KR20140022940A - Compositions for activating htrpa1 comprising extract of brassicaceae or umbelliferae plants and uses thereof - Google Patents
Compositions for activating htrpa1 comprising extract of brassicaceae or umbelliferae plants and uses thereof Download PDFInfo
- Publication number
- KR20140022940A KR20140022940A KR1020140011621A KR20140011621A KR20140022940A KR 20140022940 A KR20140022940 A KR 20140022940A KR 1020140011621 A KR1020140011621 A KR 1020140011621A KR 20140011621 A KR20140011621 A KR 20140011621A KR 20140022940 A KR20140022940 A KR 20140022940A
- Authority
- KR
- South Korea
- Prior art keywords
- htrpa1
- extract
- antagonist
- activity
- plants
- Prior art date
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Abstract
Description
본 발명은 십자화과 또는 산형과 식물 추출물을 포함하는 hTRPA1 활성화 조성물 및 그의 용도에 관한 것이다.
The present invention relates to hTRPA1 activating compositions comprising cruciferous or antagonist plant extracts and their use.
십자화과(Brassicaceae) 식물은 350속의 약 3,000종이 있으며, 주로 북반구의 온대에서 난대에 분포하고 있고 그 중에서도 서아시아에서 지중해 연안지방에 특히 종류가 많다. 한편 우리나라에서 많이 재배되고 있는 십자화과 채소류로는 양배추, 배추, 케일, 컬리플라워, 브로콜리, 무, 열무, 유채, 냉이, 갓 등이 있는 것으로 알려지고 있다. 이들 채소들의 독특한 자극적인 맛과 향기는 황을 함유한 화합물인 이소시아네이트(isothiocyanates)에 주로 기인하며 일부 설파이드(sulfides)도 관여한다. 한편, 십자화과 채소 및 이들 채소에 함유된 일부화학물질(chemical compounds)들이 발암(carcinogenesis)에 대해서 방어 효과(chemoprotection)를 나타내며, 특히, 해독효소로 작용하는 단계 Ⅰ 및 단계 Ⅱ 효소들의 활성이 유도된다고 알려져 있다. There are about 3,000 species of 350 genera, mainly in the temperate zone of the northern hemisphere, especially in the Mediterranean, especially in western Asia. Meanwhile, cruciferous vegetables grown in Korea are known to include cabbage, cabbage, kale, cauliflower, broccoli, radish, radish, rapeseed, horseradish, and gat. The unique irritating taste and aroma of these vegetables is due mainly to isothiocyanates, sulfur-containing compounds, and some of the sulfides. On the other hand, cruciferous vegetables and some chemical compounds contained in these vegetables show chemoprotection against carcinogenesis, and in particular, the activities of the enzymes I and II acting as detoxifying enzymes are induced. Known.
고추냉이속(Wasabia Matsum.)은 십자화과 중에서 가장 작은 속 중에 하나이며 세계적으로 동아시아에만 2종이 분포한다. 고추냉이속은 꽃이 흰색이고 장각의 조각들이 열 개하면서 꼬이지 않으며 꽃은 포가 있고 종자가 크고 숫자가 적으며 자엽은 기울지 않은 특징에 의해 다른 속들과 구별된다. 한국에는 고추냉이 한 종이 분포한다. 고추냉이의 학명은 일본에 분포하는 종과 같은 종으로 간주하여 Wasabia japonica(Miq.) Matsum.을 사용하며 이를 와사비라고도 칭한다. 이는 독특한 매운 맛 성분으로 생선 및 육류 요리 등의 조미 소스로 많이 사용되고 있으며 주 소비 국가인 일본에서는 최근 들어 고추냉이가 조미료 외에도 김치, 절임, 볶음, 튀김, 술, 아이스크림 등 다양한 식음료 또는 공기청정제 및 식품 방부제 등에도 활용되고 있다. 이는 고추냉이에 함유된 이소시아네이트가 식용촉진 기능 이외에도 살균, 살충, 혈소판 응집 억제, 발암 억제 작용, 노화방지 및 항산화 기능 등을 하는 것으로 연구 보고됨에 따라 고추냉이 이용도가 증가하는 것으로, 최근에는 고추냉이의 잎을 쌈채소로 활용하거나 장아찌 형태로 식용하는 사례가 늘고 있다. Wasabia Matsum . Is one of the smallest genus of cruciferaceae, with two species in East Asia worldwide. Horseshoe genus has white flowers, and each of its long fragments is not twisted. Flowers have bracts, have large seeds and small numbers, and cotyledons are not slanted. One species of horseradish is distributed in Korea. Wasabia 's scientific name is considered to be the same species distributed in Japan and uses Wasabia japonica (Miq.) Matsum. It is also called wasabi. This is a unique spicy ingredient that is widely used as a seasoning source for fish and meat dishes, and in Japan, a major consumer country, wasabi was recently added to various food and beverage or air fresheners and foods such as kimchi, pickles, fried, fried, sake, and ice cream. It is also used for preservatives. This is due to the fact that isocyanate contained in wasabi has been reported to have sterilization, insecticide, platelet aggregation suppression, carcinogenesis inhibitory effect, anti-aging and antioxidant function in addition to food promotion function. Increasingly, the leaves are used as a ssam vegetable or edible in pickles.
이와 유사한 특성을 가지는 갓(mustard leaf, mustard greens)은 겨자(Brassica juncea, brown mustard, indian mustard)의 잎을 말하는데 경엽채소류 중의 하나로 염장발효시켜 김치로 식용하며, 그 씨는 신미성 향신료로서 사용되고 있다. 갓은 중국이 원산지이지만 현재는 한국과 일본 등에서 널리 재배되고 있으며, 국내에서는 전라남도 여천군 돌산지방에서 갓을 오래 전부터 많이 재배하여 왔으며, 지역적인 독특한 기후, 토양 조건 등이 그 고유의 맛을 지배하여 갓 김치제조용으로 많은 양을 대도시 또는 타 지방으로 공급하고 있다. 갓의 독특한 자극성의 매운 맛 또한 휘발성 함황성분인 이소시아네이트류에 기인하는 것으로 이는 시니그린 등의 글루코시놀레이트류에 미로시나제(thioglucoside glucohydrolase)가 작용하여 생성되는 것으로 보고 되고 있다. Mustard greens (mustard leaf, mustard greens), which have similar characteristics, are the leaves of mustard (Brassica juncea, brown mustard, indian mustard), one of the foliage vegetables, fermented with salt and fermented as kimchi. . It is native to China, but is now widely grown in Korea and Japan. In Korea, gat has been cultivated for a long time in Dolsan province, Yeocheon-gun, Jeollanam-do, and its unique local climate and soil conditions dominate its own taste. Large quantities are supplied to large cities or other regions for kimchi production. Its spicy taste is also due to isocyanates, which are volatile sulfur-containing components, which are reported to be produced by the action of myrosinase (thioglucoside glucohydrolase) on glucosinolates such as cinigrin.
산형과(Umbelliferae)(또는 미나리과(Apiaceae)) 식물은 세계적으로 약 2500-3000종이 생육하고 있으며, 한국에는 68종류의 식물이 생육하는 것으로 보고되어 있다. 산형과 식물은 책마다 다른 내용을 서술하고 있거나 용어가 일치하지 않는 경우가 많고 체계적인 연구가 미흡한 실정으로, 생김새가 비슷하여 분류가 어려운 것으로 잘 알려져 있다. 산형과 식물은 대부분 독특한 향미를 지니며 이를 이용하여 향신료나 산나물 등으로 식용하는 경우가 많다. 이 중 미나리(Oenanthe javanica ( Blume ) DC .)는 산형과에 속하는 다년초 초본으로 습지에서 자생하며 한국, 일본, 중국, 대만, 말레이시아, 인도 등지에 분포하며 농가에서 많이 재배하고 있다. 미나리는 식품 영양학적으로 플라보노이드 화합물 뿐만 아니라 비타민과 칼륨, 칼슘 및 철분이 들어있는 대표적인 알칼리 식품이다. 우리 식생활에서 다량 섭취되어지는 채소로서 독특한 향미 때문에 연한 부분을 채취하여 김치, 나물, 강회 등에 이용되고 있고, 독특한 향미 및 약리작용으로 인해 기능성 식품 소재나 향신료로 활용도가 높은 식물이다. 이와 흡사하게 독특한 향미를 지니는 특성을 이용해 장아찌나 산나물로 식용하는 식물 중 하나로 누룩치(Pleurospermum camtschaticum Hoffm .)가 있다. 누룩치는 산형과에 속하는 여러해살이 풀로 외형적 특색은 키 50-100 cm 정도이며, 하얀색의 꽃이 6-7월경에 피어나고, 한줄기에 3개의 잎을 가지며, 꽃이 지고 난 후에는 달걀 모양의 열매가 열린다. 민간요법에서는 누룩치가 소화력을 향상시켜 식욕을 촉진시키며 산모가 섭취하면 젖이 잘 나오고 콜레스테롤 저하 기능도 있다고 알려져 있다. 누룩취는 4월 중순에서 5월 상순에 연한 잎줄기를 채취하여 날것으로 양념장에 찍어 먹거나 데쳐서 무침으로 먹기도 하는데, 이와 맛이 유사한 셀러리에 비해 탄수화물, 회분, 인, 그리고 특히 비타민 A가 더 많은 것으로 보고되고 있다. 깊은 산의 습기 있는 바위 틈에서 자라는 개회향(Ligusticum tachiroei ( Franch . & Sav .) M. Hiroe & Constance) 또한 독특한 향미 특성을 지니는데 이는 생채나 산나물로 주로 쓰이기보다 한방에서 음위, 간질, 치통, 부인병을 다스리는 약용 식물로 주로 쓰이며, 제주도, 전라남도, 경상남도, 평안북도, 함경남북도 등지에 분포한다. The Umbelliferae (or Apiaceae) plant grows around 2500-3000 species worldwide, with 68 plant species reported in Korea. The types of plants and plants describe different contents in different books or the terms do not coincide in many cases, and the systematic research is insufficient. It is well known that the appearance is similar and difficult to classify. Most types and plants have unique flavors and are often eaten as spices or wild vegetables. Among parsley (Oenanthe javanica (Blume) DC. ) Is a perennial herb native to wetland belonging to a dispersed and is distributed in Korea, Japan, China, Taiwan, Malaysia and India and has been cultivated in many farms. Buttercup is a representative alkaline food that contains vitamins, potassium, calcium and iron as well as flavonoid compounds in food nutrition. It is a vegetable that is consumed in large quantities in our diet, and is used for kimchi, herbs, and limbus because of its unique flavor. It is a plant that is highly utilized as a functional food material or spice due to its unique flavor and pharmacological action. Similarly, Pleurospermum camtschaticum Hoffm ( Pleurospermum camtschaticum Hoffm . ) Is one of the plants edible as pickles or wild vegetables. The leaven is a perennial herb belonging to the mountain family, and its external characteristic is 50-100 cm in height. The white flowers bloom around June-July, have three leaves in one stem, and the egg-shaped fruits after the flowers are lost. Is opened. In folk medicine, Nuruk is known to improve digestion and promote appetite. Yeast odor is harvested from mid-April to early May, and can be eaten raw or seasoned with marinade. It has more carbohydrates, ash, phosphorus, and especially vitamin A than celery similar in taste. Is being reported. Ligusticum grows in the damp rocks of deep mountains tachiroei ( Franch . & Sav .) M. Hiroe & Constance ) also has unique flavor characteristics, which are mainly used as medicinal plants to control the genitals, epilepsy, toothache and gynecological diseases in oriental medicine, rather than being used as raw vegetables or wild vegetables. It is distributed in Gyeongsangnam-do, North Pyongan, and South Hamgyong.
이와 같이 독특한 향미 특성으로 널리 활용되어 지는 십자화과 및 산형과 산채류의 분류학적 특성이나 유효성분 분석에 관한 연구에 주로 편중되어 있는 실정으로 식품으로써 가치를 결정짓는 가장 중요한 요소인 “맛”에 관한 연구는 전무한 것으로 사료된다. As such, the research on “flavor”, which is the most important factor that determines the value as food, is mainly focused on the research on the taxonomy and the analysis of the active ingredients of cruciferaceae and mountain and wild vegetables widely used as unique flavor characteristics. It seems to be absent.
식품의 가치를 결정짓는 가장 중요한 요소인 “맛”에 관한 연구는 분자수준의 기초연구부터 소비자 및 산업적 응용연구에 걸친 매우 다양한 학문분야를 포함한다. 맛 물질은 미뢰 속 맛세포에 있는 수용체에 ‘수용(reception)'되면 발생된 신호가 맛신경 전도로를 통해 중추에 전달하고(transmission), 이 신호는 중추에서 정보 처리되어 인지(perception)되는, 즉 말초에서 중추에 이르는 일련의 동적기작을 통해 인식된다. 최근 분자생화학 등 관련 학문의 발전과 더불어 미각수용체의 분자실체가 밝혀져 일부 GPCR(G-Protein Coupled Receptor) 및 TRP(Transient Receptor Potential) 양이온 채널 수용체가 클로닝 되었으며 최근 클로닝된 수용체를 이용한 세포수준의 연구가 가능하게 되었다. 클로닝된된 수용체를 이용한 연구기술은 새로운 맛 활성물질인 인 비트로 스크리닝이나 관능분석기술에 획기적인 진화를 가져옴과 동시에 지금까지 신약개발에 이용되던 가장 진보된, 새로운 방법을 식품의 맛 연구에 적용할 수 있게 하였다. 맛 성분에 대한 수용체 수준에서의 식품학적 연구는 현재 우리나라에서는 거의 전무한 실정이며 세계적으로도 시작단계이다. Research on "taste," the most important determinant of food value, covers a wide range of disciplines, from basic molecular research to consumer and industrial applied research. The taste substance is `` reception '' of the receptors in taste cells in taste buds and the signal generated is transmitted through the taste nerve pathway to the center, which is then processed and perceived by the information center. In other words, it is recognized through a series of dynamic mechanisms from the periphery to the center. Recently, with the development of related studies such as molecular biochemistry, the molecular substance of taste receptor has been revealed, and some GP- and GRP-transient receptor cation channel receptors have been cloned. It became possible. Research techniques using cloned receptors have revolutionized evolution of new taste active substances, in vitro screening and sensory analysis, while at the same time applying the most advanced new methods used in new drug development to the study of taste in food. It was. Food studies at the receptor level on taste components are rarely present in Korea and are in the beginning stages worldwide.
최근 맛 성분 중 매움, 시원함, 얼얼함, 쏘는 맛 등으로 표현되는 자극성 맛 물질은 TRP계 양이온 채널을 활성화시키는 것으로 보고되고 있다. TRP계 수용체는 외부자극에 대한 전형적인 세포 센서로써 다른 생체작용기작에서 중요한 역할을 하므로 TRP계 수용체 활성화물질은 이러한 관점에서도 매우 중요하다. 겨자나 와사비의 주성분인 이소시아네이트, 최루가스로 쓰이는 아크롤레인, 계피기름의 성분인 시나말데하이드 등은 TRPA1(Transient Receptor Potential ANKYRIN 1)을 활성화 시키는데, TRPA1는 유해자극에 대한 수용체로서의 역할을 가지고 있어서 외부 자극에 대해서 방어 기전에 관여하는 수용체로서 감각과 관여한다고 알려져 있다. Recently, the irritating taste substance represented by spicy, cool, tingling, stinging, etc. of the taste component is reported to activate the TRP-based cation channel. TRP receptors are also very important in this regard because TRP receptors are typical cellular sensors for external stimuli and play an important role in other biological mechanisms. Isocyanate, which is a major component of mustard or wasabi, acrolein, which is used as tear gas, and cinnamaldeide, which is a component of cinnamon oil, activates TRPA1 (Transient Receptor Potential Ankyrin 1). It is known to participate in the sense as a receptor involved in the defense mechanism against.
TRPA1(Transient Receptor Potential cation channel subfamily A, member 1)은 TRP 이온 채널의 슈퍼패밀리에 속하는 비선택적 양이온 채널이다. 다른 패밀리 멤버와 유사하게, TRPA1 채널은 4개의 서브유니트의 테트라화에 의해 형성되며, 각각의 서브유니트는 6개 트랜스막 도메인, 하나의 동공 루프 및 세포내 N-말단과 C-말단을 포함한다. TRPA1은 감각 뉴우런에서 발현되며 TRPV1, 칼시토닌 유전자-관련 펩타이드와 브래드키닌 수용체와 같이 통증 마커와 함께 국소화되어 있다(Nagata, K. et al., Journal of Neuroscience 2005, 25, 4052-4061; Story, G. M. et al., Cell 2003, 112, 819-829; Corey, D. P. et al., Nature 2004, 432, 723-730; Bautista, D. M. et al., Proceedings of the National Academy of Science U.S.A. 2005, 102, 12248-12252; Jaquemar, D. et al., Journal of Biological Chemistry 1999, 274, 7325-7333). TRPA1 (Transient Receptor Potential cation channel subfamily A, member 1) is a non-selective cation channel belonging to the superfamily of TRP ion channels. Similar to other family members, the TRPA1 channel is formed by tetralation of four subunits, each subunit comprising six transmembrane domains, one pupil loop and intracellular N-terminus and C-terminus. . TRPA1 is expressed in sensory neurons and localized with pain markers such as TRPV1, calcitonin gene-related peptides and the Bradkinin receptor (Nagata, K. et al., Journal of Neuroscience 2005, 25, 4052-4061; Story, GM et al., Cell 2003, 112, 819-829; Corey, DP et al., Nature 2004, 432, 723-730; Bautista, DM et al., Proceedings of the National Academy of Science USA 2005, 102, 12248-12252; Jaquemar, D. et al., Journal of Biological Chemistry 1999, 274, 7325-7333.
통증 모델에서, TRPA1의 녹다운은 염증과 신경 손상에 의해 유발된 냉각 통각과민을 억제하였다(Obata, K. et al., Journal of Clinical Investigation 2005, 115, 2393-2401; Jordt, S. E. et al., Nature 2004, 427, 260-265; Katsura, H. et al., Exploratory Neurology 2006, 200, 112-123). 또한, TRPA1 유전자 녹다운은 감각 기능의 손상을 초래하고 브래드키닌-유발 통증 과민성에서 결함을 나타내었다(Kwan, K. Y. et al. Neuron 2006, 50, 277-289; Bautista, D. M. et al. Cell 2006, 124, 1269-1282). 위와 같은 실험 결과들은 TRPA1이 감각기능과 통증 상태에서 매우 중요한 역할을 수행한다는 것을 보여주는 것이다. In the pain model, knockdown of TRPA1 inhibited cold hyperalgesia caused by inflammation and nerve damage (Obata, K. et al.,Journal of Clinical Investigation 2005, 115, 2393-2401; Jordt, S. E. et al.,Nature 2004, 427, 260-265; Katsura, H. et al.,Exploratory Neurology 2006, 200, 112-123). In addition, TRPA1 gene knockdown results in impaired sensory function and has been shown to be defective in Bradkinin-induced pain hypersensitivity (Kwan, K. Y. et al.Neuron 2006, 50, 277-289; Bautista, D. M. et al.Cell 2006, 124, 1269-1282). These results show that TRPA1 plays a very important role in sensory function and pain.
한편, 최근에, TRPA1 작용제(agonist)가 TRPA1과 직접적으로 상호작용한다는 실험 결과들이 나오고 있다. AITC 및 신남알데하이드는 TRPA1의 N-말단에 있는 시스테인 및 라이신 잔기를 공유결합적으로 변형시키고 이 채널을 활성화 한다는 보고가 있다(Hinman, A. et al., Proceedings of the National Academy of Science U.S.A. 2006, 103, 19564-19568; Macpherson, L. J. et al., Nature 2007, 445, 541-545).
Recently, however, experimental results have shown that the TRPA1 agonist interacts directly with TRPA1. AITC and cinnamic aldehyde have been reported to covalently modify the cysteine and lysine residues at the N-terminus of TRPA1 and activate this channel (Hinman, A. et al., Proceedings of the National Academy of Science USA 2006, 103, 19564-19568; Macpherson, LJ et al., Nature 2007, 445, 541-545).
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
본 발명자들은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규 소재를 개발하고자 노력하였다. 그 결과, 본 발명자들은 십자화과(Brassicaceae) 또는 산형과(Umbelliferae) 식물 추출물이 hTRPA1의 활성화와 관련이 있음을 규명함으로써 본 발명을 완성하게 되었다.The inventors have sought to develop new materials that help maintain homeostasis in the human body associated with the activation of hTRPA1. As a result, the present inventors have completed the present invention by clarifying that the Brassicaceae or Umbelliferae plant extract is associated with the activation of hTRPA1.
따라서 본 발명의 목적은 hTRPA1 활성화용 조성물을 제공하는 데 있다.Accordingly, an object of the present invention is to provide a composition for activating hTRPA1.
본 발명의 다른 목적은 hTRPA1 활성화 하는 자극성 향미 조성물을 제공하는 데 있다.Another object of the present invention is to provide a stimulating flavor composition that activates hTRPA1.
본 발명의 다른 목적은 hTRPA1에 대한 길항제(antagonist)의 스크리닝 방법을 제공하는 데 있다.Another object of the present invention is to provide a method of screening an antagonist for hTRPA1.
본 발명의 다른 목적은 hTRPA1 활성화 방법을 제공하는 데 있다.
Another object of the present invention is to provide a method for activating hTRPA1.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명 및 청구범위에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention and claims.
본 발명의 일 양태에 따르면, 본 발명은 (i) 고추냉이(Wasabia japonica (Miq.) Matsum.) 및 돌산갓(Brassica juncea (L.) Czern. et coss)으로 구성된 군으로부터 선택되는 십자화과(Brassicaceae) 식물, (ii) 누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 및 미나리(Oenanthe javanica (Blume) DC.)로 구성된 군으로부터 선택되는 산형과(Umbelliferae) 식물로 구성된 군으로부터 선택되는 하나 이상의 식물의 추출물을 포함하는 hTRPA1(human Transient Receptor Potential A1) 활성화용 조성물을 제공한다.
According to one aspect of the invention, the invention is (i) Wasabia japonica (Miq.) Matsum.) and dolsangat (Brassica juncea (L.) Czern. et coss) (Brassicaceae) plant selected from the group consisting of (ii) Pleurospermum camtschaticum Hoffm., Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) and Oenanthe javanica (Blume) DC.) Provides a composition for activating hTRPA1 (human Transient Receptor Potential A1) comprising an extract of one or more plants selected from the group consisting of umbelliferae plants selected from the group consisting of.
본 발명자들은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규 소재를 개발하고자 노력하였다. 그 결과, 본 발명자들은 십자화과 또는 산형과 식물 추출물이 hTRPA1의 활성화와 관련이 있음을 규명하였다.The inventors have sought to develop new materials that help maintain homeostasis in the human body associated with the activation of hTRPA1. As a result, the inventors have found that cruciferous or antagonist plant extracts are associated with the activation of hTRPA1.
본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물은 hTRPA1을 활성화 하여 자극성 향미를 유발한다. hTRPA1의 활성화와 자극성 향미 사이의 관련성은 많은 문헌에 기재되어 있기 때문에, 십자화과 또는 산형과 식물 추출물이 hTRPA1을 강력하게 활성화 한다는 하기 실시예의 데이터는 상기 식물 추출물의 자극성 향미제로서의 용도를 충분히 뒷받침한다. 자극성 향미제로서의 겨자 오일 성분인 알릴 이소티오시아네이트(AITC)(Bandell M, et al., Neuron 41:849857(2004)); Jordt SE et al., Nature 427:260265(2004))가 TRPA1 아고니스트로 잘 알려져 있다. 또한, 계피에 있는 신남 알데하이드, 마늘과 양파에서 유래된 알리신과 다이알릴 설파이드, 오레가노(oregano)에 있는 카바크롤, 이소벨레랄(isovelleral) 및 여뀌(water pepper)와 타스마니안 고추(Tasmanian pepper)에 있는 폴리고디알(polygodial) 등은 자극성 향미 성분으로서 TRPA1 아고니스트로 알려져 있다(Bandell M et al,, Neuron 41:849857(2004); Bautista DM et al., Proc Natl Acad Sci USA 102:1224812252(2005); Escalera J et al., J Biol Chem 283: 2413624144(2008); Macpherson LJ et al., Curr Biol 15: 929934(2005); Xu H et al., Nat Neurosci 9: 628635(2006)).According to a preferred embodiment of the present invention, the composition of the present invention activates hTRPA1 to induce an irritating flavor. Since the relationship between the activation of hTRPA1 and the irritating flavor has been described in many literatures, the data of the following examples that the Cruciferous or antagonist plant extracts strongly activate hTRPA1 fully supports the use of the plant extract as an irritant flavor. Allyl isothiocyanate (AITC), a mustard oil component as an irritant flavor (Bandell M, et al., Neuron 41: 849857 (2004)); Jordt SE et al., Nature 427: 260265 (2004)) are well known as TRPA1 agonists. Also, cinnamic aldehydes in cinnamon, allicin and diallyl sulfides derived from garlic and onions, cabarcrol in oregano, isovelleral and water peppers and Tasmanian peppers. Polygodial, et al., Is known as TRPA1 agonist as an irritating flavor component (Bandell M et al, Neuron 41: 849857 (2004); Bautista DM et al., Proc Natl Acad Sci USA 102: 1224812252 (2005); Escalera J et al., J Biol Chem 283: 2413624144 (2008); Macpherson LJ et al., Curr Biol 15: 929934 (2005); Xu H et al., Nat Neurosci 9: 628635 (2006).
본 발명의 조성물에 의한 자극성 향미는 미각을 통해 감작하는 ‘맛’으로, 미각은 혀와 구강점막 및 후두의 화학 수용체의 작용에 의해 맛을 느끼는 것이다. 이러한 화학 수용체에는 맛을 느끼는 감각기관인 미뢰가 있다. 미뢰의 표면에는 아주 미세한 융모들이 돋아 있으며, 여기 미공이라는 작은 구멍을 통해 맛을 느끼게 하는 이온이나 분자들이 세포막에 있는 이온채널을 통과한다. 맛의 기본이 되는 원미에는 단맛, 쓴맛, 짠맛, 신맛 및 감칠맛은 상기 언급한 수용체에 의해 인식되며, 매운맛, 떫은맛 등은 수용체 및 구강 내의 자유신경이나 혀의 점막을 통해 복합적으로 느끼는 감각이다. 예컨대, 자극성 향미(매운 맛, 얼얼함 또는 쏘는 맛)는 구강내의 자유신경에서 느끼는 일종의 아픈 감각이다.The irritating flavor of the composition of the present invention is 'taste' sensitized through the taste, the taste is to taste by the action of the chemical receptors of the tongue, oral mucosa and larynx. These chemical receptors contain taste buds, taste organs that taste. Microscopic villi appear on the surface of taste buds, and ions or molecules that taste through the tiny pores called micropores pass through ion channels in the cell membrane. Sweetness, bitterness, salty taste, sourness and umami are recognized by the above-mentioned receptors in the raw rice which is the basis of taste, and spicy, astringent taste, etc. are a sensation which is complexly felt through the receptors and free nerves in the mouth and the mucous membrane of the tongue. For example, irritating flavor (spicy, tingling or stinging) is a kind of painful sensation in the free nerves in the oral cavity.
상기 맛 성분 중 매운 맛, 시원한 맛, 얼얼한 맛 또는 쏘는 맛 등으로 표현되는 자극성 맛 물질은 TRP계 양이온 채널, 예컨대 hTRPA1을 활성화시키는 것으로 보고되고 있다. TRP계 수용체는 외부자극에 대한 전형적인 세포의 센서(cellular sensor)로써 다른 생체작용기작에서 중요한 역할을 하므로 TRP계 수용체 활성화물질은 이러한 관점에서도 매우 중요하다. It is reported that the irritating taste substance represented by the pungent taste, cool taste, tingling taste or stinging taste among the taste components activates a TRP-based cation channel such as hTRPA1. TRP receptors are also important in this regard because TRP receptors play an important role in other biological mechanisms as typical cellular sensors for external stimuli.
바람직하게는, 본 발명의 자극성 향미용 조성물은 매운 맛(신미), 쏘는 맛(결미) 또는 이의 조합 맛을 유발하는 것을 특징으로 하는 조성물이다.Preferably, the irritating flavor composition of the present invention is a composition characterized by causing a pungent taste (sour taste), stinging taste (flavour) or a combination thereof.
본 발명의 바람직한 구현예에 따르면, 십자화과 또는 산형과 식물 추출물은 hTRPA1을 활성화하여 비만의 예방, 치료 또는 개선 효능을 갖는다. According to a preferred embodiment of the invention, the cruciferous or umbel plant extract has the effect of preventing, treating or ameliorating obesity by activating hTRPA1.
따라서, 본 발명의 다른 양태에 따르면, 본 발명은 십자화과 또는 산형과 식물 추출물을 포함하는 비만의 예방, 치료 또는 개선용 조성물을 제공한다.Accordingly, according to another aspect of the present invention, the present invention provides a composition for the prevention, treatment or improvement of obesity, including cruciferous or mountain-type plant extracts.
hTRPA1의 활성화와 비만 억제 사이의 관련성은 몇몇 문헌에 기재되어 있기 때문에, 십자화과 또는 산형과 식물 추출물이 hTRPA1을 강력하게 활성화 한다는 하기 실시예의 데이터는 십자화과 또는 산형과 식물 추출물을 포함하는 조성물이 위 배출 지연을 유도하여 식욕 억제를 통하여 비만 억제 작용을 함을 뒷받침한다.Since the relationship between the activation of hTRPA1 and the inhibition of obesity has been described in some literature, the data in the examples below that cruciferous or antagonist plant extracts strongly activate hTRPA1 are shown in compositions comprising cruciferous or antagonist plant extracts to delay gastric emptying Induces obesity by inhibiting appetite to support.
Tatsuo Watanabe et al., Recent Researches in Modern Medicine, ISBN:978-960-474-278-3, p. 460-462(2011)은 TRPA1의 아고니스트(예컨대, 후추 추출물, 피페린 또는 신남알데하이드)의 TRPA1 활성화가 생체 내 에너지 대사를 강화시켜 복부 지방 축적을 억제함을 제시하고 있다. 또한, Doihara H et al., Naunyn Schmiedebergs Arch Pharmacol . 380(4):353-7(2009)는 TRPA1의 아고니스트가 위 배출을 지연시켜 식욕 억제를 유도함을 개시하고 있다. Tatsuo Watanabe et al., Recent Researches in Modern Medicine , ISBN: 978-960-474-278-3, p. 460-462 (2011) suggest that TRPA1 activation of agonists of TRPA1 (eg, pepper extract, piperine, or cinnamicaldehyde) enhances energy metabolism in vivo and inhibits abdominal fat accumulation. Doihara H et al., Naunyn Schmiedebergs Arch Pharmacol . 380 (4): 353-7 (2009) disclose that agonists of TRPA1 delay gastric emptying and induce appetite suppression.
본 발명에서 이용되는 십자화과 식물은 바람직하게는 고추냉이(Wasabia japonica (Miq.) Matsum.) 또는 돌산갓(Brassica juncea (L.) Czern. et coss)이다. Cruciferous plants used in the present invention is preferably Wasabia japonica (Miq.) Matsum.) or dolsangat (Brassica juncea (L.) Czern. et coss).
본 발명에서 이용되는 산형과 식물은 바람직하게는 누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 또는 미나리(Oenanthe javanica (Blume) DC.)이다.
The cultivars and plants used in the present invention are preferably yeast ( Pleurospermum) camtschaticum Hoffm.), Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) or Oenanthe javanica (Blume) DC.).
본 발명의 다른 양태에 따르면, 본 발명은 다음 단계를 포함하는 hTRPA1(human Transient Receptor Potential A1)에 대한 길항제(antagonist)의 스크리닝 방법을 제공한다:According to another aspect of the invention, the invention provides a method for screening an antagonist against human Transient Receptor Potential A1 (hTRPA1) comprising the following steps:
(a) hTRPA1 작용제(agonist)로서의 (i) 고추냉이(Wasabia japonica (Miq.) Matsum.) 및 돌산갓(Brassica juncea (L.) Czern. et coss)으로 구성된 군으로부터 선택되는 십자화과(Brassicaceae) 식물, (ii) 누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 및 미나리(Oenanthe javanica (Blume) DC.)로 구성된 군으로부터 선택되는 산형과(Umbelliferae) 식물로 구성된 군으로부터 선택되는 하나 이상의 식물의 추출물 및 분석하고자 하는 후보물질(candidate substance)을 hTRPA1에 처리하는 단계; 및 (a) (i) horseradish hTRPA1 as agonists (agonist) (Wasabia japonica (Miq.) Matsum.) and dolsangat (Brassica juncea (L.) Czern. et coss) Brassicaceae plant selected from the group consisting of (ii) Pleurospermum camtschaticum Hoffm.), Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) and Oenanthe javanica (Blume) treating hTRPA1 with extracts of one or more plants selected from the group consisting of Umbelliferae plants selected from the group consisting of DC.) And candidate substances to be analyzed; And
(b) 상기 hTRPA1의 활성도를 측정하는 단계; 상기 hTRPA1의 활성도가 후보물질을 처리하지 않은 대조군과 비교하여 낮은 경우에는 상기 후보물질은 hTRPA1에 대하여 길항제로 판단한다.(b) measuring the activity of the hTRPA1; When the activity of the hTRPA1 is low compared to the control group not treated with the candidate, the candidate is determined as an antagonist against hTRPA1.
하기의 실시예에서 입증된 바와 같이, 본 발명의 십자화과 또는 산형과 식물 추출물은 hTRPA1의 활성화를 유도한다. hTRPA1의 활성화제가 hTRPA1 길항제의 스크리닝에 이용되는 예는 많은 문헌에 기재되어 있다. 예를 들어, 미국 특허출원공개 제20070196866호, 제20080050750호, 제20090269280호 및 제20100273773호에 hTRPA1의 활성화제에 의해 활성화 되는 hTRPA1의 활성도를 억제 또는 감소시키는 hTRPA1 길항제를 스크리닝 하는 방법이 기재되어 있다.As demonstrated in the examples below, the cruciferous or antagonist plant extract of the present invention induces the activation of hTRPA1. Examples in which activators of hTRPA1 are used for screening hTRPA1 antagonists are described in many literatures. For example, US Patent Application Publication Nos. 20070196866, 20080050750, 20090269280, and 20100273773 describe methods for screening hTRPA1 antagonists that inhibit or reduce the activity of hTRPA1 activated by an activator of hTRPA1. .
본 발명의 방법에 따르면, 우선 hTRPA1 작용제로서의 십자화과 또는 산형과 식물 추출물 및 분석하고자 하는 후보물질을 hTRPA1에 처리한다. 본 발명의 십자화과 또는 산형과 식물 추출물은 hTRPA1을 활성화 하는데 이러한 활성화를 억제할 수 있는 물질이 hTRPA1의 길항제가 된다.According to the method of the present invention, first, a cruciferous or antagonist plant extract as an hTRPA1 agonist and a candidate substance to be analyzed are treated with hTRPA1. The cruciferous or antagonist plant extract of the present invention activates hTRPA1, and a substance capable of inhibiting this activation is an antagonist of hTRPA1.
본 발명에서 이용되는 hTRPA1은 hTRPA1 그 자체 또는 hTRPA1을 발현하는 세포이다. 바람직하게는, 본 발명에서 이용되는 hTRPA1은 hTRPA1을 안정적으로(stably) 발현하는 세포이다. 상기 hTRPA1-발현 세포는 바람직하게는 동물 세포이며, 예를 들어 HEK293 세포, 뉴우런, CHO(Chinese Hamster Ovary) 세포, COS-7, HeLa, PC-12 및 BAF를 포함하나, 이에 한정되는 것은 아니다.HTRPA1 used in the present invention is a cell expressing hTRPA1 itself or hTRPA1. Preferably, hTRPA1 used in the present invention is a cell stably expressing hTRPA1. The hTRPA1-expressing cells are preferably animal cells, including but not limited to HEK293 cells, neurons, Chinese Hamster Ovary (CHO) cells, COS-7, HeLa, PC-12 and BAF.
본 발명에서 분석하고자 하는 후보물질은 다양한 물질을 포함한다. 예를 들어, 상기 후보물질은 화학물질, 단백질, 펩타이드, 항체, 핵산 및 천연 추출물을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 스크리닝 방법에 의해 분석되는 후보물질은 단일 화합물 또는 화합물들의 혼합물(예컨대, 천연 추출물 또는 세포 또는 조직 배양물)일 수 있다. 후보물질은 합성 또는 천연 화합물의 라이브러리로부터 얻을 수 있다. 이러한 화합물의 라이브러리를 얻는 방법은 당업계에 공지되어 있다. 합성 화합물 라이브러리는 Maybridge Chemical Co.(영국), Comgenex(미국), Brandon Associates(미국), Microsource(미국) 및 Sigma-Aldrich(미국)에서 상업적으로 구입 가능하며, 천연 화합물의 라이브러리는 Pan Laboratories(미국) 및 MycoSearch(미국)에서 상업적으로 구입 가능하다. 시료는 당업계에 공지된 다양한 조합 라이브러리 방법에 의해 얻을 수 있으며, 예를 들어, 생물학적 라이브러리, 공간 어드레서블 패러럴 고상 또는 액상 라이브러리(spatially addressable parallel solid phase or solution phase libraries), 디컨볼루션이 요구되는 합성 라이브러리 방법, “1-비드 1-화합물” 라이브러리 방법, 그리고 친화성 크로마토그래피 선별을 이용하는 합성 라이브러리 방법에 의해 얻을 수 있다. 분자 라이브러리의 합성 방법은, DeWitt et al., Proc . Natl . Acad. Sci . U.S.A. 90, 6909, 1993; Erb et al. Proc . Natl . Acad . Sci . U.S.A. 91, 11422, 1994; Zuckermann et al., J. Med . Chem . 37, 2678, 1994; Cho et al., Science 261, 1303, 1993; Carell et al., Angew . Chem . Int . Ed . Engl . 33, 2059, 1994; Carell et al., Angew . Chem . Int . Ed . Engl . 33, 2061; Gallop et al., J. Med. Chem . 37, 1233, 1994 등에 개시되어 있다.Candidates to be analyzed in the present invention include various materials. For example, the candidates include, but are not limited to, chemicals, proteins, peptides, antibodies, nucleic acids, and natural extracts. Candidates analyzed by the screening methods of the invention may be a single compound or a mixture of compounds (eg, a natural extract or a cell or tissue culture). Candidates can be obtained from libraries of synthetic or natural compounds. Methods for obtaining libraries of such compounds are known in the art. Synthetic compound libraries are commercially available from Maybridge Chemical Co. (UK), Comgenex (USA), Brandon Associates (USA), Microsource (USA), and Sigma-Aldrich (USA), and libraries of natural compounds are available from Pan Laboratories (USA). ) And MycoSearch (United States). Samples can be obtained by a variety of combinatorial library methods known in the art, for example biological libraries, spatially addressable parallel solid phase or solution phase libraries, deconvolution required By a synthetic library method, a “1-bead 1-compound” library method, and a synthetic library method using affinity chromatography screening. Methods of synthesizing molecular libraries are described in DeWitt et al., Proc . Natl . Acad. Sci . USA 90, 6909, 1993; Erb et al. Proc . Natl . Acad . Sci . USA 91, 11422, 1994; Zuckermann et al., J. Med . Chem . 37, 2678, 1994; Cho et al., Science 261, 1303, 1993; Carell et al., Angew . Chem . Int . Ed . Engl . 33,2059,1994; Carell et al., Angew . Chem . Int . Ed . Engl . 33, 2061; Gallop et al., J. Med. Chem . 37, 1233, 1994, and the like.
본 발명의 방법에서 단계 (b)는 다양한 방식에 따라 hTRPA1의 활성도를 측정할 수 있다.Step (b) in the method of the present invention can measure the activity of hTRPA1 in a variety of ways.
hTRPA1은 양이온 채널 수용체이기 때문에, hTRPA1의 활성에 의해 세포막의 포텐셜 변화가 발생된다. 따라서 이러한 세포막 포텐셜의 변화를 측정하여 hTRPA1의 활성도를 측정할 수 있다. 예를 들어, 세포막 포텐셜의 변화에 대응하여 형광을 발산하는 형광제를 이용하여 hTRPA1의 활성도를 측정할 수 있다.Since hTRPA1 is a cation channel receptor, the potential change of the cell membrane is generated by the activity of hTRPA1. Therefore, the activity of hTRPA1 can be measured by measuring the change of the cell membrane potential. For example, the activity of hTRPA1 can be measured using a fluorescent agent that emits fluorescence in response to a change in cell membrane potential.
hTRPA1의 활성화에 의해 세포 내로 유입되는 대표적인 양이온은 칼슘 이온이다. 칼슘 이온의 세포 내 유입을 측정하는 데 사용되는 칼슘-민감성 형광제는 플루오3, 플루오4, 플루오5, 칼슘 그린, 칼슘 오렌지, 칼슘 옐로우, 푸라-2, 푸라-4, 푸라-5, 푸라-6, 푸라-FF, 푸라 레드, 인도-1, 인도-5, BTC(Molecular Probes) 및 FLIPR 칼슘3 워시-프리 다이(Molecular Devices)를 포함한다.Representative cations introduced into cells by activation of hTRPA1 are calcium ions. Calcium-sensitive fluorescent agents used to measure intracellular influx of calcium ions include Fluor3, Fluor4, Fluor5, Calcium Green, Calcium Orange, Calcium Yellow, Pura-2, Pura-4, Pura-5, Pura- 6, Pura-FF, Pura Red, Indo-1, Indo-5, Molecular Probes (BTC) and FLIPR Calcium 3 Wash-Free Die (Molecular Devices).
hTRPA1의 활성도를 형광제를 이용하여 측정하는 경우, 당업계에 공지된 다양한 형광 측정기를 이용하여 실시할 수 있다.When the activity of hTRPA1 is measured using a fluorescent agent, it can be carried out using various fluorimeters known in the art.
hTRPA1의 활성도를 측정한 결과, 후보물질을 처리하지 않은 대조군과 비교하여 낮은 경우에는 상기 후보물질은 hTRPA1에 대하여 길항제로 판단한다. 본 명세서에서 용어 “대조군”을 언급하면서 사용되는 용어 “낮다”는 것은, 예를 들어 칼슘-민감성 형광제를 이용하여 형광 변화로서 hTRPA1의 활성도를 측정하는 경우 RFU(relative fluorescence unit)가 2-100 배 낮은 것을 의미한다.As a result of measuring the activity of hTRPA1, it is determined that the candidate is an antagonist to hTRPA1 when compared to a control that has not been treated with the candidate. The term "low" as used herein referring to the term "control" means that the relative fluorescence unit (RFU) is 2-100 when measuring the activity of hTRPA1 as a fluorescence change using, for example, a calcium-sensitive fluorescent agent. Means pear low.
본 발명의 방법에 의해 스크리닝된 hTRPA1 길항제는 통증 치료제(예컨대, 만성 통증, 급성 통증, 신경병인성 통증, 해성 통증, 복통 및 신경통 치료제 등), 급성 뇌 허혈 치료제, 염증 치료제, 신경퇴행성 질환 치료제, 위장관 질환 치료제 및 구토 치료제로 이용될 수 있다.
HTRPA1 antagonists screened by the methods of the invention include pain treatments (e.g., chronic pain, acute pain, neuropathic pain, detrimental pain, abdominal pain and neuralgia, etc.), acute brain ischemia, inflammation, neurodegenerative diseases, gastrointestinal tract It can be used for the treatment of diseases and the treatment of vomiting.
본 발명의 다른 양태에 따르면, 본 발명은 hTRPA1 작용제(agonist)로서의 (i) 고추냉이(Wasabia japonica (Miq.) Matsum.) 및 돌산갓(Brassica juncea (L.) Czern. et coss)으로 구성된 군으로부터 선택되는 십자화과(Brassicaceae) 식물, (ii) 누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 및 미나리(Oenanthe javanica (Blume) DC.)로 구성된 군으로부터 선택되는 산형과(Umbelliferae) 식물로 구성된 군으로부터 선택되는 하나 이상의 식물의 추출물을 분리된 세포에 처리하는 단계를 포함하는 hTRPA1(human Transient Receptor Potential A1) 활성화 방법을 제공한다.According to another aspect of the invention, the invention provides (i) Wasabia as a hTRPA1 agonist. japonica (Miq.) Matsum.) and dolsangat (Brassica juncea (L.) Czern. et coss) Brassicaceae plant selected from the group consisting of (ii) Pleurospermum camtschaticum Hoffm.), Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) and Oenanthe javanica (Blume) DC.) A method of activating human Transient Receptor Potential A1 (hTRPA1) comprising treating an isolated cell with an extract of at least one plant selected from the group consisting of an umbelliferae plant selected from the group consisting of To provide.
본 발명에서 이용되는 세포는 hTRPA1 유전자를 내재적으로(endogeneously) 포함하는 세포 또는 hTRPA1 유전자로 형질전환된 세포를 포함한다.Cells used in the present invention include cells that endogeneously include the hTRPA1 gene or cells transformed with the hTRPA1 gene.
본 명세서에서 십자화과 또는 산형과 식물을 언급하면서 사용되는 용어 ‘추출물’은 십자화과 또는 산형과 식물에 추출용매를 처리하여 얻은 추출 결과물뿐만 아니라 십자화과 또는 산형과 식물 자체를 동물에게 투여할 수 있도록 제형화(예컨대, 분말화)된 가공물도 포함하는 의미를 갖는다.The term 'extract' as used herein to refer to cruciferous or antagonist plants is formulated to administer cruciferous or antler and plants themselves to animals as well as to extracts obtained by treating the extract with cruciferous or antler plants. For example, powdered workpieces.
본 발명의 조성물에서 이용되는 십자화과 또는 산형과 식물 추출물을 십자화과 또는 산형과 식물에 추출용매를 처리하여 얻는 경우에는, 다양한 추출용매가 이용될 수 있다. 바람직하게는, 극성 용매 또는 비극성 용매를 이용할 수 있다. 극성 용매로서 적합한 것은, (i) 물, (ii) 알코올(바람직하게는, 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올, 노말-부탄올, 1-펜탄올, 2-부톡시에탄올 또는 에틸렌글리콜), (iii) 아세트산, (iv) DMFO(dimethyl-formamide) 및 (v) DMSO(dimethyl sulfoxide)를 포함한다. 비극성 용매로서 적합한 것은, 아세톤, 아세토나이트릴, 에틸 아세테이트, 메틸 아세테이트, 플루오로알칸, 펜탄, 헥산, 2,2,4-트리메틸펜탄, 데칸, 사이클로헥산, 사이클로펜탄, 디이소부틸렌, 1-펜텐, 1-클로로부탄, 1-클로로펜탄, o-자일렌, 디이소프로필 에테르, 2-클로로프로판, 톨루엔, 1-클로로프로판, 클로로벤젠, 벤젠, 디에틸 에테르, 디에틸 설파이드, 클로로포름, 디클로로메탄, 1,2-디클로로에탄, 어닐린, 디에틸아민, 에테르, 사염화탄소 및 THF(Tetrahydrofuran)를 포함한다.When the cruciferous or antagonist plant extract used in the composition of the present invention is obtained by treating the cruciferous or antagonist plant with an extracting solvent, various extracting solvents may be used. Preferably, a polar solvent or a non-polar solvent can be used. Suitable polar solvents include (i) water, (ii) alcohols (preferably methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol, normal-butanol, 1-pentanol, 2-butoxyethanol Or ethylene glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMFO) and (v) dimethyl sulfoxide (DMSO). Suitable as nonpolar solvents are acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1- Pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloro Methane, 1,2-dichloroethane, anneal, diethylamine, ether, carbon tetrachloride and THF (Tetrahydrofuran).
보다 바람직하게는, 본 발명에서 이용되는 추출용매는 (a) 물, (b) 탄소수 1-4의 무수 또는 함수 저급 알코올(메탄올, 에탄올, 프로판올, 부탄올 등), (c) 상기 저급 알코올과 물과의 혼합용매, (d) 아세톤, (e) 에틸 아세테이트, (f) 클로로포름, (g) 부틸아세테이트, (h) 1,3-부틸렌글리콜, (i) 헥산 및 (j) 디에틸에테르를 포함한다. 보다 더 바람직하게는, 본 발명의 추출물은 물 또는 에탄올, 가장 바람직하게는 에탄올을 십자화과 또는 산형과 식물에 처리하여 수득한 것이다. More preferably, the extraction solvent used in the present invention is (a) water, (b) anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, propanol, butanol, etc.), (c) the lower alcohol and water Mixed solvent with (d) acetone, (e) ethyl acetate, (f) chloroform, (g) butyl acetate, (h) 1,3-butylene glycol, (i) hexane and (j) diethyl ether Include. Even more preferably, the extracts of the present invention are obtained by treating water or ethanol, most preferably ethanol, with cruciferous or acidic plants.
본 명세서에서 십자화과 및 산형과 식물을 언급하면서 사용되는 용어 ‘분획물’은 십자화과 또는 산형과 식물의 추출물에 용매 처리를 추가적으로 실시하여 hTRPA1 활성화 성분이 인리치먼트(enrichment)된 분획을 의미한다. 십자화과 또는 산형과 식물 분획물을 얻기 위하여 사용되는 용매는 당업계에서 통상적으로 이용되는 어떠한 추출용매도 가능하며, 바람직하게는, (a) 탄소수 1-4의 무수 또는 함수 저급 알코올(예: 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올 및 노말-부탄올 등), (b) 상기 저급 알코올과 물과의 혼합용매, (c) 아세톤, (d) 에틸 아세테이트, (e) 클로로포름, (f) 1,3-부틸렌글리콜, (g) 헥산, (h) 디에틸에테르, 또는 (i) 부틸아세테이트이다.As used herein, the term 'fraction' used in referring to the cruciferous family and the antagonist plant means a fraction in which the hTRPA1 activating component is enriched by additionally performing a solvent treatment on the cruciferous or antagonist plant extract. The solvent used to obtain the cruciferous or acidic plant fractions may be any extractant commonly used in the art, and preferably, (a) anhydrous or hydrous lower alcohols having 1 to 4 carbon atoms (e.g. methanol, ethanol) , Propanol, butanol, normal-propanol, iso-propanol and normal-butanol, etc.), (b) a mixed solvent of the lower alcohol with water, (c) acetone, (d) ethyl acetate, (e) chloroform, (f ) 1,3-butylene glycol, (g) hexane, (h) diethyl ether, or (i) butyl acetate.
가장 바람직하게는, 십자화과 또는 산형과 식물 분획물은 십자화과 또는 산형과 식물 에탄올 추출물에 에틸 아세테이트를 첨가하여 얻은 물 층의 분획물이다.Most preferably, the cruciferous or antagonist plant fraction is a fraction of the water layer obtained by adding ethyl acetate to the cruciferous or antagonist plant ethanol extract.
십자화과 및 산형과 식물의 추출물 또는 용매 분획물은 상술한 용매를 이용하여 얻은 것뿐만 아니라, 여기에 정제과정을 추가적으로 적용하여 얻은 것도 포함한다. 예컨대, 상기 추출물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 통해 얻어진 분획도 십자화과 및 산형과 식물 추출물 또는 분획물에 포함되는 것이다.Extracts or solvent fractions of cruciferous and antagonist plants include not only those obtained by using the above-mentioned solvents, but also those obtained by further applying a purification process thereto. For example, fractions obtained by passing the extract through an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity), etc. Fractions obtained through the purification method are also included in the cruciferous and antagonist plant extracts or fractions.
십자화과 또는 산형과 식물의 추출물 또는 분획물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다.Extracts or fractions of the cruciferous or antagonist plant may be prepared in powder form by additional processes such as distillation under reduced pressure and freeze drying or spray drying.
본 발명의 비만의 예방, 치료 또는 개선용 조성물은 약제학적 조성물로 제공될 수 있다.The composition for preventing, treating or improving obesity of the present invention may be provided as a pharmaceutical composition.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences(19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations include, but are not limited to, Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며, 바람직하게는 경구 투여 방식으로 적용된다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and is preferably administered orally.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다. The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The dosage of the pharmaceutical composition of the present invention is in the range of 0.001-100 mg / kg on an adult basis.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.
본 발명의 자극성 향미 조성물 및 비만 예방, 개선 또는 치료용 조성물은 식품 조성물로 제공될 수 있다.The irritating flavor composition of the present invention and the composition for preventing, improving or treating obesity may be provided as a food composition.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 십자화과 또는 산형과 식물의 추출물뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제[타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 메틸 시린게이트 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다.
When the composition of the present invention is prepared as a food composition, as an active ingredient, as well as extracts of cruciferaceae or antagonists, as well as components commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, Seasonings and flavoring agents. Examples of the above carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As flavoring agents, natural flavoring agents (tauumatin, stevia extract (for example rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is prepared with a drink, the citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, tofu extract, jujube extract, licorice extract, etc. Can be.
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 (i) 고추냉이(Wasabia japonica (Miq.) Matsum.) 및 돌산갓(Brassica juncea (L.) Czern. et coss)으로 구성된 군으로부터 선택되는 십자화과(Brassicaceae) 식물, (ii) 누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 및 미나리(Oenanthe javanica (Blume) DC.)로 구성된 군으로부터 선택되는 산형과(Umbelliferae) 식물로 구성된 군으로부터 선택되는 하나 이상의 식물의 추출물을 포함하는 조성물의 hTRPA1 활성 증가와 관련된 다양한 용도, 예를 들어 자극성 향미제, 비만 치료제 및 hTRPA1 길항제 스크리닝에 대한 용도를 제공한다.(a) the present invention is (i) Wasabia japonica (Miq.) Matsum.) and dolsangat (Brassica juncea (L.) Czern. et coss) Brassicaceae plant selected from the group consisting of (ii) Pleurospermum camtschaticum Hoffm.), Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) and Oenanthe javanica (Blume) DC.) Various uses related to increasing hTRPA1 activity of compositions comprising extracts of one or more plants selected from the group consisting of Umbelliferae plants, eg irritant flavors, obesity Therapeutics and hTRPA1 antagonist screening.
(b) 본 발명의 십자화과 또는 산형과 식물 추출물은 hTRPA1 활성화와 관련된 다양한 용도를 제공하며, 천연 화합물로서 인체에 부작용이 비교적 적고 산업적 이용 가능성이 크다.(b) The cruciferous or antagonist plant extract of the present invention provides various uses related to hTRPA1 activation and is a natural compound with relatively low side effects and high industrial applicability to the human body.
(c) 본 발명의 십자화과 또는 산형과 식물 추출물은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규한 의약 또는 식품 소재일 뿐만 아니라, hTRPA1의 길항제의 스크리닝에 유용하게 이용될 수 있다.
(c) The cruciferous or antagonist plant extract of the present invention is not only a novel medicine or food ingredient that helps maintain homeostasis in humans associated with the activation of hTRPA1, but can be usefully used for screening antagonists of hTRPA1.
도 1은 십자화과 및 산형과 식물의 수용성조추출물(X) 및 알코올성조추출물(EX)의 제조과정을 나타낸다.
도 2는 TRPA1 채널의 아고니스트인 AITC(Allyl isothiocyanate) 및 CALD(Cinnamaldehyde)에 대한 hTRPA1 채널 발현 세포의 반응을 Ca2 + 이미징법을 통해 규명한 실험결과이다.
도 3은 2종의 십자화과 식물 추출물에 대한 hTRPA1 채널 발현 세포의 반응을 Ca2+ 이미징법을 통해 보여주는 사진이다. RR은 TRP 채널의 블록커인 RR(Ruthenium Red)을 처리한 경우, HC-030031은 TRPA1 특이적 안타고니스트인 HC-030031를 처리한 경우이다.
도 4는 십자화과 식물 추출물에 대한 hTRPA1 채널 발현 세포의 반응을 세포 기반 분석법을 이용하여 측정한 결과이다. AITC(Allyl isothiocyanate) 및 CALD(Cinammaldehyde)는 hTRPA1의 양성대조군이다.
도 5는 십자화과 식물 추출물을 이용하여 Ca2 + 반응을 유도한 후, TRP 채널의 블록커인 RR 또는 hTRPA1의 안타고니스트인 HC-030031를 첨가하였을 때, Ca2 + 반응 변화를 측정한 결과이다.
도 6은 3종의 산형과 식물 추출물에 대한 hTRPA1 채널 발현 세포의 반응을 Ca2+ 이미징법을 통해 보여주는 사진이다. RR은 TRP 채널의 블록커인 RR(Ruthenium Red)을 처리한 경우, HC-030031은 TRPA1 특이적 안타고니스트인 HC-030031를 처리한 경우이다.
도 7은 산형과 식물 추출물에 대한 hTRPA1 채널 발현 세포의 반응을 세포 기반 분석법을 이용하여 측정한 결과이다. AITC(Allyl isothiocyanate) 및 CALD(Cinammaldehyde)는 hTRPA1의 양성대조군이다.
도 8은 산형과 식물 추출물을 이용하여 Ca2 + 반응을 유도한 후, TRP 채널의 블록커인 RR 또는 hTRPA1의 안타고니스트인 HC-030031를 첨가하였을 때, Ca2 + 반응 변화를 측정한 결과이다. Figure 1 shows the manufacturing process of the water-soluble crude extract (X) and alcoholic crude extract (EX) of the cruciferous and acid-type plants.
2 is a result of identifying the channel-expressing cells hTRPA1 response to agonists of AITC (Allyl isothiocyanate) and CALD (Cinnamaldehyde) of TRPA1 channel via the Ca 2 + imaging method.
3 is a photograph showing the response of hTRPA1 channel expressing cells to two cruciferous plant extracts through Ca 2+ imaging. RR is treated with RR (Ruthenium Red), a blocker of TRP channels, HC-030031 is treated with TRPA1-specific antagonist HC-030031.
Figure 4 is the result of measuring the response of hTRPA1 channel expressing cells to the cruciferous plant extract using a cell-based assay. Allyl isothiocyanate (AITC) and cinammaldehyde (CALD) are positive controls of hTRPA1.
Figure 5 is the addition of the blocker HC-030031 or the antagonists of the RR of hTRPA1 then induce Ca 2 + reaction using a cruciferous plant extract, TRP channel, a result obtained by measuring the Ca 2 + reaction change.
Figure 6 is a photograph showing the response of hTRPA1 channel expressing cells to the three mountain and plant extracts through Ca 2+ imaging. RR is treated with RR (Ruthenium Red), a blocker of TRP channels, HC-030031 is treated with TRPA1-specific antagonist HC-030031.
Figure 7 is the result of measuring the response of hTRPA1 channel expressing cells to the mountain and plant extracts using a cell-based assay. Allyl isothiocyanate (AITC) and cinammaldehyde (CALD) are positive controls of hTRPA1.
Figure 8 shows the result of measurement and then induce Ca 2 + reaction using the acid type and plant extracts, the addition of the blocker of HC-030031 an antagonist of RR or hTRPA1 of TRP channel, Ca 2 + reaction change.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예Example
재료 및 방법Materials and methods
실험재료Experimental material
고추냉이(Wasabia japonica (Miq.) Matsum.)와 돌산갓(Brassica juncea (L.) Czern. et coss)는 2010년 3월부터 8월까지 국내에 자생하는 식물 또는 한국자생식물원(Pyeongchang, Gangwon-do)에서 증식한 것을 사용하였다. Wasabia japonica (Miq.) Matsum.) and dolsangat (Brassica juncea (L.) Czern. et coss) used the plants grown in Korea from March to August 2010 or from Korea Botanical Garden (Pyeongchang, Gangwon-do).
누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 및 미나리(Oenanthe javanica (Blume) DC.)는 2010년 3월부터 8월까지 국내에 자생하는 식물 또는 한국자생식물원(Pyeongchang, Gangwon-do)에서 증식한 것을 사용하였다.
Pleurospermum camtschaticum Hoffm.), Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) and Oenanthe javanica (Blume) DC.) Used the plants grown in Korea from March to August 2010 or those grown in Korea Botanical Garden (Pyeongchang, Gangwon-do).
추출물 적정제조 조건 확립Establishment of extract titration conditions
산지에서 전초를 채취하여 세척한 후 동결건조하고 분쇄하여 -80℃에 보관하며 실험에 사용하였다. 도 1의 추출 방법에 따라 각 시료의 수용성조추출물 및 알콜성조추출물을 제조하였다. 수용성조추출물은 10 g의 식물 분말에 200 mL의 증류수를 첨가하여 녹이고, 16,278 x g에서 1분간 균질화한 후, 7,802 x g, 4℃에서 20 분간 원심분리하고 필터링 한 다음, 다시 16,278 x g, 4℃에서 15 분간 원심분리하고 필터링한 후 동결건조하여 수득하였다. 알콜성조추출물은 10 g의 식물 분말에 200 mL의 80% 에탄올을 첨가하여 녹이고, 16,278 x g에서 1분간 균질화한 후, 7,802 x g, 4℃에서 20 분간 원심분리하고 필터링 한 다음, 다시 16,278 x g, 4℃에서 15 분간 원심분리하고 필터링하여 농축한 후 동결건조하여 수득하였다. 수용성조추출물 및 알콜성조추출물을 각각 감압건고 및 동결건조하여 4℃에 보관하여 실험에 사용하였다.
After collecting and washing the outpost from the mountain, lyophilized and ground and stored at -80 ℃ was used in the experiment. According to the extraction method of Figure 1 was prepared a water-soluble crude extract and alcoholic crude extract of each sample. Water-soluble crude extract was dissolved by adding 200 mL of distilled water to 10 g of plant powder, homogenized at 16,278 xg for 1 minute, centrifuged and filtered at 7,802 xg, 4 ° C for 20 minutes, and again at 16,278 xg, 4 ° C. Obtained by centrifugation for 15 minutes, filtered and lyophilized. The alcoholic crude extract was dissolved by adding 200 mL of 80% ethanol to 10 g of plant powder, homogenized at 16,278 xg for 1 minute, then centrifuged and filtered at 7,802 xg, 4 ° C for 20 minutes, and then again 16,278 xg, 4 Centrifugation at 15 ° C. for 15 min, concentration after filtration and lyophilization were obtained. Aqueous crude extract and alcoholic crude extract were dried under reduced pressure and lyophilized, respectively, and stored at 4 ° C for use in experiments.
안정세포주 발현Stable Cell Line Expression
hTRPA1의 발현 유전자(coding region)를 pcDNA5/FRT Complete System (Invitrogen)의 제조사의 프로토콜에 따라 클로닝하였다. hTRPA1 유전자의 벡터 내로의 삽입 여부를 정하게 확인하기 위하여, ABI 130 또는 310 DNA generatic analyzer(Applied Biosystems)를 사용하여 시퀀싱한 후, Flin-in 293 세포에 상기 구축된 벡터 및 pOG44를 리포펙타민 2000(Invitrogen)을 이용하여 형질도입하였고 24 시간 후에 100 ㎍/ml의 하이그로마이신 B (Invitrogen)을 선택적으로 처리하여 2-3 주 더 배양하였다. 그 다음 항생제 저항성 세포만 모아 hTRPA1의 반응을 측정한 후 다시 배양하였다. 이 세포는 10% 우태아혈청이 포함된 DMEM(Dulbecco's modified Eagle's medium)에서 배양하였다.
The expression region of hTRPA1 was cloned according to the manufacturer's protocol of pcDNA5 / FRT Complete System (Invitrogen). In order to accurately confirm the insertion of the hTRPA1 gene into the vector, after sequencing using an ABI 130 or 310 DNA generatic analyzer (Applied Biosystems), the constructed vector and pOG44 were stored in Flin-in 293 cells and lipofectamine 2000 ( Invitrogen) was incubated and cultured for another 2-3 weeks after selective treatment with 100 g / ml of hygromycin B (Invitrogen) after 24 hours. Then, only antibiotic-resistant cells were collected to measure the response of hTRPA1 and cultured again. The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum.
CaCa 22 ++ 이미징법을Imaging method 이용한 Used hTRPA1hTRPA1 작용 평가 Action evaluation
hTRPA1 활성화 측정을 위하여 Ca2 + 이미징을 실시하였다. 세포내 칼슘양의 변화를 측정하기 위한 표식자로 푸라(Fura)-2/AM(Molecular Probes, 미국)을 사용하였다. 실험을 실시하기 20-26 시간전에 hTRPA1을 안정적으로 발현하는 세포주를 96웰-플레이트에 분주하였다. 푸라-2/AM(5 μM)을 첨가한 용액에서 27℃에서 30분간 배양하였다. 세포는 분석버퍼(140 mM NaCl, 10 mM HEPES, 2 mM CaCl22H2O, 2 mM EGTA, 1 mM MgCl26H2O, 10 mM 글루코즈 및 5 mM KCl)로 세척한 후, 100 μL의 분석 버퍼를 첨가하여 실온에서 15분간 방치하였다. 푸라-2/AM이 로딩된 세포는 현미경 위에 놓고 340 nm와 380 nm에서 형광흡광도를 측정하였다. 영상은 3초 마다 시간순으로 확인하고 F340과 F380의 상대적인 비율을 메타플루오르 소프트웨어(Molecular devices, 미국)을 이용하여 세포내 칼슘양의 변화를 분석하였다.
the Ca 2 + imaging was performed to measure the activation hTRPA1. Fura-2 / AM (Molecular Probes, USA) was used as a marker for measuring changes in intracellular calcium. 20-26 hours before the experiment, cell lines stably expressing hTRPA1 were dispensed into 96-well plates. Incubated at 27 ° C. for 30 minutes in a solution to which Pura-2 / AM (5 μM) was added. Cells were washed with assay buffer (140 mM NaCl, 10 mM HEPES, 2 mM CaCl 2 2H 2 O, 2 mM EGTA, 1 mM MgCl 2 6H 2 O, 10 mM glucose and 5 mM KCl), followed by 100 μL analysis. Buffer was added and left at room temperature for 15 minutes. Cells loaded with Pura-2 / AM were placed on a microscope and fluorescence absorbance was measured at 340 nm and 380 nm. The images were checked in chronological order every 3 seconds, and the relative ratios of F340 and F380 were analyzed by intracellular calcium changes using Metafluor software (Molecular devices, USA).
실험결과Experiment result
십자화과Crucifixion 및 And 산형과Mountain 식물의 선별 Selection of plants
우리 음식의 대표적 양념소재인 마늘, 고추 등의 자극성 향미특성을 갖는 식품성분은 TRP(Transient Receptor Potential) 이온채널계 수용체를 활성화시키는 것으로 이미 보고되어 있으며, 현재까지 TRPA1을 자극시킬 수 있는 물질로는 겨자나 와사비의 주성분인 이소티오시아네이트, 최루가스로 쓰이는 아크롤레인, 계피기름의 성분인 신남알데히드, 마리화나의 성분인 테트라하이드로카나비올, 브래디키닌 등이 보고되었다. 본 발명에서는 우리나라에서 오랫동안 식용으로 쓰이는 나물과 같은 식물 중 자극성 향미특성을 나타내는 소재가 다양하게 존재한다고 생각하고, 이러한 식용으로 쓰이는 산나물 중 십자화과 및 산형과 식물을 중심으로 TRP계 수용체 활성화 소재를 탐색하였다. Food ingredients with irritating flavors such as garlic and red pepper, which are representative seasoning materials of our food, have already been reported to activate TRP (Transient Receptor Potential) ion channel receptors. Isothiocyanate, a major component of mustard or wasabi, acrolein used as tear gas, cinnamic aldehyde as a component of cinnamon oil, tetrahydrocanaviol as a component of marijuana, and bradykinin have been reported. In the present invention, a variety of materials exhibiting irritating flavor characteristics among plants, such as herbs that have been used for a long time in our country, there is a variety of, and the TRP-based receptor activating material was searched around the cruciferaceae and mountain forms and plants among the wild vegetables used for such food .
매움, 얼얼함, 쏘는 맛 등의 자극성화학감각을 가지는 한국의 방향식물 중 산나물, 양념소재 등의 식용으로 널리 이용되는 십자화과 식물로 고추냉이 (Wasabia japonica (Miq.) Matsum.) 및 돌산갓(Brassica juncea (L.) Czern. et coss)를 선별(표 1)하였고, 산형과 식물로 누룩치(Pleurospermum camtschaticum Hoffm.), 개회향(Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) 및 미나리(Oenanthe javanica (Blume) DC.)를 선별(표 2)하였다.
Cruciferous plants widely used for food such as wild vegetables and seasonings among Korean aromatic plants with a pungent sensation such as spicy, tingling, stinging, etc. Wasabia japonica (Miq.) Matsum.) And Dolsangat ( Brassica) juncea (L.) Czern. et coss) (Table 1), and Pleurospermum camtschaticum Hoffm.), Ligusticum tachiroei (Franch. & Sav.) M.Hiroe & Constance) and Oenanthe javanica (Blume DC.) Was screened (Table 2).
안정세포주 발현 확인Expression of stable cell line
hTRPA의 활성을 알아보기 위하여, hTRPA1이 안정적으로 발현하는 세포주를 확립하였고, hTRPA1 안정 발현 세포주의 수용체 자극 활성을 확인하기 위하여 이들의 아고니스트인 AITC을 처리하였다. 그 결과 50 μM AITC에서 칼슘이 방출되는 것을 확인할 수 있었고 이는 반응 시간에 따라 증가하는 것으로 나타내어 본 연구에서 사용된 세포가 hTRPA1에 연구에 적합하다는 것을 알 수 있었다(도 2).
In order to examine the activity of hTRPA, a cell line stably expressing hTRPA1 was established, and AITC, their agonist, was treated to confirm receptor stimulatory activity of the hTRPA1 stable expressing cell line. As a result, it was confirmed that calcium is released from 50 μM AITC, which was shown to increase with reaction time, indicating that the cells used in this study were suitable for the study of hTRPA1 (FIG. 2).
십자화과Crucifixion 식물 추출물 Plant extract
2종의 십자화과 식물 추출물을 hTRPA1이 발현된 세포에 처리하였을 때 나타나는 칼슘 반응의 강도를 반응한 세포를 기준으로 하여 도 3에 나타내었다. hTRPA1의 아고니스트로 알려진 AITC(ally isothiocyanate) 및 CALD(cinnamaldehyde)를 각각 처리하였을 때, 모든 세포가 활성화 되는 것으로 확인 되었으나 양이온 채널의 블록커인 RR(ruthenium red)을 처리하였을 때 대부분 억제되었고, TRPA1의 안타고니스트인 HC-030031을 처리하였을 때는 AITC 활성을 억제하지 못하였다. 이는 이미 알려진 바와 같이 AITC는 TRPA1 이외에 TRPV1 채널 등을 함께 경유하기 때문인 것으로 판단된다. 선발된 2종의 식물에 대하여는 WJ, BJ 시료에서 90% 이상의 활성을 나타내는 것으로 확인되었으나, WJ는 RR 및 HC-030031에 의해 초기 반응이 억제되지 않는 것으로 나타났으나 60 초에서는 완벽하게 억제되었다. 이는 고추냉이의 주요 성분인 이소티오시아네이트류 성분이 농도가 현저하게 높거나 TRPA1이외의 다른 채널을 경유할 가능성을 시사한다. The two cruciferous plant extracts are shown in FIG. 3 on the basis of the cells that responded to the intensity of the calcium response that occurs when the hTRPA1-expressing cells were treated. When treated with AITC (ally isothiocyanate) and CALD (cinnamaldehyde), which are known as agonists of hTRPA1, all cells were found to be activated. Treatment with the antagonist of HC-030031 did not inhibit AITC activity. This is because AITC is known to pass through the TRPV1 channel in addition to TRPA1. The two selected plants were found to exhibit more than 90% activity in WJ and BJ samples, but WJ was not inhibited by RR and HC-030031, but completely inhibited at 60 seconds. This suggests that isothiocyanates, a major component of wasabi, may have a significantly higher concentration or pass through channels other than TRPA1.
한편, WJ 및 BJ은 hTRPA1의 양성대조군인 AITC 및 CALD와 비슷한 수준으로 hTRPA1을 활성화시켰다(도 4). WJ 또는 BJ에 의해 유도된 Ca2 + 반응은 양이온 채널 블록커 RR(30 μM) 및 TRPA1 안타고니스트 HC-030031(100 μM)에 의해 억제되었다(도 5).
Meanwhile, WJ and BJ activated hTRPA1 to a level similar to that of AITC and CALD, which were positive controls of hTRPA1 (FIG. 4). The Ca 2 + responses induced by WJ or BJ was inhibited by the cation channel blocker RR (30 μM) and TRPA1 antagonist HC-030031 (100 μM) (Fig. 5).
산형과Mountain 식물 추출물 Plant extract
3종의 산형과 식물 추출물을 hTRPA1이 발현된 세포에 처리하였을 때 나타나는 칼슘 반응의 강도를 반응한 세포를 기준하여 도 6에 나타내었다. hTRPA1의 아고니스트로 알려진 AITC(ally isothiocyanate) 및 CALD(cinnamaldehyde)를 각각 처리하였을 때, 모든 세포가 활성화 되는 것으로 확인 되었으나 양이온 채널의 블록커인 RR(ruthenium red)을 처리하였을 때 대부분 억제되었고, TRPA1의 안타고니스트인 HC-030031을 처리하였을 때는 AITC 활성을 억제하지 못하였다. 이는 이미 알려진 바와 같이 AITC는 TRPA1 이외에 TRPV1 채널 등을 함께 경유하기 때문인 것으로 판단된다. 선발된 3종의 식물에 대하여는 LT, OJ 시료에서 80% 이상의 활성을 나타내는 것으로 확인되었으나, PC는 다른 두 시료에 비교하여 낮은 활성을 나타내었다. 이는 시료의 특성으로 인해 혼탁되는 양상을 나타내어 수치상으로 낮게 기록 되었으나 이는 푸라-2의 파장이 아닌 다른 영역의 파장을 검출할 수 있는 다이를 사용함으로 해서 개선될 것으로 사료된다.
The three types of mountain and plant extracts are shown in FIG. 6 based on the cells that responded to the intensity of the calcium response that occurs when treated with cells expressing hTRPA1. When treated with AITC (ally isothiocyanate) and CALD (cinnamaldehyde), which are known as agonists of hTRPA1, all cells were found to be activated. However, they were mostly inhibited by treatment with cation channel blocker RU (ruthenium red). Treatment with the antagonist of HC-030031 did not inhibit AITC activity. This is because AITC is known to pass through the TRPV1 channel in addition to TRPA1. It was confirmed that the three selected plants showed more than 80% activity in LT and OJ samples, but PC showed low activity compared to the other two samples. This resulted in turbidity due to the characteristics of the sample and was recorded numerically low. However, it is believed that this can be improved by using a die that can detect wavelengths other than those of Pura-2.
한국에서 WJ, BJ, PC 및 OJ는 주로 식물 식품소재 즉, 산나물로 식용하고 있으며 LT는 약용 식물로써 한방에서 약재로 쓰이고 있다. 상기 식물들은 인체에서 나타내는 특별한 약리적 작용을 목적으로 치료에 쓰이기보다 ‘식품’으로써의 활용 가치가 큰 것으로 사료된다. 일반 대중들의 식이에서 풍미 또는 식욕 증진을 위하여 섭취하고 있는 위의 식물들에 기존에 알려진 TRPA1 자극 활성 물질이 포함되어 있거나 보고된 바 없는 새로운 성분이 포함되어 있을 것으로 판단되는 바, 오래전부터 식용해왔던 한국의 산나물이 TRPA1 조절 활성을 가지어 인체에 유효한 활성을 나타내었을 것으로 기대된다.
In Korea, WJ, BJ, PC, and OJ are mainly edible as plant food materials, that is, wild vegetables, and LT is used as a medicinal herb as a medicinal plant. These plants are considered to be of great value as 'food' rather than being used for treatment for the purpose of special pharmacological action in the human body. The above plants, which are consumed to enhance flavor or appetite in the diet of the general public, may contain known TRPA1 stimulating actives or new ingredients that have not been reported. It is expected that Korean wild herbs have TRPA1 regulating activity and showed effective activity in human body.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (6)
Dolsangat (Brassica juncea (L.) Czern. et coss) hTRPA1 (human Transient Receptor Potential A1) activating composition comprising an extract.
The composition of claim 1, wherein the composition activates hTRPA1 to induce an irritating flavor.
The composition of claim 1, wherein the composition inhibits obesity by activating hTRPA1.
(a) hTRPA1 작용제(agonist)로서의 돌산갓(Brassica juncea (L.) Czern. et coss) 추출물 및 분석하고자 하는 후보물질(candidate substance)을 hTRPA1에 처리하는 단계; 및
(b) 상기 hTRPA1의 활성도를 측정하는 단계; 상기 hTRPA1의 활성도가 후보물질을 처리하지 않은 대조군과 비교하여 낮은 경우에는 상기 후보물질은 hTRPA1에 대하여 길항제로 판단한다.
Screening method of antagonist for hTRPA1 comprising the following steps:
(a) Brassica as hTRPA1 agonist juncea (L.) Czern. et coss) treating hTRPA1 with an extract and a candidate substance to be analyzed; And
(b) measuring the activity of the hTRPA1; When the activity of the hTRPA1 is low compared to the control group not treated with the candidate, the candidate is determined as an antagonist against hTRPA1.
dolsangat (Brassica as hTRPA1 agents juncea (L.) Czern. et coss) hTRPA1 activation method comprising the step of treating the extract to isolated cells.
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