KR101773322B1 - PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA Thunb. EXTRACT FOR IMMUNE-ENHANCING - Google Patents

PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA Thunb. EXTRACT FOR IMMUNE-ENHANCING Download PDF

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KR101773322B1
KR101773322B1 KR1020170019969A KR20170019969A KR101773322B1 KR 101773322 B1 KR101773322 B1 KR 101773322B1 KR 1020170019969 A KR1020170019969 A KR 1020170019969A KR 20170019969 A KR20170019969 A KR 20170019969A KR 101773322 B1 KR101773322 B1 KR 101773322B1
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pharmaceutical composition
extract
leaf extract
leaf
gardenia
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최철웅
김재용
김미리
김영욱
강후원
조아라
최학준
신자원
반상오
박성윤
이규옥
윤효정
임소정
성락선
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재단법인 전남생물산업진흥원
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    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23V2200/308Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00Function of food ingredients
    • A23V2200/30Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324Foods, ingredients or supplements having a functional effect on health having an effect on the immune system

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Abstract

The present invention relates to a pharmaceutical composition containing an Elaeagnus multiflora leaf extract as an active ingredient for immune enhancement, and provides a pharmaceutical composition for immune enhancement or a functional food composition, capable of enhancing immunity of a living body by inducing cytokine production of IL-2 (Interlukin-2), IL-4 (Interlukine-4), or IL-10 (Interlukine-10) and by activating immune cells which directly counter tumor cells.

Description

뜰보리수나무잎 추출물을 유효성분으로 하는 면역 증강용 약학 조성물 {PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA Thunb. EXTRACT FOR IMMUNE-ENHANCING}[0001] PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA [0002] Thunb. EXTRACT FOR IMMUNE-ENHANCING}

본 발명은 뜰보리수나무잎 추출물을 유효성분으로 포함하는 면역증강용 조성물에 관한 것으로서, 보다 구체적으로는 천연원료인 뜰보리수나무 (Elaeagnus multriflora Thunb.) 잎 추출물을 이용하여 독성 및 부작용 없이 안전하게 사용될 수 있는 면역증강용 약학조성물에 관한 것이다.
The present invention relates to a composition for enhancing an immune response comprising an extract of Valium Borealis as an active ingredient and more specifically to a composition for preventing and treating diseases caused by toxicity and side effects using a natural extract of Elaeagnus multriflora Thunb. To a pharmaceutical composition for enhancing immunity.

최근 경제발전으로 많은 사람들이 풍요로운 생활을 누리고 있는 반면, 식생활의 서구화와 활동량의 감소로 인해 체중증가 및 동맥경화, 고혈압, 당뇨병 등의 여러 성인병에 위험에 노출되어 있다. 이들 만성 퇴행성 질환은 그 환자 수가 급격히 증가하고 있을 뿐 아니라 질병에 걸리는 연령도 점차 낮아지고 있어 더욱 심각한 문제로 인식되고 있다. While recent economic developments have led many people to enjoy abundant life, westernization of diet and decrease in activity have put them at risk for weight gain, atherosclerosis, hypertension and diabetes. These chronic degenerative diseases are recognized as a serious problem not only because of the rapid increase in the number of patients but also because the age of disease is gradually lowered.

또한 인간의 삶의 질을 높이기 위해 만들어졌던 여러 화학물질들은 오히려 면역력을 떨어뜨리고, 예기치 못한 질병들을 초래하고 있다. 이에 따라 전통적으로 우리 몸에 유익하다고 알려진 식재료 또는 약재료에 대해 새로운 방법으로 접근하여 신물질을 발견하거나 그 약리효과를 밝혀 이용하려는 시도가 증가하고 있다. 이전까지 단순히 보양강장식으로 알려진 천연물로부터 항암물질을 찾거나 치료제를 개발하는 사례도 증가하고 있다.In addition, many chemicals that have been created to enhance the quality of life of humans have reduced immunity and have caused unexpected diseases. As a result, there is an increasing tendency to discover new materials or discover their pharmacological effects by approaching new foods or ingredients that are traditionally found beneficial to our body. Until now, there have been an increasing number of cases of finding anticancer substances from natural products, which are simply known as ornamental plants, or developing therapeutic agents.

한편, 뜰보리수(Elaeagnus multriflora Thunb.)는 정원에 심어 그 열매를 따먹는 정도의 정원수로 알려져 있다. 뜰보리수나무는 우리나라 각지에 자생하는 Elaeagnus 속 식물로, 야앵도(野櫻桃) 또는 사월자(四月子)라고 불리며, 생약명으로 목반하(木半夏)로 알려져 있다. 흔히 집보리수나무, 참당보리수나무라고도 불리며, 어린 가지는 적갈색 비늘털로 덮여 있다. Elaeagnus multriflora Thunb., On the other hand, is known as a garden that is planted in the garden and eats its fruit. The garden borealum is an Elaeagnus plant which is native to various parts of Korea. It is known as a yamanda (桜 桃) or an ape (四月 子). It is also often called house borealis and common boreal trees, and young branches are covered with reddish brown scaly fur.

외형은 보리수나무처럼 생겼으나, 열매가 커서 재배하기 때문에 뜰보리수나무라 불리며, 약으로 쓸 때는 주로 탕으로 하여 사용한다. 잎은 어긋나며 길이 3~10cm의 긴 타원형으로서 양 끝이 좁아 날카롭고 가장자리에 톱니가 없다. 앞면에는 어릴 때 비늘털이 있으나 점차 없어지고, 뒷면에는 백색 비늘털과 갈색 비늘털이 섞여 있는 것이 특징이다. 꽃은 4~5월에 연한 황색으로 피는데 1~2개씩 잎겨드랑이에 달린다. 꽃에 흰색과 갈색의 비늘털이 있다. 꽃받침통은 밑 부분이 급히 좁아져서 씨방을 둘러싸고 끝이 4개로 갈라지고, 4개의 수술과 1개의 암술이 있으며, 7월에 길이가 1.5cm 정도 되는 긴 타원형의 핵과가 달려 밑으로 처져 빨갛게 익는다. 수관은 낙엽떨기형태이고 높이 2~3m까지 자란다.It looks like a bamboo tree, but it is called a garden bamboo tree because it grows because its fruit is large. When it is used as a medicine, it is mainly used as a bath. Leaves are alternate long oval with length of 3 ~ 10cm. Both ends are narrow and sharp, with no sawtooth on edge. On the front, there are scaly hairs at the time of childhood, but gradually disappear, and the back side is characterized by a mixture of white scaly hairs and brown scaly hairs. Flowers bloom in April ~ May with light yellow color, and 1 ~ 2 are on axilla. Flowers have white and brown scales hairs. The bottom of the calyx tube is rapidly narrowed and surrounds the ovary. The end is divided into 4 pieces. There are 4 stamens and 1 pistil. In July, a long elliptical nucleus with a length of 1.5cm is hanging down and ripen red. The water pipe is a deciduous form and grows up to 2 ~ 3m in height.

보리수나무(Elaeagnus umbellata Thunberg)와 외형적으로 유사하지만, 보리수나무는 잔가지에 흰 비늘털이 많고, 열매는 길이 1cm 미만으로 작아 뜰보리수나무와 구별된다. It is similar in appearance to Elaeagnus umbellata Thunberg, but the tree is distinguishable from the garden tree by its small twigs with white scaly hairs and its fruit with a length of less than 1 cm.

최근 전통적으로 알려진 이러한 뜰보리수나무와 같은 천연물의 효능을 연구하여 부작용이 거의 없고 질병의 예방과 회복에 도움이 되는 물질을 개발하기 위해 노력하고 있으나, 아직까지는 뜰보리수나무에 대한 영양학적 가치나 생리활성 기능성에 대한 관련정보가 부족한 실정이다.
Recently, we have been studying the efficacy of natural herbs such as yew tree, which is traditionally known, and have tried to develop substances that have little side effects and are useful for prevention and recovery of diseases. However, the nutritional value, There is a lack of relevant information on active functionality.

국내 공개특허공보 제10-2016-0012540호에는 비타민나무를 이용한 초산발효 조성물의 제조방법 및 그로부터 수득되는 초산발효 조성물에 관한 것으로 (1) 곡류, 비타민나무 잎 추출액, 코지, 개량누룩 및 물을 포함하는 제1 혼합물을 알콜발효시키는 단계에서 얻어지는 알콜발효물, 종초 및 비타민나무 열매 쥬스를 포함하는 제2 혼합물을 초산발효시키는 단계를 포함하고, 제1 혼합물에 포함되는 비타민나무 잎 추출액의 함량은 곡류 100 중량부를 기준으로 2 중량부이고, 제2 혼합물에 포함되는 비타민나무 열매 쥬스의 함량은 제2 혼합물 전체량 100 부피%를 기준으로 6 부피%인 것을 특징으로 하는 비타민 나무를 이용한 초산발효 조성물의 제조방법 및 그로부터 수득되는 초산발효 조성물에 관하여 개시되어 있다.Korean Patent Laid-Open Publication No. 10-2016-0012540 discloses a method for producing a fermented acetic acid composition using a vitamin tree and a fermented acetic acid composition obtained therefrom (1) including cereals, vitamin leaf extract, koji, modified koji and water Comprising the step of fermenting a second mixture comprising an alcoholic fermentation product obtained in the step of fermenting the first mixture with alcohol, a herbicide and a vitamin Nut fruit juice, wherein the content of the vitamin tree leaf extract contained in the first mixture is in the range And 2% by weight based on 100% by weight of the second mixture, and the content of vitamin Nut fruit juice contained in the second mixture is 6% by volume based on 100% by volume of the total amount of the second mixture. And a fermented acetic acid composition obtained therefrom. 국내 공개특허공보 제10-2014-0140902호에는 사극나무 열매 추출물은 알코올에 유발되는 간 손상을 억제하고 알코올 대사에 의해 발생하는 숙취 유발물질인 아세트알데히드의 분해를 촉진하는 효과를 가지므로, 이를 포함하는 조성물은 알코올성 간 손상 방지 또는 숙취해소를 위한 조성물로 다양하게 활용 가능한 사극나무 열매 추출물을 함유하는 간 손상 억제 또는 숙취해소용 약학적 조성물에 관하여 개시되어 있다.Korean Patent Laid-Open Publication No. 10-2014-0140902 discloses that the extract of Sadukazu Fruit has an effect of inhibiting liver damage induced by alcohol and promoting decomposition of acetaldehyde, which is a hangover inducing substance caused by alcohol metabolism, Compositions are disclosed for pharmaceutical compositions for inhibiting liver damage or hangover containing diatomaceae fruit extract which can be used as a composition for preventing alcoholic liver damage or hangover relief. 국내 등록특허번호 제10-1220519호에는 산자나무 추출물 또는 이로부터 분리된 퀘세틴 3-글루코사이드-7-람노사이드를 유효성분으로 포함함으로써, 특이적으로 IL-6에 의해 유도되는 신호 전달체계를 저해하여 IL-6으로 매개되는 질환을 예방하고 치료할 수 있음은 물론, 라이노바이러스의 감염성 질환을 예방하고 치료할 수 있는 조성물에 관하여 개시되어 있다.Korean Patent No. 10-1220519 discloses a method for inhibiting the signal transduction system specifically induced by IL-6 by including as an active ingredient quercetin 3-glucoside-7- Thereby preventing and treating diseases mediated by IL-6, as well as a composition capable of preventing and treating infectious diseases of rhinovirus. 국내 등록특허번호 제10-1276141호에는 갈매보리수나무 씨앗 추출물은 갈매보리수나무 씨앗 알콜 추출물에 규조토를 첨가하고 저온상태에서 보관한 후 여과함으로써 지질성분 및 용해도가 낮은 물질들을 응집시켜 효과적으로 제거할 수 있어, 추출물 내에 지질성분 및 용해도가 낮은 물질들이 잔존하지 않아서 시간이 경과하여도 침전물이 발생하지 않으며, 항산화 활성 및 항균 활성이 매우 우수하여, 항산화제 또는 피부노화방지에 유용한 의약품, 화장품, 건강식품으로 사용가능한 갈매보리수나무 씨앗 추출물 및 이의 제조방법에 관하여 개시되어 있다. 그러나 상기 선행문헌들은 본 발명의 IL-2(Interlukin-2), IL-4(Interlukine-4) 또는 IL-10(Interlukine-5) 의 사이토카인 생성 유도 및 종양세포에 대해 직접적으로 대항하는 자연살해세포(NK cell)를 활성화함으로써 면역증강 활성을 가지는 것을 특징으로 하는 뜰보리수나무잎 추출물을 유효성분으로 하는 면역 증강용 약학 조성물과는 그 구성 및 효과에서 차이를 보인다.In Korean Patent No. 10-1276141, diatomaceous earth extract is added to diatomaceous earth aloe extract of algae, and after storing diatomaceous earth at low temperature, it is filtered to effectively remove substances having low lipid and solubility and effectively remove , Extracts with low lipid content and low solubility do not remain, so they do not form sediments over time, and have excellent antioxidative and antimicrobial activities. They are useful as antioxidants or medicines for preventing skin aging, cosmetics and health foods. The present invention relates to a method for preparing a seaweed extract, and a process for producing the same. However, these prior art documents have shown that induction of cytokine production by IL-2 (Interlukin-2), IL-4 (Interlukine-4) or IL-10 (Interlukine-5) of the present invention, The present invention is different from the composition and effect of the pharmaceutical composition for immunity enhancement, which comprises an extract of Gardenia borealum having an immunopotentiating activity by activating a cell (NK cell) as an active ingredient.

우리나라 천연자원인 뜰보리수나무잎 추출물을 이용하여 독성 및 부작용 없이 안전하게 사용될 수 있는 면역증강용 조성물을 제공하고자 한다.
It is intended to provide a composition for immune enhancement which can be safely used without toxicity and side effects by using a garden borealis leaf extract, which is a natural resource of Korea.

상기 목적을 달성하기 위하여, 면역 지표인 IL-2(Interlukin-2), IL-4(Interlukine-4) 또는 IL-10(Interlukine-10) 의 사이토카인 생성 유도 및 종양세포에 대해 직접적으로 대항하는 자연살해세포(NK cell)를 활성화함으로써 면역증강 활성을 가지는 것을 특징으로 하는 뜰보리수나무잎 추출물을 유효성분으로 포함하는 면역증강 기능을 갖는 약학조성물 또는 기능성 식품 조성물을 제공한다.
In order to achieve the above object, the present inventors have found that induction of cytokine production of IL-2 (Interlukin-2), IL-4 (Interlukine-4) or IL-10 (Interlukine-10) The present invention provides a pharmaceutical composition or functional food composition having an immunostimulatory function, which comprises as an active ingredient an extract of Gardenia borealum having an immunoenhancing activity by activating NK cells.

본 발명은 뜰보리수나무잎을 유효성분으로 하는 면역증강용 조성물을 추출함으로써 상기 면역증강용 조성물은 종양세포에 대해 직접적으로 대항하는 자연살해세포 (NK cell)의 활성을 높이고, in vitro in vivo 상에서 마우스 비장세포 IL-2, IL-4, IL-10 과 같은 면역 사이토카인 분비량을 증가시킴으로써 면역 증강에 유용한 약학조성물 및 기능성 식품 조성물 로 유용하게 이용될 수 있다.
The present invention enhances the activity of a natural killer cell (NK cell) directly against tumor cells by extracting a composition for enhancing immunity using an extract of Gardenia borealum as an active ingredient, and in vitro and in vivo Can be usefully used as a pharmaceutical composition and a functional food composition useful for immunity enhancement by increasing the secretion amount of immunocytokines such as mouse splenocytes IL-2, IL-4, and IL-10.

도 1은 뜰보리수나무잎 추출물에 대한 비장세포 증식능의 변화를 나타낸 그래프이다.
도 2은 뜰보리수나무잎 추출물에 대한 비장세포의 IL-2 cytokine 수준의 변화를 나타낸 그래프이다.
도 3은 뜰보리수나무잎 추출물에 대한 비장세포의 IL-4 cytokine 수준의 변화를 나타낸 그래프이다.
도 4은 뜰보리수나무잎 추출물에 대한 비장세포의 IL-10 cytokine 수준의 변화를 나타낸 그래프이다.
도 5은 뜰보리수나무잎 추출물에 대한 Balb/c 마우스 혈청의 IL-4 cytokine 수준의 변화를 나타낸 그래프이다.
도 6은 뜰보리수나무잎 추출물에 대한 Balb/c 마우스 혈청의 IL-10 cytokine 수준의 변화를 나타낸 그래프이다.
도 7은 뜰보리수나무잎 추출물에 대한 자연살해세포(NK cell) 활성 효과 수준의 변화를 나타낸 그래프이다.
FIG. 1 is a graph showing changes in the splenocyte proliferative activity against the extracts of Y. bovis leaf.
FIG. 2 is a graph showing changes in IL-2 cytokine levels of spleen cells against the extracts of Y. bovis leaf.
FIG. 3 is a graph showing changes in the level of IL-4 cytokine of spleen cells against the extract of Y. bovis leaf.
FIG. 4 is a graph showing changes in the level of IL-10 cytokine in spleen cells against the extract of Y. bovis leaf.
FIG. 5 is a graph showing changes in the IL-4 cytokine level of Balb / c mouse serum against the extract of Y. bovis leaf.
FIG. 6 is a graph showing changes in the level of IL-10 cytokine of Balb / c mouse serum against the extract of Y. barkii leaf.
FIG. 7 is a graph showing changes in the level of NK cell activation effect on the extract of Y. barkii leaf.

본 발명은 뜰보리수나무잎 추출물을 유효성분으로 하는 면역 증강용 약학 조성물에 관한 것으로, IL-2(Interlukin-2), IL-4(Interlukine-4) 또는 IL-10(Interlukine-10) 의 사이토카인 생성 유도 및 종양세포에 대해 직접적으로 대항하는 자연살해세포(NK cell)를 활성화함으로써 생체 면역을 증강시킬 수 있는 면역 증강용 약학 조성물에 관한 것이다. 이하, 본 발명의 이해를 돕기 위하여 구체적인 실시예 및 비교예를 통하여 본 발명의 구성 및 효과를 보다 상세히 설명한다.
The present invention relates to a pharmaceutical composition for enhancing immunity comprising an extract of Gardenia borealum Leaf as an active ingredient and is useful as an anti-inflammatory agent for the treatment of inflammation caused by cytokines of IL-2 (Interlukin-2), IL-4 (Interlukine- The present invention relates to a pharmaceutical composition for enhancing immunity, which can induce cytokine production and activate a natural killer cell (NK cell) directly against tumor cells. Hereinafter, the structure and effects of the present invention will be described in more detail with reference to specific examples and comparative examples in order to facilitate understanding of the present invention.

1. 뜰보리수나무잎 추출물 제조1. Production of garden boreal leaf extract

뜰보리수나무잎 추출물은 물 또는 탄소수 1 내지 4의 저급 알코올 또는 이들의 혼합 용매 중에서 선택되는 어느 하나로부터 가용하여 제조한다. 일실시예에서 건조된 뜰보리수나무잎 100g을 증류수로 수세한 다음, 증류수로 500 mL를 가하여, 환류 추출기 100℃ 에서 3시간 동안 가열, 추출하였다. 여과지(와트만 41번)를 이용하여 여과 한 후, 여액을 감압 농축하여 동결건조기를 이용하여 -50℃에서 48시간 동안 동결 건조시켰다. 이상의 방법으로 상기 열수추출물은 추출용매에 따라, 뜰보리수나무잎 열수 추출물 16.8g (16.8%)를 수득하여 하기 실험예의 시료로 사용하였다.
Gardenia borealis leaf extract is prepared by solubilizing it from water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. In one embodiment, 100 g of dried gardenia leaves were washed with distilled water, 500 mL of distilled water was added, and the mixture was heated and extracted at 100 ° C for 3 hours. After filtration using a filter paper (Watts 41), the filtrate was concentrated under reduced pressure and freeze-dried at -50 ° C for 48 hours using a freeze dryer. According to the above method, 16.8 g (16.8%) of the hot-water extract of Yoshimura bamboo leaf was obtained according to the extraction solvent and used as a sample of the following experimental example.

2. 뜰보리수나무잎 추출물에 의한 비장세포 증식 측정2. Measurement of splenocyte proliferation by Y. barki leaf extract

6주령의 Balb/c 수컷 생쥐를 경추 탈골하여 치사시키고 무균적으로 비장을 적출하여 100 mesh망 위에서 분쇄하여 single 세포로 만들었다.Male Balb / c mice at 6 weeks of age were sacrificed by cervical dislocation, and the spleen was sterilized aseptically and crushed on a 100 mesh mesh to form single cells.

단핵 세포층만 취하여 12,000 rpm에서 5분씩 3회 원심 분리하여 비장세포를 준비하였다. 비장세포를 2X105 cells/mL가 되도록 10% heat-inactivated FBS가 함유된 RPMI 1640 배지로 희석하여 96 well plate에 100 uL씩 분주하였다. 뜰보리수나무잎 열수추출물을 0(Control), 50, 100 및 200 ug/mL 농도로 희석하여 분주하였으며, 30분 후 5 ug/mL, lipopolysaccharide(LPS), 0.1 ug/mL ConA(Concanavalin A)를 처리한 후 37℃의 5% CO2 incubator에서 48시간 배양하였다. 암 조건에서 5 mg/mL 농도의 WST-1(Water Soluble Tetrazolium Salts) solution 첨가하여 2시간 반응 후 440 nm에서 O.D값을 측정하였다.The mononuclear cell layer was taken and spleen cells were prepared by centrifugation three times for 5 minutes at 12,000 rpm. The spleen cells were diluted with RPMI 1640 medium containing 10% heat-inactivated FBS to a concentration of 2 × 10 5 cells / mL and dispensed in a volume of 100 μL into a 96-well plate. After 30 minutes, 5 ug / mL of lipopolysaccharide (LPS) and 0.1 ug / mL of ConA (Concanavalin A) were added to the extracts of 0, 50, 100 and 200 ug / And cultured in a 5% CO 2 incubator at 37 ° C for 48 hours. The WST-1 (Water Soluble Tetrazolium Salts) solution was added at a concentration of 5 mg / mL in the dark condition. After 2 hours of reaction, the OD value was measured at 440 nm.

도 1은 뜰보리수나무잎 열수추출물에 대한 비장세포 증식능 효과를 나타낸다. T 세포와 B세포의 mitogen인 Con A (0.1 ug/mL)와 LPS (5 ug/mL)를 처리하여 대조군으로 사용하였다. 대조군은 정상으로 유도 하는 것을 확인하였으며, 뜰보리수나무잎 추출물 50, 100 및 200 ug/mL 농도에서 무처리군(Control)에 비하여 비장세포 증식능을 증가하는 것을 확인하였다.
Fig. 1 shows the effect of splenocyte proliferative activity on the hot-water extract of the garden boreal tree leaf. T cells and B cells were treated with Con A (0.1 ug / mL) and LPS (5 ug / mL) as control cells. The control group was found to induce normal growth, and it was confirmed that splenocyte proliferative activity was increased at 50, 100 and 200 ug / mL of Gardenia borealis leaf extracts compared with no treatment group.

3. 뜰보리수나무잎 추출물에 의한 비장세포 사이토카인 분비량 측정 3. Quantification of splenocyte cytokine secretion by bark extract

비장세포가 분비하는 사이토카인(IL-2, IL-4, IL-10) 농도 측정은 ELISA법을 이용하여 측정하였다. 24시간 반응 동안 생성된 사이토카인의 양을 Duoset sandwich ELISA Mouse kit(R&D system, USA)를 사용하여 측정하였다. ELISA용 96well plate에 각 cytokine 측정에 특성화 된 1차 항체를 PBS에 희석 후 100 uL 씩 분주해 하루 동안 처리한 후, 그 다음날, washing buffer로 1차 항체를 세척한 뒤, 항체가 붙지 않은 plate 의 다른 공간을 메워 주기 위해 buffer를 넣어 2시간 동안 처리 한 뒤 세척용 완충액으로 씻어내었다. Standard, sample을 100 ul씩 각 well에 넣어 2시간 동안 반응 시킨 후 반응이 끝난 뒤 washing buffer로 씻어내고 희석된 완충액을 각 well에 100 ul씩 분주하고 2시간 동안 처리한다. 이 과정이 끝나면 세척용 완충액을 이용해 plate를 씻어내고 발색을 도와주는 기질을 100 ul 넣어 반응 시킨 뒤 ELISA reader 570 nm에서 흡광도를 측정하고 Standard curve를 이용해 세포에서 생성된 사이토카인의 양을 계산하였다.The concentration of cytokines (IL-2, IL-4, IL-10) secreted by splenocytes was measured by ELISA. The amount of cytokine produced during the 24 hour reaction was measured using a DuoSet sandwich ELISA Mouse kit (R & D system, USA). The primary antibody, which was characterized for each cytokine, was diluted in PBS and dispensed into 100-μl aliquots on a 96-well plate for ELISA for one day. The next day, the primary antibody was washed with washing buffer, In order to fill the other space, the buffer was put in and treated for 2 hours and washed with the washing buffer. Standard and sample are added to each well in 100 μl of each well for 2 hours. After completion of reaction, wash with washing buffer, dispense 100 μl of diluted buffer in each well and treat for 2 hours. At the end of this procedure, the plate was washed with the buffer solution for washing, and 100 μl of the substrate for color development was reacted. Then, the absorbance was measured at 570 nm in an ELISA reader and the amount of cytokine produced in the cells was calculated using a standard curve.

도 2, 3, 4는 뜰보리수나무잎 추출물에 대한 비장세포 IL-2, IL-4 및 IL-10 사이토카인 분비량을 나타낸다. T 세포와 B세포의 mitogen인 Con A ( 0.1 ug/mL)와 LPS (5 ug/mL)를 처리하여 대조군으로 사용하였다. 도 2에 나타낸 바와 같이 대조군은 정상으로 유도 하는 것을 확인하였으며, IL-2 분비의 경우 뜰보리수나무잎 추출물은 농도 의존적으로 분비량을 증가하는 것을 확인하였다.Figures 2, 3, and 4 show the amounts of splenocytes IL-2, IL-4, and IL-10 cytokines secreted to the extracts of Y. bovis leaf. T cells and B cells were treated with Con A (0.1 ug / mL) and LPS (5 ug / mL) as control cells. As shown in FIG. 2, it was confirmed that the control group was induced to normal. In the case of IL-2 secretion, it was confirmed that the extract of Y. bovis leaf increased the secretion amount in a dose-dependent manner.

도 3에 나타낸 바와 같이 IL-4 생성은 뜰보리수나무잎 추출물 50 ug/mL 농도이상에서 대조군에 비하여 2배 이상 그 분비량을 현저하게 증가하는 것을 확인하였으며, 도 4에 나타낸 바와 같이 IL-10 생성도 IL-2, IL-4 생성 같이 뜰보리수나무잎 추출물을 처리한 군에서 대조군에 비하여 분비량을 증가하는 것을 확인하였다.
As shown in FIG. 3, IL-4 production was remarkably increased more than twice as much as that of the control group at a concentration of 50 ug / mL or more of Y. bovis leaf extract. As shown in FIG. 4, IL-2 and IL-4, respectively, compared with control group.

4. 뜰보리수나무잎 추출물에 의한 Balb/c 마우스 혈청으로부터 사이토카인 분비량 측정4. Quantification of cytokine secretion from Balb / c mouse serum by Y. bark leaf extract

6~8주령 수컷 Balb/c 마우스를 1 주일 동안 23 ℃, 40-60 % 습도, 12시간 명암주기 조건 환경에서 적응시킨 후, 뜰보리수나무잎 추출물을 100 mg/kg의 용량으로 첨가하여 4일 동안 경구 투여하였으며, 양성대조군으로 Concanavalin A(ConA)를 2mg/kg를 4일째에 마우스의 꼬리정맥에 주사 한 후 2시간, 4시간, 6시간 및 8시간 시간별로 혈액을 채취하여 IL-4 및 IL-10 과 같은 면역 사이토카인을 ELISA reader를 이용하여 450 nm의 파장에서 흡광도를 측정하였다.Six to eight week old male Balb / c mice were adapted for one week at 23 ° C, 40-60% humidity, 12 hours of light-dark cycle, and then 100 mg / kg of Y. bark extract was added for 4 days 4, 6, and 8 hours after injection of 2 mg / kg of Concanavalin A (ConA) as a positive control in the tail vein of the mice on the 4th day. Immunocytochemicals such as IL-10 were measured for absorbance at a wavelength of 450 nm using an ELISA reader.

도 5 및 도 6은 뜰보리수나무잎 추출물에 대한 Balb/c 마우스 혈청의 사이토카인 분비량을 나타낸다. 도 5에 나타낸 바와 같이 무처리군에서 시간별 IL-4 분비량이 증가하지 않은데 비하여 뜰보리수나무잎 추출물 100 mg/kg 투여군에서는 4시간째 IL-4 분비량이 무처리군에 비하여 현저하게 증가하는 것을 확인하였다.Figures 5 and 6 show the amount of cytokine secreted from the Balb / c mouse serum against the Y. bark leaf extract. As shown in FIG. 5, the amount of IL-4 secretion did not increase with time in the untreated group, whereas the amount of IL-4 secretion increased significantly at 4 hours in the group treated with 100 mg / kg of bovine leaf extract Respectively.

도 6은 뜰보리수나무잎 추출물에 대한 Balb/c 마우스 혈청의 IL-10 cytokine 수준의 변화를 나타낸 그래프이다. IL-10의 생성량은 무처리군에서는 시간별 사이토카인 분비량이 증가하지 않은데 비하여 뜰보리수나무잎 추출물 100 mg/mL 처리구에서는 6시간째 IL-10의 분비량이 무처리군에 비하여 현저하게 증가하는 것을 알 수 있었다.FIG. 6 is a graph showing changes in the level of IL-10 cytokine of Balb / c mouse serum against the extract of Y. barkii leaf. The amount of IL-10 produced in the untreated group did not increase with time, whereas the amount of IL-10 secreted at the 6th hour in the 100 mg / mL treated group of bovine leaf extract was significantly increased compared to the untreated group I could.

5. 뜰보리수나무잎 추출물에 의한 자연살해세포 (Natural Killer cell; 이하 NK-세포라 약칭함) 활성 효과 측정5. Measurement of the activity of Natural Killer cells (hereinafter abbreviated as NK-cells)

자연살해세포 활성 실험에 사용한 mouse의 림프 암세포는 YAC-1 cell line을 사용하였으며, YAC-1세포와 mouse의 비장세포는 10% fetal bovine serum과 1% penicillin이 포함된 RPMI 1640배지에서 37℃ ,5% CO2 incubator에서 배양 후 사용하였다.The YAC-1 cells and mouse spleen cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin at 37 ° C, After incubation in 5% CO 2 incubator,

Balb/c mouse 비장세포는(1X106, 5X105cells/㎖) 50ul와 YAC-1암세포(2X105cells/㎖) 50ul를 96well plate에 접종하였다. 뜰보리수나무잎 추출물을 50, 100, 200 ug/ml을 첨가하여 37℃, 5% CO2 incubator에서 4시간 배양하였다. 반응 종료 45분 전 10X lysis buffer 10ㅅl 첨가 한 후 다시 배양하고 2,500rpm에서 4분간 원심분리하였다.Balb / c mouse splenocytes were inoculated into a 96-well plate (50 μl, 1 × 10 6 , 5 × 10 5 cells / ml) and 50 μl of YAC-1 cancer cells (2 × 10 5 cells / ml). 50, 100, and 200 ug / ml were added to the extracts of Bombyx mori L. and cultured in a 5% CO 2 incubator at 37 ° C for 4 hours. 45 minutes before the end of the reaction, 10X lysis buffer was added and incubated again, followed by centrifugation at 2,500 rpm for 4 minutes.

상층액 50ㅅl를 96well plate에 옮겨 담은 후, substrate mix 50ul를 첨가하고 차광하여 실온에서 30분간 반응시켰다. 각 well에 50ul의 stop solution을 첨가하여 반응을 정지한 후, Microplate reader을 이용하여 490nm에서 흡광도를 측정하여 아래의 식으로 NK-세포의 활성을 산출하였다. 50 μl of the supernatant was transferred to a 96-well plate, and 50 μl of a substrate mix was added, followed by shading for 30 minutes at room temperature. After stopping the reaction by adding 50 ul of stop solution to each well, the absorbance was measured at 490 nm using a microplate reader, and the activity of NK-cells was calculated by the following equation.

Figure 112017015138011-pat00001
Figure 112017015138011-pat00001

도 7은 뜰보리수나무잎 추출물에 대한 자연살해세포(NK cell) 활성 효과 수준의 변화를 나타낸 그래프이다. 뜰보리수나무잎 추출물 처리군과 무처리군을 비교한 결과, 뜰보리수나무잎 추출물은 농도 의존적으로 NK 세포 활성을 나타내었으며, 특히 200 ug/mL 농도를 처리한 군은 대조군에 비하여 약 2배 정도의 NK 세포 활성을 나타내었다.
FIG. 7 is a graph showing changes in the level of NK cell activation effect on the extract of Y. barkii leaf. Compared with the control group, the extracts of Y. bokus leaf showed the NK cell activity in a concentration dependent manner. Especially, the group treated with 200 ug / Of NK cell activity.

6. 6. 뜰보리수나무잎Yam tree leaf 추출물에 대한 독성 검증 Toxicity to extracts

뜰보리수나무잎 추출물을 포함하는 조성물은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 경피제, 좌제 또는 멸균 주사용 액 등으로 제형화되어 경구투여나 주사로 피검자에 적용될 수 있으며, 뜰보리수나무잎 추출물이 10 내지 2000 mg/kg 체중/1일의 양으로 포함하여 적용될 수 있다. 이를 확인하기 위하여 식약처의 예규에 따라 SD rat (male, 6주령, (주)오리엔트 바이오)를 대상으로 뜰보리수나무잎 추출물을 구강 투여를 통해 랫트 당 300, 2000mg/kg을 1일 간격으로 계속 투여하였으며, 14일간 사망률 및 체중을 조사하였다.The composition containing the gardenia borealis leaf extract can be formulated into powders, granules, tablets, capsules, suspensions, emulsions, syrups, transdermal preparations, suppositories or sterile injectable solutions, etc., and can be applied to the subject by oral administration or injection, Yam tree leaf extract may be applied in an amount of 10 to 2000 mg / kg body weight per day. In order to confirm this, the SD rats (male, 6 weeks old, Orient Bio Co., Ltd.) were administered 300 mg / kg / day of 2000 mg / kg per day through oral administration to the garden boreal tree leaf extract The mortality and body weight were measured for 14 days.

본 비교예에 의한 뜰보리수나무잎 추출물을 투여한 랫트의 사망률 및 체중변화량은 각각 다음의 표 1 내지 표2에 나타내었다. 표 1은 뜰보리수나무잎 추출물 을 처리한 랫트의 사망률을 나타낸 표이며, 표 2는 뜰보리수나무잎 추출물을 처리한 랫트의 체중변화량을 나타낸 것이다.Mortality and body weight changes of the rats administered with the gardenia borealis leaf extract according to this comparative example are shown in the following Tables 1 to 2, respectively. Table 1 shows the mortality of rats treated with Y. bark extract and Table 2 shows the body weight change of rats treated with Y. bark leaf extract.

뜰보리수나무잎 추출물을 투여한 랫트의 사망률Mortality of rats treated with Gardenia borealis leaf extract GroupGroup Dose(mg/kg B.W)Dose (mg / kg B.W) MortalityMortality 뜰보리수나무잎
추출물
Yam tree leaf
extract
300300 0%
(0/3)a
0%
(0/3) a
20002000 0%
(0/3)
0%
(0/3)

a : Number of dead animals/Number of tested animalsa: Number of dead animals / Number of animals tested

뜰보리수나무잎 추출물을 투여한 랫트의 체중변화량Changes in body weight of rats treated with Gardenia borealis leaf extract GroupGroup Dose
(mg/kg B.W.)
Dose
(mg / kg BW)
투여일Day of administration
0일0 days 1일1 day 3일3 days 7일7 days 14일14 days 뜰보리수나무잎
추출물
Yam tree leaf
extract
300300 209.4
±7.0
209.4
± 7.0
231.3
±6.1
231.3
± 6.1
233.3
±3.7
233.3
± 3.7
242.6
±1.4
242.6
± 1.4
255.7
±1.5
255.7
± 1.5
20002000 213.9
±10.3
213.9
± 10.3
242.3
±7.9
242.3
± 7.9
239.5
±13.6
239.5
± 13.6
248.7
±14.4
248.7
± 14.4
264.8
±12.2
264.8
± 12.2

상기 표 1에 나타낸 바와 같이 뜰보리수나무잎 추출물은 투여량에 관계없이 랫트의 생존율에 영향을 미치지 않는 것으로 나타났다. 또한 상기 표 2에 나타낸 바와 같이 뜰보리수나무잎 추출물을 처리한 실험군은 정상적인 체중 증가를 나타내었다. 이와 같은 결과는 상기 뜰보리수나무잎 추출물 2000 mg/kg 경구 투여까지 급성 독성을 보이지 않음을 확인하였으며, 뜰보리수나무잎 추출물이 면역증강용 약학 조성물 및 기능성 식품으로도 이용될 수 있음을 확인하였다.
As shown in Table 1, yam bora leaf extracts did not affect the survival rate of rats regardless of the dose. In addition, as shown in Table 2 above, the experimental group treated with Y. borealis leaf extract showed normal weight gain. The results showed that the extract of Y. bovis leaf showed no acute toxicity until oral administration of 2000 mg / kg, and that Y. bovis leaf extract could also be used as a pharmaceutical composition for enhancing immunity and functional food.

본 발명의 뜰보리수나무잎 추출물을 유효성분으로 하는 면역 증강용 약학 조성물은 IL-2(Interlukin-2), IL-4(Interlukine-4) 또는 IL-10(Interlukine-10) 의 사이토카인 생성 유도 및 종양세포에 대해 직접적으로 대항하는 자연살해세포(NK cell)를 활성화함으로써 생체 면역을 증강시킬 수 있어 인류건강과 질병치료에 도움이 되므로 산업상 이용가능성이 있다.The pharmaceutical composition for enhancing immunity comprising the extract of the gardenia bittern leaf of the present invention as an active ingredient is useful for inducing cytokine production of IL-2 (Interlukin-2), IL-4 (Interlukine-4) or IL- (NK cells) directly against tumor cells, and thus can be used industrially as it is useful for treating human health and diseases.

Claims (8)

뜰보리수나무(Elaeagnus multriflora Thunb.) 잎 추출물을 유효성분으로 포함하는 것을 특징으로 하는 면역증강용 약학 조성물A pharmaceutical composition for immune enhancement characterized by comprising Elaeagnus multriflora Thunb. Leaf extract as an active ingredient 제1항에 있어서, 뜰보리수나무 잎 추출물은 물 또는 탄소수 1 내지 4의 저급 알코올 또는 이들의 혼합 용매 중에서 선택되는 어느 하나로부터 가용한 추출물인 것을 특징으로 하는 면역증강용 약학 조성물.The pharmaceutical composition for immunotherapy according to claim 1, wherein the gardenia borealis leaf extract is an extract soluble in water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. 제2항에 있어서, 면역증강용 약학적 조성물은 뜰보리수나무 잎 추출물이 0.1 내지 2000 mg/kg 체중/1일의 양으로 포함하여 제조되는 것을 특징으로 하는 면역증강용 약학 조성물.[Claim 3] The pharmaceutical composition for immune enhancement according to claim 2, wherein the pharmaceutical composition for immunomodulation is prepared by containing a gardenia bittern leaf extract in an amount of 0.1 to 2000 mg / kg of body weight per day. 제3항에 있어서, 상기 조성물은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 경피제, 좌제 또는 멸균 주사용 액으로 제형화된 것을 특징으로 하는 면역증강용 약학 조성물.The pharmaceutical composition according to claim 3, wherein the composition is formulated as a powder, granule, tablet, capsule, suspension, emulsion, syrup, transdermal preparation, suppository or sterile injectable solution. 제1항 또는 제2항에 있어서, 뜰보리수나무 잎 추출물은 종양세포에 대해 직접적으로 대항하는 자연살해세포를 활성화함으로써 면역증강 활성을 가지는 것을 특징으로 하는 면역증강용 약학 조성물.3. The pharmaceutical composition for immunotherapy according to claim 1 or 2, wherein the gardenia leaf extract has an immunopotentiating activity by activating natural killer cells directly against tumor cells. 삭제delete 삭제delete 삭제delete
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KR102195505B1 (en) * 2020-09-24 2020-12-28 재단법인 전남바이오산업진흥원 PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA Thunb. EXTRACT FOR Treating and Preventing Benign Prostatic Hyperplasia

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KR101773322B1 (en) * 2017-02-14 2017-08-31 재단법인 전남생물산업진흥원 PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA Thunb. EXTRACT FOR IMMUNE-ENHANCING

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WO2018151406A1 (en) * 2017-02-14 2018-08-23 재단법인 전남생물산업진흥원 Immunopotentiating pharmaceutical composition having elaeagnus multriflora thunb. leaf extract as effective ingredient
KR102195505B1 (en) * 2020-09-24 2020-12-28 재단법인 전남바이오산업진흥원 PHARMACEUTICAL COMPOSITION CONTAINING ELAEAGNUS MULTRIFLORA Thunb. EXTRACT FOR Treating and Preventing Benign Prostatic Hyperplasia
WO2022065601A1 (en) * 2020-09-24 2022-03-31 재단법인 전남바이오산업진흥원 Composition for prevention and treatment of benign prostatic hyperplasia, comprising fruit extracts of elaeagnus multriflora thunb. as active ingredient

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