KR101071785B1 - Composition for Treating Atopic Dermatitis Comprising Taxifolin 3-O-β-D-Glucopyranoside Isolated from the Extract of the Roots of Rhododendron mucronulatum as an Active Ingredient - Google Patents
Composition for Treating Atopic Dermatitis Comprising Taxifolin 3-O-β-D-Glucopyranoside Isolated from the Extract of the Roots of Rhododendron mucronulatum as an Active Ingredient Download PDFInfo
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- KR101071785B1 KR101071785B1 KR1020080082778A KR20080082778A KR101071785B1 KR 101071785 B1 KR101071785 B1 KR 101071785B1 KR 1020080082778 A KR1020080082778 A KR 1020080082778A KR 20080082778 A KR20080082778 A KR 20080082778A KR 101071785 B1 KR101071785 B1 KR 101071785B1
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- KR
- South Korea
- Prior art keywords
- glucopyranoside
- composition
- atopic dermatitis
- taxifolin
- rhododendron
- Prior art date
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Abstract
본 발명은 진달래 뿌리 추출물로부터 분리한 탁시폴린 3-O-β-D-글루코피라노사이드를 유효성분으로 포함하는 아토피성 피부염 치료용 조성물에 관한 것이다. 본 발명의 조성물의 유효성분인 탁시폴린 3-O-β-D-글루코피라노사이드(Taxifolin 3-O-β-D-Glucopyranoside)는 호산성백혈구(eosinophile)의 수를 현저히 감소시키고, IL-4, 5, 13의 수준을 감소시키는 반면, IL-10의 수준을 증가시키며, MBD-1, 2, 3의 발현을 촉진하고, COX-2 및 iNOS의 발현은 강하게 억제하는 효능을 가져, 아토피성 피부염의 면역조절 치료제로 개발될 수 있다. 또한 본 발명의 화합물은 진달래 뿌리 추출물로부터 분리 정제된 천연화합물로서 인체에 매우 안전하다. The present invention relates to a composition for treating atopic dermatitis comprising Taxipoline 3-O-β-D-glucopyranoside isolated from Rhododendron root extract as an active ingredient. Taxifolin 3-O-β-D-glucopyranoside, an active ingredient of the composition of the present invention, significantly reduces the number of eosinophilic leukocytes (eosinophile), IL- While reducing levels of 4, 5, 13, while increasing the level of IL-10, promotes the expression of MBD-1, 2, 3, expression of COX-2 and iNOS has a potent inhibitory effect, atopy It can be developed as an immunomodulatory treatment for sexual dermatitis. In addition, the compound of the present invention is a natural compound purified from rhododendron root extract is very safe for the human body.
진달래 뿌리 추출물, 플라보노이드(flavonoid), 탁시폴린 3-O-β-D-글루코피라노사이드(Taxifolin 3-O-β-D-Glucopyranoside), 면역조절제, Th1, Th2 Rhododendron Root Extract, Flavonoids, Taxifolin 3-O-β-D-Glucopyranoside, Immunomodulators, Th1, Th2
Description
본 발명은 진달래 뿌리 추출물로부터 분리한 탁시폴린 3-O-β-D-글루코피라노사이드를 유효성분으로 포함하는 아토피성 피부염 치료용 조성물에 관한 것이다.The present invention relates to a composition for treating atopic dermatitis comprising Taxipoline 3-O-β-D-glucopyranoside isolated from Rhododendron root extract as an active ingredient.
진달래(Rhododendron mucronulatum)는 진달래과(Ericaceae)에 속하는 Rhododendron 속 식물로 호주를 제외한 전 세계에 걸쳐 분포하며, 약 50 속 1300 여 종이 알려져 있다. Rhododendron mucronulatum is a genus of Rhododendron belonging to the genus Ericaceae, distributed all over the world except Australia. About 50 genera and 1300 species are known.
예로부터 진달래 (R. mucronulatum)의 어린가지, 잎, 꽃을 고혈압 초기에 사용하는 것으로 알려졌으며, 만병초 (R. brachycarpum)의 잎을 이뇨제로 사용하였고, 철쭉나무 (R. schlippenbachii), 산철쭉나무 (R. yedoense var. poukhanense) 등의 잎을 고혈압의 치료에 응용하였다.1-2) 또한 일본에서는 민간적으로 진달래 꽃잎과 찹쌀로 빚는 두견주(진달래술)는 향취가 좋은 술로 하루에 한, 두잔 마시면 혈액순환을 촉진시키고, 혈액속의 콜레스테롤을 낮추어 주며 진해(鎭海), 혈압강하, 피로회복, 류마티스 치료에 효과가 있다고 하였다. 또한 진달래의 꽃과 잎은 중국 의학에서 강장, 이뇨, 건위와 같은 약리학적 효능을 가진 것으로 알려져 왔다.3-4) It has been known to use the twigs, leaves, and flowers of R. mucronulatum in the early stages of hypertension, and the leaves of R. brachycarpum were used as diuretics, R. schlippenbachii, Rhododendron ( R. yedoense var. Poukhanense) leaves were applied to the treatment of hypertension. 1-2) In Japan, the azalea, which is made of azalea petals and glutinous rice, is a scented liquor that can be used for one or two drinks a day to promote blood circulation, lower cholesterol in the blood, and reduce haeju, blood pressure. It is said to be effective in treating depression, fatigue and rheumatism. Azalea flowers and leaves have also been known to have pharmacological effects in Chinese medicine, such as tonic, diuretic and dry stomach. 3-4)
Rhododendron속 식물은 다양한 방법으로 연구가 진행되어져 왔으며, 대표적으로 본 속 식물의 특징 중 하나인 분포지역과 함유성분을 계통분류학적으로 해석하는 것으로 Harborne이 본 속 식물 52 종의 잎을 이용하여 함유된 플라보노이드(flavonoid)를 비교함으로써 분포지역에 따른 분류학적 특성을 고찰한 것이 있으며5), 이와 더불어 Cooman 등은 Rhododendron Simsii 의 꽃잎을 이용하여 플라보노이드의 생합성 과정을 추적함으로써 Rhododendron 속의 생합성과정을 밝혀 식물학적 특성을 밝히려는 시도도 하였다.6) The Rhododendron genus has been studied in various ways, and is a systematic analysis of the distribution area and constituents, which are one of the characteristics of the genus plant. By comparing the flavonoids, the taxonomic characteristics of the distribution regions were examined.5 ) In addition, Cooman et al. Traced the biosynthesis process of flavonoids using petals of Rhododendron Simsii to reveal the biosynthetic process of genus Rhododendron. Attempts have been made to clarify. 6)
본 속 식물로부터 얻어지는 성분 연구는 Hikino 등이 Rhododendron japonicum의 꽃으로부터 독성 디테르펜(toxic diterpene)인 로도자포니(rhodojaponin) I-IV을 분리, 보고하였으며7-8), Sakakibar등은 Rhododendron japonicum의 잎과 줄기로부터 수종의 디테르펜 글리코사이드(diterpene glycoside) 와 트리테르펜(triterpene) 화합물을 분리, 보고하였다9). Li 등은 Rhododendron molle의 과실로부터 디테르펜(diterpene)인 로도몰레인(rhodomollein) XV-XVIII 를 분리, 보고하였고10), Fan 등은 Rhododendron latoucheae의 잎으로부터 이리도이드류(Iridoids) 화합물인 rhodolatouside A 와 rhodolatouside B 를 분리, 보고하였다.11) Studies on the constituents obtained from this genus plant have reported that Hikino et al. Isolated and rhodojaponin I-IV, a toxic diterpene, from the flowers of Rhododendron japonicum. 7-8) , Sakakibar et al. and stem-di terpene glycosides from the species (diterpene glycoside) and triterpene (triterpene) isolating the compound was 9) report. Li et al. Reported and reported the diterpene rhodomollein XV-XVIII from the fruit of Rhododendron molle.10 ) , Fan et al. B was isolated and reported. 11)
또한 Rhododendron 속 식물의 활성에 대한 연구로는 Bao 등이 Rhododendron molle의 뿌리로부터 수종의 디테르펜 글리코사이드(diterpene glycosides)와 페놀성 글리코사이드(phenolic glycosides)를 분리하여 각각의 화합물을 대상으로 세포독성(cytotoxicity)을 측정하였으며12), Klocke 등은 Rhododendron molle의 꽃으로부터 분리한 디테르펜(diterpene) 화합물의 곤충에 대한 anti-feedant 활성 및 살충 활성을 측정하여 보고하였다.13) 또한, Takahashi 등은 Rhododendron simsii의 잎으로부터 플라바논 글리코사이드(flavanone glycosides)와 ursane-type 트리테르펜(triterpene)을 분리하고, 항산화 활성을 측정하여 보고하였다.14) In addition, studies on the activity of plants of the genus Rhododendron include Bao et al. Isolated several diterpene glycosides and phenolic glycosides from the roots of the Rhododendron molle. 12) , Klocke et al. reported the anti-feedant activity and insecticidal activity of diterpene compounds isolated from flowers of Rhododendron molle. 13) In addition, Takahashi et al. Isolated flavanone glycosides and ursane-type triterpenes from the leaves of Rhododendron simsii and measured and reported their antioxidant activity. 14)
한편, 우리나라에 분포하는 Rhododendron속 식물에 관한 연구는 홍 등이 산철쭉(R. yedoense var poukhanense)의 꽃으로부터 grayanotixin I, III, IV 및 2α, 3β-dihydroxylolean-12-ene, ursolic acid 등을 분리, 보고하였으며,15) Chung 등이 진달래 (R. mucronulatum)의 꽃으로부터 항산화 물질로서 ρ-coumaric acid, ferulic acid, caffeic acid, chlorogenic acid, 4, 5-O-dicaffeoylquinic acid, 3, 5-O-dicaffeoylquinic acid 등 6종의 페놀성 산(phenolic acids)을 분리, 보고 하였다.16-17) 또 An 등이 진달래(R. mucronulatum) 꽃 추출물의 항산화, 항암 효과 및 티로시나아제(tyrosinase) 저해 활성 등을 분획 수준에서 확인하였으며,18) Lee 등이 진달래(R. mucronulatum)의 줄기를 대상으로 분획 수준 활성에 관하여 보고 한 것 등만 있을 뿐19) 기타 연구는 아직 자세히 이루어지지 못하였다. On the other hand, research on the genus Rhododendron plants distributed in Korea is isolated from the flowers of R. yedoense var poukhanense (R. yedoense var poukhanense), grayanotixin I, III, IV and 2α, 3β-dihydroxylolean-12-ene, ursolic acid, etc. 15) Chung et al. (P-coumaric acid, ferulic acid, caffeic acid, chlorogenic acid, 4, 5-O-dicaffeoylquinic acid, 3, 5-O-dicaffeoylquinic as antioxidants from flowers of R. mucronulatum) Six types of phenolic acids, including acid, were isolated and reported. 16-17), etc. An addition of rhododendron (R. mucronulatum) flower extract, antioxidant, and anticancer effects were identified, such as tyrosinase (tyrosinase) inhibitory activity in fractions level, 18) Lee, such as the rhododendron (R. mucronulatum) as such will be only one report on activity levels fraction targeting the stem 19) study was not yet done in detail.
전통적으로 식용, 민간치료 및 약용으로 이용되어진 진달래는 상기 언급된 보고 내용에서 확인할 수 있듯 꽃, 잎, 줄기 등에서 분리된 성분이 테르페노이드(terpenoid) 및 플라보노이드(flavonoids)로 성분 연구가 한정되어져 있으며, 활성 연구도 꽃, 줄기에 대한 몇 편의 연구가 보고되었을 뿐 진달래 뿌리에 대한 활성연구는 미흡한 실정이다. Rhododendrons traditionally used for edible, folk remedies and medicinal use are limited to studies on terpenoids and flavonoids whose components are separated from flowers, leaves, and stems. However, only a few studies on flowers and stems have been reported, but studies on azalea roots are insufficient.
아토피라는 용어는 어원상 "이상한" 또는 "부적절한"이란 의미를 갖는 용어이다. 아토피성 피부염은 대부분 유아기나 소아 때 발생하여 호전과 악화를 반복하는 비교적 흔한 만성 염증성 피부질환으로, 아토피의 개인 또는 가족력, 심한 가려움증 및 습진의 3가지 특징으로 진단할 수 있으며 감염, 정신적인 스트레스, 계절과 기후변화, 자극 및 알레르기에 의해 악화될 수 있다.The term atopy is a term that has the meaning "weird" or "inappropriate" in origin. Atopic dermatitis is a relatively common chronic inflammatory skin disease that occurs most often in infancy and childhood, and improves and worsens.It can be diagnosed with three characteristics: individual or family history of atopy, severe itching, and eczema. May be exacerbated by seasonal and climate change, irritation and allergies.
아토피 피부염의 병인론은 아직 확실히 밝혀 있지 않지만, 현재까지의 연구에 의하면 IgE 항체의 증가에 따른 과감작 반응에 의하거나, 세포매개성 면역기능의 저하로 나타나는 T 림프구의 불균열 분화에 의한 기능적 결여, 피부에 존재하는 아드레날린 수용체의 차단 등이 발병의 원인이라는 설 등이 있다. 따라서, 아토피 피부염은 면역학적인 이상이 관여하는 유전적인 질환으로 생각되고 있다. The etiology of atopic dermatitis is not yet clear, but studies to date indicate a lack of functionalities due to hypersensitivity reactions with increased IgE antibodies, or due to undifferentiated differentiation of T lymphocytes resulting from decreased cellular mediated immune function, Blockage of adrenergic receptors present in the skin is the cause of the onset. Therefore, atopic dermatitis is considered to be a genetic disease involving immunological abnormalities.
아토피성 피부염의 치료 및 관리를 위해, 대부분의 피부과 진료 시 피부 표면의 수분을 유지시켜주는 보습제와 함께 염증반응을 호전시키기 위한 스테로이드 호르몬 즉, 국소 부신피질호르몬 제제를 동시에 처방하는 하는 것이 일반적이다. 하지만, 국소 부신피질호르몬을 장기간 사용하는 경우, 피부 위축, 혈관 확장, 색소 탈실 및 팽창 선조의 발생 등 다양한 피부 부작용을 야기 시킨다는 문제점이 있다. 따라서, 이러한 부작용을 나타내지 않으면서, 항염증 효능을 보유하는 아토피 치료용 원료나 제약의 개발 필요성이 꾸준히 대두되고 있는 상황이다. For the treatment and management of atopic dermatitis, it is common for most dermatologists to prescribe steroid hormones, that is, topical corticosteroids, to improve the inflammatory response along with moisturizers that keep the skin's surface moisturized. However, when the topical corticosteroids are used for a long time, there are problems that cause various skin side effects such as skin atrophy, vasodilation, pigmentation and swelling ancestors. Therefore, there is a need to develop a raw material or pharmaceuticals for treating atopic dermatitis having an anti-inflammatory effect without showing such side effects.
한편, 대한민국 공개특허 제2008-0057414호에서는 진달래 뿌리 추출물을 유효성분으로 포함하는 피부 자극 완화용 화장료 조성물이 개시되어 있으나, 단일 화합물 수준이 아닌 추출물 수준에서의 효과만을 개시하고 있고, 대한민국 등록특허 제10-0776695호에서도 진달래 추출물을 유효성분으로 하는 아토피성 피부염 개선용 화장료 조성물에 대해 개시되어 있으나, 역시 단일 화합물 수준이 아닌 추출물 수준에서의 효과만이 개시되어 있다. 지금까지 아토피성 피부염 치료 활성을 갖는 진달래 추출물로부터 분리된 화합물에 대한 연구는 심도있게 진행되어 있지 않은 실정이다. On the other hand, the Republic of Korea Patent Publication No. 2008-0057414 discloses a cosmetic composition for skin irritation relief containing azalea root extract as an active ingredient, but only discloses the effect at the extract level, not a single compound level, 10-0776695 discloses a cosmetic composition for improving atopic dermatitis using an rhododendron extract as an active ingredient, but also discloses only effects at the extract level, not at the level of a single compound. Until now, studies on compounds isolated from rhododendron extracts having therapeutic activity for atopic dermatitis have not proceeded in-depth.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조 로 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 cited papers and patent documents are incorporated herein by reference in their entirety, so that the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.
본 발명자들은 진달래 뿌리 추출물로부터 아토피성 피부염 치료 활성을 갖는 화합물을 분리하여 그 효능을 확인하고자 예의 연구 노력하였다. 그 결과 진달래 뿌리 추출물로부터 분리한 플라보노이드계 화합물인 탁시폴린 3-O-β-D-글루코피라노사이드(Taxifolin 3-O-β-D-Glucopyranoside)가 아토피 피부염 유발 Nc/Nga 마우스를 사용한 실험 및 다양한 인 비보(in vivo) 실험에서 매우 우수한 아토피성 피부염 치료 또는 개선 효능을 나타낸다는 것을 확인함으로써 본 발명을 완성하였다. The present inventors earnestly researched to isolate the compound having atopic dermatitis therapeutic activity from azalea root extract and confirm its efficacy. As a result, Taxifolin 3-O-β-D-Glucopyranoside, a flavonoid compound isolated from Rhododendron root extract, was tested using atopic dermatitis-inducing Nc / Nga mice. The present invention has been completed by confirming that various in vivo experiments show very good atopic dermatitis treatment or improvement efficacy.
따라서, 본 발명의 목적은 탁시폴린 3-O-β-D-글루코피라노사이드를 유효성분으로 포함하는 아토피성 피부염 치료용 조성물을 제공하는 것에 있다. Accordingly, it is an object of the present invention to provide a composition for treating atopic dermatitis comprising taxoxyline 3-O-β-D-glucopyranoside as an active ingredient.
본 발명의 목적 및 장점은 하기의 발명의 상세한 설명, 청구의 범위 및 도면에 의해 보다 명확하게 된다. The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 (a) 하기 화학식 1으로 표시되는 탁 시폴린 3-O-β-D-글루코피라노사이드(Taxifolin 3-O-β-D-Glucopyranoside)의 약제학적 유효량; 및 (b) 약제학적으로 허용되는 담체를 포함하는 아토피성 피부염 치료 또는 예방용 약제학적 조성물을 제공한다. According to one aspect of the present invention, the present invention provides a pharmaceutical composition of (a) Taxifolin 3-O-β-D-glucopyranoside represented by the following
[화학식 1] [Formula 1]
본 발명의 다른 일 양태에 따르면, 본 발명은 (a) 상기 화학식 1로 표시되는 탁시폴린 3-O-β-D-글루코피라노사이드의 화장품학적 유효량; 및 (b) 화장품학적으로 허용되는 담체를 포함하는 아토피성 피부염 개선용 화장품학적 조성물을 제공한다. According to another aspect of the present invention, the present invention is (a) a cosmetically effective amount of taxoxyline 3-O-β-D-glucopyranoside represented by the formula (1); And (b) provides a cosmetic composition for improving atopic dermatitis comprising a cosmetically acceptable carrier.
본 발명의 또 다른 일 양태에 따르면, 본 발명은 상기 화학식 1로 표시되는 탁시폴린 3-O-β-D-글루코피라노사이드를 유효성분으로 포함하는 아토피성 피부염 개선용 기능성 식품 조성물을 제공한다. According to another aspect of the present invention, the present invention provides a functional food composition for improving atopic dermatitis, which comprises Taxipolline 3-O-β-D-glucopyranoside represented by Formula 1 as an active ingredient. .
본 발명자들은 진달래 뿌리 추출물로부터 아토피성 피부염 치료 활성을 갖는 화합물을 분리하여 그 효능을 확인하고자 예의 연구 노력하였다. 그 결과 진달래 뿌리 추출물로부터 분리한 플라보노이드계 화합물인 탁시폴린 3-O-β-D-글루코피라노사이드(Taxifolin 3-O-β-D-Glucopyranoside)가 아토피 피부염 유발 Nc/Nga 마우스를 사용한 실험 및 다양한 인 비보(in vivo) 실험에서 매우 우수한 아토피성 피부염 치료 또는 개선 효능을 나타낸다는 것을 확인함으로써 본 발명을 완성하였다. The present inventors earnestly researched to isolate the compound having atopic dermatitis therapeutic activity from azalea root extract and confirm its efficacy. As a result, Taxifolin 3-O-β-D-Glucopyranoside, a flavonoid compound isolated from Rhododendron root extract, was tested using atopic dermatitis-inducing Nc / Nga mice. The present invention has been completed by confirming that various in vivo experiments show very good atopic dermatitis treatment or improvement efficacy.
본 발명의 조성물에서 유효성분으로 포함되는 화학식 1으로 표시되는 화합물 탁시폴린 3-O-β-D-글루코피라노사이드는 진달래의 뿌리로부터의 추출물로부터 아토피성 피부염의 치료 활성이 있는 화합물을 활성 추적 분리법에 의해 분리하여 동정한 화합물이다. Compound Taxipoline 3-O-β-D-glucopyranoside represented by Formula 1, which is included as an active ingredient in the composition of the present invention, tracks a compound having therapeutic activity of atopic dermatitis from an extract from the root of Rhododendron. It is the compound isolate | separated and identified by the isolation | separation method.
본 발명의 화합물 탁시폴린 3-O-β-D-글루코피라노사이드는 천연추출물로부터 분리된 화합물이므로 인체에 부작용이 없는 안전한 성분이다. Compounds of the Invention Taxipoline 3-O-β-D-glucopyranoside is a compound that is isolated from natural extracts and thus is a safe component having no side effects on the human body.
본 발명의 진달래 뿌리 추출물은 천연물로부터 추출물을 추출하는 당업계에 공지된 통상적인 방법에 따라, 즉, 통상적인 온도, 압력의 존건하에서 통상적인 용매를 사용하여 분리할 수 있다. Rhododendron root extracts of the present invention can be isolated according to conventional methods known in the art for extracting extracts from natural products, i.e. using conventional solvents in the presence of conventional temperature, pressure.
본 발명의 진달래 뿌리 추출물을 분리하기 위한 추출 용매로는 추출공정에서 일반적으로 사용할 수 있는 용매를 사용할 수 있는데, 물, 탄소수 1-4개의 무수 또는 함수 저급 알코올, 아세톤, 에틸아세테이트, 부틸아세테이트 및 1,3-부틸렌 글리콜로 구성된 군으로부터 선택되는 용매를 사용하여 추출되는 것이 바람직하다. As an extraction solvent for separating the rhododendron root extract of the present invention, a solvent that can be generally used in the extraction process can be used, including water, C 1-4 anhydrous or hydrous lower alcohol, acetone, ethyl acetate, butyl acetate and 1 It is preferable to extract using a solvent selected from the group consisting of, 3-butylene glycol.
본 발명의 탁시폴린 3-O-β-D-글루코피라노사이드는 아토피성 피부염의 치료 또는 예방용 약제학적 조성물의 유효성분으로 사용될 수 있다. 본 발명의 약제학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아 카시아 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. Taxifolin 3-O-β-D-glucopyranoside of the present invention can be used as an active ingredient of a pharmaceutical composition for the treatment or prevention of atopic dermatitis. The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier in addition to the active ingredient. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the preparation of 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 is not limited. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
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. 한편, 본 발명의 약제학적 조성물의 경구 투여량은 바람직하게는 1일 당 0.001-100 mg/kg(체중)이다. Suitable dosages of the pharmaceutical compositions of the present invention may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be. On the other hand, the oral dosage amount of the pharmaceutical composition of the present invention is preferably 0.001-100 mg / kg (body weight) per day.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 피부에 국소적으로 도포, 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. 본 발명의 약제학적 조성물이 아토피성 피부염의 치료를 위해 적용되는 점을 감안하면, 조성물의 투여는 피부에 국소적으로 도포되어 이루어지는 것이 바람직하다. The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered topically to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like. . Given that the pharmaceutical composition of the present invention is applied for the treatment of atopic dermatitis, administration of the composition is preferably applied topically to the skin.
본 발명의 조성물에 포함되는 유효성분인 화학식 1의 화합물의 농도는 치료 목적, 환자의 상태, 필요기간 등을 고려하여 결정할 수 있으며 특정 범위의 농도로 한정되지 않는다. The concentration of the compound of Formula 1, which is an active ingredient included in the composition of the present invention, may be determined in consideration of the purpose of treatment, the condition of the patient, the period of time, etc., and is not limited to a specific range of concentration.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식 을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다. The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporating into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or an aqueous medium, or may be in the form of extracts, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer.
본 발명의 바람직한 구현예에 의하면, 본 발명의 약제학적 조성물은 피부외용 제형을 갖는다. 피부외용 제형은 특별히 한정되지 않으며 바람직하게는 파우더, 젤, 연고, 크림, 액체 또는 에어로졸 제형이다. According to a preferred embodiment of the present invention, the pharmaceutical composition of the present invention has an external dermal formulation. The external dermal formulation is not particularly limited and is preferably a powder, gel, ointment, cream, liquid or aerosol formulation.
본 발명의 탁시폴린 3-O-β-D-글루코피라노사이드는 아토피성 피부염 개선용 화장품학적 조성물에 유효성분으로 사용될 수 있다. 본 명세서에서 사용된 용어 "화장품학적 유효량"은 상술한 본 발명의 화합물이 아토피성 피부염 개선 효능을 달성하는 데 충분한 양을 의미한다. Taxifolin 3-O-β-D-glucopyranoside of the present invention can be used as an active ingredient in cosmetic compositions for improving atopic dermatitis. As used herein, the term “cosmetic effective amount” means an amount sufficient for the compounds of the invention described above to achieve atopic dermatitis improving efficacy.
본 발명의 화장품 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 유연 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 클렌징 크림, 클렌징 포옴, 클렌징 워터, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다. The cosmetic composition of the present invention may be prepared in any form conventionally produced in the art and may be in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant- , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물 성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다. When the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components. Can be.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다. In the case where the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. Especially, in the case of a spray, a mixture of chlorofluorohydrocarbons, propane / Propane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다. When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다. When the formulation of the present invention is a suspension, liquid carrier diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다. When the formulation of the present invention is a surfactant-containing cleansing, the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide. Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
본 발명의 화장품 조성물에 포함되는 성분은 유효 성분과 담체 성분 이외에, 화장품 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제를 포함할 수 있다. In addition to the active ingredient and the carrier ingredient, the ingredients included in the cosmetic composition of the present invention include ingredients conventionally used in cosmetic compositions, and include, for example, conventional auxiliaries such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings. It may include.
또한, 본 발명의 화합물 탁시폴린 3-O-β-D-글루코피라노사이드는 아토피성 피부염 개선용 기능성 식품 조성물에서 유효성분으로 사용될 수 있다. In addition, the compound taxoxyline 3-O-β-D-glucopyranoside of the present invention may be used as an active ingredient in functional food compositions for improving atopic dermatitis.
본 발명의 기능성 식품 조성물은 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분으로서의 탁시폴린 3-O-β-D-글루코피라노사이드 이외에 향미제 또는 천연 탄수화물을 추가 성분으로서 포함시킬 수 있다. 예를 들어, 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등); 디사카라이드(예컨대, 말토스, 수크로오스 등); 올리고당; 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등); 및 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)을 포함한다. 향미제로서 천연 향미제(예컨대, 타우마틴, 스테비아 추출물 등) 및 합성 향미제(예컨대, 사카린, 아스파르탐 등)을 이용할 수 있다. Functional food compositions of the present invention include ingredients that are commonly added in the manufacture of food, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings. For example, when prepared with a drink, a flavoring agent or a natural carbohydrate may be included as an additional component in addition to taxoxyline 3-O-β-D-glucopyranoside as an active ingredient. For example, natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); Disaccharides (eg maltose, sucrose, etc.); oligosaccharide; Polysaccharides (eg, dextrins, cyclodextrins, etc.); And sugar alcohols (eg, xylitol, sorbitol, erythritol, and the like). As the flavoring agent, natural flavoring agents (e.g., taumartin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.
본 발명의 조성물은 아토피성 피부염의 증상을 개선하는데 이용된다. 본 명세서에서 용어 "아토피성 피부염의 증상의 개선"은 아토피성 피부염의 치료, 경감 및 완화를 모두 포괄하는 의미를 갖는다. The composition of the present invention is used to ameliorate the symptoms of atopic dermatitis. As used herein, the term "amelioration of the symptoms of atopic dermatitis" has the meaning encompassing all of the treatment, alleviation and alleviation of atopic dermatitis.
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(i) 본 발명의 조성물의 유효성분인 탁시폴린 3-O-β-D-글루코피라노사이드는 진달래 뿌리 추출물로부터 분리한 아토피성 피부염의 치료 활성을 갖는 성분이다. (i) Taxifolin 3-O-β-D-glucopyranoside, an active ingredient of the composition of the present invention, is a component having therapeutic activity of atopic dermatitis isolated from azalea root extract.
(ⅱ) 본 발명 조성물의 유효성분인 탁시폴린 3-O-β-D-글루코피라노사이드는 아토피성 피부염 동물모델에서 아토피성 피부염의 현저한 치료효능을 보였다. (Ii) Taxifolin 3-O-β-D-glucopyranoside, an active ingredient of the composition of the present invention, showed a remarkable therapeutic effect of atopic dermatitis in an atopic dermatitis animal model.
(ⅲ) 유효성분 탁시폴린 3-O-β-D-글루코피라노사이드는 동물모델의 혈액내에서 IL-4, 5, 13의 수준은 증가시킨 반면, IL-10의 수준은 감소시켰다. (Iii) Active ingredient Taxifolin 3-O-β-D-glucopyranoside increased the level of IL-4, 5, 13 in the blood of the animal model, while decreasing the level of IL-10.
(ⅳ) 탁시폴린 3-O-β-D-글루코피라노사이드는 항미생물 작용을 하는 펩타이드인 beta-defensin MBD-1, 2, 3의 발현을 강하게 증가시켰고, 반면, COX-2 및 iNOS의 발현은 억제하였다. (Iii) Taxifolin 3-O-β-D-glucopyranoside strongly increased the expression of beta-defensin MBD-1, 2, 3, an antimicrobial peptide, whereas COX-2 and iNOS Expression was inhibited.
본 발명은 진달래 뿌리 추출물로부터 분리한 탁시폴린 3-O-β-D-글루코피라노사이드를 유효성분으로 포함하는 아토피성 피부염 치료용 조성물에 관한 것이다. 본 발명의 조성물의 유효성분인 탁시폴린 3-O-β-D-글루코피라노사이드은 호산성백혈구(eosinophile)의 수를 현저히 감소시키고, IL-4, 5, 13의 수준을 감소시키는 반면, IL-10의 수준을 증가시키며, MBD-1, 2, 3의 발현을 촉진하고, COX-2 및 iNOS의 발현은 강하게 억제하는 효능을 가져, 아토피성 피부염의 면역조절 치료제로 개발될 수 있다. 또한 본 발명의 화합물은 진달래 뿌리 추출물로부터 분리 정제된 것으로 인체에 매우 안전하다. The present invention relates to a composition for treating atopic dermatitis comprising Taxipoline 3-O-β-D-glucopyranoside isolated from Rhododendron root extract as an active ingredient. Taxifolin 3-O-β-D-glucopyranoside, an active ingredient of the composition of the present invention, significantly reduces the number of eosinophiles and reduces the levels of IL-4, 5, 13, while IL Increasing the level of -10, promote the expression of MBD-1, 2, 3, and the expression of COX-2 and iNOS has a strong inhibitory effect, can be developed as an immunomodulatory treatment of atopic dermatitis. In addition, the compound of the present invention is isolated and purified from azalea root extract is very safe for the human body.
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 .
실시예 Example
실험방법Experiment method
1. 실험재료 1. Experimental material
본 발명의 실험에 사용한 진달래(Rhododendron mucronulatum) 뿌리는 2007년 8월 경남 거창군에서 채집하여 식물학적 감정을 거친 후 사용하였다. Rhododendron used in the experiment of the present invention mucronulatum ) roots were collected from Geochang, Gyeongnam province in August 2007 and used after botanical appraisal.
2. 기기 및 시약 2. Instruments and Reagents
본 발명의 실험에 사용한 기기 및 시약은 다음의 표 1에 정리하였다. The instruments and reagents used in the experiments of the present invention are summarized in Table 1 below.
[표 1] 본 발명의 실험에 사용한 기기 및 시약 TABLE 1 Instruments and reagents used in the experiments of the present invention
mass spectrometerLiquid chromatography
mass spectrometer
mass spectrometry (Canada) API 3000 triple quadrupole liquid chromatography
mass spectrometry (Canada)
1H-NMR spectrometer
1 H-NMR spectrometer
Bruker AMX-500, 500㎒ (Germany)
Solvent: DMSO-d 6 , D2O, Acetone-d 6
Internal standard: TMSVarian Gemini 2000, 300MHz (USA)
Bruker AMX-500, 500MHz (Germany)
Solvent: DMSO- d 6 , D 2 O, Acetone- d 6
Internal standard: TMS
13C-NMR spectrometer
13 C-NMR spectrometer
Bruker AMX-500, 125㎒ (Germany)
Solvent : DMSO-d 6 , D2O, Acetone-d 6
Internal standard : TMS Varian Gemini 2000, 75MHz (USA)
Bruker AMX-500, 125 MHz (Germany)
Solvent: DMSO- d 6 , D 2 O, Acetone- d 6
Internal standard: TMS
TLC Solvent(v/v)
TLC Solvent (v / v)
CHCl3 : MeOH : H2O = 6 : 4 : 1
Benzene : Ethylformate : Formic acid = 1 : 7 : 1 CHCl 3 : MeOH: H 2 O = 70: 30: 4
CHCl 3 : MeOH: H 2 O = 6: 4: 1
Benzene: Ethylformate: Formic acid = 1: 7: 1
TLC Detection
TLC Detection
10%-H2SO4 in ethanol (heating)
UV-lamp (254㎚) Ethanolic-FeCl 3 solution
10% -H2SO4 in ethanol (heating)
UV-lamp (254 nm)
Gels
Gels
MCI gel CHP 20P (75-150μ. Mitsubishi. Japan)
YMC-gel ODS-A (230/70, 400/230, 500/400 mesh, YMC. Japan)Sephadex LH-20 (25-100 μm, Pharmacia, Sweden)
MCI gel CHP 20P (75-150μ.Mitsubishi.Japan)
YMC-gel ODS-A (230/70, 400/230, 500/400 mesh, YMC. Japan)
Low pressure liquid
column chromatography
Low pressure liquid
column chromatography
detector: Gilson 112 UV/VIS (254nm)
gel: YMC-gel ODS-A (500/400 mesh, YMC Co., Japan)
data system: Autochro-Win 3.0 plus (Young-lin Co., Korea)pump: Gilson minipuls 3
detector: Gilson 112 UV / VIS (254 nm)
gel: YMC-gel ODS-A (500/400 mesh, YMC Co., Japan)
data system: Autochro-Win 3.0 plus (Young-lin Co., Korea)
3. 추출물의 제조 및 활성 성분의 분리 3. Preparation of Extract and Isolation of Active Ingredients
음건한 진달래 뿌리(3.2 ㎏)를 80% 아세톤(acetone)으로 실온에서 24 시간 동안 3회 추출하여 여과 후 그 추출액을 감압 농축하여 추출물(276.2g)을 얻었다. 이 추출물을 물(H2O)에 현탁하여 감압 여과한 후 수용성 부분에 대하여 Sephadex LH-20 컬럼 크로마토그래피(column chromatography)를 실시하였다. 용매는 물에서부터 메탄올을 10%씩 올려 100% 까지 농도를 높였으며, TLC 방법으로 확인하여 총 4개의 서브 분획(subfraction)으로 나누었다. Dried azalea roots (3.2 kg) were extracted three times for 24 hours at room temperature with 80% acetone (filter), and the extract was concentrated under reduced pressure to obtain an extract (276.2 g). The extract was suspended in water (H 2 O), filtered under reduced pressure, and subjected to Sephadex LH-20 column chromatography on an aqueous portion. The solvent was raised from methanol to 10% by increasing the concentration to 100%, and identified by TLC method was divided into a total of four subfractions (subfraction).
활성추적법을 사용하여 아토피성 피부염 치료 활성을 갖는 화합물을 동정하 였다. 활성추적방법으로는 자유 라디칼(Free radical) 소거능을 DPPH 방법으로 측정하였으며 양성대조군으로는 자유 라디칼 소거능이 우수한 것으로 잘 알려진 아스코르브산(L-Ascorbic acid)를 사용하였다. 일반적으로 항산화 효과는 NF-kB의 활성화, AP-1의 전사, iNOS의 발현 등 염증 반응과 관련된 반응성 산소종 (ROS, Reactive oxygen species)를 제거해 주는 효과로서 항염증 반응의 중요한 메커니즘으로 알려져 있으므로 활성추적 방법으로 항산화 효과를 측정하였다. Activity tracking was used to identify compounds having therapeutic activity for atopic dermatitis. Free radical scavenging activity was measured by DPPH method as activity tracking method, and ascorbic acid (L-Ascorbic acid), which is known to have excellent free radical scavenging ability, was used as a positive control group. In general, the antioxidant effect removes reactive oxygen species (ROS) related to the inflammatory response, such as NF-kB activation, AP-1 transcription, and iNOS expression. The antioxidant effect was measured by the follow-up method.
분획 수준에서 탁시폴린 3-O-β-D-글루코피라노사이드가 포함된 분획 2 (Fr. 2)(IC50 = 38.1 ug/ml)에서 DPPH 활성은 양성대조군 아스코르브산(L-Ascorbic acid) (IC50=20.9 ug/ml)와 비교하였을때 비교적 우수한 활성을 나타내었다. 탁시폴린 3-O-β-D-글루코피라노사이드 TLC 반응을 나타낸 분획 2 (Fr. 2)에 대해서 MCI-gel CHP 20P (20→80% methanol, gradient system)와 low pressure liquid column chromatography (0% MeOH→100% MeOH, gradient system)를 실시하여 탁시폴린 3-O-β-D-글루코피라노사이드 5700 mg을 얻었다. DPPH activity in positive control L-Ascorbic acid in fraction 2 (Fr. 2) (IC 50 = 38.1 ug / ml) containing taxoxyline 3-O-β-D-glucopyranoside at the fractional level. When compared to (IC 50 = 20.9 ug / ml) showed a relatively good activity. MCI-gel CHP 20P (20 → 80% methanol, gradient system) and low pressure liquid column chromatography (0) were performed on fraction 2 (Fr. 2) showing Taxipoline 3-O-β-D-glucopyranoside TLC reaction. % MeOH to 100% MeOH, gradient system) was carried out to obtain 5700 mg of taxoxyline 3-O-β-D-glucopyranoside.
탁시폴린 3-O-β-D-글루코피라노사이드의 단일 화합물 수준에서 DPPH 활성을 측정하였다. DPPH 활성 측정 결과, 탁시폴린 3-O-β-D-글루코피라노사이드(IC50 = 549.75 uM)가 양성대조군인 아스코르브산(L-Ascorbic acid)(IC50 = 525.15 uM)와 비교 하였을때 우수한 항산화 활성을 나타내었다. DPPH activity was measured at the level of a single compound of taxoxylin 3-O-β-D-glucopyranoside. As a result of DPPH activity measurement, Taxipoline 3-O-β-D-glucopyranoside (IC 50 549.75 uM) ascorbic acid (L-Ascorbic acid) (IC 50 ) = 525.15 uM) showed excellent antioxidant activity.
도 1a에 진달래 뿌리로부터 추출물을 얻고 이 추출물로부터 활성성분을 분리하는 과정을 나타내었다. 도 1b는 탁시폴린 3-O-β-D-글루코피라노사이드에 HPLC 분석 크로마토그래피를 보여준다. Figure 1a shows the process of obtaining an extract from the root of the rhododendron and separating the active ingredient from the extract. 1B shows HPLC analysis chromatography on Taxipoline 3-O-β-D-glucopyranoside.
4. 활성성분의 구조동정 4. Structural Identification of Active Ingredients
탁시폴린 3-O-β-D-글루코피라노사이드는 연 노란색의 무정형 분말이며, TLC에서 UV lamp 254 nm 파장에서 흡수에 의한 스폿(spot)을 나타내었고, FeCl3 분무에 의해서 양성으로, 10% H2SO4를 분무하고 가열시 노란색으로 발색한다. Negative LC-MS spectrum에서 m/z 475.5 [M-H]-의 피크(peak)를 나타내었다(도 2a). Taxipoline 3-O-β-D-glucopyranoside is a light yellow amorphous powder, showed a spot by absorption at 254 nm wavelength of UV lamp in TLC, positive by FeCl 3 spray, 10 Spray% H 2 SO 4 and color yellow when heated. The peak of m / z 475.5 [MH] − was shown in the negative LC-MS spectrum (FIG. 2A).
1H-NMR 스펙트럼의 δ 11.67 (1H, s)에서 플라보노이드(flavonoid)의 전형적인 5-OH 시그널(signal)이 나타났고, δ 6.69~6.87 (3H, br. d, H-2', 5', 6')에서 B ring의 ABX type인 3,4-디히드록실레이션(dihydroxylation) 패턴(pattern)의 구조로 추정되는 피크들이 넓게 나타났으며, δ 5.93 (2H, s, H-6 및 H-8), 5.39 (1H, d, J=8.4 Hz, H-2)와 4.73 (1H, d, J=8.4 Hz, H-3)을 통해 플라바노놀(flavanonol) 구조로 추정하였고, δ 4.68 (1H, d, J=7.5 Hz, glc H-1)에서 당의 어노메릭 수소(anomeric proton)가 나타나, 3', 4', 5, 7-테트라하이드록시 플라바노놀 글루코사이드(3', 4', 5, 7-tetrahydroxy flavanonol glucoside)로 추정하였다(도 2b). A typical 5-OH signal of flavonoids was shown at δ 11.67 (1H, s) of the 1 H-NMR spectrum, and δ 6.69˜6.87 (3H, br. D, H-2 ′, 5 ′, 6 ') showed a wide range of peaks presumed to be the structure of the 3,4-dihydroxylation pattern, ABX type of B ring, δ 5.93 (2H, s, H-6 and H-). 8), flavanonol structure was estimated through 5.39 (1H, d, J = 8.4 Hz, H-2) and 4.73 (1H, d, J = 8.4 Hz, H-3), and δ 4.68 ( 1H, d, J = 7.5 Hz, glc H-1) showed sugar's anomeric protons, 3 ', 4', 5, 7-tetrahydroxy flavanonol glucoside (3 ', 4', 5, 7-tetrahydroxy flavanonol glucoside) (Figure 2b).
13C-NMR 스펙트럼에서는 모핵인 탁시폴린(taxifolin)과 비교하였을 때 C-3 이 3.4 ppm 업필드 천이(upfield shift)되고, C-2가 1.9 ppm 다운필드 천이(downfield shift) 되는 것으로 보아 C-3에 당이 붙었음을 알 수 있었고, 1 몰(mole)의 글루코오스(glucose)에 의한 피크가 δ 102.6, 71.9, 75.4, 69.9, 75.3, 62.1에서 나타나 이는 3', 4', 5, 7 테트라하이드록시 플라노놀 글루코시드(3', 4', 5, 7 tetrahydroxy flavanonol glucoside)로 추정되었으며, 문헌의 데이터와 비교하여 탁시폴린 3-O-β-D-글루코피라노사이드(taxifolin 3-O-β-D-glucopyranoside)로 최종 확인, 동정하였다. In the 13 C-NMR spectrum, C-3 is 3.4 ppm upfield shifted and C-2 is 1.9 ppm downfield shifted compared to the parental taxifolin. It was found that sugar was attached to 3, and peaks due to 1 mole of glucose were found at δ 102.6, 71.9, 75.4, 69.9, 75.3, and 62.1, which represented 3 ', 4', 5, and 7 tetra. Estimated to be hydroxy flanonol glucoside (3 ', 4', 5, 7 tetrahydroxy flavanonol glucoside) and compared to literature data taxifolin 3-O-β-D-glucopyranoside (taxifolin 3-O- final confirmation and identification by β-D-glucopyranoside).
5. 아토피성 피부염 동물 모델 5. Atopic Dermatitis Animal Model
진달래 뿌리 추출물로부터 분리한 활성성분 탁시폴린 3-O-β-D-글루코피라노사이드의 아토피성 피부염 치료 활성을 실험하기 위해 공지된 아토피성 피부염 동물 모델인 NC/Nga 마우스를 사용하였다. NC / Nga mice, a known atopic dermatitis animal model, were used to test the atopic dermatitis therapeutic activity of the active ingredient Taxipoline 3-O-β-D-glucopyranoside isolated from Rhododendron root extract.
6. 탁시폴린 3-O-β-D-글루코피라노사이드 포함 제형의 제조 6. Preparation of Taxipoline 3-O-β-D-Glucopyranoside-Containing Formulations
6-1. 6-1. HPLCHPLC 분석 조건 및 Analysis conditions and 검량선의Calibration curve 작성 write
진달래 뿌리 추출물로부터 분리, 정제한 탁시폴린 3-O-β-D-글루코피라노사이드(taxifolin 3-O-β-D-glucopyranoside)를 증류수에 용해시켜 스탁용액(stock solution)(100 ㎍/㎖)을 조제하고, 이를 희석하여 1, 5, 10, 25, 50 ㎍/㎖의 농도의 표준용액을 조제하였다. 이동상은 아세토니트릴과 0.3% 초산액의 혼합액 (20 : 80 v/v)을 사용하였으며, 검출파장은 291 nm, 주입용량은 20 ㎕, 유속은 1 ㎖/min 으로 하였다. 이 조건에서 탁시폴린 3-O-β-D-글루코피라노사이드의 보유시간(retention time)은 3.67 분이었다. HPLC 분석을 통해, 각 농도와 피크영역(peak area)를 바탕으로 검량선을 작성하였으며, 농도범위 1-50 ㎍/㎖에서 양호한 직선성 (R2=0.999)을 나타내었다. Taxiolin 3-O-β-D-glucopyranoside isolated and purified from Rhododendron root extract was dissolved in distilled water and stock solution (100 ㎍ / ml). ) Was prepared and diluted to prepare a standard solution at a concentration of 1, 5, 10, 25, 50 μg / ml. As a mobile phase, a mixture of acetonitrile and 0.3% acetic acid solution (20: 80 v / v) was used. The detection wavelength was 291 nm, the injection volume was 20 µl, and the flow rate was 1 ml / min. In this condition, the retention time of Taxipolin 3-O-β-D-glucopyranoside was 3.67 minutes. Through HPLC analysis, a calibration curve was prepared based on each concentration and peak area, and showed good linearity (R 2 = 0.999) in the concentration range of 1-50 μg / ml.
6-2. 6-2. 탁시폴린Taxoxyline 3-O-β-D- 3-O-β-D- 글루코피라노사이드Glucopyranoside 주사제형의Injectable 제조 Produce
피하주사(subcutaneous injection)를 통한 탁시폴린 3-O-β-D-글루코피라노사이드의 효능 평가 시험을 위해 0.1, 1.0%(w/v) 탁시폴린 3-O-β-D-글루코피라노사이드를 포함하는 수성 주사제를 표 1의 조성에 따라 제조하였다. 탁시폴린 3-O-β-D-글루코피라노사이드 10, 100 mg을 각각 칭량하여 적당량의 주사용 멸균 증류수에 각각 용해시켰다. 이어서 NaOH 용액을 소량 가하여 pH를 6.5-7.4 사이로 보정하고 주사용 멸균 증류수를 가하여 최종 10 ㎖로 제조하였다. 약물의 함량은 HPLC 분석법을 통해 확인하였다. 0.1, 1.0% (w / v) Taxipoline 3-O-β-D-Glucopyyrano for Efficacy Evaluation Test of Taxipoline 3-O-β-D-Glucopyranoside by Subcutaneous Injection Aqueous injections containing the side were prepared according to the composition of Table 1. Ten and 100 mg of taxoxyline 3-O-β-D-glucopyranoside were weighed out and dissolved in an appropriate amount of sterile distilled water for injection, respectively. A small amount of NaOH solution was then added to calibrate the pH between 6.5-7.4, and sterile distilled water for injection was added to produce a final 10 mL. The drug content was confirmed by HPLC analysis.
[표 1] 탁시폴린 3-O-β-D-글루코피라노사이드 포함 수성 주사제 조성 TABLE 1 Aqueous Injectable Composition with Taxifolin 3-O-β-D-Glucopyranoside
6-3. 탁시폴린 3-O-β-D-글루코피라노사이드 연고제형의 제조 6-3. Preparation of Taxifolin 3-O-β-D-Glucopyranoside Ointment
탁시폴린 3-O-β-D-글루코피라노사이드의 함량은 1%(w/w)로 고정하였다. O/W 크림 연고를 제조하였다. O/W 크림의 조성은 표 2의 성분비율로 제조하였다. 폴리글리세릴-3-메틸글루코오스디스테아레이트, 스테아린산, 세탄올 및 유동 파라핀을 조성에 따라 첨가하고, 65℃ 에서 가온하여 유상을 제조한 후, 글리세린, 정제수, 탁시폴린 3-O-β-D-글루코피라노사이드을 넣고 65℃ 에서 가온하여 완전히 용해시켜 수상을 제조하였다. 같은 온도에서 유상을 수상에 가하고 균질기(homogenizer)를 사용하여 수 분간 유화시킨 후 냉각하여 O/W 크림을 제조하였다. The content of taxoxylin 3-O-β-D-glucopyranoside was fixed at 1% (w / w). O / W cream ointment was prepared. The composition of the O / W cream was prepared in the component ratios of Table 2. Polyglyceryl-3-methylglucose distearate, stearic acid, cetanol and liquid paraffin are added according to the composition, warmed at 65 ° C. to prepare an oil phase, and then glycerin, purified water, taxoxyline 3-O-β-D -Glucopyranoside was added and warmed at 65 ° C to completely dissolve the aqueous phase. The oil phase was added to the water phase at the same temperature, emulsified for several minutes using a homogenizer, and cooled to prepare an O / W cream.
[표 2] 탁시폴린 3-O-β-D-글루코피라노사이드 O/W 크림제형의 조성 TABLE 2 Composition of Taxifolin 3-O-β-D-Glucopyranoside O / W Cream
7. 7. 호산성Eosinophilic 백혈구 계수( Leukocyte count ( EosinophilEosinophil CountCount ) )
모세관 튜브(Capillary tube)에 마우스 혈액을 채취하고, 마우스 전혈 30 ㎕에 식염수(saline) 150 ㎕를 첨가하여 6배 희석하였다. Sysmex XE-2100 hematology analyzer를 이용하여 호산백혈구(eosinophil)를 계수하였다. 호산백혈구의 산출은 말초혈액 도말 슬라이드를 제작하고, Wright-Giemsa 염색을 한 후 200개의 백혈구를 감별 계산하여 행하였다. Mouse blood was collected in a capillary tube, and 150 µl of saline was added to 30 µl of mouse whole blood, and diluted 6-fold. Eosinophils were counted using a Sysmex XE-2100 hematology analyzer. The calculation of eosinophilic leukocytes was performed by making peripheral blood smears, staining Wright-Giemsa, and differentially calculating 200 leukocytes.
8. ELISA 측정법 8. ELISA Measurement
혈청은 대동맥의 혈액을 채취하여 준비하였다. 비장(spleen)으로부터 임피구(lymphocyte)를 채취한 후 이를 배양하였다. 간략하게 설명하면, 비장을 적출하여 분쇄한 후 메쉬(mesh)를 통과시켜 단일 세포로 분리하였다. 적혈구 용해 완충액(RBC lysis buffer)를 첨가하여 적혈구를 용해시킨 후 원심분리하여 상등액을 제거하였다. 1 X 106 세포를 RPMI 배지(1 ㎖) 에서 24 웰 플레이트에서 배양하였다. 3일 후에 배양된 세포를 포함하는 배지를 사용하여 실험을 진행하였다. Serum was prepared by collecting blood from the aorta. Lymphocytes were collected from the spleen and cultured. Briefly, the spleen was extracted and pulverized and then passed through a mesh to separate into single cells. Erythrocytes were lysed by adding red blood cell lysis buffer (RBC lysis buffer) and centrifuged to remove supernatant. 1 × 10 6 cells were incubated in 24 well plates in RPMI medium (1 mL). After 3 days, the experiment was conducted using a medium containing cultured cells.
9. Real-time PCR의 수행 9. Perform Real-time PCR
Real-time PCR 실험에 사용된 프라이머는 다음과 같다. Primers used in real-time PCR experiments are as follows.
총 RNA(total RNA)는 다음의 단계를 통해 제조하였다. 조직에 TRIZol 시약 1㎖을 처리하고 클로로포름(Chloroform) 200㎕를 넣고 4℃에서 15 분간 12,000 rpm에서 원심분리(centrifugation) 한 후, 상층액을 새로운 튜브에 넣고 1/2의 이소프로판올(isopropanol)을 첨가한 후 4ㅀC에서 15분간 12,000rpm에서 다시 원심분리하였다. 이어서, 상층액을 버린후 분리한 총 RNA에 DEPC water을 첨가하였다. Total RNA was prepared by the following steps. Treat the tissue with 1 ml of TRIZol reagent, add 200 µl of chloroform, and centrifugate at 12,000 rpm for 15 minutes at 4 ° C. Put the supernatant into a new tube and add 1/2 isopropanol. After centrifugation again at 12,000rpm for 15 minutes at 4 ° C. Subsequently, DEPC water was added to the total RNA isolated after discarding the supernatant.
cDNA는 다음의 단계를 거쳐 제조하였다. 제조한 총 RNA를 DEPC-DW 30 ㎕에 용해시키고 3 ㎍의 총 세포 RNA를, 1 ㎕의 역전사효소(reverse transcriptase), 2 ㎕의 10X 완충액, 2 ㎕의 10mM dNTP (dNTP mix), 1 ㎕의 oligo dT primer, 0.5 ㎕의 RNase 억제제, 4 ㎕의 25 mM MgCl2를 포함하는 20 ㎕ 부피의 반응혼합액에서 역전사 반응을 수행하였다. cDNA was prepared by the following steps. The total RNA prepared was dissolved in 30 [mu] l of DEPC-DW and 3 [mu] g of total cellular RNA was added with 1 [mu] l reverse transcriptase, 2 [mu] l 10X buffer, 2 [mu]
제조한 cDNA 각 2 ㎕를 PCR에 의해 증폭시켰다. PCR 반응은 59℃에서 1분을 행하고, 94℃에서 1분의 45 사이클 행한 후, 최종 연장(extension)단계는 72℃에서 1 분간 행하였다.2 μl of each of the prepared cDNAs was amplified by PCR. The PCR reaction was performed at 59 ° C for 1 minute, followed by 45 cycles of 1 minute at 94 ° C, and the final extension step was performed at 72 ° C for 1 minute.
10. 웨스턴 블로팅 (Western Blotting) 10. Western Blotting
피부세포를 포함하는 피부 조직을 용해시키고 이를 원심분리기를 이용하여 원심분리한 후 상등액을 취하여 이에 대해 15% SDS-PAGE(sodium dodecyl sulfate polyacrylamide gel electrophoresis)를 행하였다. MBD-1,2,3, COX-2 및 iNOS를 분석하기 위해, 젤 전기영동상에서 분리된 단백질들을 니트로셀룰로오스막으로 이동시켰고 1차 항체 (1:1000 in BSA, goat polyclonal anti-MBD(mouse beta defensin) 1, 2, or 3 antibody, rabbit polyclonal anti-COX-2 antibody, rabbit polyclonal iNOS antibody; Chemicon, CA, USA) 및 2차 항체 (1:2000 in BSA, anti-goat IgG, anti-rabbit IgG; Chemicon, CA, USA)와 순차적으로 반응시켰다. Skin tissue containing skin cells was lysed and centrifuged using a centrifuge, followed by 15% SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis). To analyze MBD-1,2,3, COX-2, and iNOS, proteins isolated from gel electrophoresis were transferred to nitrocellulose membranes and the primary antibody (1: 1000 in BSA, goat polyclonal anti-MBD (mouse beta). defensin) 1, 2, or 3 antibody, rabbit polyclonal anti-COX-2 antibody, rabbit polyclonal iNOS antibody; Chemicon, CA, USA) and secondary antibody (1: 2000 in BSA, anti-goat IgG, anti-rabbit IgG) Chemicon, CA, USA).
실험결과 Experiment result
1. 동물모델에서의 아토피성 피부염의 치료 효과 1. Therapeutic Effect of Atopic Dermatitis in Animal Models
아토피성 피부염에 대한 탁시폴린 3-O-β-D-글루코피라노사이드의 치료 효능을 조사하기 위해 아토피성 피부염을 발생시킨 동물모델 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드를 4주 동안 복강내 투여 또는 도포를 행한 후에, 아토피성 피부염 발생 부위의 외관 관찰에 의해 피부염의 호전여부를 검사하였다. Taxipoline 3-O-β-D-glue in animal model NC / Nga mice that developed atopic dermatitis to investigate the therapeutic efficacy of Taxipoline 3-O-β-D-glucopyranoside for atopic dermatitis After intraperitoneal administration or application of kopiranoside for 4 weeks, the improvement of dermatitis was examined by visual observation of the appearance site of atopic dermatitis.
탁시폴린 3-O-β-D-글루코피라노사이드를 투여하고 도포한 그룹에서 탁시폴린 3-O-β-D-글루코피라노사이드를 투여하지 않은 음성대조군과 비교하여 아토피성 피부염이 호전되는 결과를 얻었다. 즉, 주사제 형태로 탁시폴린 3-O-β-D-글루코피라노사이드 0.1% 및 1% 투여한 경우(도 3b, 도 3c)가 음성대조군인 PBS를 주사한 경우(도 3a)에 비해 아토피성 피부염이 현저히 향상되는 결과를 확인하였다. Atopic dermatitis improved compared to the negative control group that did not receive Taxifolin 3-O-β-D-Glucopyranoside in the group administered and applied to Taxifolin 3-O-β-D-Glucopyranoside. The result was obtained. That is, when 0.1% and 1% of Taxipoline 3-O-β-D-glucopyranoside in the form of injection (Fig. 3B, Fig. 3C) is injected into the negative control group PBS (Fig. 3A) compared to atopy The results showed that sexual dermatitis was significantly improved.
또한, 연고제 형태로 탁시폴린 3-O-β-D-글루코피라노사이드 0.1% 및 1%를 피부에 도포 적용시킨 경우(도 4b)가 음성대조군 바세린(baseline) 도포의 경우(도 4a)에 비해 아토피성 피부염이 현저히 향상되는 결과를 얻었다. In addition, when 0.1% and 1% of Taxipoline 3-O-β-D-glucopyranoside was applied to the skin in the form of an ointment (FIG. 4B), the baseline application of the negative control group (FIG. 4A) was performed. In comparison, atopic dermatitis was significantly improved.
2. 2. 호산성백혈구Eosinophilic leukocytes (( eosinophileeosinophile ) 수 측정 Number measurement
아토피성 피부염을 발생시킨 동물모델 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드를 4주 동안 복강내 투여 또는 도포 전 및 후의 마우스로부터 혈액을 채취하여 호산성백혈구(eosinophile)의 수를 측정하였다. 탁시폴린 3-O-β-D-글루코피라노사이드의 투여 전에 비해, 투여 후에 호산성 백혈구의 수가 급격히 줄어든 것을 확인하였다(도 5 참조). Eosinophil leukocytes were obtained by collecting blood from mice before and after intraperitoneal administration or application of taxoxylin 3-O-β-D-glucopyranoside for 4 weeks to animal model NC / Nga mice that developed atopic dermatitis. ) Was measured. It was confirmed that the number of eosinophilic leukocytes decreased drastically after administration, compared to before administration of taxoxyline 3-O-β-D-glucopyranoside (see FIG. 5).
3. 인터루킨(3. Interleukin ( interleukininterleukin )-4, 5, 10, 13의 수준 측정 ) -4, 5, 10, 13 level measurement
아토피성 피부염을 발생시킨 동물모델 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드를 4주 동안 복강내 투여 또는 도포한 후의 마우스로부터 혈액을 채취하여 혈청 및 비장세포(splenocyte)에서의 인터루킨 IL-4, 5, 10 및 13의 수준을 측정하였다. Serum and splenocytes were obtained by collecting blood from mice after four weeks of intraperitoneal administration or application of taxoxylin 3-O-β-D-glucopyranoside to animal model NC / Nga mice that developed atopic dermatitis. Levels of interleukin IL-4, 5, 10, and 13).
탁시폴린 3-O-β-D-글루코피라노사이드를 투여한 그룹에서 IL-4, 5, 및 13의 수준이 음성대조군에 비해 낮게 측정되었다(도 6, 7, 및 9 참조). 그러나, IL-10의 경우 탁시폴린 3-O-β-D-글루코피라노사이드를 투여한 그룹이 음성대조군에 비해 IL-10의 수준이 증가하였다. Levels of IL-4, 5, and 13 were lower in the group administered Taxipoline 3-O-β-D-glucopyranoside compared to the negative control (see Figures 6, 7, and 9). However, in the case of IL-10, the group receiving the Taxipoline 3-O-β-D-glucopyranoside increased the level of IL-10 compared to the negative control group.
IL-4는 활성화된 B 세포 및 T 세포의 증식을 촉진하며 초기(naive) T 세포(CD4+ T 세포)의 Th2 세포로의 분화를 촉진하는 작용을 한다. 아토피성 피부염 환자에서 IL-4 수준은 증가하는데, 본 발명의 활성성분 탁시폴린 3-O-β-D-글루코피라노사이드는 IL-4 수준을 감소시킴으로써 알러지(allergy) 반응을 억제하는 효과를 나타냄을 알 수 있다. IL-4 promotes proliferation of activated B cells and T cells and acts to promote differentiation of naive T cells (CD4 + T cells) into Th2 cells. IL-4 levels are increased in patients with atopic dermatitis. The active ingredient Taxipoline 3-O-β-D-glucopyranoside of the present invention has an effect of suppressing an allergy response by decreasing IL-4 levels. It can be seen that.
IL-5는 B 세포의 성장을 자극하여 면역글로블린의 분비를 촉진하는 작용을 하며, 호산성백혈구(eosinophil)의 활성화에 핵심 매개자로 역할하는 것으로 알려져 있다. 본 발명의 탁시폴린 3-O-β-D-글루코피라노사이드는 IL-5 수준을 감소시킴으로써 아토피성 피부염 환자에서 높게 나타나는 호산성백혈구의 수를 감소시킬 수 있는 효과를 가짐을 확인하였다. IL-5 stimulates the growth of B cells to promote the secretion of immunoglobulins, and is known to play a key role in the activation of eosinophils. Taxifolin 3-O-β-D-glucopyranoside of the present invention was confirmed to have the effect of reducing the number of eosinophilic leukocytes appearing high in atopic dermatitis patients by reducing IL-5 levels.
IL-10은 인간 사이토카인(cytokine) 합성 억제자(human cytokine synthesis inhibitory factor, CSIF)로도 알려진 항-염증성 사이토카인이며, 대식세포(macrophage) 및 T 헬퍼 타입 1(Th 1) 세포에서 만들어지는 IFN-γ, IL-2, IL-3, TNFα 및 GM-CSF와 같은 친-염증 사이토카인의 합성을 억제한다. 본 발명의 탁시폴린 3-O-β-D-글루코피라노사이드는 IL-10 수준을 증가시킴으로써 항 염증 효능을 나타낼 수 있음을 확인하였다. IL-10 is an anti-inflammatory cytokine, also known as the human cytokine synthesis inhibitory factor (CSIF), and is an IFN made from macrophage and T helper type 1 (Th 1) cells. inhibits the synthesis of pro-inflammatory cytokines such as -γ, IL-2, IL-3, TNFα and GM-CSF. It was found that the taxoxylin 3-O-β-D-glucopyranoside of the present invention may exhibit anti-inflammatory efficacy by increasing IL-10 levels.
IL-13은 다양한 세포 타입에서 분비되며 특히 T 헬퍼 타입 2 (Th2) 세포에서 주로 분비되며, 알러지성 염증 질환에서 중요한 매개자로 작용한다. 본 발명의 탁시폴린 3-O-β-D-글루코피라노사이드는 IL-13 수준을 감소시킴으로써 아토피성 피부염과 같은 알러지성 염증 질환의 치료 효능을 나타낼 수 있음을 확인하였다. IL-13 is secreted in various cell types, especially in T helper type 2 (Th2) cells, and acts as an important mediator in allergic inflammatory diseases. It has been found that the taxoxyline 3-O-β-D-glucopyranoside of the present invention may exhibit therapeutic efficacy in allergic inflammatory diseases such as atopic dermatitis by reducing IL-13 levels.
4. 4. RealReal timetime PCRPCR 에 의한 On by MBDMBD -1, 2, 3, -1, 2, 3, COXCOX -2, -2, iNOSiNOS 발현양Expression amount 측정 Measure
아토피성 피부염을 발생시킨 동물모델 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드를 4주 동안 복강내 투여 및 도포한 후의 마우스 피부 세포를 채취하여 MBD-1, 2, 3, COX-2, iNOS 의 발현 수준을 Real time PCR을 이용하여 측정함으로써 이 화합물의 면역반응 조절 효능을 확인하였다. Animal skin model NC / Nga mice that developed atopic dermatitis, mouse skin cells after intraperitoneal administration and application of taxoxylin 3-O-β-D-glucopyranoside for 4 weeks were collected MBD-1, 2, 3, COX-2, iNOS expression level was measured by real time PCR to confirm the immune response control effect of this compound.
MBD (mouse beta-defensin) 표피, 기관지 및 비뇨생식기 조직의 상피세포에서 주로 발현되고 비만세포(mast cell)을 자극하여 히스타민(histamin)과 프로스타글란딘 D2(prostaglandin D2)의 방출을 촉진하며, 상피에서 세균의 번식을 억제하 는 작용을 하는 것으로 알려져 있다. COX (Cyclooxygenase)는 프로스타노이드(prostanoid)라고 불리는 생물학적 매개물질의 형성에 관여하는 효소이다. COX의 발현을 억제하면 염증과 통증으로부터 발생되는 증상을 완화시키는 효과를 얻을 수 있는 것으로 알려져 있다. 또한, iNOS (inducible Nitric Oxide Synthase)는 미생물 침입에 대한 최초의 면역반응에 중요한 역할을 하는 대식세포(macrophage)를 조절하는 NO (nitrix oxide)를 생성하는 효소이다. MBD (mouse beta-defensin) is mainly expressed in epithelial cells of epidermis, bronchial and genitourinary tissues and stimulates mast cells to promote the release of histamine and prostaglandin D2, and bacteria from the epithelium It is known to act to suppress the reproduction of. COX (Cyclooxygenase) is an enzyme involved in the formation of biological mediators called prostanoids. Inhibiting the expression of COX is known to relieve the symptoms resulting from inflammation and pain. Inducible Nitric Oxide Synthase (iNOS) is an enzyme that produces nitric oxide (NO) that regulates macrophage, which plays an important role in the initial immune response to microbial invasion.
실험결과 탁시폴린 3-O-β-D-글루코피라노사이드를 투여한 마우스의 경우 MBD-1, 2, 3의 발현이 증가되었고(도 10, 11, 12 참조), 반면 COX-2 및 iNOS의 발현은 감소하였음(도 13 및 14 참조)을 확인하였다. Experimental results show that MBD-1, 2, 3 expression was increased in mice treated with Taxifolin 3-O-β-D-glucopyranoside (see FIGS. 10, 11, 12), whereas COX-2 and iNOS It was confirmed that the expression of (see Fig. 13 and 14).
5. 5. 웨스턴Weston 블로팅(western blotting)에In blotting 의한 by MBDMBD -1, 2, 3, -1, 2, 3, COXCOX -2, -2, iNOSiNOS 발현양Expression amount 측정 Measure
아토피성 피부염을 발생시킨 동물모델 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드를 4주 동안 복강내 투여 및 도포한 후의 마우스 피부 세포를 채취하여 MBD-1, 2, 3, COX-2, iNOS 의 발현 수준을 웨스턴 블로팅을 이용하여 측정함으로써 이 화합물의 면역반응 조절 효능을 확인하였다. Animal skin model NC / Nga mice that developed atopic dermatitis, mouse skin cells after intraperitoneal administration and application of taxoxylin 3-O-β-D-glucopyranoside for 4 weeks were collected MBD-1, 2, The expression level of 3, COX-2, iNOS was measured by Western blotting to confirm the immune response modulation efficacy of this compound.
Real time PCR에 의한 측정결과와 동일하게, 탁시폴린 3-O-β-D-글루코피라노사이드를 투여한 마우스의 경우 MBD-1, 2, 3의 발현이 증가되었고(도 15, 16, 17 참조),반면 COX-2 및 iNOS의 발현은 감소하였음(도 18 및 19 참조)을 확인하였다. In the same manner as the results of real time PCR, the mice treated with Taxifolin 3-O-β-D-glucopyranoside increased the expression of MBD-1, 2, and 3 (Figs. 15, 16, and 17). Whereas the expression of COX-2 and iNOS was reduced (see FIGS. 18 and 19).
이상의 실험결과에 의해 본 발명 조성물의 유효성분인 탁시폴린 3-O-β-D-글 루코피라노사이드는 MBD-1, 2, 3의 발현을 증가시키고 COX-2 및 iNOS의 발현은 감소시킴으로써 아토피성 피부염의 치료 효능을 가짐을 확인할 수 있었다. According to the above experimental results, the Taxipoline 3-O-β-D-glucopyranoside, which is an active ingredient of the present invention, increased the expression of MBD-1, 2, 3 and decreased the expression of COX-2 and iNOS. It was confirmed that the therapeutic effect of atopic dermatitis.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.
참고문헌references
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도 1a은 진달래뿌리 추출물 및 이 추출물로부터 탁시폴린 3-O-β-D-글루코피라노사이드(Taxifolin 3-O-β-D-Glucopyranoside)를 분리 정제하는 과정을 도시한 도면이다. FIG. 1A is a diagram illustrating a process of separating and purifying Taxifolin 3-O-β-D-Glucopyranoside from Rhododendron root extract and the extract.
도 1b는 탁시폴린 3-O-β-D-글루코피라노사이드의 HPLC (high performance liquid chromatography)의 분석 결과이다. FIG. 1B shows the results of high performance liquid chromatography (HPLC) analysis of taxoxyline 3-O-β-D-glucopyranoside. FIG.
도 2a는 탁시폴린 3-O-β-D-글루코피라노사이드의 LC-MS 스펙트럼이다. FIG. 2A is an LC-MS spectrum of taxoxyline 3-O-β-D-glucopyranoside. FIG.
도 2b는 탁시폴린 3-O-β-D-글루코피라노사이드의 1H-NMR 스펙트럼(300 Mhx, DMSO-d 6)측정 결과이다. Figure 2b is the result of the 1 H-NMR spectrum (300 Mhx, DMSO- d 6 ) of the taxoxylin 3-O-β-D-glucopyranoside.
도 2c는 탁시폴린 3-O-β-D-글루코피라노사이드의 13C-NMR 스펙트럼 (300 Mhx, DMSO-d 6)측정 결과이다.Figure 2c is the result of the 13 C-NMR spectrum (300 Mhx, DMSO- d 6 ) measurement of taxoxylin 3-O-β-D-glucopyranoside.
도 3a는 음성대조군으로서 아토피성 피부염을 유발시킨 NC/Nga 마우스에 PBS를 주사제 형태로 투여한 후에 피부염 치료 효능을 검사한 사진이다. Figure 3a is a negative control group after the administration of PBS in the form of injections to the NC / Nga mice that induced atopic dermatitis, the effect of the treatment of dermatitis.
도 3b는 아토피성 피부염을 유발시킨 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드 0.1%를 주사제 형태로 투여한 후에 피부염 치료 효능을 검사한 사진이다.Figure 3b is a photograph showing the efficacy of dermatitis treatment after administration of 0.1% taxoxylin 3-O-β-D-glucopyranoside in the form of an injection to NC / Nga mice that induced atopic dermatitis.
도 3c는 아토피성 피부염을 유발시킨 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드 1%를 주사제 형태로 투여한 후에 피부염 치료 효능을 검사한 사 진이다. FIG. 3C is a photograph showing the efficacy of dermatitis treatment after administration of 1% of Taxipoline 3-O-β-D-glucopyranoside in the form of an injection to NC / Nga mice causing atopic dermatitis.
도 3d는 양성대조군으로서 아토피성 피부염을 유발시킨 NC/Nga 마우스에 덱사메타손(dexamethasone)를 주사제 형태로 투여한 후에 피부염 치료 효능을 검사한 사진이다. Figure 3d is a photograph showing the efficacy of dermatitis treatment after administration of dexamethasone (dexamethasone) in the form of injection to the NC / Nga mice that induced atopic dermatitis as a positive control group.
도 4a는 음성대조군으로서 아토피성 피부염을 유발시킨 NC/Nga 마우스에 바세린(baseline)를 도포제 형태로 투여한 후에 피부염 치료 효능을 검사한 사진이다.Figure 4a is a negative control group after the administration of petrolatum (baseline) in the form of a coating agent to the NC / Nga mice that induced atopic dermatitis, a photograph showing the efficacy of the dermatitis treatment.
도 4b는 아토피성 피부염을 유발시킨 NC/Nga 마우스에 탁시폴린 3-O-β-D-글루코피라노사이드 1%를 도포제 형태로 투여한 후에 피부염 치료 효능을 검사한 사진이다. Figure 4b is a photograph showing the efficacy of dermatitis treatment after the administration of 1% Taxipoline 3-O-β-D- glucopyranoside in the form of a coating to NC / Nga mice that induced atopic dermatitis.
도 4c는 양성대조군으로서 아토피성 피부염을 유발시킨 NC/Nga 마우스에 프란콜(plancol)을 도포제 형태로 투여한 후에 피부염 치료 효능을 검사한 사진이다. 4C is a photograph showing the efficacy of treating dermatitis after administration of plancol in the form of a coating agent to NC / Nga mice that induced atopic dermatitis as a positive control group.
도 5는 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여하기 전 및 투여한 후의 마우스로부터 혈액을 채취하여 호산성 백혈구(eosinophile)의 수를 측정한 결과를 나타낸다. FIG. 5 shows NC / Nga mice injected with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a positive control material, and Taxipoline 3-O-β-D-glucopyranoside And blood collected from mice before and after administration in the form of a coating agent, respectively, and the number of eosinophilic leukocytes (eosinophile) is measured.
도 6은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여하기 전 및 투여한 후의 마우스로부터 혈액을 채취하여 혈청과 림프구에서 IL-4의 발현 수준을 ELISA로 측정한 결과를 나타낸다. FIG. 6 shows NC / Nga mice injected with PBS and petrolatum (baseline) as negative control material, dexamethasone and plancol as taxo control material, and Taxipoline 3-O-β-D-glucopyranoside And blood were collected from mice before and after administration in the form of a coating agent, respectively, and the results of ILISA expression levels in serum and lymphocytes were measured by ELISA.
도 7은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여하기 전 및 투여한 후의 마우스로부터 혈액을 채취하여 혈청과 림프구에서 IL-5의 발현 수준을 ELISA로 측정한 결과를 나타낸다. FIG. 7 shows NC / Nga mice injected with PBS and petrolatum (baseline) as negative control material, dexamethasone and plancol as taxo control material, and Taxipoline 3-O-β-D-glucopyranoside And blood were collected from mice before and after administration in the form of a coating agent, respectively, and the result of measuring IL-5 expression levels in serum and lymphocytes by ELISA.
도 8은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여하기 전 및 투여한 후의 마우스로부터 혈액을 채취하여 혈청과 림프구에서 IL-10의 발현 수준을 ELISA로 측정한 결과를 나타낸다. FIG. 8 is an injection of PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a negative control material, and Taxipoline 3-O-β-D-glucopyranoside in NC / Nga mice. And blood were collected from mice before and after administration in the form of a coating agent, respectively, and the results of ILISA expression levels in serum and lymphocytes were measured by ELISA.
도 9은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여하기 전 및 투여한 후의 마우스로부터 혈액을 채취하여 혈청과 림프구에서 IL-13의 발현 수준을 ELISA로 측정한 결과를 나타낸다. FIG. 9 shows NC / Nga mice injected with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a positive control material, and Taxipoline 3-O-β-D-glucopyranoside And blood were collected from mice before and after administration in the form of a coating agent, respectively, and the results of ILISA-13 expression levels in serum and lymphocytes were measured by ELISA.
도 10은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부 터 피부를 채취하여 MBD-1의 발현 수준을 Real-time PCR로 측정한 결과를 보여준다.Figure 10 is injected NC / Nga mice with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol, taxoxylin 3-O-β-D-glucopyranoside as a positive control material And the skin from the mouse after each administration in the form of a coating agent shows the result of measuring the expression level of MBD-1 by Real-time PCR.
도 11은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 MBD-2의 발현 수준을 Real-time PCR로 측정한 결과를 보여준다.FIG. 11 is an injection of PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a negative control material, and Taxipoline 3-O-β-D-glucopyranoside in NC / Nga mice. And skin from mice after administration in the form of a coating agent, respectively, and shows the result of measuring the expression level of MBD-2 by real-time PCR.
도 12은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 MBD-3의 발현 수준을 Real-time PCR로 측정한 결과를 보여준다.FIG. 12 shows NC / Nga mice injected with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a positive control material, and Taxipoline 3-O-β-D-glucopyranoside And skin from mice after administration in the form of a coating agent, respectively, and show the results of MBD-3 expression levels measured by real-time PCR.
도 13은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 COX-2의 발현 수준을 Real-time PCR로 측정한 결과를 보여준다.FIG. 13 shows NC / Nga mice injected with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a positive control material, and Taxipoline 3-O-β-D-glucopyranoside And skin from mice after administration in the form of a coating agent, respectively, and shows the results of COX-2 expression levels measured by real-time PCR.
도 14은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부 터 피부를 채취하여 iNOS의 발현 수준을 Real-time PCR로 측정한 결과를 보여준다. FIG. 14 shows injection of PBS and petrolatum (baseline) as negative control material, dexamethasone and plancol, and Taxipolin 3-O-β-D-glucopyranoside as negative control material in NC / Nga mice. And skin from the mouse after administration in the form of a coating agent, respectively, shows the result of measuring the expression level of iNOS by Real-time PCR.
도 15은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 MBD-1의 발현 수준을 웨스턴 블로팅으로 측정한 결과를 보여준다. FIG. 15 shows NC / Nga mice injected with PBS and petrolatum (baseline) as negative control material, dexamethasone and plancol as taxo control material, and Taxipoline 3-O-β-D-glucopyranoside And skin from mice after administration in the form of a coating agent, respectively, and shows the result of measuring the expression level of MBD-1 by western blotting.
도 16은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 MBD-2의 발현 수준을 웨스턴 블로팅으로 측정한 결과를 보여준다.FIG. 16 shows NC / Nga mice injected with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol as a positive control material, and Taxipoline 3-O-β-D-glucopyranoside And skin obtained from the mice after administration in the form of a coating agent, respectively, and the result of measuring the expression level of MBD-2 by Western blotting is shown.
도 17은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 MBD-3의 발현 수준을 웨스턴 블로팅으로 측정한 결과를 보여준다.FIG. 17 shows NC / Nga mice injected with PBS and petrolatum (baseline) as negative control material, dexamethasone and plancol as taxo control material, and Taxipoline 3-O-β-D-glucopyranoside And skin obtained from the mice after administration in the form of a coating agent, respectively, and the result of measuring the expression level of MBD-3 by Western blotting is shown.
도 18은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 COX-2의 발현 수준을 웨스턴 블로팅으로 측정한 결과를 보여준 다.Figure 18 is injected NC / Nga mice with PBS and petrolatum (baseline) as a negative control material, dexamethasone and plancol (taxcolin 3-O-β-D-glucopyranoside as a positive control material) And skin from mice after administration in the form of a coating agent, respectively, and shows the result of measuring the expression level of COX-2 by western blotting.
도 19은 NC/Nga 마우스에 음성대조군 물질로 PBS 및 바세린(baseline), 양성대조군 물질로 덱사메타손(dexamethasone) 및 프란콜(plancol), 탁시폴린 3-O-β-D-글루코피라노사이드를 주사제 및 도포제의 형태로 각각 투여한 후의 마우스로부터 피부를 채취하여 iNOS-1의 발현 수준을 웨스턴 블로팅으로 측정한 결과를 보여준다. FIG. 19 shows NC / Nga mice injected with PBS and petrolatum (baseline) as negative control material, dexamethasone and plancol as taxo control material, and Taxipoline 3-O-β-D-glucopyranoside And skin obtained from the mice after administration in the form of a coating agent, respectively, and the result of measuring the expression level of iNOS-1 by Western blotting is shown.
<110> Chung-ang University Industry Academic Cooperation Foundation <120> Composition for Treating Atopic Dermatitis Comprising Taxifolin 3-O-beta-D-glucopyranoside Isolated from the Extract of the Roots of Rhododendron mucronulatum as an Active Ingredient <160> 12 <170> KopatentIn 1.71 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MbD-1 (sense) <400> 1 acataaagga cgagcgatgg 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MBD-1 (anti-sense) <400> 2 tgcagatggg gtgtcataga 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MBD-2 (sense) <400> 3 gccatgagga ctctctgctc 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MBD-2 (anti-sense) <400> 4 aggggttctt ctctgggaaa 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MBD-3 (sense) <400> 5 tcagattggc agttgtggag 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MBD-3 (anti-sense) <400> 6 gctagggagc acttgtttgc 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for iNOS (sense) <400> 7 ctgatgcctc ttccaggtgt 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for iNOS (anti-sense) <400> 8 gagggagccc tttctgaatc 20 <210> 9 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for COX-2 (sense) <400> 9 ccacccatgg caaattccat ggca 24 <210> 10 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for COX-2 (anti-sense) <400> 10 ggtgctgctt gttaggaggt caagtaaagg gc 32 <210> 11 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for GAPDH <400> 11 ccacccatgg caaattccat ggca 24 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for GAPDH (anti-sense) <400> 12 ccctgttgct gtagccgtat 20 <110> Chung-ang University Industry Academic Cooperation Foundation <120> Composition for Treating Atopic Dermatitis Comprising Taxifolin 3-O-beta-D-glucopyranoside Isolated from the Extract of the Roots of Rhododendron mucronulatum as an Active Ingredient <160> 12 <170> KopatentIn 1.71 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for MbD-1 (sense) <400> 1 acataaagga cgagcgatgg 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for MBD-1 (anti-sense) <400> 2 tgcagatggg gtgtcataga 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for MBD-2 (sense) <400> 3 gccatgagga ctctctgctc 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for MBD-2 (anti-sense) <400> 4 aggggttctt ctctgggaaa 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for MBD-3 (sense) <400> 5 tcagattggc agttgtggag 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for MBD-3 (anti-sense) <400> 6 gctagggagc acttgtttgc 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for iNOS (sense) <400> 7 ctgatgcctc ttccaggtgt 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for iNOS (anti-sense) <400> 8 gagggagccc tttctgaatc 20 <210> 9 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> PCR primer for COX-2 (sense) <400> 9 ccacccatgg caaattccat ggca 24 <210> 10 <211> 32 <212> DNA <213> Artificial Sequence <220> PCR primer for COX-2 (anti-sense) <400> 10 ggtgctgctt gttaggaggt caagtaaagg gc 32 <210> 11 <211> 24 <212> DNA <213> Artificial Sequence <220> PCR primer for GAPDH <400> 11 ccacccatgg caaattccat ggca 24 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> PCR primer for GAPDH (anti-sense) <400> 12 ccctgttgct gtagccgtat 20
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