 화학적으로 안정한 자유 가디칼을 지니고 있는 화합물로 항산화 활성을 가진 물질을 만나면 환원되어 항산화 능력을 확인하는데 널리 사용되는 물질이다. 이에, 본 실시예에서는 DPPH를 이용하여 곰취 추출물과 분획물의 자유 라디칼 소거 효과(DPPH에 대한 수소 공여능)를 평가하여 항산화 효과를 평가하였다.DPPH is a compound with chemically stable free cardial and is widely used to check the antioxidant capacity when it meets a substance with antioxidant activity. Thus, in this embodiment, the antioxidant effect was evaluated by evaluating the free radical scavenging effect (hydrogen donating ability to DPPH) of the extract and fractions of the bear odor extract using DPPH.
곰취 추출물과 각 분획물들을 DMSO(dimethyl sulfoxide)을 이용하여 희석하여 준비하였다. 이와 같이 준비된 일정 농도의 시료 1mL에 5Χ 10-4M DPPH용액(dissolved in 99% ethanol) 2mL를 가하고 잘 혼합하여 실온에서 30분간 방치하였다. 얻어진 반응액을 517nm 흡광도에서 전자 공여능(electron donating ability)으로 측정하였다. 각 분획의 억제능은 양성대조군에 비하여 감소된 흡광도로부터 라디칼 소거율을 계산하였다. Bear extract and each fraction were prepared by diluting with DMSO (dimethyl sulfoxide). 2 mL of 5Χ 10 -4 M DPPH solution (dissolved in 99% ethanol) was added to 1 mL of the prepared sample at a constant concentration, mixed well, and left at room temperature for 30 minutes. The obtained reaction solution was measured by electron donating ability at 517 nm absorbance. The inhibitory capacity of each fraction was calculated from the radical scavenging rate from the reduced absorbance compared to the positive control.
계산식={1-(Control/Sample)}*100Calculation = {1- (Control / Sample)} * 100
이때 활성비교를 위하여 양성대조군으로는 항산화효과가 있다고 알려진 아스코르브산(Showa Chemicals Inc., Japan)를 사용하였고 이를 상기와 같은 방법으로 처리하여 DPPH소거능을 측정하여 결과를 기재하였다. 그리고 DPPH 자유 라디칼을 50% 억제하는데 요구되는 함량(IC50)과 비교하였고, 시료를 3회 반복 실험하여 얻은 결과를 평균한 값으로 나타내었다. At this time, ascorbic acid (Showa Chemicals Inc., Japan), which is known to have an antioxidant effect, was used as a positive control group, and the results were described by measuring DPPH quenching ability by treating the same method as described above. And compared with the content required for 50% inhibition of DPPH free radicals (IC 50 ), and the results obtained by the three repeated experiments the sample is shown as the average value.
곰취 추출물 및 분획물의 DPPH 소거능 비교 결과를 표 5 및 표 6에 각각 나타내었다.The results of comparing DPPH scavenging ability of the extracts of Goji odor and fractions are shown in Tables 5 and 6, respectively.
표 5. 곰취 추출물의 DPPH 라디칼 소거 효과 Table 5. DPPH Radical Scavenging Effects of Bear Extract
표 6. 곰취 분획물의 DPPH 라디칼 소거 효과Table 6. DPPH radical scavenging effect of goji odor fraction
표 5 및 표 6에 있어서,In Table 5 and Table 6,
1)IC50값은 DPPH 라디칼의 50% 억제를 보이는 농도를 나타내는 것으로, %억제율 vs. 3 가지 농도의 로그 곡선에서 최소제곱 회귀 방정식(least-square regression equation)으로 계산된 값. 1) IC 50 value represents the concentration showing 50% inhibition of DPPH radical,% inhibition vs. The calculated value is the least-square regression equation for a log curve of three concentrations.
2) 양성대조 물질(통상적인 DPPH 라디칼 소거제). 2) Positive Control (Typical DPPH Radical Scavengers).
표 5 및 표 6에서 확인되는 바와 같이, 곰취 추출물 중에서 70% 에탄올 추출물이 산화 억제 능력이 우수함을 확인하였고, 이를 바탕으로 분획하여 곰취 분획물의 DPPH 라디칼 억제 활성을 알아본 결과 IC50값을 비교하여 볼 때 에틸아세테이트 분획물과 부탄올 분획물에서 각각 0.039, 0.663 ug/mL으로 나타났다. 즉, 곰취 에틸아세테이트 분획물과 메틸렌클로라이드 분획물이 산화 억제 능력이 우수함을 확인하였다.As confirmed in Table 5 and Table 6, it was confirmed that the 70% ethanol extract in the extract of Goji odor has excellent oxidation inhibitory ability, fraction based on this to compare the DP 50 radical inhibition activity of the Goji odor fraction by comparing the IC 50 value Ethyl acetate fraction and butanol fraction showed 0.039 and 0.663 ug / mL, respectively. That is, it was confirmed that Goji odor ethyl acetate fraction and methylene chloride fractions have excellent oxidation inhibitory ability.
통계처리Statistical processing
모든 자료의 통계분석은 SAS 통계 프로그램(SAS institute, 1987)을 이용하여 분석하였으며, 분석결과는 실험군당 평균과 표준오차로 나타냈다. 처리군 간의 유의성은 Duncan’s multiple range test로 p<0.05 수준에서 유의성 검정을 실시하였다.Statistical analysis of all data was performed using the SAS statistical program (SAS institute, 1987). The results were expressed as means and standard errors per experiment group. Significance test was performed at the p <0.05 level by Duncan's multiple range test.
Claims (7)
최종당화산물(Advanced Glycation Endproducts, AGEs) 형성 억제능 및 알도오스 환원효소(Aldose reductase) 활성 억제능이 있는 것을 특징으로 하는 당뇨합병증의 예방 또는 개선용 조성물.
It contains ethyl acetate fraction or butanol fraction, which is obtained by sequentially fractionating the extract of Goji odor with hexane, methylene chloride, ethyl acetate and butanol, as an active ingredient,
A composition for the prevention or improvement of diabetic complications, which has the ability to inhibit the formation of advanced glycation endproducts (AGEs) and the aldose reductase activity.
상기 당뇨합병증은 당뇨병성 혈관장애, 당뇨병성 신경장애 또는 당뇨병성감염증인 것을 특징으로 하는 당뇨합병증의 예방 또는 개선용 조성물.
The method of claim 1,
The diabetic complications are diabetic vascular disorders, diabetic neuropathy or diabetic infectious disease, characterized in that the composition for the prevention or improvement of diabetic complications.
상기 당뇨합병증은 당뇨성 망막증(diabetic retinopathy), 당뇨성 백내장(diabetic cataract), 당뇨성 신증(diabetic nephropathy), 당뇨성 신경병증(diabetic neuropathy) 또는 당뇨성 혈관합병증인 것을 특징으로 하는 당뇨합병증의 예방 또는 개선용 조성물.The method of claim 5,
The diabetic complications are diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy or diabetic complications, characterized in that the prevention of diabetic complications Or a composition for improvement.
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