KR101366611B1 - Composition for the prevention and treatment of diabetic complications containing the extracts or fractions of Brandisia hancei Hook. f. as active ingredient - Google Patents
Composition for the prevention and treatment of diabetic complications containing the extracts or fractions of Brandisia hancei Hook. f. as active ingredient Download PDFInfo
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- KR101366611B1 KR101366611B1 KR1020110081697A KR20110081697A KR101366611B1 KR 101366611 B1 KR101366611 B1 KR 101366611B1 KR 1020110081697 A KR1020110081697 A KR 1020110081697A KR 20110081697 A KR20110081697 A KR 20110081697A KR 101366611 B1 KR101366611 B1 KR 101366611B1
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Abstract
본 발명은 밀통화(Brandisia hancei Hook . f.) 추출물 또는 이의 분획물을 유효성분으로 함유하는 당뇨합병증 예방 및 치료용 조성물에 관한 것으로서, 더욱 구체적으로는, 밀통화 추출물 또는 이의 분획물은 당뇨합병증의 지표인 최종당화산물의 생성 및 알도즈 환원효소의 활성을 억제하고, 당뇨병성 망막증을 포함한 당뇨합병증에 대한 강력한 효과를 나타내므로, 당뇨합병증 예방 및 치료용 조성물의 유효성분으로서 유용하게 이용될 수 있다.The present invention is wheatgrass ( Brandisia) hancei Hook . f. The present invention relates to a composition for preventing and treating diabetic complications, which comprises extracts or fractions thereof as an active ingredient, and more specifically, wheat flour extract or fractions thereof are used for the production of final glycosylated products and aldose reductase. It inhibits activity and exhibits a strong effect on diabetic complications including diabetic retinopathy, and thus can be usefully used as an active ingredient for preventing and treating diabetic complications.
Description
본 발명은 당뇨합병증의 예방 및 치료용 조성물에 관한 것으로서, 구체적으로 밀통화(Brandisia hancei Hook . f.) 추출물을 이용한 당뇨합병증 예방 및 치료용 약학적 조성물 및 건강식품용 조성물에 관한 것이다.
The present invention relates to a composition for the prevention and treatment of diabetic complications, specifically, the calligraphy ( Brandisia hancei Hook . f. ) It relates to a pharmaceutical composition for preventing and treating diabetic complications using the extract and a composition for health food.
당뇨병(diabetes mellitus)은 전 세계적으로 중요한 성인병 중의 하나로서, 최근 우리나라에서도 급속한 경제 성장과 더불어 당뇨병 유병률이 10%에 달하며, 현재 전 세계적으로도 당뇨환자는 2억4천만 명이 넘었으며, 2025년에는 전 세계적으로 3억8천만 명으로 증가할 것이며, 이중 60%가 아시아 지역에서 발병할 것이라고 2009년 미국의사협회(JAMA)에서 발표하였다. 특히 당뇨발병시기가 중장년으로 당겨졌으며, 수명이 연장됨으로 인해서 합병증으로 진행되는 것은 피할 수 없는 상황이 되었다. 즉, 일반적으로 당뇨병에 걸린 후 10 ~ 20년이 지나면 체내 거의 모든 기관이 손상을 받아 당뇨성 망막병증(diabetic retinopathy), 당뇨성 백내장(diabetic cataract), 당뇨성 신증(diabetic nephropathy), 당뇨성 신경병증(diabetic neuropathy), 심장병, 암 또는 골다공증 등이 나타난다. 만성 당뇨성 신증은 혈액 투석 치료 및 말기 신부전의 가장 중요한 원인이 되고 있으며, 당뇨성 백내장과 망막증은 실명을 초래하고 결국엔 죽음에 이르게 한다. 미국의 경우 25 ~ 74세 연령대의 실명의 원인이 당뇨병이며, 당뇨 발병 후 15 ~ 20년이 지나면 60%가 실명으로 이어진다. 그러므로 당뇨환자에게서 합병증이 발병하는 기간이 5 ~ 10년 정도 지연만 되더라도 환자와 그 가족의 삶의 질이 달라질 것이며, 국가재정에도 커다란 영향을 끼칠 것이다.
Diabetes mellitus is one of the most important adult diseases in the world. In recent years, with the rapid economic growth in Korea, the prevalence of diabetes has reached 10%. Currently, there are more than 240 million diabetics worldwide. It will grow to 380 million worldwide, of which 60 percent will occur in Asia, according to the 2009 American Medical Association (JAMA). In particular, the onset of diabetes mellitus has been extended to middle age, and the prolonged lifespan has led to complications. That is, almost 10 to 20 years after diabetes usually causes damage to almost all organs in the body, such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, and diabetic nerve. Diabetic neuropathy, heart disease, cancer or osteoporosis may appear. Chronic diabetic nephropathy is the most important cause of hemodialysis treatment and end-stage renal failure, and diabetic cataract and retinopathy cause blindness and eventually death. In the United States, diabetes is the leading cause of blindness for ages 25-74, and 60% of blindness occurs 15 to 20 years after the onset of diabetes. Therefore, delaying the onset of complications in diabetic patients by 5 to 10 years will affect the quality of life of patients and their families and will have a major impact on national finances.
이러한 당뇨합병증을 유발하는 기전으로는 크게 단백질의 비효소적 당화반응(nonenzymatic glycation of protein), 폴리올 경로(polyol pathway) 및 산화적 스트레스(oxidative stress) 등으로 설명되고 있다. 단백질의 비효소적 당화반응(nonenzymatic glycation of protein)이란, 단백질의 리신 잔기 등의 아미노산 그룹과 환원당이 효소 작용 없는 축합반응, 즉 밀리아드 반응에 의한 것으로, 이 반응의 결과로 최종당화산물(advanced glycation endproducts, AGEs)이 생성된다. 단백질의 비효소적 당화반응은 (1) 단백질의 리신 잔기 등의 아미노산기와 환원당의 알데히드 또는 케톤이 효소 작용 없이 친핵성 첨가 반응을 하여 초기 단계 산물인 쉬프염기(schiff base)를 형성하고, 상기 쉬프염기와 인접한 케토아민 어닥트(ketoamine adduct)가 서로 축합하여 가역적인 아마도리(Amadori)형의 조기당화산물이 생성되는 단계 및 (2) 고혈당 상태가 지속되어 가역적인 아마도리형의 조기당화산물이 분해되지 않고 재배열(rearrangement)되어 비가역산물인 최종당화산물이 생성되고, 이렇게 생성된 최종당화산물들이 단백질 또는 지질 등과 결합 또는 교차결합(cross-linking)하여 비가역적인 당화단백질 또는 당화지질 등의 산물이 생성되는 단계로 나눌 수 있다. 가역적인 아마도리형의 조기당화산물과 달리 최종당화산물은 비가역적인 반응 산물이므로, 일단 생성되면 혈당이 정상으로 회복되어도 분해되지 않고, 최종당화산물이 결합한 단백질 또는 지질의 생존기간 동안 조직에 축적되어 조직의 구조와 기능을 비정상적으로 변화시켜 조직 곳곳에서 합병증을 유발시킨다(Vinson, J. A. et al., 1996, J. Nutritinal Biochemistry 7: 559-663; Smith, P. R. et al., 1992, Eur . J. Biochem., 210: 729-739). 예를 들면, 포도당과 여러 종류의 단백질이 반응하여 생성된 최종당화산물 중 하나인 당화 알부민은 만성 당뇨성 신증을 일으키는 중요한 요인으로 작용한다. 당화 알부민은 당화가 진행되지 않은 정상 알부민에 비해 더 용이하게 신사구체 세포 내로 유입되고, 고농도의 포도당은 메산지움 세포를 자극하여 세포외 기질(extracellular matrix)합성을 증가시킨다. 과도하게 유입된 당화 알부민과 증가된 세포외 기질로 인하여 신사구체의 섬유화가 야기된다. 이와 같은 기전으로 신사구체가 계속 손상 받게 되어 혈액투석 또는 장기이식 등의 극단적인 치료방법을 쓸 수밖에 없는 단계에 이르게 되는 것이다. 또한, 만성 당뇨로 인하여 동맥벽에서는 콜라겐이, 신사구체에서는 기저막성 단백질이 최종당화산물과 결합되어 조직에 축적됨이 보고된바 있다(Brownlee, M., et al ., 1986, Sciences, 232, 1629-1632). 이처럼 비효소적 단백질 당화반응에 의하여 기저막, 혈장 알부민, 수정체 단백질, 피브린, 콜라겐 등의 단백질에서 당화가 일어나며, 생성된 최종당화산물이 조직의 구조와 기능을 비정상적으로 변화시켜 당뇨성 망막병증(diabetic retinopathy), 당뇨성 백내장(diabetic cataract), 당뇨성 신증(diabetic nephropathy), 당뇨성 신경병증(diabetic neuropathy) 등의 만성 당뇨합병증을 유발시킨다. 또한, 고혈당 상태에서 최종당화산물이 생성되는 과정에서 지질대사 이상이 일어나고 동시에 생성되는 유해한 산소 자유라디칼에 대한 방어시스템 기능이 저하되어 산화적 스트레스가 유발된다고 보고된바 있다(Yokozawa, T., et al, 2001, J. of Trad . Med., 18: 107-112). 이처럼 비효소적 당화반응과 산화적 스트레스(oxidative stress) 작용 기전이 서로 연관되어 있다. The mechanism of this diabetic complication is largely explained by nonenzymatic glycation of protein, polyol pathway, and oxidative stress. The nonenzymatic glycation of protein is a condensation reaction in which amino acid groups such as lysine residues of proteins and reducing sugars do not have enzyme activity, that is, by a milliad reaction. As a result of this reaction, glycation endproducts, AGEs) are generated. The non-enzymatic glycosylation of protein (1) an amino acid group such as a lysine residue of the protein and an aldehyde or ketone of a reducing sugar undergo a nucleophilic addition reaction without enzymatic action to form a Schiff base, which is an early product, The base and the adjacent ketoamine adduct condensate with each other to produce a reversible Amadori-type early glycosylated product, and (2) the hyperglycemic state persists to break down the reversible Amadori-type early glycosylated product. The final glycosylated product, which is an irreversible product, is produced by rearrangement, and the resulting glycosylated products are combined or cross-linked with proteins or lipids to produce an irreversible glycosylated protein or glycosylated lipid. Can be divided into the stages generated. Unlike the reversible amadori type of early glycosylated products, the final glycosylated product is an irreversible reaction product. Once produced, blood sugar does not decompose when recovered to normal, but accumulates in the tissue during the survival of the protein or lipid to which the final glycated product is bound. Abnormally alters the structure and function of the organ, causing complications throughout the tissue (Vinson, JA et. al ., 1996, J. Nutritinal Biochemistry 7: 559-663; Smith, PR et al ., 1992, Eur . J. Biochem ., 210: 729-739). For example, glycated albumin, one of the final glycation products produced by the reaction of glucose with various proteins, is an important factor in causing chronic diabetic nephropathy. Glycated albumin enters the ganglion cell more easily than normal albumin without glycosylation, and high glucose stimulates mesangial cells to increase synthesis of extracellular matrix. Overgrowth of glycosylated albumin and increased extracellular matrix cause fibrosis of the glomerulus. Such a mechanism would continue to damage the shrine sphere, leading to a stage where extreme treatment methods, such as hemodialysis or organ transplantation, are inevitable. In addition, chronic diabetes has been reported to accumulate collagen in the arterial wall and basal membrane protein in the renal glomeruli and to accumulate in tissues (Brownlee, M., et. al . , 1986, Sciences , 232, 1629-1632). This non-enzymatic protein glycosylation leads to saccharification in proteins such as basement membrane, plasma albumin, lens protein, fibrin, collagen, etc., and the resulting final glycation products abnormally change the structure and function of the tissue to cause diabetic retinopathy retinopathy, retinopathy, diabetic cataract, diabetic nephropathy, and diabetic neuropathy. In addition, it has been reported that lipid metabolism abnormalities occur in the process of producing the final glycated product in hyperglycemic state and oxidative stress is caused by deterioration of defense system function against harmful oxygen free radicals (Yokozawa, T., et. al , 2001, J. of Trad . Med ., 18: 107-112). These non-enzymatic glycation reactions and oxidative stress mechanisms are related to each other.
폴리올 경로란 (1) 알도스 또는 케토스로부터 알도스 환원효소(aldose reductase, AR)작용에 의해 환원되어 솔비톨을 형성하는 단계 및 (2) 솔비톨이 솔비톨 탈수소효소에 의해 산화되어 과당을 생성하는 단계로 이루어지는 과정이다. 정상상태에서는 알도스 환원효소가 포도당에 대하여 친화력이 매우 낮지만, 고혈당 상태에 의하여 폴리올 경로의 첫 번째 효소인 알도스 환원효소가 과도하게 활성화되어, 이로 인해 과도한 고혈당이 솔비톨과 과당으로 전환되어 조직에 축적되어 삼투압의 균형이 깨져 합병증이 유발된다. 즉, 증가한 삼투압으로 인하여 수분이 인입되어 당뇨성 망막병증(diabetic retinopathy), 당뇨성 백내장(diabetic cataract), 당뇨성 신경병증(diabetic neuropathy) 등으로 진행된다(김응진 외, 당뇨병학, 대한 당뇨병학회, 고려의학, 483쪽; Soulis-Liparota, T., et al ., 1995, Diabetologia, 38: 357-394). 최종당화산물이 사람의 미세혈관 내피세포에서 폴리올 경로의 주효소인 알도스 환원효소를 활성화시키는 것이 보고된바 있다(Nakamura, N., et al., 2000, Free Radic Biol . Med., 29: 17-25). 이때 과당은 포도당에 비하여 단백질의 비효소적 당화반응의 속도가 약 10배 정도 빠르다. 따라서 고농도의 과당이 단백질과 결합하여 결국은 최종당화산물의 형성을 가속화시킨다. 이와 같이, 비효소적 당화반응, 폴리올 경로 및 산화적 스트레스(oxidative stress) 작용 기전들이 서로 연관되어 당뇨합병증을 유발시킨다. 고혈당 상태에서 최종당화산물이 생성되는 과정에서 지질대사 이상이 일어나고 동시에 생성되는 유해한 산소 자유라디칼에 대한 방어시스템 기능이 저하되어 산화적 스트레스가 유발된다고 보고된바 있다(Yokozawa, T., et al, 2001, J. of Trad . Med., 18: 107-112). 따라서 비효소적 당화반응과 산화적 스트레스(oxidative stress) 작용 기전이 서로 연관되어 있다. 따라서 당뇨합병증의 발병을 지연하거나 예방 또는 치료하기 위해서는 최종당화산물 형성의 억제가 매우 중요한 것으로 밝혀졌다(Brownlee, M., et al., 1988, N. Engl . Med ., 318, 1315-1321).
The polyol pathway is (1) reduced by aldose reductase (AR) action from aldose or ketose to form sorbitol, and (2) sorbitol is oxidized by sorbitol dehydrogenase to produce fructose. The process consists of. At steady state, aldose reductase has a very low affinity for glucose, but the hyperglycemic state causes excessive activation of aldose reductase, the first enzyme in the polyol pathway, resulting in the conversion of excess hyperglycemia into sorbitol and fructose. Accumulation in the osmotic balance is broken, causing complications. In other words, due to the increased osmotic pressure, water is introduced and progresses to diabetic retinopathy, diabetic cataract, and diabetic neuropathy. Korea Medicine, p. 483; Soulis-Liparota, T., et al . , 1995, Diabetologia , 38: 357-394). Final glycation end products have been reported to activate aldose reductase, the main enzyme of the polyol pathway, in human microvascular endothelial cells (Nakamura, N., et. al ., 2000, Free Radic Biol . Med ., 29: 17-25). At this time, fructose is about 10 times faster than non-enzymatic glycosylation of protein. Thus, a high concentration of fructose binds to the protein and ultimately accelerates the formation of the final glycation end product. As such, non-enzymatic glycosylation, polyol pathways, and oxidative stress mechanisms of action are linked to each other to cause diabetic complications. It has been reported that lipid metabolism abnormalities occur during the production of the final glycated product in hyperglycemic state and oxidative stress is caused by a decrease in defense system function against harmful oxygen free radicals (Yokozawa, T., et. al , 2001, J. of Trad . Med ., 18: 107-112). Therefore, the non-enzymatic glycation reaction and the oxidative stress mechanism are related to each other. Therefore, in order to delay, prevent or treat the development of diabetic complications, the final glycated product Inhibition of formation has been found to be very important (Brownlee, M., et al ., 1988, N. Engl . Med . 318, 1315-1321).
현재, 단백질 당화 억제제로 합성제제인 아미노구아니딘(aminoguanidine)은 친핵성 히드라진(hydrazine)으로, 아마도리 산물과 결합하여 단백질과의 교차결합을 방지함으로써 최종당화산물의 생성을 억제하여 합병증으로 진전되는 것을 지연 또는 방지한다(Brownlee, M., et al ., 1986, Sciences, 232, 1629-1632; Edelstein, D. et al., 1992, Diabetes, 41, 26-29). 아미노구아니딘은 당뇨합병증의 예방 및 치료에 가장 유망한 합성 의약품으로 제 3상 임상실험까지 진행되었으나, 장기간 투여 시 독성이 유발되는 문제점이 나타나 중단되었다. 그러므로 안전하고 효능이 우수한 천연약제의 개발이 요망되고 있는 실정이다.
Currently, aminoguanidine, a synthetic agent as a protein glycosylation inhibitor, is a nucleophilic hydrazine, which binds with the amadori product and prevents cross-linking with the protein, thereby inhibiting the production of the final glycation product and progressing to complications. Delay or prevent (Brownlee, M., et al . , 1986, Sciences , 232, 1629-1632; Edelstein, D. et al ., 1992, Diabetes , 41, 26-29). Aminoguanidine is the most promising synthetic drug for the prevention and treatment of diabetic complications, which has progressed to Phase III clinical trials, but it has been discontinued due to toxic effects caused by long-term administration. Therefore, it is desired to develop natural medicines having safety and efficacy.
밀통화(蜜桶花)(Brandisia hancei Hook . f.)는 현삼과 (Scrophulariaceae)에 속하는 한약재이다. 밀통화(蜜桶花)는 한의학적으로 맛은 약간 쓰(微苦: bitter taste)고 성질은 차(寒: cold)며, 간염(hepatitis), 고지혈증(hyperlipemia), 고코레스테롤증(hypercholesteromia), 류마치스성 관절염(rheumatoid arthritis) 등에 민간요법으로 사용되었다(Zheng-Dan He et al., J. of Ethnopharmacology 71(2000) 483-486). 성분연구는 brandioside, acetoside, 2'-acetylacetoside, poliumside 등이 보고되었으며(Zheng-Dan He et al., Phytochemistry , 30, 2, 701-702, 1991), 또한 이러한 성분들이 항산화효능이 있다고 보고되었을 뿐(Zheng-Dan He et al., J. of Ethnopharmacology 71(2000) 483-486), 더 이상의 약리작용 및 성분연구가 전혀 보고되지 않았다.
Wheat flour ( Brandisia hancei Hook . f. ) Is a Chinese herb belonging to Scrophulariaceae. Wheatgrass is a bitter taste of Chinese medicine and cold in nature. Hepatitis, hyperlipemia, hypercholesteromia, rheumatism It has been used as a folk remedy for rheumatoid arthritis (Zheng-Dan He et. al ., J. of Ethnopharmacology 71 (2000) 483-486). Ingredient studies have reported brandioside, acetoside, 2'-acetylacetoside and poliumside (Zheng-Dan He et. al ., Phytochemistry , 30, 2, 701-702, 1991), and also reported that these components have antioxidant effects (Zheng-Dan He et. al ., J. of Ethnopharmacology 71 (2000) 483-486), no further pharmacological and component studies have been reported.
이에 본 발명자들은 당뇨합병증을 위한, 독성 및 부작용이 거의 없어 안전하고 효과적인 천연 약재를 개발하던 중, 밀통화 추출물 또는 이의 분획물이 시험관내(In vitro) 실험을 통해 최종당화산물 및 알도즈 환원효소 생성 억제 효과, 및 당뇨병성 망막증을 포함한 강력한 당뇨합병증 억제 효과가 있음을 밝힘으로써 본 발명을 완성하였다.
The present inventors have found that one was not nearly, toxicity and side effects for diabetic complications develop a safe and effective natural herbs, wheat extract monetary or fraction thereof in vitro (In The present invention was completed by revealing the effects of inhibiting the production of the final glycated product and aldose reductase and potent antidiabetic complications including diabetic retinopathy.
본 발명의 목적은 밀통화(Brandisia hancei Hook . f.) 추출물 또는 이의 분획물을 유효성분으로 함유하는 당뇨합병증 예방 및 치료용 약학적 조성물을 제공하는 것이다.
An object of the present invention is the currency of the brandisia hancei Hook . f. ) It is to provide a pharmaceutical composition for preventing and treating diabetic complications containing an extract or a fraction thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 밀통화(Brandisia hancei Hook. f.)추출물 또는 이의 분획물을 유효성분으로 함유하는 당뇨합병증 예방 및 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides prevention and treatment of diabetic complications, a pharmaceutical composition containing the wheat call (Brandisia hancei Hook. F.) The extract, or fractions thereof as an active ingredient.
또한, 본 발명은 밀통화 추출물 또는 이의 분획물을 유효성분으로 함유하는 당뇨합병증 예방 및 개선용 건강식품용 조성물을 제공한다.
In another aspect, the present invention provides a composition for preventing and improving diabetic complications containing wheatgrass extract or fractions thereof as an active ingredient.
본 발명의 밀통화(Brandisia hancei Hook . f.) 추출물 또는 이의 분획물은 당뇨합병증의 지표인 최종당화산물의 생성 및 알도즈 환원효소의 활성을 억제하며, 당뇨병성 망막증을 포함한 강력한 당뇨합병증 억제 활성을 나타내므로, 당뇨합병증 예방 및 치료용 약학적 조성물의 유효성분으로서 유용하게 사용될 수 있다.
Currency of the present invention ( Brandisia) hancei Hook . f. ) Extracts or fractions thereof inhibit the production of final glycation end products, which are indicatives of diabetic complications, and the activity of aldose reductase, and exhibit potent antidiabetic complications including diabetic retinopathy, thereby preventing and treating diabetic complications. It can be usefully used as an active ingredient.
도 1은 밀통화 분획물 제조과정의 도식도를 나타낸 도이다.
도 2는 밀통화 추출물의 망막조직내 최종당화산물 축척에 미치는 영향을 나타낸 도이다:
NOR: 정상군;
DM: 당뇨군;
MET: 메트포르민(metformin) 처리군;
BH-50: 밀통화 추출물 50 mg/kg 처리군; 및
BH-250: 밀통화 추출물 250 mg/kg 처리군.
도 3은 밀통화 추출물의 망막신경세포의 소실에 미치는 영향을 나타낸 도이다:
NOR: 정상군;
DM: 당뇨군;
MET: 메트포르민(metformin) 처리군;
BH-50: 밀통화 추출물 50 mg/kg 처리군; 및
BH-250: 밀통화 추출물 250 mg/kg 처리군.
도 4는 밀통화 추출물의 뮐러세포(Muller cell)의 활성화에 미치는 영향을 나타낸 도이다:
NOR: 정상군;
DM: 당뇨군;
MET: 메트포르민(metformin) 처리군;
BH-50: 밀통화 추출물 50 mg/kg 처리군; 및
BH-250: 밀통화 추출물 250 mg/kg 처리군.
도 5는 밀통화 추출물의 NF-kB의 활성화 및 핵내 이동에 미치는 영향을 나타낸 도이다:
NOR: 정상군;
DM: 당뇨군;
MET: 메트포르민(metformin) 처리군;
BH-50: 밀통화 추출물 50 mg/kg 처리군; 및
BH-250: 밀통화 추출물 250 mg/kg 처리군.
도 6은 밀통화 추출물의 Bax와 Bcl-2의 발현에 미치는 영향을 나타낸 도이다:
NOR: 정상군;
DM: 당뇨군;
MET: 메트포르민(metformin) 처리군;
BH-50: 밀통화 추출물 50 mg/kg 처리군; 및
BH-250: 밀통화 추출물 250 mg/kg 처리군. 1 is a schematic diagram of a process for preparing wheat flour fractions.
FIG. 2 is a diagram showing the effect of wheat flour extract on the final glycation product accumulation in the retinal tissue:
NOR: normal group;
DM: diabetic group;
MET: metformin treated group;
BH-50: whole wheat extract 50 mg / kg treated group; And
BH-250:
Figure 3 is a diagram showing the effect on the loss of retinal nerve cells of wheatgrass extract:
NOR: normal group;
DM: diabetic group;
MET: metformin treated group;
BH-50: whole wheat extract 50 mg / kg treated group; And
BH-250:
Figure 4 is a diagram showing the effect on the activation of Muller cells (Muller cell) of wheat flour extract:
NOR: normal group;
DM: diabetic group;
MET: metformin treated group;
BH-50: whole wheat extract 50 mg / kg treated group; And
BH-250:
Figure 5 is a diagram showing the effect on the activation and nuclear transfer of NF-kB of wheat flour extract:
NOR: normal group;
DM: diabetic group;
MET: metformin treated group;
BH-50: whole wheat extract 50 mg / kg treated group; And
BH-250:
6 is a diagram showing the effect on the expression of Bax and Bcl-2 of wheat flour extract:
NOR: normal group;
DM: diabetic group;
MET: metformin treated group;
BH-50: whole wheat extract 50 mg / kg treated group; And
BH-250:
이하, 본 발명을 상세히 설명한다.
Hereinafter, the present invention will be described in detail.
본 발명은 밀통화(Brandisia hancei Hook . f.)추출물을 유효성분으로 함유하는 당뇨합병증 예방 및 치료용 약학적 조성물을 제공한다.The present invention is wheatgrass ( Brandisia) hancei Hook . f. Provided is a pharmaceutical composition for preventing and treating diabetic complications containing the extract as an active ingredient.
상기 당뇨합병증은 당뇨성 망막병증, 당뇨성 백내장, 당뇨성 신증, 당뇨성 신경병증, 당뇨성 심장병, 당뇨성 암, 당뇨성 골다공증, 및 당뇨성 아테롬성 동맥경화로 구성된 군으로부터 선택되는 어느 하나인 것이 바람직하고 당뇨성 망막병인 것이 보다 바람직하나 이에 한정하지 않는다. 당뇨합병증은 당뇨병이 장기간 지속될 경우 유발되는 증상이지만, 당뇨병의 발병 기준 및 판단 기준과 상이하며, 당뇨합병증 치료제는 당뇨병 치료제와는 별개로서 사용될 수 있다.The diabetic complication is any one selected from the group consisting of diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic cancer, diabetic osteoporosis, and diabetic atherosclerosis It is more preferred that the diabetic retinopathy is not limited thereto. Although diabetic complications are caused by prolonged diabetes, they are different from the criteria for the onset and judgment of diabetes, and diabetic complications can be used separately from diabetic drugs.
상기 밀통화 추출물은 하기의 단계들을 포함하는 제조방법에 의해 제조되는 것이 바람직하나 이에 한정하지 않는다:The wheat flour extract is preferably prepared by a manufacturing method comprising the following steps, but not always limited thereto:
1) 밀통화에 추출용매를 가하여 추출하는 단계;1) extracting by adding an extraction solvent to wheat flour;
2) 단계 1)의 추출물을 식힌 후 여과하는 단계; 및2) cooling the extract of step 1) and filtering; And
3) 단계 2)의 여과한 추출물을 감압 농축한 후 건조하는 단계.3) drying the filtered extract of step 2) under reduced pressure.
상기 방법에 있어서, 단계 1)의 밀통화는 재배한 것 또는 시판되는 것 등 제한 없이 사용할 수 있다. 상기 밀통화는 밀통화 전체를 이용할 수 있고, 가지 및 줄기 또는 뿌리를 이용하는 것이 바람직하나 이에 한정하지 않는다.In the above method, the bulking of step 1) can be used without limitation, such as being grown or commercially available. The wheat currency may use the whole wheat currency, and it is preferable to use branches and stems or roots, but not always limited thereto.
상기 추출용매는 물, 알코올, 이들의 혼합물 또는 수용성 알코올을 사용하는 것이 바람직하다. 상기 알코올로는 C1 내지 C2 저급 알코올을 이용하는 것이 바람직하고, 상기 저급 알코올로는 에탄올 또는 메탄올을 이용하는 것이 바람직하며, 80% 에탄올 수용액을 이용하는 것이 더욱 바람직하나 이에 한정하지 않는다. 추출 방법으로는 여과법, 열수추출, 침지추출, 환류냉각추출 및 초음파추출 등 당업계의 통상적인 방법을 이용할 수 있으며, 열수추출 방법으로 1회 내지 5회 추출하는 것이 바람직하며, 3회 반복 추출하는 것이 더욱 바람직하나 이에 한정하지 않는다. 상기 추출용매는 건조된 밀통화 줄기에 0.1 내지 10배 첨가할 수 있으며, 0.3 내지 5배 첨가하는 것이 바람직하다. 추출온도는 20 내지 30℃인 것이 바람직하나 이에 한정하지 않는다. 또한, 추출시간은 12 내지 48시간인 것이 바람직하나 이에 한정하지 않는다.The extraction solvent is preferably water, alcohols, mixtures thereof or water-soluble alcohols. It is preferable to use C 1 to C 2 lower alcohol as the alcohol, it is preferable to use ethanol or methanol as the lower alcohol, it is more preferable to use an 80% ethanol aqueous solution, but is not limited thereto. Examples of the extraction method include filtration, hot water extraction, immersion extraction, reflux cooling extraction, ultrasonic extraction, and the like, and extraction is preferably performed once to five times by hot water extraction, But is not limited thereto. The extraction solvent may be added 0.1 to 10 times to the dried wheat bran, preferably 0.3 to 5 times. The extraction temperature is preferably 20 to 30 占 폚, but is not limited thereto. In addition, the extraction time is preferably 12 to 48 hours, but is not limited thereto.
상기 방법에 있어서, 단계 3)의 감압농축은 진공감압농축기 또는 진공회전증발기를 이용하는 것이 바람직하나 이에 한정하지 않는다. 또한, 건조는 감압건조, 진공건조, 비등건조, 분무건조 또는 동결건조하는 것이 바람직하나 이에 한정하지 않는다. In the above method, it is preferable to use a vacuum decompression concentrator or a vacuum rotary evaporator for the decompression concentration in step 3), but it is not limited thereto. In addition, the drying is preferably reduced pressure drying, vacuum drying, boiling drying, spray drying or freeze drying, but is not limited thereto.
본 발명의 구체적인 실시태양에 있어서, 밀통화 가지, 줄기 또는 뿌리를 물로 세척한 후, 그늘에서 건조시켰다. 건조된 밀통화 가지, 줄기 또는 뿌리를 분쇄하여 추출용기에 넣고, 추출용매로 상온에서 반복 추출하였다. 밀통화 추출물을 수득한 후, 거름종이 등을 이용하여 고형분을 제거하고 여과하였다. 상기 추출액을 감압 농축하여 밀통화 추출물을 제조하였다.
In a specific embodiment of the present invention, the floured branches, stems or roots are washed with water and then dried in the shade. The dried wheaten branches, stems or roots were pulverized and placed in an extraction container, and extracted repeatedly at room temperature with an extraction solvent. After obtaining the wheat flour extract, the solids were removed using a filter paper or the like and filtered. The extract was concentrated under reduced pressure to prepare a wheat flour extract.
또한, 본 발명은 밀통화 추출물을 추가적으로 유기용매로 분획하여 제조한 분획물을 유효성분으로 함유하는 당뇨합병증 예방 및 치료용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for preventing and treating diabetic complications containing the fraction prepared by further fractionating the wheat flour extract with an organic solvent as an active ingredient.
상기 밀통화 추출물의 분획물 다음과 같이 제조되는 것이 바람직하나 이에 한정하지 않는다.Fractions of the wheat flour extract is preferably prepared as follows, but not always limited thereto.
1) 밀통화 추출물을 물에 현탁한 후, n-헥산을 가하여 n-헥산층을 분리하는 단계;1) suspending the wheat flour extract in water, and then separating n-hexane layer by adding n-hexane;
2) 단계 1)의 남은 물층에 에틸아세테이트를 가하여 에틸아세테이트 층을 분리하는 단계;2) separating the ethyl acetate layer by adding ethyl acetate to the remaining water layer of step 1);
3) 단계 2)의 남은 물층에 부탄올을 가하여 부탄올층을 분리하는 단계; 및3) separating butanol layer by adding butanol to the remaining water layer of step 2); And
4) 단계 3)의 남은 물층에 물 분획물을 분리하는 단계.4) separating the water fraction in the remaining water layer of step 3).
상기 방법에 있어서, 상기 유기용매는 헥산, 에틸아세테이트 또는 부탄올인 것이 바람직하나 이에 한정하지 않는다. 상기 분획물은 상기 밀통화 추출물로부터 분획 과정을 1 내지 5회, 바람직하게는 3회 반복하여 수득할 수 있고, 분획 후 감압 농축하는 것이 바람직하나 이에 한정하지 않는다.In the above method, the organic solvent is preferably hexane, ethyl acetate or butanol, but is not limited thereto. The fraction may be obtained by repeating the fractionation process 1 to 5 times, preferably 3 times from the wheat flour extract, and preferably concentrated under reduced pressure after the fraction, but is not limited thereto.
상기 유기용매는 에틸아세테이트 또는 부탄올인 것이 보다 바람직하다.More preferably, the organic solvent is ethyl acetate or butanol.
상기 당뇨합병증은 당뇨성 망막병증, 당뇨성 백내장, 당뇨성 신증, 당뇨성 신경병증, 당뇨성 심장병, 당뇨성 골다공증, 당뇨성 암 및 당뇨성 아테롬성 동맥경화로 구성된 군으로부터 선택되는 어느 하나인 것이 바람직하나 이에 한정하지 않는다. 당뇨합병증은 당뇨병이 장기간 지속될 경우 유발되는 증상이지만, 당뇨병의 발병 기준 및 판단 기준과 상이하며, 당뇨합병증 치료제는 당뇨병 치료제와는 별개로서 사용될 수 있다.The diabetic complication is preferably any one selected from the group consisting of diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic cancer and diabetic atherosclerosis One is not limited to this. Although diabetic complications are caused by prolonged diabetes, they are different from the criteria for the onset and judgment of diabetes, and diabetic complications can be used separately from diabetic drugs.
상기 분획물은 상기 밀통화 추출물에서 용매를 증발시키고 수득한 잔사에 물과 헥산을 넣어 헥산층을 분리하여 헥산 분획물을 수득하였다. 헥산층을 제외한 물층에 에틸아세테이트를 혼합한 후 에틸아세테이트층을 분리하여 에틸아세테이트 분획물을 얻었다. 또한, 에틸아세테이트층을 제거한 후 부탄올을 혼합한 후 부탄올층을 분리하여 부탄올 분획물을 수득하였다. 마지막으로 부탄올층을 제거한 후 물층의 물 분획물을 수득하였다(도 1 참조).The fraction was obtained by evaporating the solvent from the wheat flour extract and adding water and hexane to the obtained residue to separate the hexane layer to obtain a hexane fraction. Ethyl acetate was added to the water layer except for the hexane layer, and the ethyl acetate layer was separated to obtain an ethyl acetate fraction. Further, after removing the ethyl acetate layer, butanol was mixed and the butanol layer was separated to obtain a butanol fraction. Finally, after removing the butanol layer, a water fraction of the water layer was obtained (see FIG. 1).
본 발명의 구체적인 실시태양에 있어서, 본 발명자들은 당뇨합병증의 지표 및 치료 효능 평가의 지표가 되는 최종당화산물의 생성억제 효능을 분석하기 위하여, 단백질로 우혈청알부민(bovine serum albumin; BSA)을 이용하여 과당 및 글루코스와의 결합 정도를 지표로 이용하였다. 또한, 양성대조군으로는 최종당화산물에 대한 억제 효능이 매우 우수하다고 알려진 아미노구아니딘(aminoguanidine)을 이용하였다. 그 결과, 밀통화 추출물 또는 이의 분획물을 처리한 시험군이 양성 대조물질인 아미노구아니딘에 비해 약 4.2배 효과적으로 최종당화산물 억제 효능을 나타냄을 확인하였다(표 1 참조).In a specific embodiment of the present invention, the present inventors use bovine serum albumin (BSA) as a protein to analyze the inhibitory effect of the production of the final glycated product, which is an indicator of diabetic complications and an evaluation of the therapeutic efficacy The degree of binding to fructose and glucose was used as an index. As a positive control group, aminoguanidine, which is known to have excellent inhibitory effect on the final glycation endproduct, was used. As a result, it was confirmed that the test group treated with the wheatgrass extract or fractions thereof showed about 4.2 times more effective inhibition of the final glycated product than the aminoguanidine, which is a positive control (see Table 1).
본 발명의 구체적인 실시태양에 있어서, 본 발명자들은 밀통화 추출물 또는 이의 분획물의 당뇨합병증의 또 다른 지표가 되는 알도즈 환원효소의 활성 억제를 측정하였다. 비교 대조군으로는 3,3-테트라메칠렌글루타르산(Tetramethyleneglutaric acid)을 이용하여 측정하였다. 그 결과, 본 발명의 밀통화 추출물 또는 이의 분획물은 기존에 알려진 알도즈 환원효소 억제제에 비하여 더 효과적으로 알도즈 환원효소 활성을 억제하는 것으로 나타났다(표 2 참조).In a specific embodiment of the present invention, the inventors have measured the inhibition of the activity of aldose reductase, which is another indicator of diabetic complications of wheatgrass extract or fractions thereof. As a comparative control, it was measured using 3,3-tetramethyleneglutaric acid (Tetramethyleneglutaric acid). As a result, the wheatgrass extract or fractions thereof of the present invention was found to inhibit aldose reductase activity more effectively than the known aldose reductase inhibitors (see Table 2).
본 발명의 구체적인 실시태양에 있어서, 본 발명자들은 밀통화 추출물의 당뇨병성 망막증에 대한 효능을 확인하기 위하여, 스트렙토조토신(streptozotocin)으로 유도한 1형 당뇨 쥐를 이용하여 당뇨병성 망막증에 대한 효능을 확인한 결과, 본 발명의 밀통화 추출물은 최종당화산물 망막조직 축적을 예방하고(도 2 참조), 망막조직의 세포사멸(apoptosis)을 억제하며(도 3 참조), 망막신경세포의 소실을 예방하고(도 4 참조), 뮐러 세포(Muller cell)의 활성화를 억제하며(도 5 참조), NF-kB의 핵내 이동을 억제하고, bax를 감소시키고, bcl2를 증가시키므로 당뇨병성 망막증에 대한 유의적인 효과를 나타내는 것을 확인하였다. In a specific embodiment of the present invention, the inventors of the present invention, to confirm the efficacy of diabetic retinopathy of wheat flour extract, using the type 1 diabetic rats induced with streptozotocin (streptozotocin) for diabetic retinopathy As a result, the wheat flour extract of the present invention prevents the accumulation of the final glycation product retinal tissue (see FIG. 2), inhibits apoptosis of the retinal tissue (see FIG. 3), and prevents the loss of retinal nerve cells. (See FIG. 4), inhibits the activation of Muller cells (see FIG. 5), inhibits nuclear migration of NF-kB, decreases bax, and increases bcl2, which has a significant effect on diabetic retinopathy It confirmed that it represents.
따라서, 본 발명의 밀통화 추출물 또는 이의 분획물은 장기적은 당뇨상태에서 발생하는 당화생성물의 축적을 억제하고, 알도즈 환원효소의 활성을 억제하며, 당뇨병성 망막증을 포함하는 당뇨합병증에 대한 강력한 효과를 나타내므로, 당뇨합병증 예방 및 치료용 약학적 조성물의 유효성분으로서 유용하게 사용될 수 있음을 확인하였다.
Therefore, the wheat flour extract or fractions thereof of the present invention inhibit the accumulation of glycation products occurring in long-term diabetes, inhibit the activity of aldose reductase, and have a potent effect on diabetic complications including diabetic retinopathy. Therefore, it was confirmed that it can be usefully used as an active ingredient of the pharmaceutical composition for preventing and treating diabetic complications.
본 발명의 조성물 총 중량에 대하여 본 발명의 밀통화 추출물 또는 이의 분획물을 0.1 내지 99.9 중량%를 유효성분으로 함유하고, 약제학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다.The total weight of the composition of the present invention contains 0.1 to 99.9% by weight of the wheat flour extract or fractions thereof as an active ingredient, and may include a pharmaceutically acceptable carrier, excipient or diluent.
본 발명의 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 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. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제 및 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The compositions of the present invention may be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명의 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여시 피부외용 또는 복강내, 직장, 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사 방식을 선택하는 것이 바람직하며, 가장 바람직하게는 피부외용으로 사용한다.The composition of the present invention may be administered orally or parenterally, and it is preferable to select externally or intraperitoneally, rectally, intravenously, intramuscularly, subcutaneously, intrauterine epidural or cerebrovascular injection methods for parenteral administration. For skin use externally.
본 발명의 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하며, 일일 투여량은 밀통화 추출물의 양을 기준으로 0.01 내지 1000 ㎎/㎏이고, 바람직하게는 30 내지 500 ㎎/㎏이고, 더욱 바람직하게는 50 내지 300 ㎎/㎏이며, 하루 1 ~ 6 회 투여될 수 있다. The dosage of the composition of the present invention varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, excretion rate and severity of the disease of the patient, the daily dosage is the amount of wheat flour extract 0.01 to 1000 mg / kg, preferably 30 to 500 mg / kg, more preferably 50 to 300 mg / kg, and may be administered 1 to 6 times per day.
본 발명의 조성물은 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.
The composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
또한, 본 발명은 밀통화 추출물 또는 이의 분획물을 유효성분으로 함유하는 당뇨합병증 예방 및 개선용 건강식품용 조성물을 제공한다.In another aspect, the present invention provides a composition for preventing and improving diabetic complications containing wheatgrass extract or fractions thereof as an active ingredient.
상기 당뇨합병증은 당뇨성 망막병증, 당뇨성 백내장, 당뇨성 신증, 당뇨성 신경병증, 당뇨성 심장병, 당뇨성 암, 당뇨성 골다공증, 및 당뇨성 아테롬성 동맥경화로 구성된 군으로부터 선택되는 어느 하나인 것이 바람직하나 이에 한정하지 않는다. The diabetic complication is any one selected from the group consisting of diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic cancer, diabetic osteoporosis, and diabetic atherosclerosis Preferred but not limited to this.
본 발명의 밀통화 추출물 또는 이의 분획물은 최종당화산물의 생성 및 알도즈 환원효소의 활성을 억제하고, 당뇨병성 망막증을 포함하는 당뇨합병증에 대한 강력한 효과를 나타내므로, 당뇨합병증의 예방 및 개선용 건강식품용 조성물에 유용하게 사용될 수 있다.
The wheat flour extract or fractions thereof of the present invention inhibit the production of the final glycation end products and the activity of aldose reductase, and exhibit a powerful effect on diabetic complications including diabetic retinopathy, preventing and improving diabetic complications It can be usefully used in food compositions.
본 발명의 기능성 식품은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강식품 100 중량부당 0.01~0.04 중량부, 바람직하게는 약 0.02 ~ 0.03 중량부 범위에서 선택하는 것이 바람직하다.The functional food of the present invention may contain various flavors, natural carbohydrates, and the like as additional ingredients. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is preferably 0.01 to 0.04 part by weight, more preferably 0.02 to 0.03 part by weight per 100 parts by weight of the health food of the present invention.
상기 외에 본 발명의 기능성 식품은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 기능성 식품은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 건강식품 100 중량부당 0.01~0.1 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above, the functional food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, , A carbonating agent used in carbonated drinks, and the like. In addition, the functional food of the present invention may contain flesh for the production of natural fruit juice, fruit juice drink and vegetable drink. These components may be used independently or in combination. The ratio of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health food of the present invention.
이하, 본 발명을 실시예, 실험예 및 제조예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to Examples, Experimental Examples and Preparation Examples.
단, 하기 실시예, 실험예 및 제조예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예, 실험예 및 제조예에 한정되는 것은 아니다.
However, the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples, and Preparation Examples.
<< 실시예Example 1> 1> 밀통화Currency 에탄올 수용액 추출물의 제조 Preparation of Ethanol Aqueous Extract
음건 및 세절한 밀통화의 가지 및 잎을 각각 70:30으로 196 g을 분쇄한 후 1.0 L의 80% 에탄올 수용액을 넣고, 추출용기에서 상온상태로 반복 추출하여, 상기 추출액을 여과한 후, 구성성분의 분해 및 가수분해를 방지할 수 있도록 농축 시 온도를 40 ~ 45℃ 이하로 유지하며 감압 농축시켜 에탄올 추출물을 14.5 g을 수득하였다. 또한, 증거표본(no. Diab-2008-85)은 한국한의학연구원 한의융합연구본부 당뇨합병증연구센터 표본실에 보관하였다.
After crushing 196 g of dry and fine wheat flour and leaves at 70:30, respectively, add 1.0 L of 80% ethanol aqueous solution, and repeatedly extract the mixture at room temperature in an extraction container and filter the extract. Concentration under reduced pressure while maintaining the temperature at 40 ~ 45 ℃ below concentration to prevent decomposition and hydrolysis of the components to give 14.5 g of ethanol extract. In addition, specimens of evidence (no. Diab-2008-85) were stored in the Korean Diabetes Association Center for Diabetic Complications Research Center.
<< 실시예Example 2> 2> 밀통화Currency 분획물의Fraction 제조 Produce
밀통화 분획물을 제조하기 위하여, 상기 <실시예 1>의 밀통화 추출물에서 용매를 증발시키고 수득한 잔사에 물과 헥산을 넣어 헥산층을 분리하여 헥산 분획물(6.7%)을 수득하였다. 헥산층을 제외한 물층에 에틸아세테이트를 혼합한 후 에틸아세테이트층을 분리하여 에틸아세테이트 분획물(10.7%)을 얻었다. 또한, 에틸아세테이트층을 제거한 후 부탄올을 혼합한 후 부탄올층을 분리하여 부탄올 분획물(49.8%)을 수득하였다. 마지막으로 부탄올층을 제거한 후 물층의 물 분획물(26.9%)을 수득하였다.
To prepare the wheat flour fraction, the solvent was evaporated from the wheat flour extract of <Example 1> and water and hexane were added to the obtained residue to separate the hexane layer, thereby obtaining a hexane fraction (6.7%). Ethyl acetate was mixed with the water layer except for the hexane layer, and the ethyl acetate layer was separated to obtain an ethyl acetate fraction (10.7%). Also, after removing the ethyl acetate layer, butanol was mixed and the butanol layer was separated to obtain a butanol fraction (49.8%). Finally, after removing the butanol layer, a water fraction (26.9%) of the water layer was obtained.
<실험예 1> 최종당화산물 생성억제 효능 분석 <Experimental Example 1> advanced glycation end products produced inhibitory effects analysis
상기 <실시예 1>에서 수득한 밀통화 추출물의 시험관 내 최종당화산물 생성 억제 효능을 분석하였다. In vitro final glycation product production inhibitory effect of the wheatgrass extract obtained in <Example 1> was analyzed.
구체적으로, 단백질원으로 소혈청알부민(bovine serum albumin; BSA, 미국 시그마)을 택하였다. BSA를 10 ㎎/㎖의 농도가 되도록 50 mM 인산완충용액(phosphate buffer; pH 7.4)에 첨가하여 제조하였다. 당원으로는 0.2 M 과당 및 0.2 M 글루코스가 혼합된 용액을 사용하였다. 상기의 제조된 BSA 용액에 과당 및 글루코스 혼합액을 첨가하였다. 밀통화 에탄올 추출물은 5 ㎍/㎖, 10 ㎍/㎖ 또는 25 ㎍/㎖ 농도로 제조하였다. 상기 모든 화합물을 디메틸설폭사이드(Dimethylsulfoxide; DMSO)에 녹인 후 15% 트윈(tween) 80을 첨가하였고, 총 DMSO의 함량은 0.2%이었다. 상기 제조된 추출물을 상기 BSA 및 당의 혼합액에 첨가하여 37℃에서 14일간 배양하였다. 이때, 0.02% 소디움아자이드(sodium azide) 및 안티마이코틱스(antimycotics)를 항박테리아제 및 항진균제로서 첨가하였다. BSA 및 당 혼합액을 배양한 것을 대조군으로서 사용하였고, 추출물 또는 이의 분획물을 제조하여, 배양하지 않을 것을 시험군과 대조군의 공시험군(blank)으로서 사용하였다. 한편, 효능의 우수함을 비교할 수 있는 지표인 양성대조군으로서 아미노구아니딘을 사용하였다. 구체적으로는, 아미노구아니딘을 증류수에 용해하여 상기에 기재한 방법으로 37℃에서 55.5 ㎍/㎖, 74 ㎍/㎖ 또는 92.5 ㎍/㎖의 농도로 14일 동안 각각 배양하였다. 모든 배양액은 4개씩 준비하여 최대한 오차를 피하였다. 배양 14일 후 배양액에서 생성된 최종당화산물의 함량을 분석하여 그 결과를 나타내었다. 최종당화산물은 형광, 갈색을 띠고 있으며 교차결합을 할 수 있는 물리화학적인 특성을 지니고 있을 뿐 아니라 세포막 수용체가 인지할 수 있는 배위자를 지니고 있었다. 이러한 특성을 지닌 최종당화산물의 양을 마이크로플레이트 검출기(Microplate reader; Excitation: 350 ㎚, Emission: 450 ㎚)로 측정하여 최종당화산물의 생성 억제 정도를 분석하였다(Vinson, J.A. et al., J. Nutr . Biochem ., 7: 659-663, 1996). 최종당화산물의 생성억제율은 하기의 [수학식 1]에 따라 계산하였다.
Specifically, bovine serum albumin (BSA, Sigma, USA) was selected as a protein source. BSA was prepared by adding 50 mM phosphate buffer (pH 7.4) to a concentration of 10 mg / mL. A solution mixed with 0.2 M fructose and 0.2 M glucose was used as a source. To the above-prepared BSA solution, a mixture of fructose and glucose was added. Whole wheat ethanol extract was prepared at a concentration of 5 μg / ml, 10 μg / ml or 25 μg / ml. After dissolving all the compounds in dimethylsulfoxide (DMSO), 15% tween 80 was added, and the total DMSO content was 0.2%. The prepared extract was added to the mixture of BSA and sugar and incubated at 37 ° C. for 14 days. At this time, 0.02% sodium azide and antimycotics were added as an antibacterial agent and an antifungal agent. Cultures of BSA and sugar mixtures were used as controls, and extracts or fractions thereof were prepared, and those not cultured were used as blanks of the test and control groups. On the other hand, aminoguanidine was used as a positive control, which is an index that can compare excellent efficacy. Specifically, aminoguanidine was dissolved in distilled water and incubated for 14 days at 37 ° C. at a concentration of 55.5 μg / ml, 74 μg / ml or 92.5 μg / ml by the method described above. All four cultures were prepared and avoided the maximum error. After 14 days of culture, the contents of the final glycated product produced in the culture solution were analyzed and the results are shown. The final glycation end product was fluorescent, brownish and had physicochemical properties capable of cross-linking as well as a ligand that could be recognized by cell membrane receptors. The amount of the final glycated product having such characteristics was measured by a microplate reader (Excitation: 350 nm, Emission: 450 nm) to analyze the degree of inhibition of production of the final glycated product (Vinson, JA et. al ., J. Nutr . Biochem . , 7: 659-663, 1996). The production inhibition rate of the final glycosylated product was calculated according to Equation 1 below.
그 결과, 하기 [표 1]에 나타낸 바와 같이, 밀통화 에탄올 추출물의 최종당화산물 생성억제 효능의 IC50값은 15.23 ㎍/㎖으로 나타났다. 이는 양성대조군인 아미노구아니딘(IC50값: 63.40 ㎍/㎖)보다 4.2배로 효능이 현저하게 우수한 것으로 증명되었다(표 1). 이에, 밀통화 추출물 또는 이의 분획물은 단백질과 당의 결합을 억제하여 최종당화산물의 생성을 저해하는 것으로 확인되었다.
As a result, as shown in [Table 1], the IC 50 value of the final glycation product production inhibitory efficacy of the wheat flour ethanol extract was 15.23 ㎍ / ㎖. This proved to be remarkably superior in efficacy, 4.2 times higher than the positive control aminoguanidine (IC 50 value: 63.40 μg / ml) (Table 1). Thus, it was confirmed that wheatgrass extract or fractions thereof inhibited the binding of protein and sugar to inhibit the production of the final glycosylated product.
(㎍/㎖)density
(占 퐂 / ml)
(%)Inhibition
(%)
(㎍/㎖)IC 50
(占 퐂 / ml)
밀통화 추출물
10
255
10
25
38.58 ± 1.96
81.93 ± 0.549.90 ± 0.30
38.58 ± 1.96
81.93 ± 0.54
15.23 ± 0.12
15.23 ± 0.12
아미노구아니딘
Aminoguanidine
74
92.555.5
74
92.5
60.82 ± 2.21
66.96 ± 1.3442.84 ± 2.16
60.82 ± 2.21
66.96 ± 1.34
63.40 ± 2.61
63.40 ± 2.61
<< 실험예Experimental Example 2> 2> 알도즈Aldoz 환원효소( Reducing enzyme aldosealdose reductasereductase , , ARAR ) 활성 억제 효능 분석) Analysis of inhibitory activity
밀통화 추출물, 또는 이의 헥산, 에틸아세테이트, 부탄올 및 물 분획물의 시험관 내에서 알도즈 환원효소 활성 억제 효능을 분석하였다. 듀프란(Dufrane; 1984) 방법에 따라 SD 랫트(Sprague-Dawley rat, 250 ~ 280 g)의 안구로부터 천연상태의 알도즈 환원효소를 얻기 위하여, 135 mM Na, K-인산완충용액(K-phosphate buffer; pH 7.0) 및 10 mM 2-머캡토에탄올(2-mercaptoethanol)을, 적출한 렌즈와 함께 균질기(Homogenizer)와 초음파분쇄기(Sonicater)를 이용해 분쇄하였다. 14,000 rpm에서 30분간 원심분리한 다음 상층액을 0.2 ㎛의 필터에 여과한 후 사용하였다. 상기 과정은 모두 4℃에서 수행하였다. 효소(Enzyme)의 단백질원으로 BSA을 이용하여 라우리(lowry) 방법으로 정량하였다. 135 mM Na, K-인산완충용액(pH 7.0), 100 mM 리튬 설페이트(Lithium sulfate), 0.03 mM NADPH, 0.04 mM DL-글리세알데하이드(DL-glycealdehyde) 및 100 ㎍/㎖의 효소 혼합물(mixture)을 0.1% DMSO에 녹인 후 각 농도로 희석한 시료 50 ㎕에 첨가하여 총 부피 1 ㎖가 되도록 한 뒤 37℃에서 10분간 반응시켰다. 이때, 공시험군은 0.04 mM DL-글리세알데하이드(DL-glycealdehyde)를 첨가하지 않은 혼합물을, STD는 135 mM Na, K-인산완충용액(pH 7.0), 100 mM 리튬 설페이트(Lithium sulfate)에 50 ㎕ NADP(0.2 ~ 5 μM)를 첨가한 시료를 사용하였다. 시료 0.3 ㎖의 0.5 N HCl을 첨가하여 반응을 종료시킨 뒤, 10 mM 이미다졸(imidazole)이 첨가된 6 M NaOH 1 ㎖을 가하여 60℃에서 10분간 반응시켜 NADP가 형광 산물(fluorescent product)로 전환되는 정도를 측정하였다. 시료는 3회(triplicate) 수행하였다. 효능 정도는 Spectrofluorophotometric detector(Bio-TEK, Synergy HT, 미국)를 이용하여 Ex. 360 ㎚, Em. 460 ㎚에서 측정하여, IC50값으로 나타내었다. 밀통화 추출물은 0.25 ㎍/㎖ , 0.5 ㎍/㎖ 또는 1.0 ㎍/㎖ 농도로 제조하였고, 헥산 분획물은 2.5 ㎍/㎖, 5 ㎍/㎖ 또는 10 ㎍/㎖의 농도로, 에틸아세테이트 분획물은 2.5 ㎍/㎖, 5 ㎍/㎖, 10 ㎍/㎖의 농도로, 부탄올 분획물은 2.5 ㎍/㎖, 5 ㎍/㎖ 또는 10 ㎍/㎖의 농도로, 물 분획물은 2.5 ㎍/㎖, 5 ㎍/㎖ 또는 10 ㎍/㎖의 농도로 각각 제조하였다. 비교대조군으로는 우수한 알도즈 환원효소 활성억제제 중의 하나인 3,3-테트라메칠렌 글루타르산(3,3-tetramethyleneglutaric acid)을 3.72 ㎍/㎖, 4.66 ㎍/㎖ 또는 5.59 ㎍/㎖의 농도로 제조한 후 알도즈 환원효소 활성 억제효능을 측정하였다.The efficacy of inhibiting aldose reductase activity in vitro in wheatgrass extract or its hexane, ethyl acetate, butanol and water fractions was analyzed. In order to obtain natural aldose reductase from the eyes of SD rats (Sprague-Dawley rat, 250-280 g) according to the Dufrane (1984) method, 135 mM Na, K-phosphate buffer solution (K-phosphate) buffer; pH 7.0) and 10 mM 2-mercaptoethanol were ground using a homogenizer and an ultrasonic grinder together with the extracted lens. After centrifugation at 14,000 rpm for 30 minutes, the supernatant was used after filtering through a 0.2 μm filter. All of the above procedures were carried out at 4 ° C. The protein source of the enzyme was quantified by lowry method using BSA. 135 mM Na, K-phosphate buffer solution (pH 7.0), 100 mM lithium sulfate, 0.03 mM NADPH, 0.04 mM DL-glyceraldehyde and 100 μg / ml enzyme mixture After dissolving in 0.1% DMSO, 50 μl of the sample diluted to each concentration was added to a total volume of 1 ml, and reacted at 37 ° C. for 10 minutes. At this time, the test group was a mixture without addition of 0.04 mM DL-glycerycealdehyde,
그 결과, 하기 [표 2]에서 나타낸 바와 같이, 밀통화 추출물, 추출물의 헥산 분획물, 에틸아세테이트 분획물, 부탄올 분획물 또는 물 분획물의 알도즈 환원효소 활성억제 효능은 IC50값이 각각 0.86 ㎍/㎖, 10 ㎍/㎖ 이상, 6.26 ㎍/㎖, 3.57 ㎍/㎖, 9.66 ㎍/㎖ 이었다. 양성대조군인 3,3-테트라메칠렌글루타르산(IC50값: 5.41 ㎍/㎖)이 단일합성화합물인 것을 감안하여 효능을 비교할 때, 본 발명의 분획물들의 활성억제 효능이 우수하였다(표 2). 이에 밀통화 추출물 또는 이의 분획물은 알도즈 환원효소를 활성 억제하는 것으로 확인되었다.
As a result, a table 2, wheat call extract, the hexane fraction, ethyl acetate fraction, the butanol fraction or of the water fraction Al dose reductase activity inhibitory effect of the extract was 0.86 ㎍ / ㎖ IC 50 values, respectively, as shown in, 10 µg / ml or more, 6.26 µg / ml, 3.57 µg / ml, 9.66 µg / ml. Considering that the positive control group 3,3-tetramethyleneglutaric acid (IC 50 value: 5.41 μg / ml) is a monosynthetic compound, the efficacy of the fractions of the present invention was excellent (Table 2). ). Thus, the wheatgrass extract or fractions thereof was found to inhibit the aldose reductase activity.
(㎍/㎖)density
(占 퐂 / ml)
(%)control
(%)
(%)IC 50
(%)
밀통화 추출물
Wheat Currency Extract
0.5
50.25
0.5
5
37.74 ± 1.35
55.647 ± 2.3313.23 ± 3.75
37.74 ± 1.35
55.647 ± 2.33
0.86 ± 0.03
0.86 ± 0.03
헥산
분획물Of whole wheat extract
Hexane
Fraction
5
102.5
5
10
6.38 ± 3.54
2.68 ± 2.53-12.42 ± 4.62
6.38 ± 3.54
2.68 ± 2.53
>10
> 10
에틸아세테이트
분획물Of whole wheat extract
Ethyl acetate
Fraction
5
102.5
5
10
56.73 ± 3.74
73.61 ± 3.9044.85 ± 0.91
56.73 ± 3.74
73.61 ± 3.90
6.26 ± 0.29
6.26 ± 0.29
부탄올
분획물Of whole wheat extract
Butanol
Fraction
5
102.5
5
10
26.72 ± 3.97
52.67 ± 3.9021.88 ± 0.88
26.72 ± 3.97
52.67 ± 3.90
3.57 ± 0.49
3.57 ± 0.49
물
분획물Of whole wheat extract
water
Fraction
5
102.5
5
10
24.10 ± 2.04
29.39 ± 4.0822.62 ± 1.90
24.10 ± 2.04
29.39 ± 4.08
9.66 ± 0.41
9.66 ± 0.41
(3.3-Tetramethyleneglutaric acid)3,3-tetramethylene glutaric acid
(3.3-Tetramethyleneglutaric acid)
4.66
5.993.72
4.66
5.99
40.27 ± 1.36
51.58 ± 0.7833.03 ± 4.36
40.27 ± 1.36
51.58 ± 0.78
5.41 ± 0.13
5.41 ± 0.13
<< 실험예Experimental Example 3> 3> 밀통화Currency 추출물의 Extract 항당뇨Anti-diabetic 합병증에 대한 효능 분석 Efficacy Analysis for Complications
밀통화 추출물의 당뇨병 합병증에 미치는 효능을 확인하기 위하여, 스트렙토조토신(streptozotocin)으로 유도한 1형 당뇨 쥐에 밀통화 추출물을 12주간 경구 투여하여 당뇨병성 망막증에 대한 효능을 평가하였다.
To determine the efficacy of wheatgrass extract on diabetic complications, the efficacy of diabetic retinopathy was evaluated by oral administration of wheatgrass extract for 12 weeks to type 1 diabetic rats induced with streptozotocin (streptozotocin).
<3-1> 실험동물 준비<3-1> Preparation of experimental animals
실험동물은 생후 6주령 수컷 SD 랫트((주)오리엔트바이오, 한국) 1주일 동안 적응시킨 후 사용하였다. 당뇨 유도를 위한 스트렙토조토신을 60 mg/kg으로 복강주사로 주입한 뒤 일주일 후 혈당을 검사하여 공복혈당이 350 mg/dl 이상인 개체들만을 골라 당뇨군과 당뇨군에 약물투여군으로 분리하였다. 사료와 음용수는 자유 급식하였다. 당뇨를 유도한 뒤 시험약물과 대조약물 메트포르민(metformin; MET)을 다음의 농도(밀통화 추출물 50 mg/kg, 250 mg/kg, 메트포르민 350 mg/kg)가 되도록 하여 매일 경구투여 하였다. 시험군은 다음과 같이 (1) 정상군, (2) 당뇨유도군, (3) 메트포르민 투여군, (4) 밀통화 추출물 50 mg/kg 투여군, (5) 밀통화 추출물 250 mg/kg 투여군으로 구분하였다. 각각의 군별로 12주 동안 약물을 경구투여 하였다. 부검 하루 전에 16시간 동안 절식하였으며, 적출한 장기는 -80 ℃에 보관하였다.
The experimental animals were used after adapting for 6 weeks to male 1 week old male SD rats (Orien Bio, Korea). After injecting streptozotocin for diabetic induction at 60 mg / kg into the intraperitoneal injection, blood sugar was checked one week after, and only fasting blood glucose over 350 mg / dl was selected into the diabetic and diabetic groups. Feed and drinking water were fed freely. After induction of diabetes, the test drug and the control drug metformin (MET) were administered orally every day at the following concentrations (whole flour extract 50 mg / kg, 250 mg / kg, metformin 350 mg / kg). The test group was divided into (1) normal group, (2) diabetic induction group, (3) metformin administration group, (4)
<3-2> <3-2> 최종당화산물The final glycation product (( AGEsAGEs )의 망막조직 축적 예방 효과 확인Of retinal tissue accumulation prevention effect
망막조직에 당뇨합병증의 원인 물질로 알려진 최종당화산물(AGEs)의 축적 정도를 관찰하기 위하여, 면역조직화학염색을 수행하였다.Immunohistochemical staining was performed to observe the degree of accumulation of final glycation end products (AGEs) known as the causative agent of diabetic complications in retinal tissues.
구체적으로, 부검 시 장기를 적출하여 10% 중성화 포르말린에 하룻밤 고정한 후 탈수과정을 거쳐 자일렌(xylene)으로 3회 치환한 후 파라핀으로 포매하였다. 포매된 조직 블록을 4 um 두께로 연속 절편을 제작하여 슬라이드에 올려 사용하였다. 탈파라핀 과정과 함수과정을 거친 슬라이드(slide)를 내인성 퍼록시다제(peroxidase) 활성을 제거하기 위하여 3% H2O2 용액에 10분간 반응시킨 후 0.05% tween 20이 포함된 PBS로 3회 세척하였다. 비특이적 반응을 제거하기 위하여 5% 카세인(casein)을 이용하여 블로킹(blocking)한 후, 1차 항체(antibody) 각각 1:200으로 희석하여 1시간 또는 밤새(overnight) 적용하였다. 1시간 PBS로 세척한 후 labeled streptoavidin biotin(LSAB) kit(Dako, 미국)를 적용한 후 DAB로 발색하여 광학현미경 하에서 관찰하였다. 형광염색의 경우 FITC-conjugated된 2차 항체를 각각 1:200으로 희석하여 1시간 반응시킨 후, DAPI로 염색한 뒤 형광 현미경 하에서 관찰하였다.Specifically, during autopsy, organs were extracted, fixed in 10% neutralized formalin overnight, dehydrated three times with xylene, and embedded in paraffin. Embedded tissue blocks were used to prepare a continuous section of 4 um thickness on a slide. The deparaffinized and hydrolyzed slides were reacted with 3% H 2 O 2 solution for 10 minutes to remove endogenous peroxidase activity and washed three times with PBS containing 0.05
그 결과, 도 2에 나타낸 바와 같이, 정상군(NOR)에 비해 당뇨군(DM)에 AGEs 축적이 증가되었으며, MET군에서는 유의적인 감소 효과를 나타내었고, 밀통화 추출물 고농도군에서도 당뇨군에 비하여 유의적인 감소효과를 나타내는 것을 확인하였다(도 2).
As a result, as shown in Figure 2, the accumulation of AGEs was increased in the diabetic group (DM) compared to the normal group (NOR), and showed a significant reduction effect in the MET group, even in the high concentration group wheat flour extract compared to the diabetic group It was confirmed that the significant reduction effect (Fig. 2).
<3-3> <3-3> 망막신경세포Retinal nerve cells 소실에 대한 억제 효과 확인 Identify the inhibitory effect on loss
밀통화 추출물의 망막신경세포 소실에 대한 억제효과를 확인하기 위하여, TUNEL 염색을 수행하였다.In order to confirm the inhibitory effect on the retinal nerve cell loss of wheat currency extract, TUNEL staining was performed.
구체적으로, 조직절편을 탈 파라핀 하여 수화시킨 후 PBS로 세척한 20 ug/ml 농도의 프로테이나아제 K(proteinase K) 용액에 15분간 37℃에서 처리한 다음 다시 PBS로 세척한 후, TUNEL reation mixture 용액(In situ cell death detection kit, AP, Roche, 독일)을 1시간 동안 37℃ 반응시킨 후 현미경하에서 관찰하였다. Specifically, the tissue sections were de-paraffinized and hydrated, and then treated with proteinase K solution of 20 ug / ml, washed with PBS at 37 ° C. for 15 minutes, and washed again with PBS, followed by TUNEL reation. The mixture solution (In situ cell death detection kit, AP, Roche, Germany) was reacted under 37 ℃ for 1 hour and observed under a microscope.
그 결과, 도 3에 나타낸 바와 같이, 정상군에서 사멸세포(apoptotic cell)는 신경절세포층(ganglial cell layer) 위주로 관찰이 되지 않았고, 당뇨군에서는 신경절세포(ganglial cell) 위주로 사멸 세포가 두드러지게 관찰되었다. 그러나 MET 군과 밀통화 추출물 고농도 군에서는 당뇨군에 비하여 세포사멸이 유의적으로 감소하는 것을 확인하였다(도 3).
As a result, as shown in Figure 3, apoptosis cells (apoptotic cells) were not observed mainly in the ganglial cell layer (ganglial cell layer) in the normal group, apoptosis cells were observed mainly in the ganglial cells in the diabetic group. . However, it was confirmed that apoptosis was significantly reduced in the MET group and the high concentration group of the wheat extract extract compared to the diabetic group (FIG. 3).
<3-4><3-4> 뮐러 세포(Müller cells ( MullerMuller cellcell )의 활성화() 'S activation activationactivation ) 억제 효과 확인) Confirmation of inhibitory effect
안구 망막조직 내 존재하고 형태를 유지하는 기능과 염증세포와 유사한 기능을 가진 뮐러세포는 당뇨상태에서 활성화되어 염증유발 물질 등을 분비하여 망막증을 악화시킨다. 이러한, 뮐러세포 활성화에 따른 본 발명의 밀통화 추출물의 억제 효과를 확인하기 위하여, 뮐러세포 활성화에 따라 발현되는 표지물질 GFAP의 염색을 통하여 뮐러세포의 활성화를 확인하였다.Mueller cells, which are present in the retinal tissue and maintain their shape and function similar to those of inflammatory cells, are activated in the diabetic state and secrete inflammation-causing substances to worsen retinopathy. In order to confirm the inhibitory effect of the wheatgrass extract of the present invention according to the activation of Muller cells, the activation of Muller cells was confirmed through staining of the label GFAP expressed according to the activation of Muller cells.
그 결과, 도 4에 나타낸 바와 같이, 정상군에 비하여 당뇨군에서는 GFAP 양성반응이 현저히 증가되었으며, MET군에서는 당뇨군에 비하여 유의적으로 감소함을 확인하였다. 또한, 밀통화 추출물 고농도에서는 GFAP 양성 반응이 당뇨군에 비하여 현저히 감소하는 것을 확인하였다(도 4).
As a result, as shown in Figure 4, the GFAP positive response was significantly increased in the diabetic group compared to the normal group, it was confirmed that significantly decreased in the MET group compared to the diabetic group. In addition, it was confirmed that the GFAP positive response is significantly reduced compared to the diabetic group at high concentration of wheat flour extract (Fig. 4).
<3-5> <3-5> NFNF -- kBkB 핵내Nucleus 이동( move( translocationtranslocation ) 억제 효과 확인 ) Confirmation of inhibitory effect
NF-kB 핵내 이동에 대하여 본 발명의 밀통화 추출물의 억제 효과를 확인하기 위하여, 망막조직에서 nuclear extract를 준비하여 EMSA를 실시하였다.In order to confirm the inhibitory effect of the wheatgrass extract of the present invention on NF-kB nuclear migration, nuclear extract was prepared from retinal tissues and subjected to EMSA.
구체적으로, 조직에서 nuclear extractio kit(Pnomic,Redwood city, CA)를 이용하여 Nuclear 분리하였고, NF-kB 프로브(probe)는 NF-kB consensus sequence를 토대로 프로브를 제작하였다(Dig oligonucleotide 3-end labeling kit, Roche, 독일). 상기 준비된 프로브는 형광을 라벨링(labeling)시킨 뒤, 시료를 4% native gel에 10 ug로 전기영동하여 90V, 1시간 이동시켜 형광발색을 Odyseey를 통하여 관찰하였다.Specifically, the tissue was nuclear-separated using a nuclear extractio kit (Pnomic, Redwood city, CA), and the NF-kB probe (probe) was prepared based on the NF-kB consensus sequence (Dig oligonucleotide 3-end labeling kit). , Roche, Germany). After the labeled probe was labeled (fluorescence), the sample was electrophoresed at 10 ug in 4% native gel and moved to 90V for 1 hour, and fluorescence was observed through Odyseey.
그 결과, 도 5에 나타낸 바와 같이, 정상군에 비하여 당뇨군에서 핵내 이동이 현저히 증가한 반면, MET 및 밀통화 추출물 고농도군에서는 당뇨군에 비하여 유의적으로 감소하는 것을 확인하였다(도 5).
As a result, as shown in Figure 5, compared with the normal group in the diabetic group was significantly increased in the nucleus migration, while MET and wheat flour extract was found to be significantly reduced compared to the diabetic group (Fig. 5).
<3-6> <3-6> BaxBax 및 And Bcl2Bcl2 에 대한 효과 확인Check the effect on
세포사멸 유도인자인 Bax 및 세포사멸 억제인자인 Bcl2에 대한 본 발명의 밀통화 추출물의 효과를 확인하기 위하여, 상기 실험예 <3-2>와 동일한 방법으로 면역조직화학염색을 수행하였다.In order to confirm the effect of the wheatgrass extract of the present invention on Bax, an apoptosis inducing factor, and Bcl2, an apoptosis inhibitor, immunohistochemical staining was performed in the same manner as in Experimental Example <3-2>.
그 결과, 도 6에 나타낸 바와 같이, 정상군에 비하여 당뇨군에서는 신경절세포층의 세포질 부분이 현저히 Bax염색이 강하게 되었음을 관찰하였고, MET군은 당뇨군에 비하여 염색(staining)이 약하게 되었음을 관찰하였다. 반면, 밀통화 추출물 저농도 보다는 고농도에서 당뇨군과 비교시 염색이 현저히 감소됨을 관찰할 수 있었다. 그러나 Bcl2는 당뇨군과 정상군을 비교시 당뇨군에서 유의적으로 감소되었으며, MET군에서는 당뇨군에 비하여 유의적으로 증가됨을 확인하였다. 반면, 밀통화추출물 저농도보다는 고농도고 약물 처리군에서도 당뇨군에 비하여 유의적인 차이를 나타내었다(도 6).
As a result, as shown in Figure 6, the diabetic group compared to the normal group was observed that the cytoplasmic part of the ganglion cell layer was significantly stronger Bax staining, the MET group was observed that the staining (staining) is weaker than the diabetic group. On the other hand, it was observed that staining was significantly reduced compared to the diabetic group at high concentration rather than low concentration of wheat flour extract. However, Bcl2 was significantly decreased in the diabetic group compared to the diabetic group and the normal group, and significantly increased in the MET group compared to the diabetic group. On the other hand, high concentration and high drug treatment group showed a significant difference compared to the diabetic group rather than low concentration of wheat flour extract (Fig. 6).
<< 제조예Manufacturing example 1> 약학적 제제의 제조 1> Preparation of Pharmaceutical Formulations
<1-1> <1-1> 산제의Sanje 제조 Produce
본 발명의 <실시예 1>의 에탄올 추출물 2 g2 g of ethanol extract of <Example 1> of the present invention
유당 1 gLactose 1 g
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.
The above components were mixed and packed in airtight bags to prepare powders.
<1-2> 정제의 제조<1-2> Preparation of tablets
본 발명의 <실시예 1>의 에탄올 추출물 100 ㎎100 mg of ethanol extract of <Example 1> of the present invention
옥수수전분 100 ㎎ 유당 100 ㎎Corn Starch 100 mg Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
<1-3> 캡슐제의 제조≪ 1-3 > Preparation of capsules
본 발명의 <실시예 2>의 헥산 분획물 100 ㎎100 mg of hexane fraction of <Example 2> of the present invention
옥수수전분 100 ㎎Corn starch 100 mg
유 당 100 ㎎100 mg of milk
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
<1-4> 환의 제조≪ 1-4 >
본 발명의 <실시예 2>의 헥산 분획물 1 g1 g of hexane fraction of <Example 2> of the present invention
유당 1.5 gLactose 1.5 g
글리세린 1 g1 g of glycerin
자일리톨 0.5 gXylitol 0.5 g
상기의 성분을 혼합한 후, 통상의 방법에 따라 1 환 당 4 g이 되도록 제조하였다.
After mixing the above components, they were prepared so as to be 4 g per one ring according to a conventional method.
<1-5> 과립의 제조<1-5> Preparation of granules
본발명의 <실시예 2>의 헥산 분획물 150 ㎎150 mg of hexane fraction of <Example 2> of the present invention
대두 추출물 50 ㎎Soybean extract 50 mg
포도당 200 ㎎200 mg of glucose
전분 600 ㎎600 mg of starch
상기의 성분을 혼합한 후, 30% 에탄올 100 ㎎을 첨가하여 섭씨 60℃에서 건조하여 과립을 형성한 후 포에 충진하였다.
After mixing the above components, 100 mg of 30% ethanol was added and the mixture was dried at 60 캜 to form granules, which were then filled in a capsule.
<< 제조예Manufacturing example 2> 식품의 제조 2> Manufacturing of food
본 발명의 밀통화 추출물을 포함하는 식품들을 다음과 같이 제조하였다.
Foods containing wheatgrass extract of the present invention were prepared as follows.
<2-1> 밀가루 식품의 제조<2-1> Production of flour food
본 발명의 <실시예 2>의 에탄올 추출물 0.5~5.0 중량부를 밀가루에 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하였다.
0.5-5.0 parts by weight of the ethanol extract of <Example 2> of the present invention was added to the flour, and bread, cake, cookies, crackers and noodles were prepared using this mixture.
<2-2> <2-2> 스프soup 및 육즙( And juicy ( graviesgravies )의 제조)
본 발명의 <실시예 1>의 에탄올 추출물 0.1~5.0 중량부를 스프 및 육즙에 첨가하여 건강 증진용 육가공 제품, 면류의 수프 및 육즙을 제조하였다.
0.1 to 5.0 parts by weight of ethanol extract of <Example 1> of the present invention was added to soups and broths to prepare meat products for health promotion, soups of noodles and broths.
<2-3> 그라운드 <2-3> Ground 비프(ground beef)의Beef 제조 Produce
본 발명의 <실시예 1>의 에탄올 추출물 10 중량부를 그라운드 비프에 첨가하여 건강 증진용 그라운드 비프를 제조하였다.
10 parts by weight of the ethanol extract of <Example 1> of the present invention was added to the ground beef to prepare a ground beef for health promotion.
<2-4> 유제품(<2-4> Dairy products ( dairydairy productsproducts )의 제조)
본 발명의 <실시예 1>의 에탄올 추출물 5~10 중량부를 우유에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.
5 to 10 parts by weight of ethanol extract of <Example 1> of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.
<2-5> <2-5> 선식의Solar 제조 Produce
현미, 보리, 찹쌀, 율무를 공지의 방법으로 알파화시켜 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 제조하였다.Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh.
검정콩, 검정깨, 들깨도 공지의 방법으로 쪄서 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 제조하였다.Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a conventional method, and then they were prepared into powder having a particle size of 60 mesh by a pulverizer.
본 발명의 <실시예 1>의 에탄올 추출물을 진공 농축기에서 감압농축하고, 분무, 열풍건조기로 건조하여 얻은 건조물을 분쇄기로 입도 60 메쉬로 분쇄하여 건조분말을 얻었다.The ethanol extract of <Example 1> of the present invention was concentrated under reduced pressure in a vacuum concentrator, and the dried product obtained by drying with a spray and a hot air dryer was pulverized with a particle size of 60 mesh to obtain a dry powder.
상기에서 제조한 곡물류, 종실류 및 <실시예 1>의 에탄올 추출물을 다음의 비율로 배합하여 제조하였다.The grains, seeds, and ethanol extracts of <Example 1> prepared above were prepared by combining the following ratios.
곡물류(현미 30 중량부, 율무 15 중량부, 보리 20 중량부),(30 parts by weight of brown rice, 15 parts by weight of yulmu, 20 parts by weight of barley)
종실류(들깨 7 중량부, 검정콩 8 중량부, 검정깨 7 중량부),Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds)
본 발명의 <실시예 1>의 에탄올 추출물(3 중량부),Ethanol extract (3 parts by weight) of <Example 1> of the present invention,
영지(0.5 중량부),(0.5 part by weight),
지황(0.5 중량부)
(0.5 parts by weight)
<< 제조예Manufacturing example 3> 음료의 제조 3> Manufacturing of beverage
<3-1> <3-1> 건강음료의Health drink 제조 Produce
액상과당(0.5%), 올리고당(2%), 설탕(2%), 식염(0.5%), 물(75%)과 같은 부재료와 본 발명의 <실시예 2>의 에틸아세테이트 분획물 5 g을 균질하게 배합하여 순간 살균을 한 후 이를 유리병, 패트병 등 소포장 용기에 포장하여 제조하였다.
Homogeneous components such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%) and water (75%) and 5 g of ethyl acetate fraction of Example 2 of the present invention are homogeneous. After sterilization and instant sterilization, it was prepared by packaging in small packaging containers such as glass bottles and plastic bottles.
<3-2> 야채 주스의 제조<3-2> Preparation of vegetable juice
본 발명의 <실시예 2>의 에틸아세테이트 분획물 5 g을 토마토 또는 당근 주스 1,000 ㎖에 가하여 야채 주스를 제조하였다.
5 g of the ethyl acetate fraction of <Example 2> of the present invention was added to 1,000 ml of tomato or carrot juice to prepare vegetable juice.
<3-3> 과일 주스의 제조<3-3> Production of fruit juice
본 발명의 <실시예 2>의 에틸아세테이트 분획물 1 g을 사과 또는 포도 주스 1,000 ㎖ 에 가하여 과일 주스를 제조하였다.
1 g of the ethyl acetate fraction of <Example 2> of the present invention was added to 1,000 ml of apple or grape juice to prepare a fruit juice.
Claims (9)
A pharmaceutical composition for preventing and treating diabetic complications, which contains an eggplant or stem extract of Branisia hancei Hook.f. as an active ingredient.
The pharmaceutical composition for preventing and treating diabetic complications according to claim 1, wherein the branch or stem extract of the wheat flour is extracted with water, lower alcohols of C 1 to C 2 , mixed solvents or water-soluble alcohols thereof.
4. The pharmaceutical composition for preventing and treating diabetic complications of claim 3, wherein the lower alcohol is ethanol or methanol.
Fractions prepared by adding an organic solvent to the branch or stem extract of wheat bran, are added as an active ingredient, and the organic solvent is diabetic complication of any one or combination thereof selected from the group consisting of ethanol, hexane, ethyl acetate, butanol and water. Prophylactic and therapeutic pharmaceutical compositions.
The hexane fraction, ethyl acetate fraction, butanol fraction or water fraction according to claim 5, wherein the fraction is obtained by suspending the branch or stem extract of wheat flour in water and then systematically fractionating the mixture with hexane, ethyl acetate, butanol and water. Pharmaceutical composition for preventing and treating diabetic complications, characterized in that any one.
The method according to any one of claims 1 to 6, wherein the diabetic complications include diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, and diabetic atherosclerosis. Pharmaceutical composition for preventing and treating diabetic complications, characterized in that any one selected from the group consisting of.
Fractions prepared by adding an organic solvent to the branch or stem extract of wheat bran, are added as an active ingredient, and the organic solvent is diabetic complication of any one or combination thereof selected from the group consisting of ethanol, hexane, ethyl acetate, butanol and water. Preventive and improving health food composition.
9. The method of claim 8, wherein the diabetic complication is any one selected from the group consisting of diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, and diabetic atherosclerosis. Health food composition for preventing and improving diabetic complications, characterized in that.
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| PCT/KR2011/006046 WO2012023803A2 (en) | 2010-08-17 | 2011-08-17 | Composition for preventing and treating complications of diabetes mellitus, containing brandisia hancei hook. f. extract or fraction thereof as active ingredient |
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Non-Patent Citations (6)
| Title |
|---|
| A. Guvenc et al. Food Chemistry. Vol.118 pp.686-692 (2010.2.1.) * |
| A. Guvenc et al. Food Chemistry. Vol.118 pp.686-692 (2010.2.1.)* |
| H. Kohda et al. Chemical and Pharmaceutical Bulletin. Vol.37, No.11, pp.3153-3154 (1989) * |
| H. Ravn et al. Phytochemistry, Vol.29, No. 1, pp.3627-3631 (1990) * |
| Z.-D. He et al. Journal of Ethnopharmacology. Vol.71, pp.483-486 (2000) * |
| Z.-D. He et al. Journal of Ethnopharmacology. Vol.71, pp.483-486 (2000)* |
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