KR101356082B1 - Compositions for Acitivating hTRPA1 Comprising Coniferyl Alcohol and Uses thereof - Google Patents
Compositions for Acitivating hTRPA1 Comprising Coniferyl Alcohol and Uses thereof Download PDFInfo
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- KR101356082B1 KR101356082B1 KR1020110121155A KR20110121155A KR101356082B1 KR 101356082 B1 KR101356082 B1 KR 101356082B1 KR 1020110121155 A KR1020110121155 A KR 1020110121155A KR 20110121155 A KR20110121155 A KR 20110121155A KR 101356082 B1 KR101356082 B1 KR 101356082B1
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- htrpa1
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- coniferyl alcohol
- taste
- alcohol
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Abstract
발명은 코니페릴 알코올의 hTRPA1 활성 증가와 관련된 다양한 용도, 예를 들어 자극성 향미제, 최루제, 당뇨 또는 비만 억제제 및 hTRPA1 길항제 스크리닝에 대한 용도를 제공한다. 본 발명의 코니페릴 알코올은 hTRPA1 활성화와 관련된 다양한 용도를 제공하며, 천연 화합물로서 인체에 부작용이 비교적 적고 산업적 이용 가능성이 크다. 본 발명의 코니페릴 알코올은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규한 의약 또는 식품 소재일 뿐만 아니라, 최루제 등으로도 개발될 수 있으며, hTRPA1의 길항제의 스크리닝에 유용하게 이용될 수 있다. ] The invention provides a variety of uses associated with increasing hTRPA1 activity of coniferyl alcohol, such as irritant flavours, tearing agents, diabetes or obesity inhibitors and hTRPA1 antagonist screening. The coniferyl alcohol 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. Coniferyl alcohol of the present invention is not only a novel medicine or food material that helps maintain homeostasis in the human body associated with the activation of hTRPA1, but can also be developed as a tear agent, and can be usefully used for screening antagonists of hTRPA1. Can be. ]
Description
본 발명은 코니페릴 알코올을 포함하는 hTRPA1 활성화 조성물 및 그의 용도에 관한 것이다.
FIELD OF THE INVENTION The present invention relates to hTRPA1 activating compositions comprising coniferyl alcohol and uses thereof.
TRPA1(Transient Receptor Potential cation channel subfamily A, member 1)은 TRP 이온 채널의 슈퍼패밀리에 속하는 비선택적 양이온 채널이다. 다른 패밀리 멤머와 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, 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 tetratization of four subunits, each subunit containing six transmembrane domains, a pupil loop and intracellular N-terminal and C-terminal . TRPA1 is expressed in sensory neurons and is localized with pain markers such as TRPV1, calcitonin gene-related peptides and bradykinin receptors (Nagata, K. et al., Journal of Neuroscience 2005, 25, 4052-4061; Story, GM Bautista, DM et al., Proceedings of the National Academy of Science, 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). In the pain model, knockdown of TRPA1 suppressed cooling hyperalgesia induced by inflammation and nerve injury (Obata, K. et al., Journal of Clinical Investigation 2005, 115, 2393-2401; Jordt, SE et al. Nature 2004, 427, 260-265; Katsura, H. et al., Exploratory Neurology 2006, 200, 112-123). In addition, TRPA1 gene knockdown causes impairment of sensory function and defects in bradykinin-induced pain hypersensitivity (Kwan, KY et al. Neuron 2006, 50, 277-289; Bautista, DM et al. , 1269-1282).
위와 같은 실험 결과들은 TRPA1이 감각기능과 통증 상태에서 매우 중요한 역학을 함을 보여주는 것이다. These results show that TRPA1 plays a very important role in sensory and pain states.
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., Chuang, H. H., Bautista, D. M., and Julius, D. Proceedings of the National Academy of Science U.S.A. 2006, 103, 19564-19568; Macpherson, L. J., Dubin, A. E., Evans, M. J., Marr, F., Schultz, P. G., Cravatt, B. F., and Patapoutian, A., Nature 2007, 445, 541-545).
Recently, however, experimental results have shown that the TRPA1 agonist interacts directly with TRPA1. AITC and Shinnam aldehyde have been reported to covalently transform cysteine and lysine residues at the N-terminus of TRPA1 and activate this channel (Hinman, A., Chuang, HH, Bautista, DM, and Julius, D. MacFerson, LJ, Dubin, AE, Evans, MJ, Marr, F., Schultz, PG, Cravatt, BF, and Patapoutian, A., Nature 2007, Proc. Of the National Academy of Science USA 2006, 103, 19564-19568; 445, 541-545).
한편, 매운 맛, 얼얼함 및 쏘는 맛 등의 자극성화학감각을 가지는 한국의 방향식물 중 산나물 및 양념소재 등의 식용으로 널리 이용되는 자생식물로 음나무(학명: Kalopanax pictus, 영문명: Carstor Araila)의 순(sprout, 개두릅, 이하 KPs라 함)이 있다. 음나무는 오갈피나무과에 속하는 식물로서 그 수피를 해동피라 하여 신경통, 관절염 및 당뇨병에 사용되어 왔다. 해동피의 성분으로는 사포닌이 주류를 이루며 페놀계 물질로서 시린진(syringin), 코니페릴 알데하이드 글루코시드(coniferyl aldehyde glucoside) 및 리리오덴드린(liriodendrin) 등이 밝혀져 있으며, 잎에서도 유사한 성분군이 알려져 있다. 사포닌은 주로 헤더라게니(hederagenin)의 배당체로서 모노데스모사이드(monodesmoside) 및 비스데스모사이드(bisdesmoside)로 구성된 칼로파낙스사포닌(Kalopanaxsaponin) 계열물질이 있다. 한편 음나무의 순은 한국에서 통칭하여 개두릅이라고 하여 나물로 이용하며 음나무의 잎은 계절이 지남에 따라 잎이 거칠어지고 맛이 변하기 때문에 식용하지 않고 그 새순이 식용을 널리 사용되어지고 있다. On the other hand, it is a native plant which is widely used for edible purposes such as wild vegetables and seasoning among Korean oriental plants having a stimulant chemical sense such as spicy taste, tingling and shoot taste, pictu s, English name: Carstor Araila) (sprout, hereinafter referred to as KPs). The chestnut is a plant belonging to the Acanthopanax acacia tree and has been used for neuralgia, arthritis and diabetes by the bark of the bark. Saponin is the major component of the sea tangle, and syringin, coniferyl aldehyde glucoside, and liriodendrin are known as phenolic materials. have. Saponins are mainly Kalopanaxsaponin-based materials composed of monodesmoside and bisdesmoside as glycosides of hederagenin. On the other hand, the seeds of chestnut are collectively used as herbs in Korea, and the leaves of the chestnut are widely used for edible purposes because they are not edible because their leaves are rough and their taste changes as the season passes.
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 G-단백질 결합 수용체(G-Protein Coupled Receptor;GPCR) 및 TRP(Transient Receptor Potential) 양이온 채널 수용체가 클로닝 되었으며 최근 클론된 수용체를 이용한 세포수준의 연구가 가능하게 되었다. 클론된 수용체를 이용한 연구기술은 새로운 맛 활성물질인 인 비트로(in vitro) 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 factor determining the value of food, involves a wide variety of disciplines ranging from basic research at the molecular level to consumer and industrial application studies. The taste substance is "receptive" to receptors in the taste bud cells of the taste buds and transmits the signals to the central nervous system via the taste nerve conduction path, That is, through a series of dynamic mechanisms, from peripheral to central. Recently, molecular genetics of taste receptors have been clarified with the development of related biochemistry such as molecular biochemistry, and some G-protein coupled receptors (GPCR) and TRP (cationic receptor potential) cation channel receptors have been cloned and recently cloned receptors And it became possible to study the cell level used. The cloned receptor research technique using the new taste of the active substance in vitro (in vitro screening and sensory analysis techniques, and at the same time, the most advanced and new methods used for the development of new drugs have been applied to the study of the taste of foods. Food studies at the receptor level for taste components are rarely present in Korea at present and are also in the beginning stages in the world.
최근 맛 성분 중 매운 맛, 시원한 맛, 얼얼함 및 쏘는 맛 등으로 표현되는 자극성 맛 물질은 TRP계 양이온 채널을 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. 고추의 매운맛을 내는 주요 성분인 캡사이신은 hTRPV1(Transient Receptor Potential cation channel subfamily V member 1) 수용체를 활성화함으로써 통증을 초래한다. hTRPV1은 고전적으로 열민감성 및 리간드관문성 특징을 갖는 비선택적 양이온채널로 분류되며 감각뉴런에서 통증자극(nociceptive stimuli)을 통합하는 것으로 알려져 있다. hTRPV1은 통증과 온도를 감지하는 뉴런의 막에 존재하는데, 우리가 고추를 먹을 때 즉시 작열감을 느끼는 이유는, 고추의 성분인 캡사이신이 통증뉴런의 hTRPV1를 활성화시키기 때문이다. 고농도의 캡사이신은 혀뿐만이 아니라 피부의 다른 민감한 부분에서도 작열감을 초래할 수 있다. 이 hTRPA1을 활성화 시키는 식물유래 성분으로는 마늘의 성분인 알리신(allicin)은 hTRPA1 및 hTRPV1 모두를 자극할 수 있다.
Recently, it has been reported that the irritating taste substance, which is represented by spicy taste, cool taste, tingling and stinging taste among taste components, activates TRP-based cation channels. TRP-based receptor activators are also important from this point of view because TRP-based receptors play an important role in other biological mechanisms as a typical cellular sensor for external stimulation. Capsaicin, a major component of the hot pepper, causes pain by activating the hTRPV1 receptor (Transient Receptor Potential cation channel subfamily V member 1) receptor. hTRPV1 is classically classified as a non-selective cation channel with heat-sensitive and ligand-gated features and is known to integrate nociceptive stimuli in sensory neurons. hTRPV1 is present in the membrane of neurons that sense pain and temperature. The reason we feel burning immediately when we eat pepper is because capsaicin, a component of pepper, activates hTRPV1 in pain neurons. High concentrations of capsaicin may cause burning sensation in other sensitive areas of the skin as well as the tongue. As a plant-derived component that activates this hTRPA1, allicin, a component of garlic, can stimulate both hTRPA1 and hTRPV1.
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.
발명자들은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규 소재를 개발하고자 노력하였다. 그 결과, 본 발명자들은 음나무(Kalopanax pictus) 순 추출물 및 분획물이 hTRPA1의 활성화와 관련이 있으며, 음나무 순 추출물 및 분획물에 포함되어 있는 코니페릴 알코올이 hTRPA1의 활성화에 기여하는 가장 중요한 유효성분임을 규명함으로써 본 발명을 완성하게 되었다.The inventors 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 kalopanax (Kalopanax pictus ) Net extracts and fractions are related to the activation of hTRPA1, and the present invention was completed by identifying that the coniferyl alcohol contained in the net extracts and fractions of narcissus is the most important active ingredient contributing to 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 또 다른 목적은 hTRPA1 활성화 하는 최루(lacrimatory) 조성물을 제공하는 데 있다.It is yet another object of the present invention to provide a lacrimatory composition that activates hTRPA1.
본 발명의 다른 목적은 hTRPA1 활성화 하는 당뇨 또는 비만 억제 조성물을 제공하는 데 있다.Another object of the present invention is to provide a diabetic or obesity inhibiting 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, 청구범위 및 도면에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
발명의 일 양태에 따르면, 본 발명은 코니페릴 알코올을 유효성분으로 포함하는 hTRPA1(human Transient Receptor Potential A1) 활성화용 조성물을 제공한다.
According to one aspect of the invention, the present invention provides a composition for activating human Transient Receptor Potential A1 (hTRPA1) containing coniferyl alcohol as an active ingredient.
본 발명자들은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규 소재를 개발하고자 노력하였다. 그 결과, 본 발명자들은 음나무(Kalopanax pictus) 순 추출물 및 분획물이 hTRPA1의 활성화와 관련이 있으며, 음나무 순 추출물 및 분획물에 포함되어 있는 코니페릴 알코올이 hTRPA1의 활성화에 기여하는 가장 중요한 유효성분임을 규명하였다.
The present inventors have sought to develop a new material that helps maintain homeostasis in the body associated with activation of hTRPA1. As a result, the present inventors have found that the extracts and fractions of Kalopanax pictus are related to the activation of hTRPA1, and that the coniferyl alcohol contained in the extracts and fractions of the lactose is the most important active ingredient that contributes to the activation of hTRPA1. .
본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물은 hTRPA1을 활성화 하여 자극성 향미를 유발한다. 따라서, 본 발명의 다른 양태에 따르면, 본 발명은 코니페릴 알코올을 유효성분으로 포함하는 자극성 향미 조성물을 제공한다.According to a preferred embodiment of the present invention, the composition of the present invention activates hTRPA1 to induce irritating flavor. Therefore, according to another aspect of the present invention, the present invention provides an irritating flavor composition comprising coniferyl alcohol as an active ingredient.
hTRPA1의 활성화와 자극성 향미 사이의 관련성은 많은 문헌에 기재되어 있기 때문에, 코니페릴 알코올이 hTRPA1을 강력하게 활성화 한다는 하기 실시예의 데이터는 코니페릴 알코올이 자극성 향미제로서의 용도를 충분히 뒷받침한다. 자극성 향미제로서의 겨자 오일 성분인 알릴 이소티오시아네이트(AITC)(Bandell M, et al., Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849857(2004)); Jordt SE et al., Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. 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,, Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849857(2004); Bautista DM et al., Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci USA 102:1224812252(2005); Escalera J et al., TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem 283: 2413624144(2008); Macpherson LJ et al., The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15: 929934(2005); Xu H et al., Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat Neurosci 9: 628635(2006)).Since the relationship between the activation of hTRPA1 and the irritating flavor has been described in many literatures, the data in the following examples that coniferyl alcohol strongly activates hTRPA1 fully supports the use of coniferryl alcohol as an irritant flavor. Allyl isothiocyanate (AITC), which is a mustard oil component as a stimulative flavoring agent (Bandell M, et al., Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41: 849857 (2004)); Jordt SE et al., Mustard oils and cannabinoids excite sensory nerve fibers through the TRP channel ANKTM1. Nature 427: 260265 (2004)) are well known as TRPA1 agonists. Also, cinnamon aldehyde in cinnamon, alicin and diallyl sulfide in garlic and onion, carbacol, isovelleral and water pepper and Tasmanian pepper in oregano, Polygodial, etc., are known as TRPA1 agonists as a stimulant flavor component (Bandell et al., 2004); Bautista DM (2004), a noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin et al., Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci USA 102: 1224812252 (2005); Escalera J et al., TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem 283: 2413624144 2008); Macpherson LJ et al., The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15: 929934 (2005); Xu H et al., Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channe Nat Neurosci 9: 628635 (2006)).
본 발명의 코니페릴 알코올에 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.Coniferous alcohol of the present invention is a 'flavor' sensitized through 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 (pungent, tingling or stinging taste) is a kind of sick feeling that is felt in the free nerves in the mouth.
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 spicy taste (surname), a stinging taste (smut) or a combination taste thereof.
본 발명의 바람직한 구현예에 따르면, 코니페릴 알코올은 hTRPA1을 활성화 하여 최루(lacrimatory)를 유발한다. 따라서, 본 발명의 또 다른 양태에 따르면, 본 발명은 코니페릴 알코올을 유효성분으로 포함하는 최루 조성물을 제공한다.According to a preferred embodiment of the present invention, coniferyl alcohol activates hTRPA1 to cause lacrimatory. Therefore, according to another aspect of the present invention, the present invention provides a tear tear composition comprising coniferyl alcohol as an active ingredient.
hTRPA1의 활성화와 최루 특성 사이의 관련성은 많은 문헌에 기재되어 있기 때문에, 코니페릴 알코올이 hTRPA1을 강력하게 활성화 한다는 하기 실시예의 데이터는 코니페릴 알코올이 최루제로서의 용도를 충분히 뒷받침한다. 최루 특성과 hTRPA1의 활성화 사이의 관련성은 Brone B et al., Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol. Appl. Pharmacol. 231(2): 1506(2008); 미국 특허출원 공개 제20100273773호; 및 미국 특허출원 공개 제20110144137호에 명확하게 기재되어 있다.
The data in the following examples, in which coniferyl alcohol strongly activates hTRPA1, fully supports the use of coniferyl alcohol as a tear agent, since the association between hTRPA1 activation and tear properties is described in many documents. The relationship between tear properties and activation of hTRPA1 was confirmed by Brone et al., Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol. Appl. Pharmacol. 231 (2): 1506 (2008); U.S. Patent Application Publication No. 20100273773; And U.S. Patent Application Publication No. 20110144137.
본 발명의 바람직한 구현예에 따르면, 코니페릴 알코올은 hTRPA1을 활성화 하고 GLP-1(glucagon-like peptide-1)의 분비를 촉진하여 당뇨, 비만, 고혈압, 아테롬성 동맥경화증 또는 심근경색의 예방 또는 치료 효능을 갖는다. 따라서, 본 발명의 다른 양태에 따르면, 본 발명은 코니페릴 알코올을 유효성분으로 포함하는 당뇨, 비만, 고혈압, 아테롬성 동맥경화증 또는 심근경색의 예방, 개선 또는 치료 조성물을 제공한다.According to a preferred embodiment of the present invention, coniferyl alcohol activates hTRPA1 and promotes the secretion of glucagon-like peptide-1 (GLP-1) to prevent or treat diabetes, obesity, hypertension, atherosclerosis or myocardial infarction. Has Therefore, according to another aspect of the present invention, the present invention provides a prophylactic, ameliorating or treating composition of diabetes mellitus, obesity, hypertension, atherosclerosis or myocardial infarction comprising coniferyl alcohol as an active ingredient.
hTRPA1의 활성화와 비만 억제 사이의 관련성은 몇 몇 문헌에 기재되어 있기 때문에, 코니페릴 알코올이 hTRPA1을 강력하게 활성화 한다는 하기 실시예의 데이터는 코니페릴 알코올이 위 배출 지연을 유도하여 식욕 억제를 통하여 비만 억제 작용을 함을 뒷받침한다.Since the link between the activation of hTRPA1 and the inhibition of obesity has been described in several literatures, the data in the examples below show that coniferyl alcohol strongly activates hTRPA1, suggesting that coniferyl alcohol induces gastric emptying delay and thus suppresses obesity through appetite suppression. Support the action.
Tatsuo Watanabe et al., Food components activating TRPA1, 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., TRPA1 agonists delay gastric emptying in rats through serotonergic pathways, Naunyn Schmiedebergs Arch Pharmacol . 380(4):353-7(2009)는 TRPA1의 아고니스트가 위 배출을 지연시켜 식욕 억제를 유도함을 개시하고 있다. Tatsuo Watanabe et al., Food components activating TRPA1, 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. Also, Doihara H et al., TRPA1 agonists delay gastric emptying in rats through serotonergic pathways, Naunyn Schmiedebergs Arch Pharmacol . 380 (4): 353-7 (2009) disclose that agonists of TRPA1 delay gastric emptying and induce appetite suppression.
한편, GLP-1(Glucagon-like-peptide-1)은 영양분의 섭취에 반응하여 장의 L-세포로부터 분리되는 프로글루카곤-유래 펩타이드이다(Drucker, D J: The Glucagon-Like Peptides. Diabetes 47:159-169(1998)). GLP-1은 췌장의 베타세포로부터 인슐린의 분비를 촉진하는 작용을 한다. 또한, GLP-1은 위 배출 및 음식물 섭취를 억제하는 작용도 한다. 이에, GLP-1 및 이의 아고니스트(예컨대, GLP-1 분비 촉진제)는 당뇨(특히, 2형 당뇨)(Toft-Nielsen M, et al., "Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes". J Clin Endocrinol Metab 86(8):385360(2001)), 비만(Hayes MR et al., Comparative effects of the long-acting GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats. Obesity (Silver Spring). Jul;19(7):1342-9(2011), 고혈압(Tanaka T et al., The role of incretins in salt-sensitive hypertension: the potential use of dipeptidyl peptidase-IV inhibitors. Curr Opin Nephrol Hypertens . Sep;20(5):476-81(2011)); 아테롬성 동맥경화증(Arakawa M et al., Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4; Diabetes . Apr;59(4):1030-7(2010); Rizzo M et al, Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors. Expert Opin Investig Drugs . Oct;18(10):1495-503(2009)); 심근경색(Ku HC et al., DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion. Naunyn Schmiedebergs Arch Pharmacol. Aug;384(2):197-207(2011); Dokken BB et al., Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents. Horm Metab Res . May;43(5):300-5(2011))의 치료에 이용되고 있다.
On the other hand, GLP-1 (Glucagon-like-peptide-1) is a proglucagon-derived peptide that is separated from intestinal L-cells in response to nutrient ingestion (Drucker, DJ: The Glucagon-Like Peptides. Diabetes 47: 159- 169 (1998)). GLP-1 acts to promote secretion of insulin from beta cells of the pancreas. GLP-1 also acts to inhibit gastric emptying and food intake. Thus, GLP-1 and its agonists (such as GLP-1 secretion promoters) have been shown to be effective in the treatment of diabetes (especially
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 코니페릴 알코올 및 분석하고자 하는 후보물질(candidate substance)을 hTRPA1에 처리하는 단계; 및 (a) treating hTRPA1 with coniferyl alcohol as a hTRPA1 agonist and a candidate substance 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 코니페릴 알코올은 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 coniferyl alcohol 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 코니페릴 알코올 및 분석하고자 하는 후보물질을 hTRPA1에 처리한다. 본 발명의 코니페릴 알코올은 hTRPA1을 활성화 하는데 이러한 활성화를 억제할 수 있는 물질이 hTRPA1의 길항제가 된다.According to the method of the present invention, first, coniferyl alcohol as an hTRPA1 agonist and the candidate substance to be analyzed are treated with hTRPA1. Coniferyl alcohol of the present invention activates hTRPA1, and a substance capable of inhibiting this activation becomes 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.(UK), Comgenex(USA), Brandon Associates(USA), Microsource(USA) 및 Sigma-Aldrich(USA)에서 상업적으로 구입 가능하며, 천연 화합물의 라이브러리는 Pan Laboratories(USA) 및 MycoSearch(USA)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., Comgenex (USA), Brandon Associates (USA), Microsource (USA) and Sigma-Aldrich (USA) ) And MycoSearch (USA). 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 Fluo3, Fluo4, Fluo5, 칼슘 그린, 칼슘 오렌지, 칼슘 엘로우, Fura-2, Fura-4, Fura-5, Fura-6, Fura-FF, Fura Red, indo-1, indo-5, BTC(Molecular Probes) 및 FLIPR Calcium3 wash-free 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 Fluo3, Fluo4, Fluo5, Calcium Green, Calcium Orange, Calcium Yellow, Fura-2, Fura-4, Fura-5, Fura-6, Fura -FF, Fura Red, indo-1, indo-5, BTC (Molecular Probes) and FLIPR Calcium3 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 스크리닝 된 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.
The hTRPA1 antagonist screened by the method of the present invention can be used as a therapeutic agent for pain (for example, chronic pain, acute pain, neuropathic pain, seborrheic pain, abdominal pain and neuralgia), acute cerebral ischemia, inflammation, neurodegenerative disease, Can be used as a therapeutic agent for diseases and a therapeutic agent for vomiting.
본 발명의 다른 양태에 따르면, 본 발명은 hTRPA1 작용제(agonist)로서의 코니페릴 알코올을 분리된 세포에 처리하는 단계를 포함하는 hTRPA1(human Transient Receptor Potential A1) 활성화 방법을 제공한다.According to another aspect of the present invention, the present invention provides a method for activating human Transient Receptor Potential A1 (hTRPA1) comprising treating isolated cells with coniferyl alcohol as an hTRPA1 agonist.
본 발명에서 이용되는 세포는 hTRPA1 유전자를 내재적으로(endogeneously) 포함하는 세포 또는 hTRPA1 유전자로 형질전환된 세포를 포함한다.
Cells used in the present invention include cells endogenously containing the hTRPA1 gene or cells transformed with the hTRPA1 gene.
본 발명의 바람직한 구현예에 따르면, 본 발명에서 사용되는 코니페릴 알코올은 음나무순 추출물 또는 음나무순 분획물에 포함되어 있는 것이다.According to a preferred embodiment of the present invention, the coniferyl alcohol used in the present invention is contained in the extract of the labia majora or the labia minora fraction.
본 명세서에서 음나무순을 언급하면서 사용되는 용어 ‘추출물’은 음나무 순에 추출용매를 처리하여 얻은 추출 결과물뿐만 아니라 음나무순 자체를 동물에게 투여할 수 있도록 제형화(예컨대, 분말화)된 음나무순 가공물도 포함하는 의미를 갖는다.The term " extract " used herein to refer to the order of the Chinese cabbage includes not only the extract obtained by treating the extract in the order of the cabbage, but also the resultant product obtained by treating the Chinese cabbage (e.g., powdered) . ≪ / RTI >
본 발명의 조성물에서 이용되는 음나무순 추출물을 음나무순에 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 extracting the net extract of the genus Xanthium used in the composition of the present invention in the order of extracting the extract, various extracting solvents can 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 음나무순에 처리하여 수득한 것이다.More preferably, the extraction solvent used in the present invention is (a) water, (b) anhydrous or hydrated lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, propanol, butanol, etc.) (E) ethyl acetate, (f) chloroform, (g) butyl acetate, (h) 1,3-butylene glycol, (i) hexane and (j) diethyl ether. . Even more preferably, the extract of the present invention is obtained by treating water or ethanol, most preferably ethanol, in the order of the beech.
본 명세서에서 음나무순을 언급하면서 사용되는 용어 ‘분획물’은 음나무 순의 추출물에 용매 처리를 추가적으로 실시하여 hTRPA1 활성화 성분이 인리치먼트(enrichment)된 분획을 의미한다. 음나무순 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.The term " fraction " used herein to refer to the chestnut tree means a fraction enriched with the hTRPA1 activating component by further performing a solvent treatment on the extract of chestnut tree. The solvent used to obtain the pure water fraction may be any extraction solvent conventionally used in the art, preferably (a) an anhydrous or a lower alcohol having 1 to 4 carbon atoms (e.g., methanol, ethanol, propanol, (C) acetone, (d) ethyl acetate, (e) chloroform, (f) 1, 2-propanol, 3-butylene glycol, (g) hexane, (h) diethyl ether, or (i) butyl acetate.
가장 바람직하게는, 음나무순 분획물은 음나무순 에탄올 추출물에 에틸 아세테이트를 첨가하여 얻은 물 층의 분획물이다.Most preferably, the net fraction of the muniskill is a fraction of the water layer obtained by adding ethyl acetate to the pure ethanol extract of the oak tree.
음나무순 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 음나무순 추출물 또는 분획물에 포함되는 것이다.The net extracts or the solvent fractions obtained by the method of the present invention include not only those obtained by using the above-mentioned solvents, but also those obtained by additionally applying a purification process thereto. For example, a fraction obtained by passing the above extract through an ultrafiltration membrane having a constant molecular weight cut-off value, and a separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity) The fraction obtained by the purification method is also included in the net extract or fraction.
음나무순 추출물 또는 분획물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다.
The net extract or fraction may be prepared in powder form by an additional process such as vacuum distillation and freeze drying or spray drying.
본 명세서에서 용어 ‘유효성분으로 포함하는’이란 본 명세서에 기재된 코니페릴 알코올의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다.
As used herein, the term "comprising as an active ingredient" is meant to include an amount sufficient to achieve the efficacy or activity of the coniferyl alcohol described herein.
본 발명의 조성물 중에서, 비만 예방, 개선 또는 치료용 조성물은 약제학적 조성물로 제공될 수 있다.Among the compositions of the present invention, a composition for preventing, ameliorating or treating obesity can 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 are described in detail in 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 조성물 중에서, 자극성 향미 조성물 및 비만 예방, 개선 또는 치료용 조성물은 식품 조성물로 제공될 수 있다.Among the compositions of the present invention, irritating flavor compositions and compositions for preventing, improving or treating obesity can be provided as food compositions.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 코니페릴 알코올뿐만 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 코니페릴 알코올 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 with a food composition, it contains not only coniferyl alcohol as an active ingredient, but also ingredients normally added in the course of food production, for example, protein, carbohydrate, fat, nutrients, . 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. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings. For example, when the food composition of the present invention is prepared as a drink, it may further contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract etc. in addition to the coniferyl alcohol of the present invention .
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 코니페릴 알코올의 hTRPA1 활성 증가와 관련된 다양한 용도, 예를 들어 자극성 향미제, 최루제, 당뇨 또는 비만 억제제 및 hTRPA1 길항제 스크리닝에 대한 용도를 제공한다.(a) The present invention provides a variety of uses associated with increasing hTRPA1 activity of coniferyl alcohol, eg, for screening irritant flavors, tearing agents, diabetes or obesity inhibitors and hTRPA1 antagonists.
(b) 본 발명의 코니페릴 알코올은 hTRPA1 활성화와 관련된 다양한 용도를 제공하며, 천연 화합물로서 인체에 부작용이 비교적 적고 산업적 이용 가능성이 크다.(b) Coniferyl alcohol of the present invention provides a variety of uses associated with hTRPA1 activation and is a natural compound with relatively low side effects and high industrial applicability to the human body.
(c) 본 발명의 코니페릴 알코올은 hTRPA1의 활성화와 관련된 인체내 항상성 유지에 도움이 되는 신규한 의약 또는 식품 소재일 뿐만 아니라, 최루제 등으로도 개발될 수 있으며, hTRPA1의 길항제의 스크리닝에 유용하게 이용될 수 있다.
(c) Coniferyl alcohol of the present invention is not only a novel drug or food material that helps maintain homeostasis in human body associated with activation of hTRPA1, but can also be developed as a tear agent and useful for screening antagonists of hTRPA1. Can be used.
도 1은 음나무 순의 수용성조추출물(KPsx) 및 알코올성조추출물(KPsEtx)의 제조과정을 나타낸다.
도 2는 조추출물로부터 물분획(DW) 및 아세트산 분획(EA)을 수득하는 분획과정을 나타낸다. 도 2a는 KPsx로부터 KPsx-DW 및 KPsx-EA를, 도 2b는 KPsEtx로부터 KPsEtx-DW 및 KPsEtx-EA를 수득하는 과정이다.
도 3은 KPs의 표준물질 및 페놀계 화합물의 화학구조를 보여준다. 왼쪽의 화학구조는 사포닌계 화합물의 구조로, R 그룹에 따라 칼로파낙스사포닌 A(R1=α-L-Rha-(1→2)-α-L-Ara, R2=OH, R3=H) 및 칼로파낙스사포닌 B(R1=α-L-Rha-(1→2)-α-L-Ara, R2=OH, R3=α-L-Rha-(1→4)-β-D-Glc-(1→6)-β-D-Glc)의 구조를 보여준다. 오른쪽 화학구조는 페놀계 화합물의 구조로, a는 시린진(R1=CH2OH, R2=OMe, R3=H) 및 코니페릴 알코올(R1=CH2OH, R2=H, R3=Api), b는 프로토카테큐산(R1=-H, R2=H, R3=Me), Chlrogenic acidB(R1=-H, R2=OMe, R3=Glc) 및 메틸 시린게이트(R1=-Me, R2=OMe, R3=Rha)의 화학 구조를 나타낸다.
도 4는 사포닌계 화합물과 페놀계 화합물의 HPLC 표준 크로마토그램을 보여준다.
도 5는 KPsEx의 크로마토그램을 나타낸다.
도 6은 KPsEtx-DW의 크로마토그램을 나타낸다.
도 7은 KPsEtx-EA의 크로마토그램을 나타낸다.
도 8은 KPs 추출물에 대한 hTRPA1 채널 발현 세포의 반응을 Ca2 + 이미징법을 통해 보여준다.
도 9는 코니페릴 알코올에 대한 hTRPA1 채널 발현 세포의 반응을 Ca2 + 이미징법을 통해 보여주는 사진이다. RR(-)는 TRP 채널의 블록커인 RR(Ruthenium Red)을 처리하지 않은 경우, RR(+)는 처리한 경우이다. AITC(Allyl isothiocyanate)는 양성대조군으로 이용되었다.
도 10은 코니페릴 알코올에 대한 hTRPA1 채널 발현 세포의 반응을 세포 기반 분석법을 이용하여 측정한 결과이다. AITC(Allyl isothiocyanate) 및 (Cinammaldehyde)는 hTRPA1의 양성대조군이다
도 11은 코니페릴 알코올에 의해 유도된 Ca2 + 반응에 대한 hTRPA1의 안타고니스트인 HC-030031를 첨가하였을 때의 결과를 나타낸 그래프이다. AITC(Allyl isothiocyanate) 및 (Cinammaldehyde)는 hTRPA1의 양성대조군이다. 코니페릴 알코올에 의해 유도된 Ca2 + 반응은 양이온 채널 블록커 RR(30 μM) 및 TRPA1 안타고니스트 HC-030031(100 μM)에 의해 억제되었다. 흑색 컬럼은 AITC(0.01, 0.03 mM), CALD(0.03, 0.3 mM) 및 코니페릴 알코올(0.1, 3 mM)에 의한 TRPA1 활성을 나타낸다. 회색 및 백색 컬럼은 각각 RR 및 HC-030031 처리된 경우의 TRPA1 활성을 나타낸다. 각 컬럼은 평균± SEM으로 기재되어 있다. *,** 및 ***는 각각 p<0.05, 0.01 및 0.001을 나타낸다(언페어드 t-검정).
도 12는 코니페릴 알코올에 대한 NCI-H716 세포의 GLP-1 분비 반응 결과를 보여주는 그래프이다. 데이터는 평균± S.D.로 표시되었다(n = 3). ** P <0.01; *** P <0.001 vs. 비처리 대조군.Fig. 1 shows the production process of a water-soluble crude extract (KPsx) and an alcoholic extract (KPsEtx) in the order of a pine tree.
Figure 2 shows a fractionation process to obtain a water fraction (DW) and an acetic acid fraction (EA) from a crude extract. 2A is a process of obtaining KPsx-DW and KPsx-EA from KPsx and FIG. 2b is a process of obtaining KPsEtx-DW and KPsEtx-EA from KPsEtx.
Figure 3 shows the chemical structure of KPs standards and phenolic compounds. The chemical structure of the left side of the structure of the saponin-based compounds, depending on the R group knife Panax saponin-A (R 1 = α-L -Rha- (1 → 2) -α-L-Ara,
Figure 4 shows HPLC standard chromatograms of saponin compounds and phenolic compounds.
Figure 5 shows the chromatogram of KPsEx.
Figure 6 shows the chromatogram of KPsEtx-DW.
Figure 7 shows the chromatogram of KPsEtx-EA.
Figure 8 shows the expression of hTRPA1 channel cellular response to KPs extract through a Ca 2 + imaging method.
Figure 9 is a photograph showing the expression of hTRPA1 channel cellular response to Konishi perylene alcohol through the Ca 2 + imaging method. RR (-) is the case where RR (+) is processed when the block kernel RR (Ruthenium Red) of the TRP channel is not processed. AITC (Allyl isothiocyanate) was used as a positive control.
10 shows the response of hTRPA1 channel expressing cells to coniferyl alcohol using a cell based assay. AITC (Allyl isothiocyanate) and (Cinammaldehyde) are positive controls of hTRPA1
11 is a graph showing a result of the addition to the antagonist of HC-030031 of hTRPA1 for the Ca 2 + responses induced by Konishi perylene alcohol. Allyl isothiocyanate (AITC) and (Cinammaldehyde) are positive controls of hTRPA1. Coney Ca 2 + responses induced by alcohol perylene was inhibited by the cation channel blocker RR (30 μM) and TRPA1 antagonist HC-030031 (100 μM). Black columns show TRPA1 activity by AITC (0.01, 0.03 mM), CALD (0.03, 0.3 mM) and coniferyl alcohol (0.1, 3 mM). Gray and white columns show TRPA1 activity when treated with RR and HC-030031, respectively. Each column is described as mean ± SEM. *, ** and *** represent p <0.05, 0.01 and 0.001, respectively (unpaired t -test).
12 is a graph showing the results of GLP-1 secretion response of NCI-H716 cells to coniferyl alcohol. Data are expressed as mean ± SD ( n = 3). ** P < 0.01; *** P < 0.001 vs. Untreated control.
예를 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.
By way of example, the present invention will be described in more detail. 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
실험재료Experimental material
매운 맛, 얼얼함 및 쏘는 맛 등의 자극성화학감각을 가지는 한국의 방향식물 중 산나물, 양념소재 등의 식용으로 널리 이용되는 음나무(학명: Kalopanax pictus, 영문명: Carstor Araila) 의 순(sprout, 개두릅, 이하 KPs라 함)을 사용하였다. 코니페릴 알코올(화학식 1)은 Wako Pure Chem. Ind.(Osaka, Japan)에서 구입하여 사용하였다.(Sprout, hornbeam, and pearl) of Kalopanax pictus (English name: Carstor Araila), widely used for edible wild plants and seasonings among Korean oriental plants with spicy taste, tingling and stinging taste, Hereinafter referred to as KPs) was used. Coniferyl alcohol (Formula 1) is obtained from Wako Pure Chem. It was purchased from Ind. (Osaka, Japan).
화학식 1
실험방법 Experimental Method
추출물 적정제조 조건 확립Establishment of extract titration conditions
산지에서 KPs의 전초를 채취하여 세척한 후 동결건조하고 분쇄하여 -80℃에 보관하며 실험에 사용하였다. 도 1의 추출 방법에 따라 각 시료의 수용성조추출물(KPsx) 및 알코올성조추출물(KPsEtx)를 제조하고 각각을 감압건고 및 동결건조 하여 4℃에 보관하며 실험에 사용하였다.The outposts of KPs were collected from the mountainous area, washed, lyophilized, pulverized and stored at -80 ° C. Water-soluble crude extracts (KPsx) and alcoholic extracts (KPsEtx) of each sample were prepared according to the extraction method of FIG. 1 and each was stored at 4 ° C under reduced pressure drying and freeze drying.
활성 소재 KPs에 대해 도 2의 방법에 따라 KPsx 및 KPsEtx로 추출하고 추출물을 분획하여 물 수용성 분획(KPsx-DW 및 KPsEtx-DW) 및 EA(ethyl acetate) 수용성분획(KPsx-EA 및 KPsEtx-EA)을 제조하였다.
(KPsx-DW and KPsEtx-DW) and EA (ethyl acetate) water-soluble fractions (KPsx-EA and KPsEtx-EA) were fractionated by KPsx and KPsEtx according to the method of FIG. .
KPs 추출물의 활성성분 HPLC 분석HPLC Analysis of Active Ingredients of KPs Extracts
KPs의 6가지 분획물(KPsx, KPsEtx, KPsx-DW, KPsEtx-DW, KPsx-EA 및 KPsEtx-EA)에 대하여 칼로파낙스사포닌(Kalopanaxsaponin) A(α-헤더린) 및 칼로파낙스사포닌 B(헤더라코시드 C) 등의 표준물질과 페놀계 화합물로써 시린진(syringin), 메틸 시린게이트(methyl syringate), 클로로겐산(chlorogenic acid), 코니페릴 알코올(coniferyl alcohol) 및 프로토카테큐산(protocatechuic acid) 등의 표준물질(도 3)을 이용하여 HPLC 분석으로 정량하였다. KPsEtx-DW, KPsx-EA and KPsEtx-EA) of six fractions of KPs (KPsx, KPsEtx, KPsx-DW, KPsx-EA and KPsEtx- C), and standard substances such as syringin, methyl syringate, chlorogenic acid, coniferyl alcohol, and protocatechuic acid as a phenolic compound, (Fig. 3).
페놀계 성분 분석은 본드팩(Bondpack) C18(Waters, 미국, 10 , 300×3.9 mm) 컬럼을 이용하여 이동상은 2% 아세트산(acetic acid)이 함유된 증류수(용매 A)와 0.5% 아세트산이 함유된 50% 아세토니트릴(acetonitrile, 용매 B)을 초기 용매 B 10%에서 60분 후 80%로 기울기 용리를 주어 0.8 ㎖/분의 속도로 용출하였다. 컬럼의 온도는 40℃로 유지 하였으며 시료의 검출은 280 ㎚에서 측정하였다. The phenolic components were analyzed by using Bondpack C18 (Waters, USA, 10, 300 × 3.9 mm) column, distilled water containing 2% acetic acid (solvent A) and 0.5% acetic acid (50% acetonitrile, solvent B) was eluted at a rate of 0.8 ml / min with an elution gradient of 80% after 60 minutes from the initial solvent B of 10%. The temperature of the column was maintained at 40 ° C and the detection of the sample was measured at 280 nm.
사포닌계 성분 분석은 본드팩 C18 컬럼(Waters, 미국, 10 ㎛, 300×3.9 mm)을 사용하여 이동상은 증류수(용매 A)와 아세토니트릴(용매 B)를 초기에 용매 A 80%에서 70분 후 35%로 농도구배를 주어 용출하였다. 용출속도는 1.6 ㎖/분, 컬럼의 온도는 25℃로 유지하였으며 시료의 검출은 203 ㎚에서 측정하였다.
Saponin components were analyzed using a Bond pack C18 column (Waters, USA, 10 μm, 300 × 3.9 mm) and the mobile phase was distilled water (solvent A) and acetonitrile (solvent B) And eluted with a gradient of 35%. The elution rate was maintained at 1.6 ml / min and the temperature of the column was maintained at 25 ° C. The detection of the sample was carried out at 203 nm.
hTRPA1 안정 발현 세포주hTRPA1 stable expression cell line
hTRPA1의 유전자(coding region)를 pcDNA5/FRT Complete System (Invitrogen)에 제조사의 프로토콜에 따라 클로닝 하였다. hTRPA1 유전자의 벡터 내로의 삽입 여부를 정하게 확인하기 위하여, ABI 130 또는 310 DNA genetic analyzer(Applied Biosystems)를 사용하여 시퀀싱한 후, HEK 293 세포에 상기 구축된 벡터와 pOG44(Invitrogen)를 Lipofectamine 2000 (Invitrogen)을 이용하여 형질도입 하였고 24 시간 후, 100 ㎍/ml의 하이그로마이신 B(Invitrogen)을 선택적으로 처리하여 2-3 주 더 배양하였다. 그 후 항생제 내성 세포만 수집하여 hTRPA1의 반응을 측정한 후 다시 배양하였다. 이 세포는 10%의 우태아혈청이 포함된 DMEM(Dulbecco's modified Eagle's medium)에서 배양하였다.
The coding region of hTRPA1 was cloned into the pcDNA5 / FRT Complete System (Invitrogen) according to the manufacturer's protocol. To confirm whether or not the hTRPA1 gene was inserted into the vector, the vector was sequenced using ABI 130 or 310 DNA genetic analyzer (Applied Biosystems), and the constructed vector and pOG44 (Invitrogen) were transferred to HEK 293 cells using Lipofectamine 2000 ). After 24 hours, 100 μg / ml of hygromycin B (Invitrogen) was selectively treated and cultured for another 2 to 3 weeks. After that, only the antibiotic resistant cells were collected and the reaction of hTRPA1 was measured and then cultured again. The cells were cultured in DMEM (Dulbecco's modified Eagle's medium) containing 10% fetal bovine serum.
CaCa 2+2+ 이미징법을 이용한 hTRPA1 작용 평가 Evaluation of hTRPA1 Action Using Imaging
hTRPA1 활성화 측정을 위하여 Ca2+ 이미징을 실시하였다. 세포내 칼슘양의 변화를 측정하기 위한 표식자로 푸라(Fura)-2/AM(Molecular Probes, 미국)을 사용하였다. 실험을 실시하기 20-26시간 전에, hTRPA1을 안정적으로 발현하는 세포주를 96웰-플레이트에 분주하였다. 푸라-2/AM(5 μM)을 첨가한 용액에서 27℃에서 30분간 배양하였다. 세포를 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 ㎕ 분석버퍼를 첨가하여 실온에서 15분간 방치하였다. 푸라-2/AM이 로딩된 세포를 현미경 위에 놓고 340 ㎚와 380 ㎚에서 형광흡광도를 측정하였다. 영상은 3초 마다 시간 순으로 확인하고 F340과 F380(380 ㎚)의 상대적인 비율을 메타플루오르 소프트웨어(Molecular devices, 미국)를 이용하여 세포내 칼슘양의 변화를 분석하였다.
Ca 2+ imaging was performed to measure hTRPA1 activation. Fura-2 / AM (Molecular Probes, USA) was used as a marker for measuring changes in intracellular calcium. Twenty to twenty-two hours prior to conducting 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) And the mixture was allowed to stand at room temperature for 15 minutes. Fura - 2 / AM - loaded cells were placed on a microscope and fluorescence absorbance was measured at 340 nm and 380 nm. The images were checked every 3 seconds in chronological order and the relative proportions of F340 and F380 (380 nm) were analyzed for changes in intracellular calcium levels using Metafluor software (Molecular devices, USA).
세포 기반 분석법을 이용한 세포내 CaIntracellular Ca using cell-based assays 2+2+ 측정 Measure
세포내 Ca2+ 측정은 플렉스스테이션TMⅢ(Molecular Devices, Sunnyvale, CA, 미국)을 이용하여 실시하였다. 세포는 측정 24시간 전에 분주 하고, 세포내 칼슘양의 변화를 측정하기 위한 표식자로 5 μM 플루오(Fluo)-4-AM(Molecular Probes, Eugene, OR, 미국)를 처리하여 27 ℃에서 30분간 반응하였다. 그 후, 세포를 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 ㎕의 분석버퍼를 첨가하여 실온에서 15분간 방치한 후, 각각의 추출물 및 조성물을 처리하여, 486 nm(F486) 및 516 nm(F516)에서 형광흡광도를 측정하였다. 세포내 칼슘양의 변화는 ΔRFU(Relative Fluorescence Unit)로 표시하고, 소프트맥스(Softmax) 소프트웨어(Molecular devices, 미국)를 이용하여 분석하였다.
Intracellular Ca 2+ measurements were performed using Flex Station ™ III (Molecular Devices, Sunnyvale, Calif., USA). Cells were plated 24 hours prior to measurement and treated with 5 μM Fluo-4-AM (Molecular Probes, Eugene, OR, USA) as a marker for measuring changes in intracellular calcium content Respectively. The cells were then 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) Was added and the mixture was allowed to stand at room temperature for 15 minutes. Each of the extracts and the compositions were treated to measure fluorescence absorbance at 486 nm (F486) and 516 nm (F516). The change in intracellular calcium amount was expressed as [Delta] RFU (Relative Fluorescence Unit) and analyzed using Softmax software (Molecular devices, USA).
관능시험Sensory test
코니페릴 알코올에 의한 자극성 향미에 대하여 관능검사를 실시하였다. 코니페릴 알코올 1 μM 용액을 사용하였으며 자극적인 맛의 강도를 15점 척도 내에 표시하도록 하였다(n=6).
Sensory tests were conducted for irritating flavors caused by coniferyl alcohol. A 1 μM solution of coniferyl alcohol was used and the intensity of the irritating taste was indicated within a 15-point scale (n = 6).
최루 Tear 유발능Inducibility 검사 inspection
코니페릴 알코올에 의한 최루 유발능을 시험하였다. 코니페릴 알코올 1 μM 용액을 사용하였으며 눈에 분무하여 나타나는 느낌을 서술하도록 하였다(n=6).
Tear induction with coniferyl alcohol was tested. A 1 μM solution of coniferyl alcohol was used to describe the feeling of nebulization in the eye (n = 6).
GLPGLP -1 분비에 미치는 영향 분석(-1 on the secretion of 항당뇨Anti-diabetic 및 And 항비만Anti-obesity 효능 분석) Efficacy analysis)
장(gut)으로부터 분비되는 호르몬인 GLP-1(glucagon-like peptide-1)은 포도당 자극 인슐린 분비를 증폭시키며 베타세포 사멸을 억제함으로써, 항당뇨 작용에 관여 한다. 또한, GLP-1은 위 비움(gastric emptying) 속도를 감소시키며 식욕을 억제함으로써 항비만 작용에도 관여한다. 따라서 GLP-1 분비 소재는 항당뇨 및 항비만 효과를 기대할 수 있다.
Glucagon-like peptide-1 (GLP-1), a hormone secreted from the gut, is involved in antidiabetic actions by amplifying glucose-stimulated insulin secretion and inhibiting beta cell death. In addition, GLP-1 is also involved in anti-obesity action by reducing gastric emptying rate and inhibiting appetite. Therefore, GLP-1 secretion material can antidiabetic and anti-obesity effect.
1. 세포배양1. Cell culture
인간 유래 세포주인 NCI-H716 세포는 ATCC(the American Type Culture Collection (Manassas, VA).)으로부터 구입하였으며 이 세포주는 코케이시언(Caucasian) 성인 남자(33살)의 대장 아데노카시노마로부터 분리된 비부착(suspension cell) 세포로, 주로 GLP-1을 분비하는 세포주로 알려져 있다. 세포주의 증식과 배양을 유지하기 위하여 세포는 10% FBS(fetal bovine serum), 2 mM L-글루타민, 100 IU/ml 페니실린 및 100 /ml 스트렙토마이신이 함유된 RPMI 1640 배지에서 배양하였으며 세포의 부착 및 분화를 위하여 세포는 마트리젤 매트릭스(Becton Dickinson and Co., Bedford, MA)를 플레이트에 코팅하여 10% FBS, 2 mM L-글루타민, 100 IU/ml 페니실린 및 100 /ml 스트렙토마이신이 함유된 고-글루오오스 DMEM에 배양하여 실험에 이용하였다.
NCI-H716 cells, which are human-derived cell lines, were obtained from ATCC (the American Type Culture Collection (Manassas, VA). This cell line is a suspension cell cell isolated from the colon adenocasinoma of a Caucasian adult male (33-year-old), which mainly secretes GLP-1 It is known as a cell line. To maintain cell line proliferation and culture, cells were maintained in 10% FBS bovine serum), 2 mM L-glutamine, 100 IU / ml penicillin and 100 / ml streptomycin. For cell attachment and differentiation, cells were cultured in a Becton Dickinson ' Co., Bedford, MA) was coated on a plate to obtain a 10% Glucose DMEM containing FBS, 2 mM L-glutamine, 100 IU / ml penicillin and 100 / ml streptomycin and used for the experiments.
2. NCI-H716 세포에서 GLP-1의 분비 효과2. Secretion effect of GLP-1 in NCI-H716 cells
NCI-H716 세포주는 2 x 105 cells/mL의 농도로 마트리젤이 코팅된 96-웰 배양 플레이트에 3일간 배양하였다. 실험 당일, 세포는 1X PBS(phosphated buffered saline)로 수세과정을 거친 뒤, 대조군으로는 KRB(Krebs-Ringer bicarbonate buffer, 128.8 mmol/l NaCl, 4.8 mmol/l KCl, 1.2 mmol/l KH2PO4, 1.2 mmol/l MgSO4, 2.5 mmol/l CaCl2, 5 mmol/l NaHCO3, 및 10 mmol/l HEPES, 0.2% BSA, pH 7.4)을 이용하였고 여기에 분석하기 위한 시료를 농도별로 첨가하여 37oC에서 1시간 배양하였다. 배양 후 GLP-1 분석을 위하여 상층액을 취하고(100 μL), GLP-1 활성 ELISA 키트(EGLP-35K, Millipore)을 이용하여 제조사의 매뉴얼에 따라 분석하였다. GLP-1의 농도는 공급된 GLP-1 표준물질에 준하여(pmole) 계산되었다.
The NCI-H716 cell line was cultured on a 96-well culture plate coated with Matrigel at a concentration of 2 x 10 5 cells / mL for 3 days. On the day of the experiment, the cells were washed with 1X PBS (phosphated buffered saline), and KRB (Krebs-Ringer bicarbonate buffer, 128.8 mmol / l NaCl, 4.8 mmol / l KCl, 1.2 mmol / l KH 2 PO 4 , 1.2 mmol / l MgSO 4, 2.5 mmol /
결과 및 고찰Results and Discussion
KPsKPs 추출물의 활성성분 Active ingredient of extract HPLCHPLC 분석 analysis
본 연구에서 사용한 칼로파낙스사포닌(Kalopanaxsaponin) A 및 칼로파낙스사포닌 B(헤더라게니 비스데스모사이드) 등의 사포닌계 표준물질 및 페놀계 화합물로서 시린진, 메틸 시린게이트, 클로로겐산, 코니페릴 알코올 및 프로토카테큐산 등은 껍질과 잎에 분포하고 있는 것으로 보고되어 있으나 사포닌계 화합물과 페놀계화합물의 비는 부위에 따라 다른 것으로 알려져 있다. 최근 연구에 따르면 껍질에는 잎에 비해 사포닌이 적게 함유되어 있고 리리오덴드린 및 시린진이 높은 함량으로 존재하여 이들 두 화합물이 해동피를 대변하는 중요한 활성 물질로 평가된 반면, 식용으로 하는 산나물인 음나무순(개두릅)은 클로로겐산의 높은 함유량을 보여 이 화합물이 기능성 화합물로서 존재하는 것으로 평가하고 있다. 이에 근거하여, KPs 분획물 6가지에 대해 성분 분석을 시행한 결과 클로로겐산이 가장 높은 함유량을 나타내었다(참조: 도 1-도 7). 그러나 Ca2 + 이미징을 통한 hTRPA1 작용 평가에 있어서 클로로겐산은 효과를 나타내지 않았으며, HPLC 결과에서 소량으로 확인된 코니페릴 알코올이 hTRPA1에 특이적 작용하는 것으로 확인되었다.
Examples of saponin standards and phenolic compounds such as Kalopanaxsaponin A and Kalopanax saponin B (hederagenibis desmoside) used in the present study include silinin, methylsyringate, chlorogenic acid, conipheryl alcohol and protophenol And cathechic acid are reported to be distributed in the skin and leaves, but the ratio of the saponin compound to the phenolic compound is known to vary depending on the site. Recent studies have shown that the shells contain less saponins than leaves and are present in high contents of lyrodendrine and syringine, and these two compounds are evaluated as important active substances for representing the sea tangle. On the other hand, (Open field) showed a high content of chlorogenic acid, and this compound was evaluated to exist as a functional compound. On the basis of this, component analysis of six KPs fractions showed the highest content of chlorogenic acid (cf. FIGS. 1 - 7). However, according to hTRPA1 action Evaluation of Ca 2 + imaging is chlorogenic acid did not show any effect, it was confirmed that the conical perylene alcohol check by HPLC resulting in a small amount in the specific action hTRPA1.
KPsKPs 분획물의Fraction hTRPA1hTRPA1 활성 평가 Activity evaluation
KPsEtx, KPsEtx-DW 및 KPsEtx-EA에 대한 hTRPA1 활성을 측정하였다. hTRPA1에서 KPsEtx 및 KPsEtx-DW는 시간 의존적 효과를 나타내었고 RR을 처리하였을 때 완전히 억제되는 것을 확인하였다. 도 8에서 보는 바와 같이 hTRPA1의 양성대조군인 AITC(Allyl isothiocyanate)를 처리하였을 때 나타나는 세포내 Ca2 +의 유입과 동일한 양상을 보이는 것으로 생각되며 이는 30 μM AITC 정도의 효과를 나타낼 것으로 판단된다. 또한, RR에 의하여 완전히 억제되고 시간 의존적인 양상을 나타내는 것으로 보아 hTRPA1 발현 안정세포주에서 KPs 추출물에 의한 세포내 칼슘 농도가 더 증가가 되는 것으로 판단된다(도 8).
HTRPA1 activity was measured for KPsEtx, KPsEtx-DW and KPsEtx-EA. In hTRPA1, KPsEtx and KPsEtx-DW showed a time-dependent effect and were completely inhibited by RR treatment. As shown in FIG. 8, it seems that the intracellular Ca 2 + influx appeared when AITC (Allyl isothiocyanate), which is a positive control of hTRPA1, is treated, and it is considered that the effect is about 30 μM AITC. Furthermore, it was judged that the intracellular calcium concentration by KPs extract in the hTRPA1-expressing stable cell line was further increased as shown by the RR completely suppressed and time-dependent pattern (FIG. 8).
CaCa 22 ++ 이미징을Imaging 이용한 Used 코니페릴Connie Perry 알코올의 Of alcohol TRPA1TRPA1 활성 평가 Activity evaluation
TRPA1을 안정적으로 발현하는 세포에서 Ca2 + 이미징을 실시한 결과, hTRPA1이 발현된 hTRPA1 안정 세포에서 코니페릴 알코올은 시간-의존적으로 세포내 Ca2 + 유입량을 증가시킴을 함을 알 수 있으며, 이는 코니페릴 알코올이 시간-의존적으로 hTRPA1을 활성화시키는 것을 나타낸다(도 9). 또한, TRP 채널의 일반적 블록커인 RR(Ruthenium Red)(Sigma-aldrich, USA)을 처리하였을 때 코니페릴 알코올이 작용이 완전히 차단되는 것을 확인하였다. 따라서, 코니페릴 알코올은 hTRPA1을 활성화 하여 세포내 Ca2 + 유입량을 증가시키고 이를 통하여 hTRPA1에 의한 다양한 생리학적 반응을 나타냄을 알 수 있다.
As a result of the Ca 2 + imaging in cells stably expressing the TRPA1, Connie perylene alcohol in hTRPA1 stable cells hTRPA1 the expression time-are found to be the Sikkim dependently increase intracellular Ca 2 + influx, which Coney Indicating that peryl alcohol activates hTRPA1 in a time-dependent manner (Figure 9). In addition, when treated with RR (Ruthenium Red) (Sigma-aldrich, USA), a general blocker of the TRP channel, it was confirmed that coniferyl alcohol completely blocked the action. Thus, Connie perylene alcohol can be enable hTRPA1 increase intracellular Ca + 2 influx was seen through it indicates a variety of physiological responses by hTRPA1.
세포 기반 분석을 이용한 Using cell-based analysis TRPA1TRPA1 활성 평가 Activity evaluation
앞의 실험에서 코니페릴 알코올의 TRPA1 특이적 활성이 확인됨에 따라, 세포 반 분석법을 이용하여 코니페릴 알코올의 농도 변화와 TRPA1의 특이적 블록커로 확인된 HC-030031[2-(1,3-다이메틸-2,6-디옥소-1,2,3,6-테트라하이드로-7H-퓨린-7-일)-N-(4-이소프로필페닐)아세타마이드](Sigma-aldrich, USA)에 의한 반응을 확인하였다. 실험 결과, 코니페릴 알코올의 EC50은 654.5 μM이며 AITC는 8.465 μM로 나타났다(도 10). 따라서, 본 발명의 코니페릴 알코올은 우수한 hTRPA1 아고니스트임을 알 수 있다.As TRPA1-specific activity of coniferyl alcohol was identified in the previous experiment, HC-030031 [2- (1,3-) was identified as a change in the concentration of coniferyl alcohol and the specific blocker of TRPA1 using semi-cell assay. Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl) -N- (4-isopropylphenyl) acetamide] (Sigma-aldrich, USA) The reaction by was confirmed. Experimental results showed that the EC 50 of coniferyl alcohol was 654.5 μM and AITC was 8.465 μM (FIG. 10). Thus, it can be seen that the coniferyl alcohol of the present invention is a good hTRPA1 agonist.
또한, hTRPA1의 안타고니스트인 HC-030031 100 μM 첨가하였을 때, 코니페릴 알코올에 의한 Ca2 + 반응이 유의적으로 감소하였다(도 11).
Further, this significant decreased Coney perylene Ca 2 + reaction by the addition of alcohol ever antagonists of 100 μM HC-030031 of hTRPA1 (Fig. 11).
관능시험Sensory test
코니페릴 알코올의 관능검사 결과, 자극적인 맛(매움, 얼얼함, 쏘는 맛)의 강도는 11.83± 1.6로 나타났으며 첫 맛보다 뒤에 남는 맛이 매우 강하며 아린맛, 쓴맛, 매운맛, 떫은 맛 등의 자극적인 맛뿐만 아니라 혀가 얼얼하거나 통증이 생기는 것으로 평가되었다. 또한 입안에 남는 지속성이 매우 강한 것으로 나타났다.
According to the sensory test of Coniferyl alcohol, the intensity of irritating taste (hotness, tingling, stinging) was 11.83 ± 1.6, and the taste remaining behind the first taste was very strong, and it was irritating such as arin, bitter, spicy, astringent taste. It was evaluated that the tongue tingles or pains as well as the taste. In addition, the persistence remaining in the mouth was very strong.
최루 Tear 유발능Inducibility 시험 exam
코니페릴 알코올을 분무하여 눈에 나타나는 눈물 또는 자극성을 시험한 결과, 눈에 통증(욱신 거림, 따가움, 어지러움)을 나타내었으며 관능검사와 마찬가지로 처음보다 뒤에 나타나는 강도가 강한 것으로 판단되었으며 지속성이 매우 강하게 유지되었다.
A test of tear or irritation in the eyes by spraying coniferyl alcohol showed pain in the eyes (throbbing, stinging, and dizziness). It became.
GLPGLP -1 분비에 미치는 영향 분석(-1 on the secretion of 항당뇨Anti-diabetic 및 And 항비만Anti-obesity 효능) efficacy)
NCI-H716 세포주를 이용하여 코니페릴 알코올에 대한 GLP-1 분비 반응을 살펴보았다. 그 결과 비처리구(untreated control)의 시료에 비해 코니페릴 알코올 3 μM의 농도로 처리된 그룹에서 3.0배, 10 μM 농도 이상에서 처리된 그룹은 4배 이상의 GLP-1 분비 반응을 보였다(도 12). 양성 대조군으로 사용된 500 μM AITC는 3.9배 정도의 GLP-1 분비를 보였다. 따라서 GLP-1 분비를 촉진시킨 코니페릴 알코올에 대하여 항당뇨 및 항비만 효과를 기대할 수 있다.
The NLP-H716 cell line was used to examine GLP-1 secretion response to coniferyl alcohol. As a result, in the group treated with the concentration of 3 μM coniferyl alcohol compared to the sample of the untreated control group 3.0 times, GLP-1 secretion response was more than four times the group treated at 10 μM concentration (Fig. 12) . 500 μM AITC used as a positive control showed a 3.9-fold GLP-1 secretion. Therefore, antidiabetic and anti-obesity effects can be expected for coniferyl alcohol which promotes GLP-1 secretion.
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. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (7)
Food composition for inducing irritant flavor selected from the group consisting of pungent taste and stinginess containing coniferyl alcohol as an active ingredient.
A tear agent containing coniferyl alcohol as an active ingredient.
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