KR20220043862A - A composition for improving, preventing and treating of diabetic complications comprising Hippophae rhamnoides leaf extracts - Google Patents
A composition for improving, preventing and treating of diabetic complications comprising Hippophae rhamnoides leaf extracts Download PDFInfo
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- KR20220043862A KR20220043862A KR1020210119723A KR20210119723A KR20220043862A KR 20220043862 A KR20220043862 A KR 20220043862A KR 1020210119723 A KR1020210119723 A KR 1020210119723A KR 20210119723 A KR20210119723 A KR 20210119723A KR 20220043862 A KR20220043862 A KR 20220043862A
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- diabetic
- vitamin tree
- extract
- diabetic complications
- preventing
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Abstract
Description
본 발명은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하여 당뇨합병증을 개선, 예방 또는 치료할 수 있는 조성물에 관한 것이다.The present invention relates to a composition capable of improving, preventing or treating diabetic complications by containing a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
당뇨병(diabetes mellitus, DM)은 인슐린 결핍, 인슐린 저항성 또는 둘 모두를 특징으로 하는 흔히 비만과 관련되는 진행성 질환(progressive disease)이다. 공복 및 식후 혈당이 증가하면 실명, 신부전, 심장 질환, 졸중(stroke) 및 절단(amputation)을 야기하는 급성 및 만성 합병증(미세혈관 및 대혈관(micro- and macrovascular))에 환자가 노출된다. Diabetes mellitus (DM) is a progressive disease, often associated with obesity, characterized by insulin deficiency, insulin resistance, or both. Elevated fasting and postprandial blood glucose exposes patients to acute and chronic complications (micro- and macrovascular) leading to blindness, renal failure, heart disease, stroke and amputation.
혈당 조절의 개선이 이러한 당뇨합병증의 위험성을 낮추는 것으로 입증되었다. 이러한 질환의 진행적 속성 때문에, 혈당 조절을 유지하기 위해서는 진화하는 치료 전략이 필요하다. 2가지 형태의 당뇨병이 있으며, 제1형 당뇨병으로는 소아 당뇨병 또는 인슐린 의존성 당뇨병(IDDM)이 있고, 제2형 당뇨병으로는 성인형 당뇨병 또는 비인슐린 의존성 당뇨병(NIDDM)이 있다. 상기 제1형 당뇨병 환자는 인슐린을 합성 및 분비하는 췌장 β세포의 면역학적 파괴로 인하여 절대적으로 인슐린이 부족하다. 상기 제2형 당뇨병은 병인이 더 복합적이며 상대적인 인슐린 결핍, 인슐린 작용 감소 및 인슐린 저항성을 특징으로 한다. Improved blood sugar control has been proven to lower the risk of these diabetic complications. Because of the progressive nature of these diseases, evolving therapeutic strategies are needed to maintain glycemic control. There are two types of diabetes.
한편, 당뇨합병증은 당뇨병성 신경병증, 당뇨병성 신장병증, 당뇨병성 심근경색증, 당뇨병성 망막병증, 당뇨병성 백내장, 당뇨병성 혈관합병증 또는 당뇨발궤양을 포함하며, 이의 주요 원인은 폴리올 경로의 알도스 환원 효소(aldose reductase) 활성으로 비롯한 과다 솔비톨 축적으로 알려져 있다. 따라서, 알도스 환원 효소의 억제가 당뇨합병증 치료 및 예방에 중요한 역할을 하는 것으로 알려져 있다. 지금까지 개발된 알도스 환원 효소 억제제인 zopolrestat, ponalrestat, sorbinil, tolrestat, fidarestat, ranireatat와 epalrestat 등이 여러 동물 실험에서 당뇨합병증을 예방, 지연시킨다는 보고가 있다.On the other hand, diabetic complications include diabetic neuropathy, diabetic nephropathy, diabetic myocardial infarction, diabetic retinopathy, diabetic cataract, diabetic vascular complications, or diabetic foot ulcer, the main cause of which is aldose in the polyol pathway. Excessive sorbitol accumulation, including due to aldose reductase activity, is known. Therefore, it is known that inhibition of aldose reductase plays an important role in the treatment and prevention of diabetic complications. Aldose reductase inhibitors such as zopolrestat, ponalrestat, sorbinil, tolrestat, fidarestat, ranireatat, and epalrestat, which have been developed so far, have been reported to prevent and delay diabetic complications in several animal experiments.
그러나 임상에서 zopolrestat와 ponalrestat은 효능이 낮았고, sorbinil의 과민반응과 tolrestat의 간기능 장애와 같은 부작용으로 개발 과정에서 중단되었다. 현재 일본과 미국에서는 ranireatat와 fidarestat의 임상실험이 진행되고 있다. Epalrestat는 미국식품의약국 (FDA)에는 승인되지 않았지만, 일본에서만 1992년에 승인되어 시판중이다. However, in clinical trials, zopolrestat and ponalrestat had low efficacy and were discontinued during development due to side effects such as sorbinil hypersensitivity reaction and tolrestat liver dysfunction. Clinical trials of ranireatat and fidarestat are currently underway in Japan and the United States. Epalrestat has not been approved by the US Food and Drug Administration (FDA), but was approved and marketed in Japan only in 1992.
최종당화산물(Advanced glycation encproducts)은 (Nonenzymatic glycation reaction)으로 단백질의 리신 잔기 등의 아미노산 그룹과 환원당이 효소의 작용없이 일어나는 마이야르반응 (Maillard reaction)으로, 이 반응의 결과로 형성되는 물질이다. 단백질의 비효소적 당화반응은 단백질의 유리 아미노기 리신(lysine)이나, 알기닌(arginine)과 환원당의 카르보닐기(carbonyl group)가 반응하여 초기 당화반응 생성물인 쉬프 염기(Shciff base)를 형성하고 이때 형성된 화합물들이 계속적으로 축합, 재전위, 산화, 분열, 고리화 등의 일련의 복잡한 반응을 통하여 갈색의 화합물을 만들어 총체적인 개념의 비가역적 최종당화산물을 형성하는 반응이다. Advanced glycation encproducts (Advanced glycation encproducts) are (Nonenzymatic glycation reaction), a Maillard reaction in which an amino acid group such as a lysine residue of a protein and a reducing sugar occur without the action of an enzyme. It is a substance formed as a result of this reaction. The non-enzymatic glycosylation of proteins is the free amino group lysine of the protein, but arginine and the carbonyl group of the reducing sugar react to form a Shciff base, which is the initial glycation reaction product, and the compound formed at this time It is a reaction that continuously forms a brown compound through a series of complex reactions such as condensation, retranslocation, oxidation, cleavage, and cyclization to form an irreversible final glycation product of the overall concept.
최종당화산물은 비가역적인 반응산물이므로 일단 생성되면 혈당이 정상적으로 회복되어도 분해되지 않고 단백질의 생존기간 동안 조직에 축적되어 조직의 구조와 기능을 비정상적으로 변화시킨다. 비교적 반감기가 긴 콜라겐(collagen)은 쉽게 당화반응이 일어나고 이미 형성된 최종당화산물과 콜라겐의 교차결합(cross-linking)을 형성하여 체내의 구조 및 기타 단백질 결합 조직 등의 비정상적인 물리화학적 변화를 초래한다. 또한, 다양한 세포 타임의 대한 특이적 수용체에 의해 인식되어 당뇨병성 망막변증(retinopathy), 당뇨병성 신경병증(diabetic neuropathy), 당뇨병성 백내장(cataract), 당뇨병성 신증(nephropathy)등과 같은 당뇨합병증과 당뇨, 만성 신장질환, 심장질환, 혈관질환 및 노화등 각종 질병을 일으키는 원인이 된다. Since the final glycation product is an irreversible reaction product, once it is created, it is not decomposed even when blood sugar is restored to normal, but accumulates in the tissue during the protein's survival period and abnormally changes the structure and function of the tissue. Collagen, which has a relatively long half-life, easily undergoes a glycation reaction and forms cross-linking between the already formed final glycation product and collagen, resulting in abnormal physicochemical changes in the structure of the body and other protein-connected tissues. In addition, diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic cataract, and diabetic nephropathy and diabetes , chronic kidney disease, heart disease, vascular disease, and various diseases such as aging.
따라서 최종당화산물을 억제하여 최종당화산물로 기인하는 질병을 치료하고자 하는 연구가 시도되고 있고, 종래 개발된 대표적인 최종당화산물의 억제제로는 아미노구아니딘(aminoguanidine) 및 ALT-711이 있다. 합성의약품인 아미노구아니딘은 친핵성 히드라진으로 축합반응의 산물과 결합하여 최종당화산물의 생성을 억제하여 합병증으로 진전되는 것을 방지한다. 아미노구아니딘은 당뇨합병증의 예방 및 치료에 가장 유망한 의약품으로 제 3상 임상시험까지 진행되었으나, 장기간 투여 시 독성이 유발되는 문제점이 있어 더욱 안전한 약제의 개발 및 예방제의 개발이 필요한 실정이다. 또한 ALT-711은 이미 형성된 최종당화산물의 교차결합을 분해하는 약물로 개발되었고, 친핵성 물질로서 이미 형성된 최종당화산물 교차결합의 친전자성인 디카로보닐기(dicarbonyl group)등을 공격한다. 스트렙토조토신으로 유도한 당뇨쥐에 ALT-711을 투여하면 당뇨로 인한 합병증을 완화해준다는 보고가 있다. Therefore, studies to treat diseases caused by the final glycation product by inhibiting the final glycation product are being attempted, and conventionally developed representative inhibitors of the final glycation product include aminoguanidine and ALT-711. Synthetic drug, aminoguanidine, is a nucleophilic hydrazine and binds to the product of the condensation reaction to inhibit the production of final glycation products, thereby preventing the development of complications. Aminoguanidine is the most promising drug for the prevention and treatment of diabetic complications and has progressed up to
그러나 종래 개발된 최종당화산물 억제제들은 대부분 합성화합물로서 체내 부작용이 초래되는 등 장기적 복용에 안전성 문제가 대두되고 있어 체내 부작용이 없는 천연소재의 새로운 최종당화산물 억제제의 개발이 필요한 실정이다.However, since most of the conventionally developed inhibitors of final glycation products are synthetic compounds, safety issues arise in long-term administration, such as causing side effects in the body.
한편, 비타민나무(Hippophae rhamnoides L.; 산자나무)는 보리수과에 속하는 관목으로서 100여종 이상의 성분을 포함하고 있으며, 특히 비타민(A, B, C, E, F, K)등 유효한 성분을 많이 함유하고 있다. 겨울철 추위 및 여름철 고온에서도 잘 자라며, 척박한 지대에서도 잘 자라는 강한 적응성을 지녔다. 이미 비타민나무를 이용하여 항산화 활성, 암 예방 및 면역 체계 분야 등 다양한 연구 분야가 이루어지고 있다. 또한, 비타민나무를 이용하여 다양한 식품을 만들어 사용하고 있으나, 국내에서는 아직 그 연구가 활발하게 이루어지지 않고 있다.On the other hand, the vitamin tree (Hippophae rhamnoides L.) is a shrub belonging to the Bodhi family and contains more than 100 kinds of ingredients. there is. It grows well in the cold in winter and high in the summer, and has strong adaptability to grow well in barren areas. Various research fields, such as antioxidant activity, cancer prevention, and immune system fields, have already been made using the vitamin tree. In addition, various foods are made and used by using the vitamin tree, but the study has not been actively conducted in Korea.
대한민국 등록특허 제1224196호에는 '비타민나무 추출물과 생약제가 함유된 오메가-3 제조방법'이 개시되어 있고, 대한민국 등록특허 제1229748호에는 '비타민나무 발효 추출물을 함유하는 화장료 조성물'이 개시되어 있으나, 비타민나무 잎 추출물을 유효성분으로 함유하는 당뇨합병증의 개선, 예방 또는 치료용 조성물에 대해서는 밝혀진 바가 없다.Korean Patent No. 1224196 discloses a 'method for producing omega-3 containing vitamin tree extract and herbal medicine', and Korean Patent No. 1229748 discloses 'cosmetic composition containing fermented vitamin tree extract', A composition for improving, preventing or treating diabetic complications containing the vitamin tree leaf extract as an active ingredient has not been disclosed.
본 발명의 목적은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하여 당뇨합병증을 예방 또는 치료할 수 있는 약학 조성물을 제공하는데 있다.It is an object of the present invention to provide a pharmaceutical composition capable of preventing or treating diabetic complications by containing a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
또한, 본 발명의 다른 목적은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하여 당뇨합병증을 예방 또는 개선할 수 있는 식품 조성물을 제공하는데 있다. In addition, another object of the present invention is to provide a food composition that can prevent or improve diabetic complications by containing the leaf extract of a vitamin tree ( Hippophae rhamnoides ) as an active ingredient.
또한, 본 발명의 또 다른 목적은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하여 당뇨합병증을 예방 또는 개선할 수 있는 사료 조성물을 제공하는데 있다. In addition, another object of the present invention is to provide a feed composition that can prevent or improve diabetic complications by containing a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
또한, 본 발명의 또 다른 목적은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하여 당뇨합병증을 예방 또는 치료할 수 있는 동물용 약학 조성물을 제공하는데 있다.In addition, another object of the present invention is to provide a pharmaceutical composition for animals capable of preventing or treating diabetic complications by containing a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
상기한 목적을 달성하기 위한 본 발명의 당뇨합병증을 예방 또는 치료할 수 있는 약학 조성물은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유할 수 있다.The pharmaceutical composition capable of preventing or treating diabetic complications of the present invention for achieving the above object may contain a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
상기 당뇨합병증은 당뇨병성 신경병증, 당뇨병성 신장병증, 당뇨병성 심근경색증, 당뇨병성 망막병증, 당뇨병성 백내장 및 당뇨발궤양으로 이루어진 군에서 선택된 1종 이상일 수 있다.The diabetic complications may be at least one selected from the group consisting of diabetic neuropathy, diabetic nephropathy, diabetic myocardial infarction, diabetic retinopathy, diabetic cataract, and diabetic foot ulcer.
상기 당뇨합병증은 최종당화산물(advanced glycation end products, AGEs)의 생성 억제 및 분해촉진에 의해 예방 또는 치료될 수 있다.The diabetic complications can be prevented or treated by inhibiting the production of advanced glycation end products (AGEs) and promoting degradation.
상기 비타민나무 잎 추출물은 물, 탄소수 1 내지 4의 저급알코올 또는 이들의 혼합용매로 추출된 것일 수 있다.The vitamin tree leaf extract may be extracted with water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof.
상기 혼합용매는 20 내지 80 부피%의 메탄올, 에탄올, 부탄올 또는 프로판올 수용액일 수 있다.The mixed solvent may be an aqueous solution of 20 to 80% by volume of methanol, ethanol, butanol or propanol.
상기 혼합용매는 20 내지 80%의 에탄올 수용액일 수 있다.The mixed solvent may be an aqueous solution of 20 to 80% ethanol.
또한, 상기한 다른 목적을 달성하기 위한 본 발명의 당뇨합병증을 예방 또는 개선할 수 있는 식품 조성물은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유할 수 있다.In addition, the food composition capable of preventing or improving diabetic complications of the present invention for achieving the above other object may contain a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
상기 식품 조성물은 당뇨합병증의 예방 또는 개선용 건강기능식품일 수 있다.The food composition may be a health functional food for preventing or improving diabetic complications.
또한, 상기한 또 다른 목적을 달성하기 위한 본 발명의 당뇨합병증을 예방 또는 개선할 수 있는 사료 조성물은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유할 수 있다.In addition, the feed composition capable of preventing or improving diabetic complications of the present invention for achieving the above another object may contain a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
또한, 상기한 또 다른 목적을 달성하기 위한 본 발명의 당뇨합병증을 예방 또는 치료할 수 있는 동물용 약학 조성물은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유할 수 있다.In addition, the pharmaceutical composition for animals capable of preventing or treating diabetic complications of the present invention for achieving the above another object may contain a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
또한, 상기한 또 다른 목적을 달성하기 위한 본 발명의 비타민나무(Hippophae rhamnoides) 잎 추출물은 최종당화산물(advanced glycation end products, AGEs)의 생성 억제 및 분해촉진 활성을 가질 수 있다.In addition, the vitamin tree ( Hippophae rhamnoides ) leaf extract of the present invention for achieving the above another object may have the activity of inhibiting the production of advanced glycation end products (AGEs) and promoting degradation.
본 발명의 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하는 조성물은 최종당화산물(AGEs) 생성 억제 효과와, 최종당화산물과 콜라겐 사이의 교차결합 절단 효과를 통해 AGEs 축적에 따른 당뇨합병증을 개선, 예방 또는 치료할 수 있다.The composition containing the vitamin tree ( Hippophae rhamnoides ) leaf extract of the present invention as an active ingredient reduces the diabetic complications caused by the accumulation of AGEs through the effect of inhibiting the production of final glycation products (AGEs) and the cross-linking effect between the final glycation products and collagen. can be improved, prevented or treated.
또한, 본 발명의 조성물은 독성이 없으므로 약학 조성물, 사료 조성물, 동물용 약학 조성물, 식품 조성물, 나아가 건강기능식품으로 활용될 수 있다.In addition, since the composition of the present invention is non-toxic, it can be used as a pharmaceutical composition, a feed composition, a pharmaceutical composition for animals, a food composition, and even a health functional food.
도 1은 본 발명의 실시예 1 및 비교예 1에 따라 제조된 비타민나무 추출물의 최종당화산물(AGEs) 생성억제 정도를 나타낸 그래프이다.
도 2는 본 발명의 실시예 1 및 비교예 1에 따라 제조된 비타민나무 추출물의 최종당화산물(AGEs) 교차결합 억제 정도를 나타낸 그래프이다.
도 3은 본 발명의 실시예 1 및 비교예 1에 따라 제조된 비타민나무 추출물의 최종당화산물(AGEs) 교차결합 절단 정도를 나타낸 그래프이다.
도 4는 본 발명의 실시예 1 내지 4에 따라 제조된 비타민나무 잎 추출물의 최종당화산물(AGEs) 생성억제 정도를 나타낸 그래프이다.
도 5는 본 발명의 실시예 1 내지 4에 따라 제조된 비타민나무 잎 추출물의 최종당화산물(AGEs) 교차결합 억제 정도를 나타낸 그래프이다.
도 6은 본 발명의 실시예 1 내지 4에 따라 제조된 비타민나무 잎 추출물의 최종당화산물(AGEs) 교차결합 절단 정도를 나타낸 그래프이다.
도 7은 본 발명의 실시예 1에 따라 제조된 비타민나무 잎 추출물의 세포독성을 측정한 그래프이다.
도 8은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 공복혈당 변화를 측정한 그래프이다.
도 9는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 PAS 염색 후 사진이다.
도 10은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 AGEs IHC를 확인한 사진이다.
도 11은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 RAGE IHC를 확인한 사진이다.
도 12a는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 GLO1을 측정한 웨스턴 블롯이며; 도 12b는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 AGEs를 측정한 웨스턴 블롯이다.
도 13은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 GLO1 활성을 나타낸 그래프이다.
도 14는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군의 GLO1 및 AGEs를 db/db 마우스의 신장 조직에서 확인한 사진이다.
도 15는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 MGO-derived AGEs를 ELISA 방법으로 측정한 그래프이다.
도 16a는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 NOX4를 측정한 웨스턴 블롯이며; 도 16b는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 NOX2를 측정한 웨스턴 블롯이다.
도 17은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군의 소변 내에서 8-OHdG의 함량을 나타낸 그래프이다.
도 18은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군의 신장 조직에서 Nrf2, NOX4 및 8-OHdG를 확인한 사진이다.
도 19는 본 발명의 실시예 1에 따라 제조된 비타민나무 잎 추출물 및 비타민나무 열매 추출물의 용매에 따른 isorhamnetin과 rutin의 함량을 측정한 도면이다.1 is a graph showing the degree of inhibition of final glycation products (AGEs) production of vitamin tree extracts prepared according to Example 1 and Comparative Example 1 of the present invention.
Figure 2 is a graph showing the degree of inhibition of cross-linking of the final glycation products (AGEs) of the vitamin tree extract prepared according to Example 1 and Comparative Example 1 of the present invention.
3 is a graph showing the degree of cross-linking cleavage of the final glycation products (AGEs) of the vitamin tree extract prepared according to Example 1 and Comparative Example 1 of the present invention.
4 is a graph showing the degree of inhibition of final glycation products (AGEs) production of the leaf extract of vitamin tree prepared according to Examples 1 to 4 of the present invention.
5 is a graph showing the degree of inhibition of cross-linking of final glycation products (AGEs) of vitamin tree leaf extracts prepared according to Examples 1 to 4 of the present invention.
6 is a graph showing the degree of cross-linking cleavage of the final glycation products (AGEs) of the vitamin tree leaf extract prepared according to Examples 1 to 4 of the present invention.
7 is a graph measuring the cytotoxicity of a vitamin tree leaf extract prepared according to Example 1 of the present invention.
8 is a graph measuring changes in fasting blood glucose in the normal group,
9 is a photograph after PAS staining of the normal group, the
10 is a photograph confirming the AGEs IHC of the normal group, the
11 is a photograph confirming the RAGE IHC of the normal group, the
Figure 12a is a Western blot measuring GLO1 in a normal group, a
13 is a graph showing GLO1 activity in a normal group, a
14 is a photograph confirming GLO1 and AGEs in the kidney tissue of db/db mice in the normal group, the
15 is a graph of MGO-derived AGEs measured by an ELISA method in a normal group, a
Figure 16a is a Western blot measuring NOX4 in the normal group, the
17 is a graph showing the content of 8-OHdG in the urine of a normal group, a
18 is a photograph confirming Nrf2, NOX4 and 8-OHdG in the kidney tissue of a normal group, a
19 is a diagram illustrating the measurement of the content of isorhamnetin and rutin according to the solvent of a vitamin tree leaf extract and a vitamin tree fruit extract prepared according to Example 1 of the present invention.
본 발명은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유하여 당뇨합병증을 개선, 예방 또는 치료할 수 있는 조성물에 관한 것이다.The present invention relates to a composition capable of improving, preventing or treating diabetic complications by containing a vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
구체적으로, 본 발명의 조성물은 비타민나무 잎 추출물을 유효성분으로 함유함으로써, 최종당화산물(advanced glycation end products, AGEs)의 생성 억제 및 분해촉진에 의해 당뇨합병증을 개선, 예방 또는 치료할 수 있다. Specifically, the composition of the present invention contains a vitamin tree leaf extract as an active ingredient, thereby improving, preventing or treating diabetic complications by inhibiting the production of advanced glycation end products (AGEs) and promoting decomposition.
본 발명의 당뇨합병증은 당뇨병성 신경병증, 당뇨병성 신장병증, 당뇨병성 심근경색증, 당뇨병성 망막병증, 당뇨병성 백내장 및 당뇨발궤양으로 이루어진 군에서 선택된 1종 이상을 들 수 있다.The diabetic complications of the present invention may include one or more selected from the group consisting of diabetic neuropathy, diabetic nephropathy, diabetic myocardial infarction, diabetic retinopathy, diabetic cataract, and diabetic foot ulcer.
이하, 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
본 발명의 당뇨합병증의 개선, 예방 또는 치료용 조성물은 비타민나무(Hippophae rhamnoides) 잎 추출물을 유효성분으로 함유한다. The composition for improving, preventing or treating diabetic complications of the present invention contains vitamin tree ( Hippophae rhamnoides ) leaf extract as an active ingredient.
비타민나무 잎 추출물은 비타민나무 잎과 추출용매가 1 : 5 내지 25의 중량비, 바람직하게는 1 : 8 내지 15의 중량비로 혼합하여 30 내지 60 ℃에서 추출함으로써 추출물을 제조한다. 상기 비타민나무 잎과 추출용매의 중량비가 상기 범위를 벗어나는 경우에는 추출물에 비타민나무 잎의 유효성분이 적은 양으로 추출될 수 있다. 또한, 추출온도가 상기 하한치 미만인 경우에는 비타민나무 잎의 유효성분이 추출되지 않을 수 있으며, 상기 상한치 초과인 경우에는 비타민나무 잎의 유효성분이 적은 양으로 추출되고 특히, 80 ℃이상이면 추출물이 변질될 수 있다. The vitamin tree leaf extract is prepared by mixing the vitamin tree leaf and the extraction solvent in a weight ratio of 1: 5 to 25, preferably 1: 8 to 15, and extracting at 30 to 60 ° C. When the weight ratio of the vitamin tree leaf and the extraction solvent is out of the above range, the active ingredient of the vitamin tree leaf may be extracted in a small amount in the extract. In addition, if the extraction temperature is less than the lower limit, the active ingredient of the leaf of the vitamin tree may not be extracted, and if it exceeds the upper limit, the active ingredient of the leaf of the vitamin tree is extracted in a small amount, and in particular, if it is 80 ° C or higher, the extract may be altered. there is.
상기 추출용매로는 물, 탄소수 1 내지 4의 알코올 또는 그들의 혼합 용매를 들 수 있다. 상기 물은 식품 제조에 적합할 경우 특별히 한정할 필요는 없으나 예를 들어 지하수, 정제수, 증류수, 탈이온수 등이 이용될 수 있다. The extraction solvent may include water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. The water does not need to be particularly limited when suitable for food production, but for example, groundwater, purified water, distilled water, deionized water, etc. may be used.
상기 탄소수 1 내지 4의 알코올은 특별히 한정할 필요는 없으나 예들 들어 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올 또는 노말-부탄올 등이 이용될 수 있고, 바람직하게는 에탄올을 들 수 있다. The alcohol having 1 to 4 carbon atoms does not need to be particularly limited, but for example, methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol or normal-butanol may be used, and preferably ethanol. .
상기 혼합 용매는 특별히 한정할 필요는 없으나, 바람직하게는 20 내지 80 부피%의 메탄올, 에탄올, 부탄올 또는 프로판올 수용액을 들 수 있으며, 더욱 바람직하게는 20 내지 80 부피%의 에탄올 수용액을 들 수 있다.The mixed solvent does not need to be particularly limited, but preferably 20 to 80% by volume of an aqueous solution of methanol, ethanol, butanol or propanol, and more preferably 20 to 80% by volume of an aqueous ethanol solution.
상기 물 추출물의 제조는 특별히 한정할 필요는 없으나 비타민나무 잎을 10 내지 100 ℃의 물로 2 내지 60시간 동안 추출하여 제조할 수 있다.The preparation of the water extract does not need to be particularly limited, but it can be prepared by extracting the leaves of the vitamin tree with water at 10 to 100° C. for 2 to 60 hours.
상기 알코올 추출물, 또는 물과 알코올의 혼합 용매의 추출물의 제조는 특별히 한정할 필요는 없으나 예를 들어 비타민나무 잎을 20 내지 80 중량%의 에탄올 수용액으로 20 내지 100 ℃에서 2 내지 48시간 추출하여 제조한다.The preparation of the alcohol extract or the extract of a mixed solvent of water and alcohol does not need to be particularly limited, but for example, it is prepared by extracting vitamin tree leaves with 20 to 80% by weight of an ethanol aqueous solution at 20 to 100° C. for 2 to 48 hours. do.
상기 비타민나무 잎의 물, 탄소수 1 내지 4의 알코올 또는 그들의 혼합 용매에 의한 추출물은, 물, 탄소수 1 내지 4의 알코올 또는 그들의 혼합 용매에 의한 추출물을 유기용매로 재분획한 분획물을 포함한다. 상기 유기용매는 탄소수 1 내지 4의 알코올, 헥산, 아세톤, 에틸아세테이트, 클로로포름 및 디에틸에테르 등에서 선택되는 하나 이상의 유기용매일 수 있고, 바람직하게는 헥산 또는 에틸아세테이트일 수 있다.The extract of the vitamin tree leaf with water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof includes a fraction obtained by refractionation of an extract using water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof with an organic solvent. The organic solvent may be one or more organic solvents selected from alcohols having 1 to 4 carbon atoms, hexane, acetone, ethyl acetate, chloroform and diethyl ether, and preferably hexane or ethyl acetate.
본 발명에서 사용되는 용어 '추출물'은 상기 용매를 이용하여 비타민나무 잎에 포함된 성분을 추출한 추출물, 이들로부터 분획한 분획물, 이들 추출물 또는 분획물을 추가적으로 농축한 농축물, 이를 정제 또는 분리한 정제물도 포함하고, 상기 추출물, 분획물, 농축물 또는 정제물을 건조한 건조물 또는 그를 분쇄한 분말을 포함하는 의미로 사용된다. The term 'extract' used in the present invention is an extract obtained by extracting the components contained in the leaves of a vitamin tree using the solvent, a fraction fractionated therefrom, a concentrate obtained by further concentrating these extracts or fractions, and a purified or separated purified product. It is used in the sense of including a dried product of the extract, fraction, concentrate or purified product or a powder obtained by pulverizing it.
상기 정제물의 제조를 위해 분자량 컷-오프 값을 갖는 한외 여과막을 통과시키거나, 또는 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 부가할 수 있다.For the production of the purified product, various additionally performed, such as passing through an ultrafiltration membrane having a molecular weight cut-off value, or separation by various chromatography (those prepared for separation according to size, charge, hydrophobicity or affinity) A purification method may be added.
본 발명은 비타민나무 잎 추출물을 유효성분으로 포함하는 당뇨합병증의 예방 또는 개선용 식품 조성물에 관한 것이다.The present invention relates to a food composition for preventing or improving diabetic complications comprising a vitamin tree leaf extract as an active ingredient.
상기 '식품 조성물'은 유효성분으로 비타민나무 잎 추출물 이외에, 식품 제조에 통상적으로 사용되는 식품의 기준 및 규격('식품공전')에 기재된 식품으로 사용가능한 식품 원료, 식품첨가물 공전에 기재된 식품첨가물을 포함한다.The 'food composition' includes, as an active ingredient, in addition to the vitamin tree leaf extract, food ingredients that can be used as foods described in the standards and standards ('Food Code') of foods commonly used in food manufacturing, and food additives described in the Food Additives Code. include
특별히 한정할 필요는 없으나 예를 들어 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상기 탄수화물은 단당류, 예를 들어, 포도당, 과당 등; 이당류, 예를 들어 말토스, 설탕, 유당 등; 올리고당 또는 폴리사카라이드, 예를 들어 덱스트린, 물엿, 사이클로덱스트린 등; 당알코올, 예를 들어 자일리톨, 소르비톨, 에리트리톨 등을 사용할 수 있다. 상기 향미제는 천연 향미제[타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.Although not particularly limited, examples thereof include proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. The carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sugar, lactose and the like; oligosaccharides or polysaccharides such as dextrin, starch syrup, cyclodextrin and the like; Sugar alcohols such as xylitol, sorbitol, erythritol and the like can be used. As the flavoring agent, natural flavoring agents [taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) may be used.
상기 비타민나무 잎 추출물을 유효성분으로 식품 조성물을 제조하는 경우 비타민나무 잎 추출물은 당뇨합병증을 예방 또는 치료할 수 있는 함량이면 특별히 한정할 필요는 없으나, 예를 들어 0.1 내지 99 중량%, 0.5 내지 95 중량%, 1 내지 90 중량%, 2 내지 80 중량%, 3 내지 70 중량%, 4 내지 60 중량%, 5 내지 50 중량%로 포함될 수 있다.When preparing a food composition using the vitamin tree leaf extract as an active ingredient, the vitamin tree leaf extract does not need to be particularly limited as long as the content can prevent or treat diabetic complications, for example, 0.1 to 99% by weight, 0.5 to 95% by weight %, 1 to 90% by weight, 2 to 80% by weight, 3 to 70% by weight, 4 to 60% by weight, 5 to 50% by weight may be included.
상기 식품 조성물에서 유효성분인 비타민나무 잎 추출물은 섭취자의 상태, 체중, 질병의 유무나 정도 및 기간에 따라 다르지만, 통상의 기술자에 의해 적절하게 선택될 수 있다. 예들 들어 1일 투여량을 기준으로 1 내지 5,000 mg, 바람직하게는 5 내지 2,000 mg, 더욱 바람직하게는 10 내지 1,000 mg, 더더욱 바람직하게는 20 내지 800 mg, 가장 바람직하게는 50 내지 500 mg일 수 있고, 투여 횟수는 특별히 한정할 필요는 없으나 1일 3회 내지 1주일에 1회의 범위 내에서 통상의 기술자가 조절할 수 있다. 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있다.Although the vitamin tree leaf extract, which is an active ingredient in the food composition, varies depending on the condition, weight, presence or extent and duration of the disease, it may be appropriately selected by those skilled in the art. For example, it may be 1 to 5,000 mg, preferably 5 to 2,000 mg, more preferably 10 to 1,000 mg, still more preferably 20 to 800 mg, and most preferably 50 to 500 mg based on the daily dose. And, the number of administration does not need to be particularly limited, but can be adjusted by those skilled in the art within the range of 3 times a day to once a week. In the case of long-term intake for the purpose of health and hygiene or health control, it may be less than the above range.
상기 식품 조성물은 특별히 한정할 필요는 없으나 예를 들어 산제, 과립제, 정제, 캡슐제, 환제, 엑스제, 젤리 제형, 티백 제형 또는 음료 제형일 수 있다.The food composition is not particularly limited, but may be, for example, a powder, granules, tablets, capsules, pills, extracts, jelly formulations, tea bag formulations or beverage formulations.
또한 일반 식품에 당뇨합병증의 예방 또는 개선의 기능성을 부여하기 위하여 상기 비타민나무 잎 추출물을 첨가할 수 있으며, 첨가가 가능한 식품은, 특별히 한정할 필요는 없으나 예를 들어 식품위생법 제7조에 따른 식품의 기준 및 규격('식품공전')에 예시된 과자류, 빵 또는 떡류, 코코아가공품류 또는 초콜릿류, 식육 또는 알가공품, 어육가공품, 두부류 또는 묵류, 면류, 다류, 커피, 음료류, 특수용도식품, 장류, 조미식품, 드레싱류, 김치류, 젓갈류, 절임식품, 조림식품, 주류, 건포류, 기타 식품류 등에 첨가될 수 있다. 또한 축산물위생관리법 제4조에 따른 축산물의 가공기준 및 성분규격('축산물공전')에 예시된 유가공품, 식육가공품 및 포장육, 알가공품에 첨가될 수 있다.In addition, the vitamin tree leaf extract can be added to general food to give the function of preventing or improving diabetic complications, and the food that can be added is not particularly limited, but for example, food according to Article 7 of the Food Sanitation Act. Confectionery, bread or rice cakes, cocoa processed products or chocolates, edible meat or egg products, fish meat products, tofu or jelly products, noodles, teas, coffee, beverages, special purpose foods, sauces exemplified in the standards and specifications ('Food Code') , seasoned foods, dressings, kimchi, salted fish, pickled foods, stewed foods, alcoholic beverages, raisins, and other foods. In addition, it can be added to dairy products, processed meat products, packaged meat, and processed eggs exemplified in the processing standards and ingredient specifications of livestock products according to Article 4 of the Livestock Products Sanitation Control Act ('Livestock Products Code').
한편, 상기 비타민나무 잎 추출물을 유효성분으로 하는 식품 조성물은 단독으로 "당뇨합병증의 예방 또는 개선용 건강기능식품"으로 이용될 수 있다. On the other hand, the food composition containing the vitamin tree leaf extract as an active ingredient can be used alone as "health functional food for preventing or improving diabetes complications".
상기 '건강기능식품'은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 법적 기준에 따라 제조(가공을 포함)한 식품(건강기능식품에 관한 법률 제3조 제1호)을 말한다. 상기 '건강기능식품'은 국가마다 용어나 범위에 차이가 있을 수 있으나, 미국의 '식이 보충제(Dietary Supplement)', 유럽의 '식품 보충제(Food Supplemnet)', 일본의 '보건기능식품' 또는 '특정보건용식품(Food for Special Health Use, FoSHU)', 중국의 '보건식품' 등에 해당할 수 있다.The 'health functional food' refers to food manufactured (including processing) according to legal standards using raw materials or ingredients useful for the human body (
상기 식품 조성물 또는 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, 식품첨가물로서의 적합여부는 다른 규정이 없는 한 '식품첨가물공전'의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 따른다.The above food composition or health functional food may additionally contain food additives, and the suitability as a food additive is determined by the standards and standards for the item in accordance with the general rules and general test methods of the 'Food Additives Codex', unless otherwise specified. follow
또한 상기 건강기능식품에는 상기 비타민나무 잎 추출물과 함께 "당뇨합병증의 예방 또는 개선용 건강기능식품"에 사용되는 '기능성 원료'로 고시된 원료 또는 개별인정된 원료로서, 난소화성 말토덱스트린, 바나바주정 추출물, 피니톨, 홍경천 추출물, 구아바잎 추출물, 달맞이꽃종자 주정 추출물, 솔잎증류 농축액, 콩발효 추출물, 알부민 등의 혈당 조절과 관련된 건강기능식품 소재를 복합하여 당뇨합병증의 예방 또는 개선용 건강기능식품을 제조할 수 있다.In addition, in the health functional food, as a raw material announced as a 'functional raw material' or an individually recognized raw material used in "health functional food for the prevention or improvement of diabetes complications" together with the vitamin tree leaf extract, indigestible maltodextrin, Banaba alcohol Manufactures health functional food for preventing or improving diabetic complications by combining health functional food ingredients related to blood sugar control, such as extract, pinitol, rhododendron extract, guava leaf extract, evening primrose seed alcohol extract, pine needle distillation concentrate, soybean fermented extract, and albumin can do.
본 발명은 비타민나무 잎 추출물을 유효성분으로 포함하는 당뇨합병증의 예방 또는 개선용 사료 조성물에 관한 것이다.The present invention relates to a feed composition for preventing or improving diabetic complications comprising a vitamin tree leaf extract as an active ingredient.
상기 '사료 조성물'은 유효성분으로 비타민나무 잎 추출물 이외에, 식품의 기준 및 규격('식품공전')에 기재된 식품으로 사용가능한 식품 원료, 식품첨가물 공전에 기재된 식품첨가물을 사용할 수 있고, 식품으로 사용가능한 식품 원료 또는 식품첨가물이 아니더라도 '사료 등의 기준 및 규격' 별표 1의 단미사료의 범위에 해당하는 원료, 별표 2의 보조사료의 범위에 해당하는 원료를 사용할 수 있다.In the 'feed composition', in addition to the vitamin tree leaf extract as an active ingredient, food ingredients that can be used as foods described in food standards and specifications ('Food Code') and food additives described in the Food Additives Code can be used, and used as food Even if it is not a possible food raw material or food additive, raw materials that fall within the range of single feed in Attached Table 1 of 'Standards and Specifications for Feed, etc.' and those that fall within the range of Supplementary Feed in Attached Table 2 may be used.
상기 '사료 조성물'은 '사료 등의 기준 및 규격'에 따른 보조사료 중 추출제일 수 있고, 상기 보조사료를 포함하는 배합사료일 수 있다.The 'feed composition' may be an extractant among auxiliary feeds according to the 'standards and specifications of feed, etc.', and may be a compound feed including the auxiliary feed.
상기 비타민나무 잎 추출물을 유효성분으로 사료 조성물을 제조하는 경우 비타민나무 잎 추출물은 당뇨합병증의 예방 또는 개선을 나타내는 함량이면 특별히 한정할 필요는 없으나, 예를 들어 0.1 내지 99 중량%, 0.5 내지 95 중량%, 1 내지 90 중량%, 2 내지 80 중량%, 3 내지 70 중량%, 4 내지 60 중량%, 5 내지 50 중량%로 포함될 수 있다.When preparing a feed composition using the vitamin tree leaf extract as an active ingredient, the vitamin tree leaf extract does not need to be particularly limited as long as the content shows prevention or improvement of diabetic complications, for example, 0.1 to 99% by weight, 0.5 to 95% by weight %, 1 to 90% by weight, 2 to 80% by weight, 3 to 70% by weight, 4 to 60% by weight, 5 to 50% by weight may be included.
상기 사료 조성물에서 유효성분인 비타민나무 잎 추출물은 섭취 동물의 상태, 체중, 질병의 유무나 정도 및 기간에 따라 다르지만, 통상의 기술자에 의해 적절하게 선택될 수 있다. 예들 들어 1일 투여량을 기준으로 1 내지 5,000 mg, 바람직하게는 5 내지 2,000 mg, 더욱 바람직하게는 10 내지 1,000 mg, 더더욱 바람직하게는 20 내지 800 mg, 가장 바람직하게는 50 내지 500 mg일 수 있고, 투여 횟수는 특별히 한정할 필요는 없으나 1일 3회 내지 1주일에 1회의 범위 내에서 통상의 기술자가 조절할 수 있다. 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있다.The vitamin tree leaf extract, which is an active ingredient in the feed composition, varies depending on the condition, body weight, presence or absence or extent and duration of the ingested animal, but may be appropriately selected by those skilled in the art. For example, it may be 1 to 5,000 mg, preferably 5 to 2,000 mg, more preferably 10 to 1,000 mg, still more preferably 20 to 800 mg, and most preferably 50 to 500 mg based on the daily dose. And, the number of administration does not need to be particularly limited, but can be adjusted by those skilled in the art within the range of 3 times a day to once a week. In the case of long-term intake for the purpose of health and hygiene or health control, it may be less than the above range.
본 발명은 비타민나무 잎 추출물을 유효성분으로 포함하는 당뇨합병증의 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating diabetic complications comprising a vitamin tree leaf extract as an active ingredient.
또한 본 발명은 비타민나무 잎 추출물을 유효성분으로 포함하는 당뇨합병증의 예방 또는 치료용 동물용 약학 조성물에 관한 것이다.In addition, the present invention relates to a pharmaceutical composition for animals for preventing or treating diabetic complications comprising a vitamin tree leaf extract as an active ingredient.
또한 본 발명은 인간, 또는 인간을 제외한 동물에게 상기 조성물을 투여하는 당뇨합병증의 치료방법을 제공한다.The present invention also provides a method for treating diabetic complications by administering the composition to a human or non-human animal.
또한 본 발명은 당뇨합병증의 예방 또는 치료용 의약, 또는 동물용 의약 제조를 위한 비타민나무 잎 추출물의 신규 용도를 제공한다.In addition, the present invention provides a novel use of the vitamin tree leaf extract for the prevention or treatment of diabetic complications, or for the manufacture of medicaments for animals.
상기 '약학 조성물', '의약', '동물용 약학 조성물' 또는 '동물용 의약'은 유효성분으로 비타민나무 잎 추출물 이외에, 약학 조성물 등의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The 'pharmaceutical composition', 'medicine', 'pharmaceutical composition for animals' or 'medicine for animals' includes, as an active ingredient, suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions, in addition to the vitamin tree leaf extract. may include
상기 '담체'는 세포 또는 조직 내로의 화합물의 부가를 용이하게 하는 화합물이다. 상기 '희석제'는 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키게 되는 물에서 희석되는 화합물이다. The 'carrier' is a compound that facilitates the addition of the compound into a cell or tissue. The 'diluent' is a compound that is diluted in water to not only stabilize the biologically active form of the compound of interest, but also to dissolve the compound.
상기 담체, 부형제 및 희석제로는 특별히 한정할 필요는 없으나 예를 들어, 유당, 포도당, 설탕, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다.The carrier, excipient and diluent are not particularly limited, but for example, lactose, glucose, sugar, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.
상기 약학 조성물, 의약, 동물용 약학 조성물 또는 동물용 의약의 사용량은 환자 또는 치료대상 동물의 나이, 성별, 체중에 따라 달라질 수 있으며, 무엇보다도, 치료대상 개체의 상태, 치료 대상 질환의 특정한 카테고리 또는 종류, 투여 경로, 사용되는 치료제의 속성에 의존적일 것이다.The amount of the pharmaceutical composition, medicine, pharmaceutical composition for animals or veterinary medicine may vary depending on the age, sex, and weight of the patient or animal to be treated, and above all, the condition of the subject to be treated, a specific category of the disease to be treated, or It will depend on the type, route of administration, and the nature of the therapeutic agent used.
상기 약학 조성물, 의약, 동물용 약학 조성물 또는 동물용 의약은 체내에서 활성성분의 흡수도, 배설속도, 환자 또는 치료대상 동물의 연령 및 체중, 성별 및 상태, 치료할 질병의 중증정도 등에 따라 적절히 선택되나, 일반적으로 1일 0.1 내지 1,000 mg/kg, 바람직하게는 1 내지 500 mg/kg, 더욱 바람직하게는 5 내지 250 mg/kg, 가장 바람직하게는 10 내지 100 mg/kg으로 투여하는 것이 바람직하다. 이렇게 제형화된 단위 투여형 제제는 필요에 따라 일정시간 간격으로 수회 투여할 수 있다.The pharmaceutical composition, medicament, pharmaceutical composition for animals or medicament for animals is appropriately selected according to the absorption rate of the active ingredient in the body, the rate of excretion, the age and weight of the patient or the animal to be treated, sex and condition, the severity of the disease to be treated, etc. , It is generally preferred to administer 0.1 to 1,000 mg/kg, preferably 1 to 500 mg/kg, more preferably 5 to 250 mg/kg, and most preferably 10 to 100 mg/kg per day. The unit dosage form formulated in this way can be administered several times at regular time intervals as needed.
상기 약학 조성물, 의약, 동물용 약학 조성물 또는 동물용 의약은 개별적으로 예방제 또는 치료제로서 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다.The pharmaceutical composition, medicament, pharmaceutical composition for animals or medicament for animals may be administered individually as a prophylactic or therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.
상기 약학조성물, 의약, 동물용 약학 조성물 또는 동물용 의약은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 트로키제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구 제형으로 제형화하여 사용될 수 있다. 제형화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.The pharmaceutical composition, medicine, pharmaceutical composition for animals or medicine for animals may be formulated into oral dosage forms such as powders, granules, tablets, capsules, troches, suspensions, emulsions, syrups, aerosols, etc. there is. In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트, 설탕 또는 유당, 젤라틴 등을 섞어 조제될 수 있다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, and such solid preparations include at least one excipient to the compound, for example, starch, calcium carbonate, sugar or lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. .
상기 당뇨합병증의 치료방법은 인간, 또는 인간을 제외한 동물, 특히 포유동물에게 상기 조성물을 투여 하는 것으로, 예를 들어 당뇨합병증을 가진 치료대상 개체에게 상기 조성물을 투여하는 것이다.The method for treating diabetic complications is to administer the composition to a human or non-human animal, particularly a mammal, for example, administering the composition to a subject to be treated with diabetic complications.
상기 당뇨합병증을 가진 치료대상 개체 여부는, 당뇨합병증을 가지고 있는 경우일 수 있다.Whether the subject to be treated with the diabetic complications may be a case of having diabetic complications.
상기 치료를 위한 투여량, 투여 방법 및 투여 횟수는 상기 약학 조성물, 의약, 동물용 약학 조성물 또는 동물용 의약의 투여량, 투여 방법 및 투여 횟수를 참고할 수 있다.The dosage, administration method, and frequency of administration for the treatment may refer to the dosage, administration method, and frequency of administration of the pharmaceutical composition, medicine, pharmaceutical composition for animals or medicament for animals.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Hereinafter, preferred examples are presented to help the understanding of the present invention, but the following examples are merely illustrative of the present invention, and it will be apparent to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention, It goes without saying that such variations and modifications fall within the scope of the appended claims.
[비타민나무 잎 추출물과 열매 추출물의 비교][Comparison of vitamin tree leaf extract and fruit extract]
실시예 1. 비타민나무 잎 추출물Example 1. Vitamin tree leaf extract
비타민 잎(강원도 횡성)과 70 중량%의 에탄올 수용액을 1 : 10의 중량비로 혼합하여 50 ℃에서 3시간 동안 환류 추출한 후 Whatman NO. 1여과지로 여과하는 과정을 2번 반복하였다. 상기 여과액을 회전식 농축기(rotary vaccum evaporator, eyela, Japan)를 사용하여 40 ℃에서 회전 속도 60 rpm으로 감압 농축 한 후 동결 건조하여 비타민나무 잎 추출물을 수득하였다.Vitamin leaf (Hoengseong, Gangwon-do) and 70 wt% ethanol aqueous solution were mixed in a weight ratio of 1:10 and extracted under reflux at 50 °C for 3 hours, followed by Whatman NO. The process of filtration with one filter paper was repeated twice. The filtrate was concentrated under reduced pressure at 40 ° C. at a rotation speed of 60 rpm using a rotary vacuum evaporator (rotary vacuum evaporator, eyela, Japan), and then freeze-dried to obtain a vitamin tree leaf extract.
비교예 1.Comparative Example 1. 비타민나무 열매 추출물Vitamin Tree Fruit Extract
상기 실시예 1과 동일하게 실시하되, 비타민나무 잎 대신 비타민나무 열매를 사용하여 비타민나무 열매 추출물을 수득하였다. The same procedure as in Example 1 was performed, except that the vitamin tree fruit extract was obtained using the vitamin tree fruit instead of the vitamin tree leaf.
<시험예 Ⅰ><Test Example I>
시험예 1. 최종당화산물(AGEs) 생성억제 효능Test Example 1. Efficacy of inhibiting the formation of final glycation products (AGEs)
도 1은 본 발명의 실시예 1 및 비교예 1에 따라 제조된 비타민나무 추출물의 최종당화산물(AGEs) 생성억제 정도를 나타낸 그래프이다.1 is a graph showing the degree of inhibition of final glycation products (AGEs) production of vitamin tree extracts prepared according to Example 1 and Comparative Example 1 of the present invention.
시험방법은 10 mg/mL의 BSA를 700 μL의 50 mM phosphate buffer에 녹이고, 0.2 M의 fructose와 glucose를 각각 100 μL씩 넣은 후 0.02% sodium azide를 넣어 반응 기간 동안 미생물의 오염을 방지하였다. 상기 혼합물에 실시예 1 및 비타민 1의 추출물 또는 in vitro 표준 최종당화산물 생성 억제제인 AG 200 μL를 각각 첨가하여 최종 1 mL이 되도록 한 후 37 ℃에서 14일 동안 반응시켰다. 반응 14일 후 exitation 350 nm, emission 450 nm fluorescence analysis(Molecular Devices, Sunnyvale, CA, USA)로 측정하였다. For the test method, 10 mg/mL of BSA was dissolved in 700 µL of 50 mM phosphate buffer, 0.2 M fructose and 100 µL of glucose were added each, and 0.02% sodium azide was added to prevent contamination of microorganisms during the reaction period. To the mixture, 200 µL of each of the extracts of Example 1 and
도 1에 도시된 바와 같이, AGEs 생성능을 100%(AGEs, 대조군)로 나타낼 경우 양성 대조군인 AG 1 mM은 54%의 AGEs 생성억제 효능을 나타내었다. 한편, 비교예 1의 비타민나무 열매 추출물은 50 μg/mL, 200 μg/mL에서 각각 31%, 75%의 AGEs 생성억제효능을 나타내었고, 실시예 1의 비타민나무 잎 추출물은 50 μg/mL, 200 μg/mL에서 각각 77%, 88%의 효능을 나타내는 것을 확인하였다. As shown in FIG. 1 , when the AGEs generating ability was expressed as 100% (AGEs, control), 1 mM of AG, a positive control, exhibited 54% AGEs production inhibitory efficacy. On the other hand, the vitamin tree fruit extract of Comparative Example 1 showed AGEs production inhibitory effects of 31% and 75% at 50 μg/mL and 200 μg/mL, respectively, and the vitamin tree leaf extract of Example 1 was 50 μg/mL, It was confirmed that the efficacy of 77% and 88% at 200 μg/mL, respectively.
즉, 실시예 1의 비타민나무 잎 추출물이 비교예 1의 비타민나무 열매 추출물에 비하여 저농도, 고농도에서 모두 최종당화산물(AGEs) 생성억제능이 우수한 것을 확인하였다.That is, it was confirmed that the vitamin tree leaf extract of Example 1 was superior to the vitamin tree fruit extract of Comparative Example 1 in inhibiting the formation of final glycation products (AGEs) at both low and high concentrations.
시험예 2. 최종당화산물 교차결합 억제 효능 분석Test Example 2. Analysis of the efficacy of cross-linking of final glycated products
도 2는 본 발명의 실시예 1 및 비교예 1에 따라 제조된 비타민나무 추출물의 최종당화산물(AGEs) 교차결합 억제 정도를 나타낸 그래프이다.Figure 2 is a graph showing the degree of inhibition of cross-linking of the final glycation products (AGEs) of the vitamin tree extract prepared according to Example 1 and Comparative Example 1 of the present invention.
시험방법은 최종당화산물 교차결합 억제 효능평가를 위하여 Glycoaldehyde-AGE-BSA(Biovision, CA, USA)로서 horseradish peroxidase(HRP) tagging된 Kit-NH2 Unit(Dojin do Molecular Technologies, Inc., Tokyo, Japan)를 사용하였다. 최종당화산물 교차결합 억제 효능평가는 10 μg/mL AGE-BSA와, AG, 실시예 1 또는 비타민 1의 추출물을 collagen coated 96-well microtiter plate에 분주한 후 37 ℃에서 18시간 동안 배양하였다. 0.05% PBST(PBS에 0.05% Tween 20이 되도록 제조한 것)에 3번 세척하고 TMB를 기질(substrate)로 하여 발색한 후 450 nm에서 흡광도를 측정하였다. AGE-BSA의 cross-linking inhibition %는 하기 [수학식 1]에 따라 계산하였다. The test method is a kit-NH 2 Unit (Dojin do Molecular Technologies, Inc., Tokyo, Japan) tagged with horseradish peroxidase (HRP) as Glycoaldehyde-AGE-BSA (Biovision, CA, USA) for the evaluation of the final glycation product cross-linking inhibition efficacy. ) was used. To evaluate the efficacy of final glycation product cross-linking inhibition, 10 μg/mL AGE-BSA, AG, Example 1, or
[수학식 1][Equation 1]
AGE-BSA(%)=(약물을 첨가한 well의 흡광도/약물을 첨가하지 않은 well의 흡광도) X 100AGE-BSA(%)=(absorbance of wells with drug added/absorbance of wells without drug)
최종당화산물과 콜라겐(collagen)의 비가역적 교차결합을 억제하는지를 알아보기 위하여 최종당화산물 교차결합의 억제 효능을 AGEs의 중간 생성제인 글리코알데히드(glycoaldehyde)를 이용하여 in vitro에서 평가하였다.In order to investigate whether the irreversible cross-linking between the final glycosylated product and collagen was inhibited, the inhibitory efficacy of the final glycosylated product was evaluated in vitro using glycoaldehyde, an intermediate product of AGEs.
도 2에 도시된 바와 같이, 최종당화산물 교차결합 억제제로 알려져 있는 AG 1 mM은 교차결합 억제 효능이 67%인 것을 확인하였다. 한편, 비교예 1의 비타민나무 열매 추출물은 50 μg/mL, 200 μg/mL에서 각각 19%, 19%의 AGEs 교차결합 억제효능을 나타내었고, 실시예 1의 비타민나무 잎 추출물은 50 μg/mL, 200 μg/mL에서 각각 52%, 74.5%의 AGEs 교차결합 억제효능을 나타내는 것을 확인하였다. As shown in FIG. 2 , it was confirmed that 1 mM of AG, known as a final glycosylation cross-linking inhibitor, had a cross-linking inhibitory effect of 67%. On the other hand, the vitamin tree fruit extract of Comparative Example 1 showed 19% and 19% AGEs cross-linking inhibitory effects at 50 μg/mL and 200 μg/mL, respectively, and the vitamin tree leaf extract of Example 1 was 50 μg/mL , it was confirmed that at 200 μg/mL, AGEs cross-linking inhibitory effects of 52% and 74.5% were shown, respectively.
즉, 실시예 1의 비타민나무 잎 추출물이 비교예 1의 비타민나무 열매 추출물에 비하여 저농도, 고농도에서 모두 최종당화산물 교차결합 억제 효능이 우수한 것을 확인하였다.That is, it was confirmed that the vitamin tree leaf extract of Example 1 was superior to the vitamin tree fruit extract of Comparative Example 1 in inhibiting cross-linking of final glycated products at both low and high concentrations.
시험예 3. 최종당화산물 교차 결합절단 효능 분석 Test Example 3. Analysis of Efficacy of Cross-Linking Cleavage of Final Glycosylation Products
도 3은 본 발명의 실시예 1 및 비교예 1에 따라 제조된 비타민나무 추출물의 최종당화산물(AGEs) 교차결합 절단 정도를 나타낸 그래프이다.3 is a graph showing the degree of cross-linking cleavage of the final glycation products (AGEs) of the vitamin tree extract prepared according to Example 1 and Comparative Example 1 of the present invention.
시험방법은 최종당화산물 교차결합 절단 효능평가를 위하여 시험예 2와 동일한 방법으로 10 μg/mL AGE-BSA를 collagen coated 96-well microtiter plate에 분주한 후 37 ℃에서 4시간 동안 배양하여 AGE-BSA와 collagen을 cross linking시켰다. 0.05% PBST에 3번 세척한 후 교차결합 억제제로 알려진 약물인 ALT-711 1 mg/mL 또는 비타민나무 추출물을 각 well에 분주하고 37 ℃, 18시간 동안 배양하였다. 이후 각 well을 0.05% PBST로 3번 세척하고 TMB를 substrate로 하여 발색한 후 450 nm에서 흡광도를 측정하여 하기 [수학식 2]에 따라 계산하였다. In the test method, 10 μg/mL AGE-BSA was dispensed in a collagen-coated 96-well microtiter plate in the same manner as in Test Example 2 to evaluate the efficacy of final glycation cross-linkage cleavage, followed by incubation at 37° C. for 4 hours. and collagen were cross-linked. After washing 3 times in 0.05% PBST, 1 mg/mL of ALT-711, a drug known as a cross-linking inhibitor, or vitamin tree extract was dispensed into each well and incubated at 37 °C for 18 hours. Then, each well was washed 3 times with 0.05% PBST, and after color development using TMB as a substrate, absorbance was measured at 450 nm and calculated according to the following [Equation 2].
[수학식 2][Equation 2]
AGE-BSA(%)=(약물을 첨가한 well의 흡광도/약물을 첨가하지 않은 well의 흡광도) X 100AGE-BSA(%)=(absorbance of wells with drug added/absorbance of wells without drug)
도 3에 도시된 바와 같이, 최종당화산물과 콜라겐(collagen) 사이에 이미 형성된 비가역적 교차결합(glycoaldehyde)을 절단하는 효능을 살펴본 결과, 최종당화산물 교차결합 절단약물로 알려져 있는 ALT-711는 1 mg/mL에서 78%의 절단효능을 보이는 것을 확인하였다. 한편, 비교예 1의 비타민나무 열매 추출물은 50 μg/mL, 200 μg/mL에서 각각 14%, 64%의 AGEs 교차결합 절단효능을 나타내었고, 실시예 1의 비타민나무 잎 추출물은 50 μg/mL, 200 μg/mL에서 각각 88%, 98%의 AGEs 교차결합 절단효능을 나타내는 것을 확인하였다. As shown in FIG. 3 , as a result of examining the efficacy of cleaving the irreversible cross-linkage (glycoaldehyde) already formed between the final glycosylated product and collagen, ALT-711, known as a final glycosylated cross-linkage cleaving drug, was 1 It was confirmed that the cleavage efficiency of 78% was shown at mg/mL. On the other hand, the vitamin tree fruit extract of Comparative Example 1 showed 14% and 64% AGEs cross-linking cleavage efficacy at 50 μg/mL and 200 μg/mL, respectively, and the vitamin tree leaf extract of Example 1 was 50 μg/mL , it was confirmed that AGEs cross-linking cleavage efficacy of 88% and 98% at 200 μg/mL, respectively.
즉, 실시예 1의 비타민나무 잎 추출물이 비교예 1의 비타민나무 열매 추출물에 비하여 저농도, 고농도에서 모두 최종당화산물 교차결합 절단효능이 우수한 것을 확인하였다.That is, it was confirmed that the vitamin tree leaf extract of Example 1 was superior to the vitamin tree fruit extract of Comparative Example 1 in both the low and high concentrations of the final glycation product cross-linking cleavage effect.
[추출용매별 비교][Comparison by extraction solvent]
실시예 1. 70 중량% 에탄올 수용액 Example 1. 70 wt% ethanol aqueous solution
상기 실시예 1에 따라 제조된 비타민나무 잎 추출물이다.It is a vitamin tree leaf extract prepared according to Example 1.
실시예 2. 30 중량% 에탄올 수용액 Example 2. 30 wt% ethanol aqueous solution
상기 실시예 1과 동일하게 실시하되, 70 중량% 에탄올 수용액 대신 30 중량%의 에탄올 수용액을 이용하여 비타민나무 잎 추출물을 수득하였다.It was carried out in the same manner as in Example 1, but using a 30% by weight aqueous ethanol solution instead of a 70% by weight aqueous ethanol solution to obtain a vitamin tree leaf extract.
실시예 3. 50 중량% 에탄올 수용액 Example 3. 50 wt% ethanol aqueous solution
상기 실시예 1과 동일하게 실시하되, 70 중량% 에탄올 수용액 대신 50 중량%의 에탄올 수용액을 이용하여 비타민나무 잎 추출물을 수득하였다.It was carried out in the same manner as in Example 1, but using a 50 wt% ethanol aqueous solution instead of a 70 wt% ethanol aqueous solution to obtain a vitamin tree leaf extract.
실시예 4. 증류수 Example 4. Distilled Water
상기 실시예 1과 동일하게 실시하되, 70 중량% 에탄올 수용액 대신 증류수를 이용하여 비타민나무 잎 추출물을 수득하였다.It was carried out in the same manner as in Example 1, but using distilled water instead of 70 wt% ethanol aqueous solution to obtain a vitamin tree leaf extract.
<시험예 Ⅱ><Test Example II>
시험예 4. 최종당화산물(AGEs) 생성억제 효능Test Example 4. Efficacy of inhibiting the formation of final glycation products (AGEs)
도 4는 본 발명의 실시예 1 내지 4에 따라 제조된 비타민나무 잎 추출물의 최종당화산물(AGEs) 생성억제 정도를 나타낸 그래프이다.4 is a graph showing the degree of inhibition of final glycation products (AGEs) production of the leaf extract of vitamin tree prepared according to Examples 1 to 4 of the present invention.
시험방법은 상기 시험예 1과 동일하게 수행하였다.The test method was performed in the same manner as in Test Example 1.
도 4에 도시된 바와 같이, 실시예 1 내지 3에 따라 제조된 비타민나무 잎 추출물이 실시예 4에 따라 제조된 비타민나무 잎 추출물에 비하여 최종당화산물(AGEs) 생성억제능이 우수한 것을 확인하였으며, 실시예 1 내지 3의 비타민나무 잎 추출물 간에는 최종당화산물(AGEs) 생성억제능이 유사한 것을 확인하였다.As shown in Figure 4, it was confirmed that the vitamin tree leaf extract prepared according to Examples 1 to 3 was superior to the vitamin tree leaf extract prepared according to Example 4 to inhibit the formation of final glycation products (AGEs). It was confirmed that the ability to inhibit the formation of final glycation products (AGEs) was similar between the leaf extracts of the vitamin tree of Examples 1 to 3.
즉, 물 추출물에 비하여 에탄올 수용액 추출물이 최종당화산물(AGEs) 생성억제능이 우수한 것을 확인하였다. That is, it was confirmed that the ethanol aqueous solution extract was superior to the water extract in inhibiting the formation of final glycation products (AGEs).
시험예 5. 최종당화산물 교차결합 억제 효능 분석Test Example 5. Efficacy analysis of cross-linking of final glycated products
도 5는 본 발명의 실시예 1 내지 4에 따라 제조된 비타민나무 잎 추출물의 최종당화산물(AGEs) 교차결합 억제 정도를 나타낸 그래프이다.5 is a graph showing the degree of inhibition of cross-linking of final glycation products (AGEs) of vitamin tree leaf extracts prepared according to Examples 1 to 4 of the present invention.
시험방법은 상기 시험예 2와 동일하게 수행하였다.The test method was performed in the same manner as in Test Example 2.
도 5에 도시된 바와 같이, 실시예 1 및 3에 따라 제조된 비타민나무 잎 추출물이 실시예 2 및 4에 따라 제조된 비타민나무 잎 추출물에 비하여 최종당화산물 교차결합 억제 효능이 우수한 것을 확인하였다.As shown in FIG. 5 , it was confirmed that the vitamin tree leaf extract prepared according to Examples 1 and 3 was superior to the vitamin tree leaf extract prepared according to Examples 2 and 4 to inhibit cross-linking of final glycated products.
즉, 50 중량% 에탄올 수용액 및 70 중량% 에탄올 수용액으로 추출한 추출물이 30 중량% 에탄올 수용액 및 물로 추출한 추출물에 비하여 최종당화산물 교차결합 억제 효능이 우수한 것을 확인하였다.That is, it was confirmed that the extract extracted with 50 wt% ethanol aqueous solution and 70 wt% ethanol aqueous solution was superior to the 30 wt% ethanol aqueous solution and the extract extracted with water to inhibit cross-linking of final glycated products.
시험예 6. 최종당화산물 교차 결합절단 효능 분석 Test Example 6. Analysis of Efficacy of Cross-Linking Cleavage of Final Glycosylation Products
도 6은 본 발명의 실시예 1 내지 4에 따라 제조된 비타민나무 잎 추출물의 최종당화산물(AGEs) 교차결합 절단 정도를 나타낸 그래프이다.6 is a graph showing the degree of cross-linking cleavage of the final glycation products (AGEs) of the vitamin tree leaf extract prepared according to Examples 1 to 4 of the present invention.
시험방법은 상기 시험예 3과 동일하게 수행하였다.The test method was performed in the same manner as in Test Example 3.
도 6에 도시된 바와 같이, 실시예 1 및 3에 따라 제조된 비타민나무 잎 추출물이 실시예 2 및 4에 따라 제조된 비타민나무 잎 추출물에 비하여 최종당화산물 교차결합 절단효능이 우수한 것을 확인하였다.As shown in FIG. 6 , it was confirmed that the vitamin tree leaf extract prepared according to Examples 1 and 3 was superior to the vitamin tree leaf extract prepared according to Examples 2 and 4 for cross-linking cleavage of final glycated products.
즉, 50 중량% 에탄올 수용액 및 70 중량% 에탄올 수용액으로 추출한 추출물이 30 중량% 에탄올 수용액 및 물로 추출한 추출물에 비하여 최종당화산물 교차결합 절단효능이 우수한 것을 확인하였다.That is, it was confirmed that the extracts extracted with 50 wt% ethanol aqueous solution and 70 wt% ethanol aqueous solution had superior cross-linkage cleavage efficiency of the final saccharified product compared to the 30 wt% ethanol aqueous solution and the extract extracted with water.
시험예 7. MGO에 의한 세포독성 억제 효능Test Example 7. Efficacy of inhibiting cytotoxicity by MGO
도 7은 본 발명의 실시예 1에 따라 제조된 비타민나무 잎 추출물의 세포독성을 측정한 그래프이다. 7 is a graph measuring the cytotoxicity of a vitamin tree leaf extract prepared according to Example 1 of the present invention.
세포 배양cell culture
Mouse renal glomerular으로부터 기원한 SV40MES13세포는 ATCC(Manassas, VA)에서 분양받아 실험에 사용하였다. 세포를 5% FBS, 1% P&S, HEPES 14 mM가 포함된 DMEM/F12 3:1비율의 배지에 접종하여 37 ℃, 5% CO2 조건에서 배양하였다. SV40MES13 cells originating from the mouse renal glomerular were purchased from ATCC (Manassas, VA) and used in the experiment. Cells were inoculated in a medium of 3:1 ratio DMEM/F12 containing 5% FBS, 1% P&S, and 14 mM HEPES, and cultured at 37 ° C., 5% CO 2 condition.
세포독성 측정Cytotoxicity measurement
96 well plate에 5×104 cells/well씩 분주한 뒤 37 ℃, CO2 incubator에 18시간 배양한 후, MGO 1 mM과 비타민나무 잎 추출물 각각 10, 50, 100, 200 μg/mL가 되도록 세포에 처리하여 18시간 배양하였다. 이후 3-(4,5-dimethysssl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide(MTT; Sigma)용액을 0.1 mg/mL로 PBS에 녹여서 처리한 후 37 ℃, CO2 incubator에 추가 3시간 더 배양하여 MTT를 환원시켜 생성된 formazan이 배지에 떨어져나가지 않도록 배지를 조심스럽게 제거하였다. DMSO를 200 μL 분주하여 10분 동안 혼합한 뒤 540 nm에서 흡광도를 측정하였다. After dispensing 5×10 4 cells/well in a 96 well plate, incubate for 18 hours in an incubator at 37 ° C and CO 2 , cells to become 1 mM MGO and 10, 50, 100, and 200 μg/mL of vitamin tree leaf extract, respectively. was treated and incubated for 18 hours. After that, 3-(4,5-dimethysssl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT; Sigma) solution was dissolved in PBS at 0.1 mg/mL and treated, and then added to an incubator at 37 ℃,
신장세포에 MGO 유도 독성 모델을 확립하고 비타민나무 잎 추출물의 신장세포 독성 억제 효능을 MTT로 확인하였다. 신장세포주에 비타민나무 추출물을 농도별로 처리하여 세포 생존율을 측정하였다.An MGO-induced toxicity model was established in kidney cells, and the renal cytotoxicity inhibitory effect of vitamin tree leaf extract was confirmed with MTT. The cell viability was measured by treating the kidney cell line with vitamin tree extract by concentration.
도 7에 도시된 바와 같이, MGO 처리군(C)에서 68% 생존율을 확인하여 MGO에 의해 세포사멸이 일어남을 확인하였다. 한편, 비타민나무 잎 추출물을 10, 50, 100 μg/ml 처리한 세포주에서는 각각 73.1%, 79.4%, 80.2%의 생존율을 확인하여 세포 보호 효과가 있음을 확인하였다.As shown in Figure 7, it was confirmed that apoptosis occurs by MGO by confirming the 68% survival rate in the MGO-treated group (C). On the other hand, in the cell lines treated with vitamin tree leaf extract at 10, 50, and 100 μg/ml, the survival rates of 73.1%, 79.4%, and 80.2%, respectively, were confirmed, confirming that there was a cytoprotective effect.
<시험예 Ⅲ><Test Example Ⅲ>
동물실험animal testing
실험동물은 제2형 당뇨 동물모델인 BKS.Cg-Dock7m +/+ Leprdb/+/J(db/m)마우스(수컷, 5주령), BKS.Cg-Dock7m +/+ Leprdb/db/J(db/db)마우스(수컷, 5주령)을 Jackson Laboratories(Bar Harbor, Maine, USA)에서 수입하여 사용하였다. 동물 사육실의 환경은 항온(25±2 ℃), 항습(50±5%)이 유지되며, 12시간 간격으로 낮과 밤을 교대시키는 일정한 환경 내에서 사료와 음용수를 급여하여 사육하였다. 1주간 사육 환경에 적응시킨 후 혈당과 체중이 유사하도록 난괴법에 의해 실험동물을 db/m(정상군), db/db(대조군 1), db/db에 AG 50 mg/mL을 경구투여(대조군 2), db/db에 실시예 1의 추출물 100 mg/mL을 경구투여(실시예 1(100)), db/db에 실시예 1의 추출물 200 mg/mL을 경구투여(실시예 1(200))로 각 8마리 5그룹으로 분류하였다. 모든 마우스는 정상식이를 하였다. 실험은 13주간 진행되었으며 2주에 12시간 절식시킨 후 꼬리정맥으로부터 채혈하여 혈당측정기를 이용하여 측정하였다. 본 동물실험의 연구는 한국식품연구원 동물실험윤리위원회의 심의 및 승인을 거쳐 수행되었다(IACUC : KFRI-M-20004). 실험에 사용된 Aminoguanidine hydrochloride(AG)는 Sigma-Aldrich (St Louis, MO, USA)에서 구입하여 사용하였으며, 조직염색을 위한 항체는 AGEs(ab23722), RAGE(ab3611)은 Abcam (Cambridge, MA, USA)에서 구입하여 사용하였다.Experimental animals were type 2 diabetes animal model BKS.Cg-Dock7m +/+ Leprdb/+/J(db/m) mouse (male, 5 weeks old), BKS.Cg-Dock7m +/+ Leprdb/db/J( db/db) mice (male, 5 weeks old) were imported from Jackson Laboratories (Bar Harbor, Maine, USA) and used. In the environment of the animal breeding room, constant temperature (25±2 ℃) and constant humidity (50±5%) were maintained, and feed and drinking water were fed and reared in a constant environment that alternates day and night at 12-hour intervals. After acclimatization to the breeding environment for 1 week, 50 mg/mL of AG was orally administered to db/m (normal group), db/db (control group 1), and db/db to test animals by the egg mass method so that blood sugar and body weight were similar ( Control 2), 100 mg/mL of the extract of Example 1 was orally administered to db/db (Example 1 (100)), and 200 mg/mL of the extract of Example 1 was orally administered to db/db (Example 1 ( 200)), each of 8 animals was classified into 5 groups. All mice were fed a normal diet. The experiment was conducted for 13 weeks, and after fasting for 12 hours in 2 weeks, blood was collected from the tail vein and measured using a blood glucose meter. This study on animal experiments was conducted after the deliberation and approval of the Animal Experimental Ethics Committee of the Korea Food Research Institute (IACUC: KFRI-M-20004). Aminoguanidine hydrochloride (AG) used in the experiment was purchased from Sigma-Aldrich (St Louis, MO, USA), and antibodies for tissue staining were AGEs (ab23722), and RAGE (ab3611) was Abcam (Cambridge, MA, USA). ) was purchased and used.
사육이 끝난 실험동물은 isoflurane을 이용하여 흡입시켜 마취시킨 다음 복부 하대정맥으로부터 전혈을 채취하였다. 실험동물의 신장조직을 채취한 후 조직학적 염색 분석을 위해 조직을 전단하고 10% 포르말린에 고정하였다. After breeding, the animals were anesthetized by inhalation using isoflurane, and whole blood was collected from the inferior vena cava. After collecting the kidney tissue of the experimental animal, the tissue was sheared and fixed in 10% formalin for histological staining analysis.
-5개 군의 마우스--5 groups of mice-
정상군: db/m 마우스에 생리식염수 투여 Normal group: administration of physiological saline to db/m mice
대조군 1: db/db 마우스에 생리식염수 투여 Control 1: Administration of physiological saline to db/db mice
대조군 2: db/db 마우스에 AG 50 mg/mL 투여 Control 2:
실시예 1(100): db/db 마우스에 실시예 1의 추출물 100 mg/mL 투여Example 1 (100): Administration of 100 mg/mL of the extract of Example 1 to db/db mice
실시예 1(200): db/db 마우스에 실시예 1의 추출물 200 mg/mL 투여Example 1 (200): 200 mg/mL of the extract of Example 1 administered to db/db mice
시험예 8. 공복혈당 변화 측정 Test Example 8. Measurement of changes in fasting blood sugar
도 8은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 공복혈당 변화를 측정한 그래프이다.8 is a graph measuring changes in fasting blood glucose in the normal group,
도 8에 도시된 바와 같이, 정상군은 실험 시작 시 공복 혈당이 59 mg/dl이고 실험 종료 시 73.25 mg/dl이므로 큰 변화가 없었으나, 당뇨병 모델인 대조군 1은 실험 시작 시 128 mg/dl에서 실험 종료 시 467 mg/dl로 나타나는 것을 확인하였다.As shown in FIG. 8 , the normal group had a fasting blood sugar of 59 mg/dl at the start of the experiment and 73.25 mg/dl at the end of the experiment, so there was no significant change, but the diabetes model,
또한, 대조군 2와 실시예 1(100)군은 실험 종료 시 각각 430 mg/dl, 418 mg/dl로 대조군 1과 유의적인 차이가 나지 않았으나 실시예 1(200)군은 277.75 mg/dl로 나타나 혈당이 유의하게 감소된 것을 확인하였다. In addition, the control group 2 and the Example 1 (100) group did not differ significantly from the
시험예 9. PAS(Periodic Acid Schiff)염색Test Example 9. PAS (Periodic Acid Schiff) staining
고정된 조직을 조직처리 과정을 거쳐 파라핀에 포매한 후 파라핀 블록을 3마이크로 두께로 박절하여 절편을 만들고 탈 파라핀, 함수과정을 거쳐 증류수로 세척하였다. Periodic Acid Solution으로 5분 반응시키고 세척한 후 Schiff's solution으로 15분 동안 반응시켰다. 세척 후 Mayer hematoxylin으로 1분 동안 염색하였다.After the fixed tissue was subjected to tissue treatment and embedded in paraffin, the paraffin block was cut into 3 micro-thick sections to make a section, followed by deparaffinization and hydrolysis, followed by washing with distilled water. After 5 minutes of reaction with Periodic Acid Solution, washing, and reaction with Schiff's solution for 15 minutes. After washing, it was stained with Mayer hematoxylin for 1 minute.
당뇨병성 신증의 병리소견은 신사구체과 세뇨관간질, 혈관 등에서 전반적으로 나타나며 전형적인 또는 비전형적인 형태를 보인다. 특히 사구체 병변에 대한 분류로 메산지움 확장과 증식 부분을 확인할 수 있는데, 이는 현미경으로 관찰할 수 있는 비교적 초기 병변이다. The pathological findings of diabetic nephropathy are generally found in the glomeruli, tubulointerstitium, and blood vessels, and show a typical or atypical form. In particular, mesangial expansion and proliferation can be identified as a classification for glomerular lesions, which are relatively early lesions that can be observed under a microscope.
메산지움은 메산지움 세포와 기질로 이루어져서 신사구체를 구조적으로 지지하는 중심역할을 한다. 메산지움 세포는 메산지움 기질의 성분과 조절을 하는 한편 족세포와 혈관내피세포와 긴밀하게 상호작용하여 사구체 혈류량을 조절하여 한외여과를 결정하는 중요한 역할을 한다. 당뇨병성 신손상의 초기에 혈압이 정상임에도 불구하고 신사구체 내 고혈압이 발생하는데, 이는 메산지움 세포의 stretch로 인한 여러가지 물질들을 분비시켜 메산지움 세포의 비대와 증식을 더불어 메산지움 확장을 유발시킨다. Mesangium is composed of mesangium cells and matrix and plays a central role in structurally supporting the glomeruli. Mesangial cells play an important role in determining ultrafiltration by regulating glomerular blood flow by closely interacting with podocytes and vascular endothelial cells while controlling the components and regulation of mesangium matrix. In the early stage of diabetic kidney injury, although blood pressure is normal, intraglomerular hypertension occurs, which secretes various substances due to the stretching of mesangium cells, which causes mesangial enlargement and proliferation along with mesangial expansion.
도 9는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 PAS 염색 후 사진이다.9 is a photograph after PAS staining of the normal group, the
도 9에 도시된 바와 같이, 정상군에서 사구체 안의 진한 보라색으로 나타난 메산지움 세포가 대조군 1에서는 연한 보라색을 띠며 동시에 크기가 확장되어있는 것을 확인하였다. 이렇게 확장된 메산지움 세포는 AG를 투여하였을 때 정상군과 유사하게 메산지움 세포의 확장과 증식이 줄어든 것을 확인하였다. 또한, 실시예 1(100)군 및 실시예 1(200)군은 대조군 1에 비해 메산지움 세포의 크기가 줄어든 것을 확인하였다. As shown in FIG. 9 , it was confirmed that the mesangium cells, which appeared dark purple in the glomerulus in the normal group, were light purple in the
시험예 10. AGEs 면역염색(Immunohistochemistry: IHC) Test Example 10. AGEs immunostaining (Immunohistochemistry: IHC)
고정된 조직을 조직처리 과정을 거쳐 파라핀에 포매한 후 파라핀 블록을 4마이크로 두께로 박절하여 절편을 만들고 탈 파라핀, 함수과정을 거쳐 증류수로 세척하였다. 항원복원 작업 후 내인성 Peroxidased의 활성을 없애기 위해 3% hydrogen peroxidase solution으로 실온에서 10분간 처리하였다. 1차항체 AGEs(abcam, 1:100), RAGE(abcam, 1:100)를 반응시킨 후, Envision+ Rabbit으로 30분간 반응시키고 Mayer hematoxylin으로 대조 염색하였다.After the fixed tissue was subjected to tissue treatment and embedded in paraffin, the paraffin block was cut to a thickness of 4 micrometers to make a section, followed by deparaffinization and hydrolysis, followed by washing with distilled water. After antigen restoration, in order to eliminate the activity of endogenous peroxidase, it was treated with 3% hydrogen peroxidase solution at room temperature for 10 minutes. After reacting with primary antibodies AGEs (abcam, 1:100) and RAGE (abcam, 1:100), they were reacted with Envision+ Rabbit for 30 minutes and counterstained with Mayer hematoxylin.
당뇨병성 신증에서 고 포도당 노출 시 메산지움 세포의 손상은 advanced glycation end-products(AGEs) 증가, protein kinase C 활성화, reactive oxygen species(ROS) 등에 의해서 발생한다. 이 중 AGEs의 축적을 확인하기 위해 AGEs IHC를 확인하였다. In diabetic nephropathy, mesangial cell damage is caused by an increase in advanced glycation end-products (AGEs), activation of protein kinase C, and reactive oxygen species (ROS) upon high glucose exposure. Among them, AGEs IHC were checked to confirm the accumulation of AGEs.
도 10은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 AGEs IHC를 확인한 사진이다.10 is a photograph confirming the AGEs IHC of the normal group, the
도 10에 도시된 바와 같이, 대조군 1에서 진한 갈색으로 사구체 내부, 외부로 AGEs가 많이 축적된 것을 확인할 수 있었다. 이는 당뇨병에 의해 다량 생성된 AGEs가 신장에 축적됐다는 것을 의미한다. 대조군 2에서는 AGEs의 축적이 확연하게 줄어든 것을 확인하였으며, 실시예 1(100)군에서는 AGEs의 염색이 대조군 1에 비하여 줄어든 것을 확인하였고, 실시예 1(200)군은 대조군 2와 유사하게 AGEs가 확연하게 줄어든 것을 확인하였다. As shown in FIG. 10 , it was confirmed that a large amount of AGEs were accumulated inside and outside the glomerulus in dark brown color in
시험예 11. RAGE IHCTest Example 11. RAGE IHC
Receptors of advanced glycation end-products(RAGE)는 대표적인 AGEs 수용체인데, RAGE와 AGEs의 결합에 의하여 세포 내 PKC 및 mitogen-activated protein kinase 등의 신호전달체계의 활성화, ROS의 증가 그리고 NF-κB 등의 전사 인자의 활성화가 일어나게 된다. 당뇨에 의해 메산지움 세포의 증식과 더불어 RAGE IHC을 확인함으로써 당뇨병성 신증의 발생 및 진행에 조직학적 병변을 확인하였다. Receptors of advanced glycation end-products (RAGE) are representative AGEs receptors. By combining RAGE and AGEs, intracellular signaling systems such as PKC and mitogen-activated protein kinase are activated, ROS increases, and transcription of NF-κB Activation of the factor occurs. Histological lesions were confirmed in the development and progression of diabetic nephropathy by confirming RAGE IHC along with proliferation of mesangial cells due to diabetes.
도 11은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군(실시예 1(100) 및 실시예 1(200))의 RAGE IHC를 확인한 사진이다.11 is a photograph confirming the RAGE IHC of the normal group, the
도 11에 도시된 바와 같이, 대조군 1에서 갈색으로 사구체 주변 피질에 RAGE가 과발현된 것을 확인하였다. 이는 AGEs가 RAGE와 결합에 의해 당뇨병성 신증에 영향을 준다는 것을 의미한다. 대조군 2는 RAGE 발현이 정상군과 유사하게 줄어든 것을 확인하였으며, 실시예 1(100)군 및 실시예 1(200)에서도 정상군과 유사하게 RAGE가 적게 염색된 것을 확인하였다. As shown in FIG. 11 , it was confirmed that RAGE was overexpressed in the glomerular cortex in brown color in
시험예 12. Glyoxalase 1(GLO1) 활성 측정Test Example 12. Glyoxalase 1 (GLO1) activity measurement
마우스 신장 조직의 Glyoxalase 1(GLO1) 활성을 분석하기 위해 QuantiChrom™ Glyoxalase I Assay Kit(BioAssay Systems, CA, USA)를 이용하여 측정하였다. 각각의 시료 40 μL를 분석 시약 160 μL과 혼합하여 실온에서 20분간 반응시킨 후, 4 M의 HClO4 70 μL를 각 반응물에 첨가한 혼합물을 얼음 위에서 15분 동안 반응시켰다. 그 후, 반응물을 12,000 rpm에서 10분간 원심분리 한 뒤, 상층액 200 μL를 96-well plate에 첨가하여 spectrophotometer를 사용하여 240 nm 파장에서 GLO1 활성을 측정하였다.In order to analyze the Glyoxalase 1 (GLO1) activity of mouse kidney tissue, it was measured using the QuantiChrom ™ Glyoxalase I Assay Kit (BioAssay Systems, CA, USA). 40 μL of each sample was mixed with 160 μL of an assay reagent and reacted at room temperature for 20 minutes, and then the mixture in which 70 μL of 4 M HClO 4 was added to each reaction was reacted on ice for 15 minutes. Thereafter, the reaction mass was centrifuged at 12,000 rpm for 10 minutes, 200 μL of the supernatant was added to a 96-well plate, and GLO1 activity was measured at 240 nm wavelength using a spectrophotometer.
도 12a는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 GLO1을 측정한 웨스턴 블롯이며; 도 12b는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 AGEs를 측정한 웨스턴 블롯이다.Figure 12a is a Western blot measuring GLO1 in a normal group, a
도 12a 및 도 12b에 도시된 바와 같이, GLO1은 정상군 대비 대조군 1(제2형 당뇨병 유발로 인한 당뇨병성 신증 마우스)의 발현량이 감소되는 것을 확인하였으며, 실시예 1 200의 투여로 인해 발현이 증가하는 것을 확인하였다. 또한, AGEs의 결과에서는 정상군 대비 대조군 1의 발현량이 현저히 증가하는 것을 확인하였으며, 실시예 1 200의 투여로 인해 발현이 감소되는 것을 확인하였다.As shown in FIGS. 12A and 12B , it was confirmed that the expression level of control 1 (diabetic nephropathy mouse caused by induction of type 2 diabetes) of GLO1 was decreased compared to the normal group, and the expression was decreased due to the administration of Example 1 200. was confirmed to increase. In addition, in the results of AGEs, it was confirmed that the expression level of
이러한 결과를 통해 실시예 1의 추출물이 GLO1 발현 및 AGEs의 발현을 조절하는 것을 확인하였다.Through these results, it was confirmed that the extract of Example 1 regulates the expression of GLO1 and the expression of AGEs.
도 13은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 GLO1 활성을 나타낸 그래프이다.13 is a graph showing GLO1 activity in a normal group, a
도 13에 도시된 바와 같이, 대조군 1에서 GLO1 활성이 유의적으로 감소한 것으로 나타났으며, 이와 대조적으로 실시예 1 200의 투여로 인해 GLO1의 활성이 유의적으로 증가하는 것을 확인하였다.As shown in FIG. 13 , the GLO1 activity was significantly decreased in
이를 통하여, 실시예 1의 추출물의 투여로 인해 GLO1의 활성이 회복된 것을 확인하였다. Through this, it was confirmed that the activity of GLO1 was restored due to the administration of the extract of Example 1.
도 14는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군의 GLO1 및 AGEs를 db/db 마우스의 신장 조직에서 확인한 사진이다.14 is a photograph confirming GLO1 and AGEs in the kidney tissue of db/db mice in a normal group, a
도 14에 도시된 바와 같이, 정상군에 비해 대조군 1의 GLO1 발현량이 조직 전반적인 구획에서 현저히 감소하였고, 이와 대조적으로 실시예 1 200군의 GLO1 발현량은 증가한 결과를 나타내었다. 또한, AGEs의 결과에서는 정상군에 비해 대조군 1의 조직에서 발현량이 증가한 것으로 나타났으며 실시예 1 200의 투여로 인해 그 발현량이 감소하여 실시예 1 200의 투여로 GLO1 및 AGEs의 발현이 조절되는 것을 확인하였다.As shown in FIG. 14 , compared to the normal group, the GLO1 expression level of the
시험예 13. MGO(메틸글라이옥살)-derived AGEs 분석 Test Example 13. MGO (methylglyoxal)-derived AGEs analysis
MGO-derived AGEs 분석을 위해 OxiSelect™ methylglyoxal Competitive ELISA kit(Cell Biolabs, Inc., San Diego, CA, USA)를 이용하여 분석하였다. 실험은 제공된 매뉴얼에 따라 수행 및 분석하였다.MGO-derived AGEs were analyzed using OxiSelect™ methylglyoxal Competitive ELISA kit (Cell Biolabs, Inc., San Diego, CA, USA). Experiments were performed and analyzed according to the provided manual.
도 15는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 MGO-derived AGEs를 ELISA 방법으로 측정한 그래프이다.15 is a graph of MGO-derived AGEs measured by an ELISA method in a normal group, a
도 15에 도시된 바와 같이, 제2형 당뇨병 유발로 인한 당뇨병성 신증 마우스군(대조군 1)에서 MGO가 유의적으로 증가한 것으로 확인되었며, 이와 대조적으로 실시예 1 200의 투여로 인해 MGO가 유의적으로 감소한 것을 확인하였다.As shown in FIG. 15 , it was confirmed that MGO was significantly increased in the diabetic nephropathy mouse group (control group 1) caused by the induction of type 2 diabetes, and in contrast, MGO was significantly increased due to the administration of Example 1 200 It was confirmed that there was a negative decrease.
이는 실시예 1의 추출물이 MGO 분해를 촉진하므로 당뇨성 신증(Diabetic nephropathy)의 예방, 개선 또는 치료에 적합하다는 것을 의미한다.This means that the extract of Example 1 promotes the decomposition of MGO, so it is suitable for the prevention, improvement or treatment of diabetic nephropathy.
시험예 14. NOX2, NOX4, 8-OHdG 및 Nrf2 측정Test Example 14. Measurement of NOX2, NOX4, 8-OHdG and Nrf2
상기 NOX2 및 NOX4는 신장조직의 단백질을 추출 한 후 NOX2, NOX4 항체를 사용하여 Western blot 방법으로 단백질 발현량을 측정한 것이며, 8-OHdG는 8-Hydroxy-2'-deoxyguanosine ELISA kit(Abcam, Cambridge, MA, USA)를 이용하여 제공된 매뉴얼에 따라 수행 및 분석하였고, 특히, Nrf2와 NOX4는 신장 조직내에서 Immunohistochemistry 방법으로 조직내 발현량을 측정하였다. The NOX2 and NOX4 proteins were extracted from kidney tissue and protein expression levels were measured by Western blot using NOX2 and NOX4 antibodies, and 8-OHdG was 8-Hydroxy-2'-deoxyguanosine ELISA kit (Abcam, Cambridge). , MA, USA) was performed and analyzed according to the provided manual. In particular, Nrf2 and NOX4 expression levels were measured in kidney tissue by Immunohistochemistry method.
도 16a는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 NOX4를 측정한 웨스턴 블롯이며; 도 16b는 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군에서 NOX2를 측정한 웨스턴 블롯이다.Figure 16a is a Western blot measuring NOX4 in the normal group, the
도 16a 및 도 16b에 도시된 바와 같이, NOX4의 결과에서는 정상군 대비 대조군 1에서 현저한 발현 증가가 나타났으며, 실시예 1 200군에서는 대조군 1에 비해 발현량이 감소된 것을 확인하였다. 한편, NOX2의 결과에서는 정상군과 대조군 1 간의 변화가 나타나지 않았고 실시예 1 200군에서 발현량이 감소한 경향을 보였으나 미미한 수준인 것을 확인하였다.As shown in FIGS. 16A and 16B , in the results of NOX4, a significant increase in expression was observed in
도 17은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군의 소변 내에서 8-OHdG의 함량을 나타낸 그래프이다. 17 is a graph showing the content of 8-OHdG in the urine of a normal group, a
도 17에 도시된 바와 같이, 정상군은 3.1 ng/mL 수준을 나타내었고 대조군 1은 5.7 ng/mL 수준으로 약 1.9배가량 증가한 결과를 확인하였다. 한편, 실시예 1 200을 투여한 군에서는 3.5 ng/mL로 측정되어 대조군 1과 비교 시 유의적인 감소를 나타내는 것을 확인하였고, 대조군 2(양성 대조군, AG)와 유사한 결과를 나타내는 것을 확인하였다. As shown in FIG. 17 , the normal group exhibited a level of 3.1 ng/mL, and the
도 18은 정상군, 대조군 1, 대조군 2 및 본 발명의 실시예 1에 따라 제조된 추출물을 투여한 군의 신장 조직에서 Nrf2, NOX4 및 8-OHdG를 확인한 사진이다.18 is a photograph confirming Nrf2, NOX4 and 8-OHdG in the kidney tissue of a normal group, a
도 18에 도시된 바와 같이, 정상군에 비해 대조군 1의 신장 조직에서 Nrf2의 발현량이 현저히 감소하였고, 반대로 실시예 1 200군의 발현량은 증가한 것을 확인하였다. 이와 대조적으로 NOX4의 발현은 정상군에 비해 대조군 1의 신장 조직에서 증가하였고 실시예 1 200군에서는 발현량이 감소한 것을 확인하였다. 또한, 8-OGdG의 발현 결과에서도 유사하게 정상군에 대비 대조군 1에서 확연히 발현량이 증가한 것을 확인하였고, 이와 대조적으로 실시예 1 200군에서는 발현량이 감소된 것을 확인하였다.As shown in FIG. 18 , it was confirmed that the expression level of Nrf2 in the kidney tissue of the
이는 실시예 1의 추출물이 신장 조직 내 산화스트레스를 조절하는 것으로 판단된다. It is determined that the extract of Example 1 regulates oxidative stress in kidney tissue.
상기 결과들을 통해, AGEs 전구물질인 MGO의 분해를 촉진하며, MGO에 의한 신장세포 독성을 억제하고 항산화 물질에 관여하는 transcription factor인 Nrf2 및 RAGE 하위 경로를 통해 GLO-1, NOX4, 8-OHdG를 조절함으로서 항산화 효과의 유의미한 활성 증대를 나타내는 바, 이를 유효성분으로 함유하여 당뇨성 신증(Diabetic nephropathy)의 예방, 개선 또는 치료에 이용할 수 있다.Through the above results, it promotes the decomposition of MGO, a precursor of AGEs, suppresses renal cytotoxicity by MGO, and reduces GLO-1, NOX4, and 8-OHdG through the transcription factor Nrf2 and RAGE sub-pathways involved in antioxidants By controlling it, it shows a significant increase in the activity of the antioxidant effect, and it can be used for prevention, improvement or treatment of diabetic nephropathy by containing it as an active ingredient.
시험예 15. 비타민나무 추출물의 성분 분석Test Example 15. Component Analysis of Vitamin Tree Extract
표 1 및 도 19는 본 발명의 실시예 1에 따라 제조된 비타민나무 잎 추출물 및 비타민나무 열매 추출물의 용매에 따른 isorhamnetin과 rutin의 함량을 측정한 것이다.Table 1 and FIG. 19 show isorhamnetin and rutin contents measured according to the solvent of the vitamin tree leaf extract and the vitamin tree fruit extract prepared according to Example 1 of the present invention.
표준용액 및 시료 제조Preparation of standard solutions and samples
분석 조건을 설정하기 위하여 isorhamnetin과 rutin을 적정량 weighing하여 eppendorf tube에 옮긴 뒤, 1 mg/mL의 농도를 가질 수 있도록 적정량의 아세톤을 가하였다. 이후 LCMS grade water를 사용하여 15.625, 31.25, 62.50, 125.00, 250.00, 500.00, 1000.00, 2000.00, 4000.00, 그리고 8000.00 ng/mL가 되도록 표준용액을 제조하였다.To set the analysis conditions, appropriate amounts of isorhamnetin and rutin were weighed and transferred to an eppendorf tube, and then an appropriate amount of acetone was added to have a concentration of 1 mg/mL. Thereafter, standard solutions were prepared at 15.625, 31.25, 62.50, 125.00, 250.00, 500.00, 1000.00, 2000.00, 4000.00, and 8000.00 ng/mL using LCMS grade water.
추출물 시료의 경우, 4.0 mg에서 8.0 mg 사이의 비타민나무 추출물을 2.0 ML eppendorf tube에 옮긴 후 4 mg/mL의 농도를 가질 수 있도록 적정량의 50% ethanol을 가하여 제조하였다. 이후 추출물 내 isorhamnetin과 rutin을 용액상으로 전환하기 위하여 2시간동안 sonication을 수행하였다. In the case of the extract sample, 4.0 mg to 8.0 mg of the vitamin tree extract was transferred to a 2.0 ML eppendorf tube, and an appropriate amount of 50% ethanol was added so as to have a concentration of 4 mg/mL. Then, sonication was performed for 2 hours to convert isorhamnetin and rutin in the extract to a solution phase.
HPLC-MS/MS 분석HPLC-MS/MS analysis
비타민나무 추출물에서 두 성분을 분석하기 위하여 Waters사의 Xevo TQ MS를 활용하였다. 분리를 위해 Waters사의 ACQUITY BEH C18 column을 사용하였으며, 0.1% formic acid (FA) water와 0.1% FA methanol을 이동상으로 사용하였다. 또한 Waters사의 Intellistart 프로그램을 활용하여 두 성분을 분석하기 위한 MS 조건을 설정하였다. Isorhamnetin의 경우 cone voltage와 collision energy, precursor ion과 product ion의 mass-to-charge ratio이 38.0 V, 34.0 V, m/z 317.2, m/z 302.1로 설정되었고, rutin의 경우 14.0 V, 28.0 V, m/z 611.4, m/z 303.2로 설정되었다. Waters' Xevo TQ MS was used to analyze the two components in the vitamin tree extract. For separation, ACQUITY BEH C18 column from Waters was used, and 0.1% formic acid (FA) water and 0.1% FA methanol were used as mobile phases. In addition, MS conditions for analyzing two components were set using Waters' Intellistart program. For isorhamnetin, cone voltage, collision energy, and mass-to-charge ratio of precursor ion and product ion were set to 38.0 V, 34.0 V, m / z 317.2, m / z 302.1, and for rutin, 14.0 V, 28.0 V, m / z 611.4, m / z 303.2.
상기 비교예 2는 실시예 1과 동일하게 실시하되, 비타민나무 잎을 증류수로 110 ℃에서 열수 추출한 추출물이며, 비교예 3은 실시예 1과 동일하게 실시하되, 비타민나무 열매를 증류수로 110 ℃에서 열수 추출한 추출물이다. Comparative Example 2 was carried out in the same manner as in Example 1, except that the vitamin tree leaf was extracted with hot water at 110 ° C. with distilled water, and Comparative Example 3 was carried out in the same manner as in Example 1, except that the vitamin tree fruit was extracted with distilled water at 110 ° C. It is a hot water extract.
위 표 1 및 도 19에 도시된 바와 같이, isorhamnetin과 rutin이 14.3분과 11.1분에 elution됨을 확인하였다. 또한, 정량 분석을 통해 isorhamnetin과 rutin 모두 열매보단 잎에서의 함량이 높았으며, 모든 경우에서 주정 추출이 두 성분의 추출물 내 함량을 높이는데 효과적임을 확인하였다.As shown in Table 1 and Figure 19 above, it was confirmed that isorhamnetin and rutin were elution at 14.3 minutes and 11.1 minutes. Also, through quantitative analysis, the content of both isorhamnetin and rutin was higher in the leaf than in the fruit, and in all cases, it was confirmed that alcohol extraction was effective in increasing the content of the two components in the extract.
아래에 본 발명의 추출물을 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, a formulation example of a composition comprising the extract of the present invention will be described, but the present invention is not intended to limit the present invention, but merely to describe it in detail.
제제예 1: 산제의 제조Formulation Example 1: Preparation of powder
실시예 1의 추출물 분말 20 mg20 mg of extract powder of Example 1
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight bag to prepare a powder.
제제예 2: 정제의 제조Formulation Example 2: Preparation of tablets
실시예 1의 추출물 분말 10 mg10 mg of extract powder of Example 1
옥수수전분 100 mg100 mg cornstarch
유당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional manufacturing method of tablets.
제제예 3: 캡슐제의 제조Formulation Example 3: Preparation of capsules
실시예 1의 추출물 분말 10 mg10 mg of extract powder of Example 1
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mg0.2 mg magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
제제예 4: 과립제의 제조Formulation Example 4: Preparation of granules
실시예 1의 추출물 분말 1,000 mg1,000 mg of extract powder of Example 1
비타민 혼합물 적량appropriate amount of vitamin mixture
비타민 A 아세테이트 70 ㎍70 μg vitamin A acetate
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 B1 0.13 mgVitamin B1 0.13 mg
비타민 B2 0.15 mgVitamin B2 0.15 mg
비타민 B6 0.5 mg0.5 mg of vitamin B6
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 mg
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 mgNicotinamide 1.7 mg
엽산 50 ㎍50 μg of folic acid
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture appropriate amount
황산제1철 1.75 mgferrous sulfate 1.75 mg
산화아연 0.82 mgZinc Oxide 0.82 mg
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mgPotassium monophosphate 15 mg
제2인산칼슘 55 mgDibasic calcium phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mg100 mg of calcium carbonate
염화마그네슘 24.8 mgMagnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 건강기능식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강기능식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강기능식품 조성물 제조에 사용할 수 있다.The composition ratio of the vitamin and mineral mixture is mixed with ingredients suitable for health functional food in a preferred embodiment, but the blend ratio may be arbitrarily modified, and the ingredients are mixed according to a conventional health functional food manufacturing method. Next, the granules can be prepared and used in the preparation of a health functional food composition according to a conventional method.
제제예 5: 음료 제형의 제조Formulation Example 5: Preparation of beverage formulations
실시예 1의 추출물 분말 1,000 mg1,000 mg of extract powder of Example 1
구연산 1,000 mg1,000 mg citric acid
올리고당 100 g100 g of oligosaccharides
매실농축액 2 g2 g of plum concentrate
타우린 1 g1 g taurine
정제수를 가하여 전체 900 mLAdd purified water to total 900 mL
통상의 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1 시간 동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 기능성 음료 조성물 제조에 사용한다. After mixing the above ingredients according to a conventional beverage manufacturing method, stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized, then refrigerated and then stored in the present invention used in the manufacture of functional beverage compositions.
제제예 6: 사료 조성물의 제조Formulation Example 6: Preparation of feed composition
실시예 1의 추출물 분말 0.1 kg, 옥수수 25.5 kg, 소맥 15.04 kg, 소맥분 8.15 kg, 미강 7.4 kg, 대두박 18 kg, 옥구르텐 1kg, 닭부산물 14 kg, 동물성유지 9 kg, 가공염 0.3 kg, 인산제삼칼슘 0.3 kg, 석회석 1 kg, 염화콜린 0.01 kg, 비타민 0.05 kg, 미네랄 0.05 kg 및 소화효소제 0.1 kg을 혼합하여 동물(개, 애완견) 사료 조성물을 제조하였다. Example 1 extract powder 0.1 kg, corn 25.5 kg, wheat 15.04 kg, wheat flour 8.15 kg, rice bran 7.4 kg, soybean meal 18 kg, okgurten 1 kg, chicken by-product 14 kg,
Claims (12)
Vitamin tree ( Hippophae rhamnoides ) leaf extract having activity to inhibit the production of advanced glycation end products (AGEs) and promote degradation.
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KR102038866B1 (en) | 2012-12-24 | 2019-10-31 | 서울대학교산학협력단 | Use of PPARδ Agonists as Antibiotics, Therapeutics for Treatment of Burns, Wounds and Diabetic Ulcers |
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KR102032739B1 (en) | 2018-01-31 | 2019-10-16 | 한림대학교 산학협력단 | Pharmaceutical composition for preventing and treating diabetic complications containing the novel chrysin derivative |
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