KR20220002149A - Composition for preventing, improving or treating non-alcoholic fatty liver disease comprising mixed extract of Cirsium japonicum, Artemisia annua and Curcuma longa as effective component - Google Patents
Composition for preventing, improving or treating non-alcoholic fatty liver disease comprising mixed extract of Cirsium japonicum, Artemisia annua and Curcuma longa as effective component Download PDFInfo
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- KR20220002149A KR20220002149A KR1020210085248A KR20210085248A KR20220002149A KR 20220002149 A KR20220002149 A KR 20220002149A KR 1020210085248 A KR1020210085248 A KR 1020210085248A KR 20210085248 A KR20210085248 A KR 20210085248A KR 20220002149 A KR20220002149 A KR 20220002149A
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- Prior art keywords
- extract
- turmeric
- fatty liver
- alcoholic fatty
- mixed extract
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Abstract
Description
본 발명은 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물을 유효성분으로 포함하는 비알코올성 지방간 질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating non-alcoholic fatty liver disease, comprising a mixed extract of milk thistle, mugwort and turmeric as an active ingredient.
지방간은 간세포 속에 지방이 축적된 상태를 말하며, 정상 간은 지방이 차지하는 비율은 5% 정도인데, 이보다 많은 지방이 축적된 상태를 지방간이라고 한다. 지방간이 악화되어 간세포 속의 지방 덩어리가 커지면 핵을 포함한 세포의 중요한 구성성분이 한쪽으로 밀려 간세포의 기능이 저하되며, 세포 내에 축적된 지방으로 인하여 팽창된 간세포들이 간세포 사이에 있는 미세 혈관과 임파선을 압박하여 간 내의 혈액과 임파액의 순환에 장애가 생기게 된다. 이렇게 되면 간세포는 산소와 영양공급을 적절히 받을 수 없어 간기능이 저하된다.Fatty liver refers to a state in which fat is accumulated in hepatocytes. In a normal liver, fat accounts for about 5%, and a state in which more fat is accumulated is called fatty liver. When the fatty liver worsens and the fat mass in the liver cells grows, important components of the cells, including the nucleus, are pushed to one side, and the function of the liver cells decreases. As a result, the circulation of blood and lymph in the liver is impaired. In this case, hepatocytes cannot receive adequate oxygen and nutrients, and liver function deteriorates.
지방간은 알코올성 지방간과 비알코올성 지방간으로 나눌 수 있다. 알코올성 지방간은 술이 원인이다. 술을 많이 마실수록 잘 발생하며, 지속적으로 술을 섭취하면 간에서 알코올을 대사하는 능력이 떨어져 지방간 발생이 더 심해진다. 또 영양상태가 나쁜 경우에도 잘 발생한다. 알코올성 지방간 중 일부는 알코올성 간염과 간경변으로 진행되어 사망할 수 있다.Fatty liver can be divided into alcoholic fatty liver and nonalcoholic fatty liver. Alcoholic fatty liver is caused by alcohol. It occurs more frequently when you drink a lot of alcohol, and if you drink alcohol continuously, the liver's ability to metabolize alcohol decreases, which makes fatty liver more severe. It also occurs when the nutritional status is poor. Some alcoholic fatty liver can lead to alcoholic hepatitis and cirrhosis, which can lead to death.
비알코올성 지방간은 술 또는 바이러스 감염과 상관없이 간 내 지방축적이 증가한 경우로(간세포의 5% 초과), 간에서 지방 합성 증가 및 배출의 문제로 발생한다. 유리지방산(fatty acid)의 투입(input)과 배출(output)의 불균형에 의해 유발되는 비알코올성 지방간 환자의 약 59%는 외부로부터 유리지방산의 흡수 증가에 의해 발생하고, 약 26% 환자는 간 내 지방 생합성의 증가에 따른 유리지방산의 투입(input) 증가를 원인으로 유발되는 것으로 알려져 있다.Nonalcoholic fatty liver is a case of increased fat accumulation in the liver (>5% of hepatocytes) regardless of alcohol or viral infection. About 59% of patients with nonalcoholic fatty liver caused by an imbalance in the input and output of free fatty acids are caused by increased absorption of free fatty acids from the outside, and about 26% of patients with fatty acid in the liver It is known to be caused by an increase in the input of free fatty acids according to the increase in fat biosynthesis.
지방간은 병의 원인과 심각성이 밝혀졌고, 식이 조절과 운동을 통하여 증상을 개선해야 하지만, 지방간 환자가 이를 실천하지 못하는 경우가 많다. 따라서 효과적인 지방간 치료 약물의 개발 필요성이 요구되고 있다.The cause and severity of fatty liver disease have been identified, and symptoms need to be improved through diet control and exercise, but there are many cases in which fatty liver patients fail to practice it. Therefore, there is a need for the development of an effective drug for treating fatty liver.
한편, 엉겅퀴(Cirsium japonicum var. ussuriense)는 국화과(Compositae)에 속하는 다년생 초본으로 한방에서 지상부 또는 지하부(뿌리)를 대계라하여 약용으로 활용해왔다. 꽃, 잎, 줄기, 씨 등 지상부는 개화시기에서 씨가 여무는 5~6월에 채취하고, 뿌리는 가을에 채취하여 건조시킨 후 열수 또는 알코올 추출하여 토혈, 혈뇨, 대하, 간염, 고혈압 등 치료에 활용해 왔다.On the other hand, thistle ( Cirsium japonicum var. ussuriense) is a perennial herb belonging to the Compositae family, and has been used medicinally in oriental medicine by calling its above-ground or underground part (root) as Daegye. The above-ground parts such as flowers, leaves, stems, and seeds are collected from the flowering period to the ripening of the seeds in May to June, and the roots are collected in autumn, dried, and extracted with hot water or alcohol to treat hematemesis, hematuria, lobster, hepatitis, hypertension, etc. has been used for
울금(Curcuma longa L.)은 생강과에 속하는 다년생 초목으로서 원산지는 인도, 중국, 일본 등이고, 고온다습한 남부 아시아, 아프리카 및 중남미에서 자생하고 있으며 동인도 지방에서 재배가 시작되었다고 알려져 있다. 울금은 한약재, 향신료 및 식용으로, 열대지방의 남아시아와 동남아시아에서 오랜 기간 동안 사용되어 왔는데, 울금의 가루나 추출액은 "본초강목"과 "동의보감" 등의 고서나 기타 동물 실험에서 이담 작용, 위액 분비 촉진 작용, 이뇨 작용, 해독 기능, 항암 작용, 항염 작용, 항산화 작용 등이 알려져 있다.Turmeric ( Curcuma longa L.) is a perennial plant belonging to the ginger family, and its origins are India, China, Japan, etc., and grows wild in hot and humid southern Asia, Africa and Central and South America, and it is known that cultivation began in the East India region. Turmeric has been used for a long time in South and Southeast Asia in the tropics as herbal medicine, spice and food. It is known for its accelerating action, diuretic action, detoxification action, anticancer action, anti-inflammatory action, antioxidant action, and the like.
개똥쑥(Artemisia annua)은 주로 중국에서 자생하나 국내 여러 지역에서 재배하는 국화과의 한해살이 풀이다. 개똥쑥은 전통적으로 발열, 감기, 학질, 소아경기, 소화불량, 이질 등의 치료에 사용해 왔고 항말라리아제인 아르테미시닌의 원료 식물로서 알려져 있다. Artemisia annua ( Artemisia annua ) is an annual grass of the Asteraceae family that is mainly native to China, but cultivated in various areas in Korea. Artemisia wormwood has traditionally been used to treat fever, cold, dysentery, pediatric dyspepsia, dyspepsia, and dysentery, and is known as a raw material plant for the antimalarial agent, Artemisinin.
한편, 한국공개특허 제2020-0014567호에는 '엉겅퀴를 함유하는 간질환의 개선, 예방 또는 치료용 조성물'에 대해 개시하고 있으며, 한국등록특허 제1539289호에는 '개똥쑥 추출물을 함유하는 지방간 또는 비만의 예방 또는 치료용 조성물'에 대해 개시하고 있다. 하지만, 본 발명의 '엉겅퀴, 개똥쑥 및 울금의 혼합 추출물을 유효성분으로 포함하는 비알코올성 지방간 질환의 예방, 개선 또는 치료용 조성물'에 대해서는 아직까지 개시된 바가 없다. On the other hand, Korea Patent Application Publication No. 2020-0014567 discloses 'a composition for improving, preventing or treating liver disease containing milk thistle', and Korean Patent No. 1539289 discloses 'fatty liver or obesity containing wormwood extract. It discloses a composition for the prevention or treatment of '. However, the 'composition for preventing, improving or treating non-alcoholic fatty liver disease comprising a mixed extract of milk thistle, wormwood and turmeric as an active ingredient' of the present invention has not been disclosed yet.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명은 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 유효성분으로 포함하는 비알코올성 지방간 질환의 예방, 개선 또는 치료용 조성물을 제공하며, 간세포 모델에서 엉겅퀴 추출물, 개똥쑥 추출물 및 울금 추출물 단독에 비해 본 발명의 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 처리군에서 중성지방 및 과산화물(MDA) 함량이 유의미하게 더 감소였고, 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물의 투여에 따른 동물 모델의 체중변화, 간 지방조직의 무게 변화 및 지질생화학적 지표들이 유의미하게 변화한다는 것을 확인함으로써, 본 발명을 완성하였다.The present invention has been derived from the above needs, and the present invention provides a composition for preventing, improving or treating non-alcoholic fatty liver disease comprising a mixed extract of thistle leaf, wormwood leaf and turmeric root as an active ingredient, In the hepatocyte model, the triglyceride and peroxide (MDA) contents were significantly reduced in the mixed extract treatment group of thistle, wormwood and turmeric of the present invention compared to thistle extract, wormwood extract and turmeric extract alone. The present invention was completed by confirming that the weight change of the animal model, the weight change of the liver adipose tissue, and the lipid biochemical indices significantly changed according to the administration of the mixed extract of leaves and turmeric root.
상기 과제를 해결하기 위하여, 본 발명은 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 유효성분으로 함유하는 비알코올성 지방간 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In order to solve the above problems, the present invention provides a health functional food composition for preventing or improving non-alcoholic fatty liver disease containing a mixed extract of thistle leaf, wormwood leaf and turmeric root as an active ingredient.
또한, 본 발명은 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 유효성분으로 함유하는 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating non-alcoholic fatty liver disease containing a mixed extract of thistle leaf, wormwood leaf and turmeric root as an active ingredient.
본 발명은 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 유효성분으로 포함하는 비알코올성 지방간 질환의 예방, 개선 또는 치료용 조성물에 관한 것으로, 간세포 모델에서 엉겅퀴 추출물, 개똥쑥 추출물 및 울금 추출물 단독에 비해 본 발명의 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 처리군에서 중성지방 및 과산화물(MDA) 함량이 유의미하게 더 감소였을 뿐만 아니라, 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물의 투여에 따른 동물 모델의 체중변화, 간 지방조직의 무게 변화 및 지질생화학적 지표들의 변화가 유의하게 나타났으므로, 본 발명의 조성물은 비알코올성 지방간 질환의 예방, 개선 또는 치료를 위한 건강기능식품 또는 의약품 소재 개발에 매우 유용하게 사용될 수 있다. The present invention relates to a composition for the prevention, improvement or treatment of non-alcoholic fatty liver disease, comprising a mixed extract of thistle leaf, wormwood leaf and turmeric root as an active ingredient, and in a hepatocyte model, thistle extract, wormwood extract and turmeric extract alone In the group treated with the mixed extract of thistle, mugwort and turmeric, the triglyceride and peroxide (MDA) content was significantly further reduced as compared to the Since the weight change of the animal model, the weight change of the liver adipose tissue, and the change of the lipid biochemical indicators were significant, the composition of the present invention is a health functional food or pharmaceutical material development for the prevention, improvement or treatment of non-alcoholic fatty liver disease can be very useful for
도 1은 3T3-L1 세포(A) 및 HepG2 세포(B)에서 엉겅퀴 추출물, 개똥쑥 추출물 및 울금 추출물의 세포독성을 확인한 것이다.
도 2는 엉겅퀴 추출물, 개똥쑥 추출물, 울금 추출물 및 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 HepG2 세포 내 지방구 염색이다. 혼합 추출물 1은 엉겅퀴:개똥쑥:울금=60:35:5의 중량비로 혼합한 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물이고, 혼합 추출물 2는 엉겅퀴:개똥쑥:울금=70:25:5의 중량비로 혼합한 것이며, 혼합 추출물 3은 엉겅퀴:개똥쑥:울금=80:15:5의 중량비로 혼합한 것이다.
도 3은 엉겅퀴 추출물, 개똥쑥 추출물, 울금 추출물 및 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 HepG2 세포 내 축적된 중성지방 함량을 확인한 것이다. Normal은 정상군이며, Control은 지방산으로 비알콜성 지방간을 유도한 대조군이다. CAC는 지방산으로 비알콜성 지방간을 유도한 세포에 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 실험군이고, 엉겅퀴, 울금 및 개똥쑥은 비교예로서, 각각 단독 추출물을 처리한 것이다. a~f는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 4는 엉겅퀴 추출물, 개똥쑥 추출물, 울금 추출물 및 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 HepG2 세포 내 축적된 지질과산화물(MDA) 함량을 확인한 것이다. Normal은 정상군이며, Control은 지방산으로 비알콜성 지방간을 유도한 대조군이다. CAC는 지방산으로 비알콜성 지방간을 유도한 세포에 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 실험군이고, 엉겅퀴, 울금 및 개똥쑥은 비교예로서, 각각 단독 추출물을 처리한 것이다. a~d는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 5는 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 HepG2 세포 내 AST(A) 및 ALT(B)의 함량을 확인한 것이다. Normal은 정상군이며, Control은 지방산으로 비알콜성 지방간을 유도한 대조군이다. CAC는 지방산으로 비알콜성 지방간을 유도한 세포에 본 발명의 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 처리한 실험군이고 MT는 양성대조군으로 밀크씨슬이다. a~d는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 6은 고지방 식이한 동물 모델에 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 따른 혈액 내 중성지방(TG)(A), GOT(B) 및 GPT(C) 함량을 확인한 결과이다. a~c는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 7은 고지방 식이한 동물 모델에 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여한 후, 간조직(A) 및 지방조직(B)에서의 중성지방(TG) 함량 변화를 확인한 것이다.
도 8은 고지방 식이한 동물 모델에 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여한 후, 간조직에서 중성지방(A) 및 산화손상(B, C) 변화를 확인한 것이다. a~c는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 9는 고지방 식이 동물모델에 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여한 후, 지방간염 관련 염증인자(COX-2(A), iNOS(B) 및 TNF-α(C))의 발현량 변화를 확인한 것이다. a~d는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 10은 고지방 식이 동물모델에 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여한 후, 간조직에서 고지방식이에 의해 증가된 PPAR-r의 발현량(A) 및 감소된 CEBPA의 발현량(B) 변화를 확인한 것이다. a~d는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.
도 11은 고지방 식이 동물모델에 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여한 후, 간조직에서 고지방식이에 의해 증가된 사이토카인 IL-17 발현량 변화를 확인한 것이다. a~c는 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.1 shows the cytotoxicity of milk thistle extract, wormwood extract and turmeric extract in 3T3-L1 cells (A) and HepG2 cells (B).
Fig. 2 shows the staining of fat cells in HepG2 cells treated with thistle extract, wormwood extract, turmeric extract, and a mixed extract of thistle leaf, wormwood leaf and turmeric root of the present invention. Mixed
Figure 3 confirms the content of accumulated triglycerides in HepG2 cells treated with thistle extract, wormwood extract, turmeric extract, and a mixed extract of thistle leaf, ragweed leaf and turmeric root of the present invention. Normal is a normal group, and Control is a control group in which non-alcoholic fatty liver is induced with fatty acids. CAC is an experimental group in which the mixed extracts of thistle leaf, wormwood leaf and turmeric root of the present invention were treated in cells induced by nonalcoholic fatty liver with fatty acids, and thistle, turmeric and wormwood were treated as comparative examples, each single extract did it a~f indicates that there is a statistically significant difference, p<0.05.
Figure 4 confirms the content of accumulated lipid peroxide (MDA) in HepG2 cells treated with thistle extract, wormwood extract, turmeric extract, and a mixed extract of thistle leaf, ragweed leaf and turmeric root of the present invention. Normal is a normal group, and Control is a control group in which non-alcoholic fatty liver is induced with fatty acids. CAC is an experimental group in which the mixed extracts of thistle leaf, wormwood leaf and turmeric root of the present invention were treated in cells induced by nonalcoholic fatty liver with fatty acids, and thistle, turmeric and wormwood were treated as comparative examples, each single extract did it a~d indicates that there is a statistically significant difference, p<0.05.
5 shows the contents of AST (A) and ALT (B) in HepG2 cells treated with a mixed extract of thistle leaf, ragweed leaf and turmeric root of the present invention. Normal is a normal group, and Control is a control group in which non-alcoholic fatty liver is induced with fatty acids. CAC is an experimental group in which non-alcoholic fatty liver-induced cells with fatty acids are treated with a mixed extract of thistle leaf, wormwood leaf, and turmeric root of the present invention, and MT is milk thistle as a positive control. a~d indicates that there is a statistically significant difference, p<0.05.
6 is a result of confirming the content of triglycerides (TG) (A), GOT (B) and GPT (C) in the blood according to the administration of mixed extracts of milk thistle, wormwood and turmeric in an animal model on a high-fat diet. a~c indicates that there is a statistically significant difference, p<0.05.
7 shows the change in triglyceride (TG) content in liver tissue (A) and adipose tissue (B) after administration of mixed extracts of milk thistle, wormwood and turmeric to an animal model on a high-fat diet.
8 is a graph showing changes in triglycerides (A) and oxidative damage (B, C) in liver tissue after administration of mixed extracts of milk thistle, mugwort and turmeric to an animal model on a high-fat diet. a~c indicates that there is a statistically significant difference, p<0.05.
Figure 9 is after administration of mixed extracts of milk thistle, mugwort and turmeric to a high-fat diet animal model, changes in the expression level of steatohepatitis-related inflammatory factors (COX-2 (A), iNOS (B) and TNF-α (C)) will confirm a~d indicates that there is a statistically significant difference, p<0.05.
10 is after administration of mixed extracts of milk thistle, mugwort and turmeric to a high-fat diet animal model, the expression level of PPAR-r increased by a high-fat diet in liver tissue (A) and the expression level of CEBPA decreased (B) change was confirmed. a~d indicates that there is a statistically significant difference, p<0.05.
11 is a graph showing changes in the expression level of cytokine IL-17 increased by a high-fat diet in liver tissue after administration of mixed extracts of milk thistle, mugwort and turmeric to a high-fat diet animal model. a~c indicates that there is a statistically significant difference, p<0.05.
본 발명의 목적을 달성하기 위하여, 본 발명은 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 유효성분으로 함유하는 비알코올성 지방간 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In order to achieve the object of the present invention, the present invention provides a health functional food composition for preventing or improving non-alcoholic fatty liver disease containing a mixed extract of thistle leaf, wormwood leaf and turmeric root as an active ingredient.
본 발명의 비알코올성 지방간 질환의 예방 또는 개선용 건강기능식품 조성물에서, 상기 혼합 추출물은 울금 뿌리 1중량부에 대하여, 개똥쑥 잎 2~10 중량부 및 엉컹퀴 잎 10~20 중량부로 혼합하는 것이 바람직하며, 더욱더 바람직하게는 울금 뿌리 1중량부에 대하여, 개똥쑥 잎 2~4 중량부 및 엉컹퀴 잎 15~17 중량부로 혼합하는 것이고, 가장 바람직하게는 울금 뿌리 1중량부에 대하여, 개똥쑥 잎 3 중량부 및 엉컹퀴 잎 16 중량부로 혼합하는 것이지만 이에 한정하는 것은 아니다.In the health functional food composition for preventing or improving non-alcoholic fatty liver disease of the present invention, the mixed extract is preferably mixed with 2 to 10 parts by weight of wormwood leaves and 10 to 20 parts by weight of turmeric leaves with respect to 1 part by weight of turmeric root. and even more preferably, 2 to 4 parts by weight of wormwood leaves and 15 to 17 parts by weight of turmeric leaves are mixed with respect to 1 part by weight of turmeric root, and most preferably, 3 parts by weight of wormwood leaves per 1 part by weight of turmeric root. It is mixed in parts by weight and 16 parts by weight of squid leaves, but is not limited thereto.
또한, 혼합 추출물은 물, C1~C4의 저급 알코올 또는 이들의 혼합물을 용매로 이용하여 제조될 수 있으나, 이에 제한되지 않는다.In addition, the mixed extract may be prepared by using water, a C 1 to C 4 lower alcohol or a mixture thereof as a solvent, but is not limited thereto.
상기 비알코올성 지방간 질환의 예방 또는 개선용 건강기능식품 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽, 발포정 및 음료 중에서 선택된 어느 하나의 제형으로 제조될 수 있으나, 이에 제한되지 않는다. The health functional food composition for preventing or improving non-alcoholic fatty liver disease may be prepared in any one formulation selected from powder, granule, pill, tablet, capsule, candy, syrup, effervescent tablet and beverage, but is not limited thereto.
본 발명의 건강기능식품 조성물을 식품첨가물로 사용하는 경우, 상기 건강기능식품 조성물을 그대로 첨가하거나 다른 식품 또는 식품성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 양은 그의 사용 목적(예방 또는 개선)에 따라 적절하게 사용될 수 있다. 일반적으로, 식품 또는 음료의 제조시 본 발명의 건강기능식품 조성물은 원료에 대하여 15 중량부 이하, 바람직하게는 10 중량부 이하의 양으로 첨가된다. 그러나 건강을 목적으로 하는 장기간의 섭취인 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로 사용될 수 있다.When the health functional food composition of the present invention is used as a food additive, the health functional food composition may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The amount of the active ingredient may be appropriately used depending on the purpose of its use (prevention or improvement). In general, in the production of food or beverage, the health functional food composition of the present invention is added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less, based on the raw material. However, in the case of long-term intake for health purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
상기 건강기능식품의 종류에 특별한 제한은 없다. 상기 건강기능식품 조성물을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the type of the health functional food. Examples of foods to which the health functional food composition can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea There are drinks, alcoholic beverages, vitamin complexes, etc., and includes all health foods in the ordinary sense.
또한, 본 발명의 건강기능식품 조성물은 식품, 특히 기능성 식품으로 제조될 수 있다. 본 발명의 기능성 식품은 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분 이외에 천연 탄수화물 또는 향미제를 추가 성분으로서 포함할 수 있다. 상기 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등), 디사카라이드(예컨대, 말토스, 수크로오스 등), 올리고당, 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등) 또는 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)인 것이 바람직하다. 상기 향미제는 천연 향미제(예컨대, 타우마틴, 스테비아 추출물 등)와 합성 향미제(예컨대, 사카린, 아스파르탐 등)를 이용할 수 있다.In addition, the health functional food composition of the present invention may be prepared as a food, particularly a functional food. The functional food of the present invention includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients and seasonings. For example, when manufactured as a drink, a natural carbohydrate or flavoring agent may be included as an additional ingredient in addition to the active ingredient. The natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, etc.), oligosaccharides, polysaccharides (eg, dextrin, cyclodextrin, etc.) or sugar alcohols (eg, , xylitol, sorbitol, erythritol, etc.) is preferable. As the flavoring agent, natural flavoring agents (eg, taumartin, stevia extract, etc.) and synthetic flavoring agents (eg, saccharin, aspartame, etc.) may be used.
상기 건강기능식품 조성물 이외에 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 더 함유할 수 있다. 이러한 상기 첨가되는 성분의 비율은 크게 중요하진 않지만 본 발명의 건강기능식품 조성물 100 중량부에 대하여, 0.01~0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the health functional food composition, various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonic acid It may further contain a carbonation agent and the like used in beverages. The ratio of these added ingredients is not very important, but is generally selected in the range of 0.01 to 0.1 parts by weight based on 100 parts by weight of the health functional food composition of the present invention.
또한, 본 발명은 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리의 혼합 추출물을 유효성분으로 함유하는 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating non-alcoholic fatty liver disease containing a mixed extract of thistle leaf, wormwood leaf and turmeric root as an active ingredient.
본 발명의 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물에서, 상기 비알코올성 지방간 질환은 단순 지방간, 영양성 지방간, 기아성 지방간, 비만성 지방간, 당뇨성 지방간, 지방간염, 간섬유화 및 간경화로 이루어진 군으로부터 선택된 어느 하나일 수 있으나, 이에 제한되지 않는다.In the pharmaceutical composition for preventing or treating nonalcoholic fatty liver disease of the present invention, the nonalcoholic fatty liver disease is a group consisting of simple fatty liver, nutritive fatty liver, starvation fatty liver, obese fatty liver, diabetic fatty liver, steatohepatitis, liver fibrosis and cirrhosis. It may be any one selected from, but is not limited thereto.
본 발명의 약학 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. The pharmaceutical composition of the present invention may further include an appropriate carrier, excipient or diluent commonly used in the preparation of the pharmaceutical composition.
본 발명에 따른 조성물의 약학적 투여 형태는 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다.The pharmaceutical dosage form of the composition according to the present invention may be used alone or in combination with other pharmaceutically active compounds, as well as in any suitable group.
본 발명에 따른 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으나 이에 한정되는 것은 아니다. 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 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 광물유를 들 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 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(Calcium carbonate), 수크로스(Sucrose) 또는 락토오스(Lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(Witepsol), 마크로골, 트윈(Tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. However, the present invention is not limited thereto. Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, Witepsol, macrogol, Tween 61, cacao butter, laurin fat, glycerogelatin, etc. may be used.
본 발명의 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장, 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다.The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. The pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.
이하, 실시예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다. Hereinafter, the present invention will be described in more detail using examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited thereto.
실시예 1. 엉겅퀴, 개똥쑥 및 울금 혼합 추출물의 제조Example 1. Preparation of mixed extracts of thistle, wormwood and turmeric
(1) 열수 추출(1) hot water extraction
건조한 엉겅퀴 잎 80g, 개똥쑥 잎 15g 및 울금 뿌리 5g을 혼합한 후, 증류수 1.5ℓ에 첨가하였다. 이후 105℃에서 8시간 동안 추출하고 여과(와트만 종이 No. 2) 및 동결건조하여 엉겅퀴, 개똥쑥 및 울금 혼합 물 추출물을 제조하였다. 비교예로, 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리 각각 100g을 사용한 것을 제외하고 상기와 동일한 방법으로 엉겅퀴 물 추출물, 개똥쑥 물 추출물 및 울금 물 추출물을 제조하였다.After mixing 80 g of dried thistle leaves, 15 g of wormwood leaves and 5 g of turmeric root, it was added to 1.5 liters of distilled water. Thereafter, extraction was performed at 105° C. for 8 hours, filtered (Whatman paper No. 2), and freeze-dried to prepare a mixture extract of milk thistle, mugwort and turmeric. As a comparative example, a milk thistle water extract, an wormwood water extract and a turmeric water extract were prepared in the same manner as above, except that 100 g of each of thistle leaf, wormwood leaf and turmeric root was used.
(2) 30%(v/v) 에탄올 추출(2) 30% (v/v) ethanol extraction
건조한 엉겅퀴 잎 80g, 개똥쑥 잎 15g 및 울금 뿌리 5g을 혼합한 후, 30%(v/v) 에탄올 1.5ℓ에 첨가하였다. 이후 78℃에서 8시간 동안 추출하고 여과(와트만 종이 No. 2)하여 회전진공농축기로 농축한 후 동결건조하여 엉겅퀴, 개똥쑥 및 울금 혼합 에탄올 추출물을 제조하였다. 비교예로, 엉겅퀴 잎, 개똥쑥 잎 및 울금 뿌리 각각 100g을 사용한 것을 제외하고 상기와 동일한 방법으로 엉겅퀴 에탄올 추출물, 개똥쑥 에탄올 추출물 및 울금 에탄올 추출물을 제조하였다. After mixing 80 g of dried thistle leaves, 15 g of wormwood leaves and 5 g of turmeric root, it was added to 1.5 L of 30% (v/v) ethanol. Thereafter, extraction was performed at 78° C. for 8 hours, filtered (Whatman paper No. 2), concentrated with a rotary vacuum concentrator, and freeze-dried to prepare a mixed ethanol extract of milk thistle, mugwort and turmeric. As a comparative example, an ethanol extract of thistle, an ethanol extract of mugwort thistle, and an ethanol extract of turmeric were prepared in the same manner as above, except that 100 g of each of thistle leaf, wormwood leaf and turmeric root was used.
이하 실시예 2~6에서는 상기 열수 추출물을 이용하여 그 효능을 평가하였다.In Examples 2 to 6 below, the efficacy was evaluated using the hot water extract.
실시예 2. 세포 생존율 분석Example 2. Cell viability assay
3T3-L1 세포 및 HepG2 세포 각각에서 엉겅퀴 추출물, 울금 추출물 및 개똥쑥 추출물의 세포독성을 측정하기 위하여, 96웰 플레이트에 5×104 세포/㎖로 100㎕씩 분주한 후, 37℃, 5% CO2 인큐베이터에서 24시간 배양한 후 각 추출물을 농도별로 처리하고 24시간 동안 배양하였다. 세포생존율은 Ez-Cytox 증진된 세포 생존율 어세이 키트(DoGenbio Seoul, Korea)를 사용하였으며, 웰당 EZ-Cytox 시약 10㎕를 넣고 3시간 동안 배양한 후 450nm에서 흡광도를 측정하였고, 세포생존율은 대조군에 대한 생존율로 나타내었다. In order to measure the cytotoxicity of thistle extract, turmeric extract, and mugwort extract in 3T3-L1 cells and HepG2 cells, respectively, 100 μl of each of 5×10 4 cells/ml was dispensed in a 96-well plate, 37°C, 5% CO 2 After culturing for 24 hours in an incubator, each extract was treated by concentration and incubated for 24 hours. For cell viability, an Ez-Cytox enhanced cell viability assay kit (DoGenbio Seoul, Korea) was used, and 10 μl of EZ-Cytox reagent per well was added and the absorbance was measured at 450 nm after incubation for 3 hours. It was expressed as the survival rate for
그 결과, 3T3-L1 지방세포에 대한 엉겅퀴 추출물, 개똥쑥 추출물 및 울금 추출물의 세포독성은 없는 것으로 나타났으며, HepG2 세포에 대한 엉겅퀴 추출물 및 개똥쑥 추출물의 세포 독성은 없는 것으로 나타났고, 울금은 고농도인 500㎍/㎖에서 세포 생존율이 15% 정도 약간 감소하는 것으로 나타났다.As a result, it was found that there was no cytotoxicity of thistle extract, wormwood extract and turmeric extract on 3T3-L1 adipocytes, and there was no cytotoxicity of thistle extract and wormwood extract on HepG2 cells. At a high concentration of 500 μg/ml, the cell viability was slightly decreased by about 15%.
실시예 3. 간세포(HepG2) 내 중성지방 축적 억제 효과 확인Example 3. Confirmation of the inhibitory effect on the accumulation of triglycerides in hepatocytes (HepG2)
HepG2 세포 내 지방축적을 유도하기 위하여 60mm 세포 배양 디쉬에 2×105 세포/㎖로 세포를 분주하여 24시간 동안 배양한 후 지방산(2:1의 올레산(oleic acid) 및 팔미트산(palmitic acid), 최종농도=0.3 mM)을 첨가한 DMEM 배지로 교환하여 비알콜성 지방간 세포모델을 유도하였다. 지방산을 첨가한 배지교환과 동시에 엉겅퀴, 개똥쑥 및 울금 혼합 추출물(100㎍/㎖); 엉겅퀴 추출물(100㎍/㎖); 울금 추출물(100㎍/㎖); 개똥쑥 추출물(100㎍/㎖); 및 양성대조군으로 밀크씨슬(100㎍/㎖);을 각각 처리하고 1일 간격으로 2일 동안 배양하였다.In order to induce fat accumulation in HepG2 cells , the cells were aliquoted at 2×10 5 cells/ml in a 60 mm cell culture dish and cultured for 24 hours. Then, fatty acids (2:1 oleic acid and palmitic acid) ), final concentration = 0.3 mM) was exchanged with the added DMEM medium to induce a non-alcoholic fatty liver cell model. Milk thistle, wormwood and turmeric mixed extract (100 μg/ml) at the same time as medium exchange with fatty acid added; milk thistle extract (100 μg/ml); turmeric extract (100 μg/ml); Mugwort extract (100㎍/㎖); and milk thistle (100 μg/ml) as a positive control; each was treated and cultured for 2 days at 1 day intervals.
(1) 간세포 내 오일 레드 오(Oil red O) 지방구 염색(1) Staining of oil red O fat cells in hepatocytes
비알콜성 지방간 세포모델에서 간세포 내 축적된 중성지방을 확인하기 위해서 오일 레드 오 염색을 실시하였다. 배양이 끝난 HepG2 세포를 PBS로 2회 세척한 후 10% 포르말린을 2㎖씩 넣어 실온에서 1시간 동안 고정하였다. 포르말린을 제거하고 증류수로 2회 세척한 후 60% 이소프로판올 2㎖을 넣어 5분 동안 방치한 뒤 제거하였다. 오일 레드 오 용액 및 증류수를 3:2의 비율로 혼합한 후, 10분 동안 방치하였고 사용하기 직전에 여과하여 2㎖씩 넣고 20분 동안 염색하였다. 이후, 증류수로 3~4회 세척 후, 현미경으로 40배 또는 100배로 관찰하였다.In order to check the accumulated triglycerides in hepatocytes in the non-alcoholic fatty liver cell model, Oil Red O staining was performed. After the cultured HepG2 cells were washed twice with PBS, 2 ml of 10% formalin was added and fixed at room temperature for 1 hour. After removing the formalin and washing twice with distilled water, 2 ml of 60% isopropanol was added and left for 5 minutes, and then removed. Oil Red O solution and distilled water were mixed in a ratio of 3:2, left for 10 minutes, filtered immediately before use, and 2 ml of each was added and dyed for 20 minutes. Then, after washing 3 to 4 times with distilled water, it was observed under a microscope at 40 times or 100 times.
그 결과, HepG2세포에 유리지방산을 처리하여 간세포에 중성지방 축적을 유도하였으며 Control군에서는 Normal군에 비해 지방구가 빽빽하게 축적된 것을 확인하였다. 반면 엉겅퀴 추출물과 개똥쑥 추출물을 처리하였을 때 간세포 내 중성지방이 현저히 감소한 것을 확인하였고, 특히 엉겅퀴 추출물의 효과가 가장 우수한 것을 확인하였다. 양성대조군으로 사용한 밀크씨슬은 Control군에 비해 감소되었으나 엉겅퀴 추출물 또는 개똥쑥 추출물 처리군 보다 효과가 미비한 것을 확인하였다. As a result, hepG2 cells were treated with free fatty acid to induce accumulation of triglycerides in hepatocytes, and it was confirmed that the control group had a denser accumulation of fat cells compared to the normal group. On the other hand, it was confirmed that triglycerides in hepatocytes were significantly reduced when milk thistle extract and mugwort extract were treated, and in particular, it was confirmed that the effect of this extract was the best. Milk thistle used as a positive control group was reduced compared to the control group, but it was confirmed that the effect was less than that of the milk thistle extract or wormwood extract treatment group.
한편, 본 발명의 엉겅퀴, 개똥쑥 및 울금 혼합 추출물을 다양한 비율로 혼합하여 제조한 혼합 추출물에 대한 간세포 내 중성지방 축적 억제 효능을 평가한 결과 도 2에 개시한 바와 같이 혼합 추출물 1(엉겅퀴:개똥쑥:울금=60:35:5의 중량비로 혼합) 또는 혼합 추출물 2(엉겅퀴:개똥쑥:울금=70:25:5의 중량비로 혼합)보다 혼합 추출물 3(엉겅퀴:개똥쑥:울금=80:15:5의 중량비로 혼합)의 효과가 가장 우수한 것으로 나타났다. On the other hand, as a result of evaluating the inhibitory efficacy of triglyceride accumulation in hepatocytes for the mixed extract prepared by mixing the mixed extract of thistle, mugwort and turmeric in various ratios of the present invention, as shown in FIG. Mugwort: Turmeric = 60:35:5 mixed extract) or Mixed Extract 2 (milk thistle: wormwood: Turmeric = 70:25:5 weight ratio mixed), rather than Mixed Extract 3 (Thistle: wormwood: Turmeric = 80: The effect of mixing in a weight ratio of 15:5) was found to be the most excellent.
(2) 간세포 내 중성지방 함량 변화 확인 (2) Confirmation of changes in triglyceride content in hepatocytes
비알콜성 지방간 세포 모델에서 간세포 내 축적된 중성지방 함량을 측정하기 위해서 중성지방 비색 어세이 키트(Cayman chemical, E.Ellsworth Rd·Ann Arbor, MI, USA)를 사용하였다. 배양이 끝난 비알콜성 지방간 유도 HepG2 세포를 PBS로 2회 세척한 후 PBS 2㎖을 주입하여 세포를 떨어뜨린 후 원심분리(2,000×4℃, 10분)하였다. 상등액을 제거하고 재 부유시켜 초음파 처리하였고 제조사의 표준액을 이용하여 표준곡선을 작성하여 시험군의 중성지방 함량을 산출하였다.A triglyceride colorimetric assay kit (Cayman chemical, E. Ellsworth Rd·Ann Arbor, MI, USA) was used to measure the amount of triglycerides accumulated in hepatocytes in the nonalcoholic fatty liver cell model. After the cultured non-alcoholic fatty liver-induced HepG2 cells were washed twice with PBS, 2 ml of PBS was injected to drop the cells, and then centrifuged (2,000×4° C., 10 minutes). The supernatant was removed, resuspended, and sonicated, and the triglyceride content of the test group was calculated by creating a standard curve using the manufacturer's standard solution.
그 결과, 도 3에 개시한 바와 같이, 정상군(Normal) 대비 비알콜성 지방간을 유도한 대조군(Control)의 중성지방 함량이 통계적으로 유의미하게 증가하였으며, 이에 대비하여, 엉겅퀴, 개똥쑥 및 울금 혼합 추출물; 엉겅퀴 추출물; 울금 추출물; 개똥쑥 추출물을 처리한 군의 중성지방 함량이 통계적으로 유의미하게 감소하였고, 특히, 본 발명의 엉겅퀴, 개똥쑥 및 울금 혼합 추출물이 각각의 엉겅퀴, 울금, 개똥쑥 추출물 단독에 비해 중성지방 함량이 더 감소하였다. As a result, as shown in FIG. 3 , the triglyceride content of the non-alcoholic fatty liver-induced control group increased statistically significantly compared to the normal group. In contrast, thistle, wormwood and turmeric mixed extract; thistle extract; turmeric extract; The triglyceride content of the group treated with the mugwort extract was statistically significantly reduced, and in particular, the extract of the present invention mixed extract with thistle, wormwood and turmeric had higher triglyceride content than each thistle, turmeric, and mugwort extract alone. decreased.
실시예 4. 비알콜성 지방간 세포모델에서 엉겅퀴, 개똥쑥 및 울금 혼합 추출물의 지질과산화물(MDA) 측정Example 4. Lipid peroxide (MDA) measurement of milk thistle, mugwort and turmeric mixed extract in non-alcoholic fatty liver cell model
HepG2 세포에서 지질과산화물을 측정하였으며 TBARS 어세이 키트(Cayman, chemical, E.Ellsworth Rd·Ann Arbor, MI, USA)를 이용하여 측정하였다. 배양이 끝난 비알콜성 지방간 유도 HepG2 세포를 PBS로 2회 세척한 후 PBS 1mL을 주입하여 세포를 떨어뜨린 뒤 균질화하여 분석에 이용하였다. Lipid peroxide was measured in HepG2 cells and was measured using a TBARS assay kit (Cayman, chemical, E. Ellsworth Rd·Ann Arbor, MI, USA). After the cultured non-alcoholic fatty liver-induced HepG2 cells were washed twice with PBS, 1 mL of PBS was injected to drop the cells, and then homogenized and used for analysis.
그 결과, 도 4에 개시한 바와 같이, 정상군(Normal) 대비 비알콜성 지방간을 유도한 대조군(Control)의 MDA 함량이 통계적으로 유의미하게 증가하였으며, 이에 대비하여, 엉겅퀴, 개똥쑥 및 울금 혼합 추출물; 엉겅퀴 추출물; 울금 추출물; 개똥쑥 추출물을 처리한 군의 MDA 함량이 통계적으로 유의미하게 감소하였고, 특히, 본 발명의 엉겅퀴, 개똥쑥 및 울금 혼합 추출물이 각각의 엉겅퀴, 울금, 개똥쑥 추출물 단독에 비해 MDA 함량이 더 감소하였다. As a result, as shown in FIG. 4 , the MDA content of the control group inducing non-alcoholic fatty liver compared to the normal group was statistically significantly increased. In contrast, thistle, wormwood and turmeric mixture extract; thistle extract; turmeric extract; The MDA content of the group treated with the mugwort extract was statistically significantly decreased, and in particular, the thistle, mugwort and turmeric mixed extract of the present invention had a more decreased MDA content compared to each thistle, turmeric, and wormwood extract alone. .
실시예 5. 비알콜성 지방간 세포모델에서 엉겅퀴, 개똥쑥 및 울금 혼합 추출물의 아미노전이효소 활성 측정Example 5. Measurement of aminotransferase activity of milk thistle, wormwood and turmeric mixed extract in non-alcoholic fatty liver cell model
HepG2 세포에서 아미노전이효소 활성을 측정하였으며 AST(Aspartate aminotransferase) 활성 어세이 키트(Sigma-aldrich, St. Louis, MO, USA)와 ALT(Alanine aminotransferase) 활성 어세이 키트(Sigma-aldrich, St. Louis, MO, USA)를 이용하였다. 배양이 끝난 비알콜성 지방간 유도 HepG2 세포를 PBS로 2회 세척한 후 PBS 2mL을 주입하여 세포를 떨어뜨린 뒤 원심분리(2,000×4℃, 10분)하였다. 상등액을 제거하고 AST(또는 ALT)어세이 버퍼를 첨가하여 균질화한 다음 원심분리(15,000×4℃, 10분)한 후, 아미노전이효소 활성을 측정하였다.Aminotransferase activity was measured in HepG2 cells, and AST (Aspartate aminotransferase) activity assay kit (Sigma-aldrich, St. Louis, MO, USA) and ALT (Alanine aminotransferase) activity assay kit (Sigma-aldrich, St. Louis) activity assay kit (Sigma-aldrich, St. Louis) , MO, USA) were used. After the cultured non-alcoholic fatty liver-induced HepG2 cells were washed twice with PBS, 2 mL of PBS was injected to drop the cells, and then centrifuged (2,000×4° C., 10 minutes). The supernatant was removed, homogenized by adding an AST (or ALT) assay buffer, followed by centrifugation (15,000×4° C., 10 minutes), and then aminotransferase activity was measured.
그 결과, 지방산 첨가로 인해 Control군에서 간세포 내 AST와 ALT 수치가 유의적으로 증가하였으며 지방산 첨가와 동시에 엉겅퀴, 개똥쑥 및 울금 혼합 추출물을 처리하였을 때 AST와 ALT 수치가 감소한 것을 확인하였다. 양성대조군인 밀크씨슬 처리군보다 엉겅퀴, 개똥쑥 및 울금 혼합 추출물 처리군에서 현저히 감소한 것으로 나타났다(도 5).As a result, it was confirmed that the AST and ALT levels in the hepatocytes were significantly increased in the control group due to the addition of fatty acids, and the AST and ALT levels decreased when the extracts of milk thistle, wormwood and turmeric were treated simultaneously with the addition of fatty acids. It was found to be significantly reduced in the milk thistle, wormwood, and turmeric mixed extract treatment group than in the milk thistle treatment group, which is a positive control group (FIG. 5).
실시예 6. Example 6. in vivo in vivo 유용성 평가 usability evaluation
[동물 모델의 사육 및 식이][Breeding and diet of animal models]
실험 동물은 4주령의 C57BL/6 수컷 마우스(18~20 g)를 오리엔트바이오에서 구입했으며, 1주일 동안 사육실 환경에 적응시켰다. 사육장의 온도는 18~24℃, 상대습도는 50~60%로 유지하였으며, 명암은 12시간 주기 (09:00~21:00)로 조절하였다. Experimental animals were purchased from Orient Bio, a 4-week-old C57BL/6 male mouse (18-20 g), and acclimatized to the breeding room environment for 1 week. The temperature of the kennel was maintained at 18~24℃ and the relative humidity at 50~60%, and the light and dark was adjusted in a 12-hour cycle (09:00~21:00).
실험디자인은 난괴법에 따라 군당 6마리씩 아래와 같은 군으로 설정하였다.According to the egg mass method, the experimental design was set as the following groups of 6 animals per group.
(1) 엉겅퀴, 개똥쑥 및 울금 혼합 추출물(CAC)의 투여에 따른 체중, 간 조직의 무게, 부고환 주변 지방의 무게 및 지방 크기 관찰(1) Observation of body weight, liver tissue weight, weight of fat around epididymis and fat size following administration of milk thistle, wormwood and turmeric mixed extract (CAC)
- 정상 사료 투여군(정상군 ND)- Normal feed group (Normal group ND)
- 고지방 사료 투여군(대조군 HFD)- High-fat feed group (control group HFD)
- 고지방 사료 및 엉겅퀴, 개똥쑥 및 울금 혼합 추출물 투여군(CAC 100mg/kg, 200mg/kg)- High-fat feed, milk thistle, wormwood, and turmeric mixed extract group (CAC 100mg/kg, 200mg/kg)
- 고지방 사료 및 밀크시슬 추출물투여군(MT 100mg/kg)- High-fat feed and milk thistle extract group (MT 100mg/kg)
엉겅퀴, 개똥쑥 및 울금 혼합 추출물은 하루에 한 번씩 경구투여하였다. 일반 사료는 D12450B(10% kcal fat), 고지방 사료는 D12492 (60 % kcal fat) 사료를 중앙실험동물(주)에서 구입하여 사용하였다. 고지방 사료는 4℃에 냉장 보관하면서 급여하였고, 음수와 사료는 자유롭게 섭취하도록 하였다. 체중은 일주일 간격으로 측정하였다. 본 발명은 전주대학교 동물실험윤리위원회의 규정에 맞추어서 진행하였다.Milk thistle, wormwood and turmeric mixed extracts were orally administered once a day. D12450B (10% kcal fat) for general feed and D12492 (60% kcal fat) for high fat feed were purchased from Central Laboratory Animals Co., Ltd. and used. High-fat feed was fed while refrigerated at 4°C, and drinking water and feed were allowed to be freely consumed. Body weight was measured at weekly intervals. The present invention was carried out in accordance with the regulations of Jeonju University Animal Experimental Ethics Committee.
그 결과, 표 1에 나타난 바와 같이 고지방 식이에 의해 마우스의 체중이 증가하는 것을 확인하였고, 엉겅퀴, 개똥쑥 및 울금 혼합 추출물 투여에 의해 체중의 증가량이 고지방식이군에 비해 약 6.7% 감소하였다. As a result, as shown in Table 1, it was confirmed that the weight of the mice increased by the high-fat diet, and the amount of increase in body weight decreased by about 6.7% compared to the high-fat group by administering the milk thistle, wormwood, and turmeric mixed extracts.
또한, 실험이 종료되는 마지막 12주에 12시간 동안 절식시키고, 간 조직을 적출하여 정밀전자저울로 전체 무게를 측정하였으며, 부고환 주변 지방 조직을 적출하여 정밀전자저울로 무게를 측정하였다. In addition, in the last 12 weeks of the experiment, they were fasted for 12 hours, the liver tissue was removed and the total weight was measured with a precision electronic scale, and the adipose tissue surrounding the epididymis was removed and the weight was measured with a precision electronic scale.
식염수로 세척한 후 물기를 제거한 후, 4%(v/v) 파라포름알데히드(paraformaldehyde, pH 7.4)로 고정하고 일련의 과정을 통하여 파라핀 블록을 제작하였다. 상기 파라핀 블록 조직은 5㎛ 두께로 절단하였으며, 절단된 조직 절편은 탈파라핀(deparaffin)과 함수 과정을 거친 후 H&E로 염색하여 현미경(Olympus, Tokyo, Japan)으로 지방의 크기를 확인하였다. 그 결과, 간 조직 및 부고환 지방 조직의 무게 또한 추출물 투여에 의해 감소하는 것을 확인하였다(표 1). After washing with saline and removing water, it was fixed with 4% (v/v) paraformaldehyde (pH 7.4) and a paraffin block was prepared through a series of procedures. The paraffin block tissue was cut to a thickness of 5 μm, and the cut tissue section was subjected to deparaffin and hydrous processes, and then stained with H&E to confirm the size of fat under a microscope (Olympus, Tokyo, Japan). As a result, it was confirmed that the weight of the liver tissue and epididymal adipose tissue was also reduced by the administration of the extract (Table 1).
a~c: 통계적으로 유의미한 차이가 있다는 것으로, p<0.05이다.a~c: There is a statistically significant difference, p<0.05.
[혈액의 채취 및 보관][Collection and storage of blood]
혈액은 실험이 종료되는 마지막 12주에 12시간 동안 절식시키고, 마취한 후 심장에서 채혈하였다. 채혈한 혈액은 4℃에서 3,000rpm으로 15분 동안 원심분리하여 혈청을 분리하였으며, 분리된 혈청은 분석 전까지 -80℃에 보관하면서 사용하였다. Blood was fasted for 12 hours in the last 12 weeks at the end of the experiment, anesthetized, and blood was collected from the heart. The collected blood was centrifuged at 3,000 rpm at 4° C. for 15 minutes to separate serum, and the separated serum was stored at -80° C. until analysis.
(2) 혈액의 생화학적 분석(2) biochemical analysis of blood
혈액 내 중성지방, GOT, GPT의 함량은 측정용 키트(Asan)를 사용하여 분석하였다.The contents of triglycerides, GOT, and GPT in the blood were analyzed using a kit for measurement (Asan).
그 결과, 고지방 식이에 의해 증가된 총 중성지방의 함량은 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물(CAC) 투여에 의해 고지방식이군에 비해서 약 17% 정도 감소하였고(도 6A), 고지방 식이에 의해 증가된 GOT 및 GPT는 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 의해 고지방식이군에 비해서 GOT 함량이 약 31% 정도, GPT 함량이 약 34% 감소하였다(도 6B, 6C).As a result, the content of total triglycerides increased by the high-fat diet was decreased by about 17% compared to the high-fat group by administration of the mixed extract (CAC) of milk thistle, wormwood and turmeric (FIG. 6A), and by the high-fat diet As for the increased GOT and GPT, the GOT content and the GPT content were decreased by about 31% and the GPT content by about 34% compared to the high-fat diet group by administration of the mixed extract of milk thistle, wormwood and turmeric ( FIGS. 6B and 6C ).
(3) 지방 축적, 콜라겐 관찰 및 생화학적 분석(3) fat accumulation, collagen observation and biochemical analysis
간 무게를 측정한 후, 간 조직의 일부는 급속으로 냉동(-80℃)시켰고, 조직 일부는 식염수로 세척한 후 물기를 제거하고, 4%(v/v) 파라포름알데히드(paraformaldehyde, pH 7.4)로 고정한 후 파라핀 블록으로 제작하였다.After measuring the weight of the liver, a part of the liver tissue was rapidly frozen (-80 ° C), and a part of the tissue was washed with saline and then dried, and 4% (v/v) paraformaldehyde (pH 7.4). ), and then manufactured as a paraffin block.
상기 파라핀 블록은 5㎛ 두께로 절단하여 탈파라핀(deparaffin)과 함수 과정을 거친 후 간 조직의 지방 축적은 H&E로 염색하여 현미경(Olympus, Tokyo, Japan)으로 관찰하였고, 간섬유화 정도는 콜라겐 섬유 생성을 확인하는 트라이크롬 염색 키트(trichrome staining kit, Abcam, Inc., Cambridge, UK)로 염색하여 현미경으로 관찰하였다. 간 조직에서의 중성지방, MDA, 카탈라아제(catalase) 활성은 상업적으로 이용 가능한 분석 키트(Cayman Chemical., 미국)를 제조업자의 프로토콜에 따라 사용하여 측정하였다.After the paraffin block was cut to a thickness of 5 μm, deparaffinized and hydroused, the fat accumulation in the liver tissue was stained with H&E and observed with a microscope (Olympus, Tokyo, Japan), and the degree of liver fibrosis was produced by collagen fiber It was stained with a trichrome staining kit (Abcam, Inc., Cambridge, UK) to confirm and observed under a microscope. Triglyceride, MDA, and catalase activity in liver tissue were measured using a commercially available assay kit (Cayman Chemical., USA) according to the manufacturer's protocol.
적출한 간 조직을 H&E 염색한 결과, 고지방 식이에 의해 간 조직 내 증가된 지방 함량이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여시 감소하는 것을 확인할 수 있었다(도 7A).As a result of H&E staining of the extracted liver tissue, it was confirmed that the increased fat content in the liver tissue due to a high-fat diet was decreased when the mixed extracts of milk thistle, wormwood and turmeric were administered (FIG. 7A).
또한, 지방 조직을 H&E 염색하여 100배율로 관찰한 결과, 고지방 식이에 의해 비대해진 지방조직이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여시 크기가 작아지는 것을 확인할 수 있었다(도 7B). In addition, as a result of H&E staining of the adipose tissue and observing it at a magnification of 100 times, it was confirmed that the size of the adipose tissue enlarged by the high-fat diet decreased when the mixed extracts of milk thistle, wormwood and turmeric were administered (FIG. 7B).
(4) 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물의 간 조직의 생화학적 분석 (4) Biochemical analysis of liver tissue of mixed extracts of milk thistle, wormwood and turmeric
고지방 식이 동물모델 간에서 중성지방 및 산화손상에 대한 변화를 확인한 결과, 고지방 식이에 의해 증가된 총 중성지방의 함량은 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 의해 감소하였다(도 8). 이러한 효과는 밀크시슬 처리군보다 우수하였으며, 고지방식이군에 비해서 중성지방 함량이 약 15.9% 감소하였다(도 8).As a result of confirming the changes in triglycerides and oxidative damage in the liver of a high-fat diet animal model, the content of total triglycerides increased by a high-fat diet was decreased by administration of a mixed extract of milk thistle, mugwort and turmeric (FIG. 8). This effect was superior to the milk thistle-treated group, and the triglyceride content was reduced by about 15.9% compared to the high-fat diet group (FIG. 8).
또한, 간의 과산화반응을 알아보기 위해 MDA 농도를 측정하였다. 고지방 식이에 의해 증가된 MDA 농도는 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여시 고지방식이군에 비해서 MDA 함량이 약 50% 감소하였다. 간 내 항산화 효소인 catalase 활성을 분석한 결과, 고지방 식이에 의해 감소한 효소 활성이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여 시 고지방식이군에 비해 약 25% 증가하였다(도 8).In addition, the concentration of MDA was measured to determine the peroxidation reaction of the liver. The MDA concentration increased by the high-fat diet decreased by about 50% compared to the high-fat diet group when the mixed extracts of milk thistle, wormwood and turmeric were administered. As a result of analyzing the activity of catalase, an antioxidant enzyme in the liver, the enzyme activity decreased by the high-fat diet was increased by about 25% compared to the high-fat diet group when the mixed extracts of milk thistle, mugwort and turmeric were administered (FIG. 8).
(5) 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물의 지방간염 관련 염증인자 발현 분석(5) Analysis of expression of inflammatory factors related to steatohepatitis in mixed extracts of milk thistle, mugwort and turmeric
고지방 식이 동물모델 간에서 지방간염 관련 염증인자의 발현에 대한 변화를 확인하였다. 그 결과, 간 조직에서 고지방식이에 의해 증가된 COX-2, iNOS 및 TNF-α의 발현량이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 의해 감소하는 것을 확인하였다(도 19). Changes in the expression of steatohepatitis-related inflammatory factors were confirmed in the liver of a high-fat diet animal model. As a result, it was confirmed that the expression levels of COX-2, iNOS and TNF-α increased by a high-fat diet in liver tissue were decreased by administration of a mixed extract of milk thistle, wormwood, and turmeric ( FIG. 19 ).
(6) 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물의 지방산 산화 및 지방 형성 인자 발현 분석 (6) Analysis of fatty acid oxidation and adipogenic factor expression of mixed extracts of milk thistle, wormwood and turmeric
고지방 식이 동물모델 간에서 지방산 산화 및 지방 형성 인자의 발현에 대한 변화를 확인하였다. 그 결과, 간 조직에서 고지방식이에 의해 증가된 PPAR-r의 발현량이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 의해 감소하는 것을 확인하였고, 고지방식이에 의해 감소된 CEBPA의 발현량이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 의해 증가하는 것을 확인하였다(도 10).Changes in fatty acid oxidation and expression of fat-forming factors were confirmed in the liver of a high-fat diet animal model. As a result, it was confirmed that the expression level of PPAR-r increased by a high-fat diet in liver tissue was decreased by administration of a mixed extract of milk thistle, wormwood, and turmeric, and the expression level of CEBPA decreased by the high-fat diet was decreased by milk thistle, It was confirmed that the increase was increased by administration of the mixed extract of wormwood and turmeric (FIG. 10).
(7) 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물의 지방간염 관련 사이토카인 IL-17 발현 분석 (7) Analysis of the expression of steatohepatitis-related cytokine IL-17 in mixed extracts of milk thistle, mugwort and turmeric
고지방 식이 동물모델 간에서 지방간염 관련 사이토카인 IL-17의 발현에 대한 변화를 확인하였다. 그 결과, 간 조직에서 고지방식이에 의해 증가된 사이토카인 IL-17의 발현량이 엉겅퀴, 개똥쑥 및 울금의 혼합 추출물 투여에 의해 감소하는 것을 확인하였다(도 11).Changes in the expression of the steatohepatitis-related cytokine IL-17 were confirmed in the liver in a high-fat diet animal model. As a result, it was confirmed that the expression level of the cytokine IL-17 increased by a high-fat diet in liver tissue was decreased by administration of the mixed extract of milk thistle, wormwood and turmeric ( FIG. 11 ).
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