KR101217181B1 - Composition for preventing, improving or treating atopyic dermatitis comprising tannic acid and quercetin as an active ingredient - Google Patents
Composition for preventing, improving or treating atopyic dermatitis comprising tannic acid and quercetin as an active ingredient Download PDFInfo
- Publication number
- KR101217181B1 KR101217181B1 KR1020090117766A KR20090117766A KR101217181B1 KR 101217181 B1 KR101217181 B1 KR 101217181B1 KR 1020090117766 A KR1020090117766 A KR 1020090117766A KR 20090117766 A KR20090117766 A KR 20090117766A KR 101217181 B1 KR101217181 B1 KR 101217181B1
- Authority
- KR
- South Korea
- Prior art keywords
- quercetin
- atopic dermatitis
- tannic acid
- composition
- present
- Prior art date
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- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 title claims abstract description 118
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Abstract
본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물, 식품 조성물 또는 화장료 조성물에 관한 것으로, 보다 상세하게는 20:1 내지 1:1의 중량비로 혼합된 탄닌산과 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물, 식품 조성물 또는 화장료 조성물에 관한 것이다. 본 발명의 조성물은 아토피성 피부염의 병변을 개선시키며, 혈관신생을 억제하여 아토피 피부염의 진행을 막아 아토피 피부염 예방 또는 치료에 효과적이다.The present invention relates to a pharmaceutical composition, a food composition or a cosmetic composition for preventing or treating atopic dermatitis containing tannic acid and quercetin as an active ingredient, and more specifically, tannin acid mixed with a weight ratio of 20: 1 to 1: 1. A pharmaceutical composition, food composition, or cosmetic composition for preventing or treating atopic dermatitis containing quercetin as an active ingredient. The composition of the present invention improves the lesions of atopic dermatitis, inhibits angiogenesis and prevents the progression of atopic dermatitis, and is effective in preventing or treating atopic dermatitis.
아토피, 피부염, 탄닌산, 퀘르세틴 Atopic dermatitis, tannic acid, quercetin
Description
본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물, 식품 조성물 또는 화장료 조성물에 관한 것으로, 보다 상세하게는 20:1 내지 1:1의 중량비로 혼합된 탄닌산과 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물, 식품 조성물 또는 화장료 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition, a food composition or a cosmetic composition for preventing or treating atopic dermatitis containing tannic acid and quercetin as an active ingredient, and more specifically, tannin acid mixed with a weight ratio of 20: 1 to 1: 1. A pharmaceutical composition, food composition, or cosmetic composition for preventing or treating atopic dermatitis containing quercetin as an active ingredient.
아토피성 피부염은 만성 염증성 피부질환이다. 이는 대기오염, 진드기, 정신적 스트레스 등과 같은 여러 가지 유전적 환경적 요인(Mutou et al., (2007) Photodermatol Photoimmunol Photomed 23:135-144.)을 내재한 복합적인 피부의 이상증이다.Atopic dermatitis is a chronic inflammatory skin disease. This is a complex skin abnormality incorporating several genetic and environmental factors (Mutou et al. , (2007) Photodermatol Photoimmunol Photomed 23: 135-144 .) Such as air pollution, ticks, and mental stress.
아토피 피부염은 심한 가려움을 동반한 홍반성 구진과 인설로 시작하여 심해지면 수포 및 장액성 삼출액과 가피를 보이는 급성 증상으로 진행한다. 가장 특징 적인 증상인 소양증은 그 정도가 매우 심해서 피가 날 정도로 긁게 되며, 가려움-긁기-가려움의 악순환으로 계속 악화되며, 더 지속되면 피부가 두꺼워지고 주름이 뚜렷해지는 태선화 현상이 나타난다. 대부분의 임상 양상은 긁거나 문지른 결과에 의해 발생하며, 밤에는 소양증이 더욱 심해져 수면장애를 일으킨다. Atopic dermatitis starts with erythematous papules and epiglottis with severe itching and progresses to acute symptoms with blistering and serous effusion and scarring. The most characteristic symptom is pruritus, which is so severe that it bleeds to bleeding, and it continues to worsen with a vicious cycle of itching-scratching-itching. Most clinical manifestations are caused by scratching or rubbing, and at night, pruritus becomes more severe and causes sleep disturbances.
근래에 전세계적으로 아토피 피부염의 발생 빈도가 증가하는 양상을 보이고 있는데 이는 대기오염, 주거 환경의 변화로 항원에 대한 노출 증가, 모유 수유의 감소, 소아기 감염 질환의 감소 등을 그 원인으로 추정하고 있다. 1995년 대한 소아과 알레르기 및 호흡기학회에서 시행한 전국적 역학 조사에 의하면 초등학생의 경우 12 내지 24%, 중학생의 경우 6 내지 8%에서 아토피 피부염으로 진단받은 적이 있으며, 2000년도에는 초등학생의 24.9%, 중학생의 12.8%가 아토피 피부염을 진단받은 것을 비롯하여 성인 아토피 피부염도 국내에서 그 빈도가 점증하고 있다.In recent years, the incidence of atopic dermatitis has been increasing worldwide, which may be attributed to air pollution, changes in residential environment, increased exposure to antigens, reduced breastfeeding, and reduced childhood disease. . According to a national epidemiological study conducted by the Korean Academy of Pediatric Allergy and Respiratory Diseases in 1995, 12 to 24% of elementary school students and 6 to 8% of middle school students were diagnosed with atopic dermatitis.In 2000, 24.9% of elementary school students and In addition to 12.8% diagnosed atopic dermatitis, adult atopic dermatitis is also increasing in Korea.
비록 아토피 피부염의 병리학적 기작이 명확하게 밝혀지지는 않았지만 아토피 피부염은 심한 가려움, IgE 상승 및 Th2 극성 증가 등의 특징을 보인다고 기록되어 있다(De Benedetto et al., (2009) J Invest Dermatol 129:14-30; Esparza-Gordillo et al., (2009) Nat Genet 41:596-601.). 아토피 피부염은 또한 혈관신생을 유도하는 염증적 변화 및 상피 이형성증으로 특징지워 진다(Groneberg et al., (2005) Allergy 60:90-97). 혈관신생형성은 또한 아토피 피부염에서 표피층에 가까이 존재하는 메스트 세포에 의해 자극되며 이는 염증세포를 아토피 피부염 부위의 표피층으로 이동시켜 만성 염증을 지속하도록 한다(Groneberg et al., (2005) Allergy 60:90-97). 따라서 이러한 혈관신생은 아토피 피부염의 진행에 있어서 중추적 요인으로 여겨진다.Although the pathological mechanism of atopic dermatitis has not been clearly identified, it has been reported that atopic dermatitis is characterized by severe itching, elevated IgE and increased Th2 polarity (De Benedetto et al. , (2009) J Invest Dermatol 129: 14 -30; Esparza-Gordillo et al. , (2009) Nat Genet 41: 596-601.). Atopic dermatitis is also characterized by inflammatory changes and epithelial dysplasia leading to angiogenesis (Groneberg et al. , (2005) Allergy 60: 90-97). Angiogenesis is also stimulated by mast cells that are close to the epidermal layer in atopic dermatitis, which causes inflammatory cells to migrate to the epidermal layer of the atopic dermatitis site to sustain chronic inflammation (Groneberg et al. , (2005) Allergy 60: 90-97). Therefore, such angiogenesis is considered to be a central factor in the progression of atopic dermatitis.
아토피 피부염은 Th2 극성 이상증으로 특징지워 지는데, 이는 아토피 피부염 환자가 IL-4와 IL-13과 같은 Th2 관련 사이토카인을 과발현함으로써 입증되었다(Howell, (2007) Curr Opin Allergy Clin Immunol 7:413-417; Ong et al., (2002) N Engl J Med 347:1151-1160). 흉선 및 활성 조절된 케모카인 (TARC/CCL17)은 CCR4를 통하여 Th2 세포와 조절 T 세포를 공격한다(Pokharel et al., 2008). TARC는 CC 또는 베타 케모카인 패밀리의 일종이다. 이는 전구 단백질로서 94개의 아미노산으로 되어있으며 전사후 프로세싱으로 성숙 단백질이 되면 71 개의 아미노산으로 구성된다(Imai et al., (1996) J Biol Chem 271:21514-21521). 성숙 TARC 단백질은 글리코실화되지 않고, 약 8.0 kDa의 중량을 가진다(Lieberam and Forster, (1999) Eur J Immunol 29:2684-2694). 일반적으로 흉선에서 발현되고 keratinocytes, monocytes, CD4+ T cells, 및 fibroblasts의 활성에 의해 생산된다(Campbell et al., (1999) Nature 400:776-780; Imai et al., (1999) Int Immunol 11:81-88; Sallusto et al., (1999) Eur J Immunol 29:1617-1625; Sekiya et al., (2000) J Immunol 165:2205-2213). 실제로, 이들의 생산은 아토피 피부염에 연관되어 있고, TARC의 상승은 아토피 피부염의 중증도와 상관성이 있다(Kakinuma et al., (2001) J Allergy Clin Immunol 107:535-541). 따라서 TARC는 아토피 피부염 관련 염증 반응의 중요한 매개체로 여겨진다.Atopic dermatitis is characterized by Th2 polarity dysfunction, which has been demonstrated by patients with atopic dermatitis overexpressing Th2-related cytokines such as IL-4 and IL-13 (Howell, (2007) Curr Opin Allergy Clin Immunol 7: 413-417 Ong et al. , (2002) N Engl J Med 347: 1151-1160). Thymus and activity modulated chemokines (TARC / CCL17) attack Th2 and regulatory T cells via CCR4 (Pokharel et al. , 2008). TARC is a type of CC or beta chemokine family. It is a precursor protein of 94 amino acids and 71 amino acids when it is mature protein by post-transcriptional processing (Imai et al. , (1996) J Biol Chem 271: 21514-21521). The mature TARC protein is not glycosylated and has a weight of about 8.0 kDa (Lieberam and Forster, (1999) Eur J Immunol 29: 2684-2694). Usually expressed in the thymus and produced by the activity of keratinocytes, monocytes, CD4 + T cells, and fibroblasts (Campbell et al. , (1999) Nature 400: 776-780; Imai et al. , (1999) Int Immunol 11: 81-88; Sallusto et al. , (1999) Eur J Immunol 29: 1617-1625; Sekiya et al. , (2000) J Immunol 165: 2205-2213). Indeed, their production is associated with atopic dermatitis, and elevated TARC correlates with the severity of atopic dermatitis (Kakinuma et al. , (2001) J Allergy Clin Immunol 107: 535-541). TARC is thus considered an important mediator of inflammatory responses associated with atopic dermatitis.
탄닌산(TA)은 자연적으로 발생하는 식물 폴리페놀으로 황백 또는 엷은 갈색 의 무정형의 분말, 광택이 있는 비늘모양 또는 해면상 물질로 냄새가 없거나 약간 특이한 냄새를 가지며 떫은맛이 있다. 탄닌산은 여러 암에서 항암작용은 물론 항산화제 및 항염증작용을 가진다(Bradford, (1976) Anal Biochem 72:248-254; Brouet and Ohshima, (1995) Biochem Biophys Res Commun 206:533-540; Chiesi and Schwaller, (1995) Biochem Pharmacol 49:495-501; Hortelano et al., (1992) J Biol Chem 267:24937-24940).Tannic acid (TA) is a naturally occurring plant polyphenol that is a yellowish white or pale brown amorphous powder, glossy scaly or spongy substance with a odorless or slightly peculiar odor and astringent taste. Tannic acid has antioxidant and anti-inflammatory as well as anticancer activity in several cancers (Bradford, (1976) Anal Biochem 72: 248-254; Brouet and Ohshima, (1995) Biochem Biophys Res Commun 206: 533-540; Chiesi and Schwaller, (1995) Biochem Pharmacol 49: 495-501; Hortelano et al. , (1992) J Biol Chem 267: 24937-24940).
퀘르세틴은 자연에서 가장 일반적인 플라보노이드이며, 대개 루티노스(quercetin-3-rutinoside)나 포도당(isoquercetrin)과 같은 당에 결합되어 있다(Anderson and Coyle, (1994) Trends Pharmacol Sci 15:324-332; Faccioli et al., (1996) Mediators Inflamm 5:24-31; Wills-Karp, (1999) Annu Rev Immunol 17:255-281). 이는 항-고혈압 및 항-발암효과(Formica and Regelson, (1995) Food Chem Toxicol 33:1061-1080; Murota and Terao, (2003) Arch Biochem Biophys 417:12-17; Nakayama, (1994) Cancer Res 54:1991s-1993s)를 포함하여 항산화 특성을 가진다(Kandaswami and Middleton, (1994) Adv Exp Med Biol 366:351-376; Robak and Gryglewski, (1988) Biochem Pharmacol 37:837-841). 또한, 퀘르세틴은 정상 말초혈액 단핵구 세포에 있어서 Th2-유도성-IL4발현을 저하시키며, 복합적인 염증 관련 이상증인 천식의 동물모델에 있어서 항-염증 치료효과를 가진다(Dorsch et al., (1992) Int Arch Allergy Immunol 97:1-7; Rogerio et al., (2007) Inflamm Res 56:402-408).Quercetin is the most common flavonoid in nature and is usually bound to sugars, such as quercetin-3-rutinoside or glucose (Anderson and Coyle, (1994) Trends Pharmacol Sci 15: 324-332; Faccioli et. al. , (1996) Mediators Inflamm 5: 24-31; Wills-Karp, (1999) Annu Rev Immunol 17: 255-281). It has anti-hypertensive and anti-carcinogenic effects (Formica and Regelson, (1995) Food Chem Toxicol 33: 1061-1080; Murota and Terao, (2003) Arch Biochem Biophys 417: 12-17; Nakayama, (1994) Cancer Res 54 (1991s-1993s), and antioxidant properties (Kandaswami and Middleton, (1994) Adv Exp Med Biol 366: 351-376; Robak and Gryglewski, (1988) Biochem Pharmacol 37: 837-841). In addition, quercetin lowers Th2-induced-IL4 expression in normal peripheral blood monocytes and has anti-inflammatory effects in an animal model of asthma, a complex inflammation-related disorder (Dorsch et al. , (1992)). Int Arch Allergy Immunol 97: 1-7; Rogerio et al. , (2007) Inflamm Res 56: 402-408.
그러나 현재까지 아토피 피부 병변에 있어서 탄닌산 및 퀘르세틴의 효과는 잘 알려져 있지 않다. However, the effects of tannic acid and quercetin on atopic dermatological lesions to date are not well known.
현재까지 알려진 아토피 피부염의 병인, 기전, 증상 등을 감안하여 다양한 아토피 피부염에 대한 치료제가 개발되고 있으며, 그 결과 천연 또는 합성의 면역억제제, 항히스타민제제, 스테로이드 제제 등 다수가 개발되어 있다. 예를 들면, 면역 억제제로는 싸이클로스포린(Cyclosporine) A, FK506(타크로리무스, Tacrolimus; Wasik et al, (1990) Immunopharmacology 20:57-61)과 SDZ ASM981(피메크로리무스, Pimecrolimus; Grassberger et al, (1999) Br. J. Dermatology 141:264-273)이 각광받고 있다. 반면 기존의 아토피 피부염에 대한 치료제로 사용되는 스테로이드제제와 항히스타민제 등은 증상을 일시적으로 완화해주는 효과는 있으나 외용 또는 경구용 스테로이드 호르몬제의 장기 사용 환자들에 있어서 피부가 엷어지는 현상 및 골다공증의 유발, 어린이의 경우 성장 저해 등 그에 따른 국소 및 전신 부작용으로 인하여 임상적으로 문제가 된다. 따라서 아토피를 치료에 뛰어난 효과를 가지면서도, 부작용은 적은 새로운 기작의 아토피 치료제의 개발이 요구되고 있다.In consideration of the etiology, mechanisms, and symptoms of atopic dermatitis known to date, various therapeutic agents for atopic dermatitis have been developed, and as a result, a large number of natural or synthetic immunosuppressants, antihistamines, and steroid agents have been developed. For example, immunosuppressants include Cyclosporine A, FK506 (Tacrolimus; Tacrolimus; Wasik et al , (1990) Immunopharmacology 20: 57-61) and SDZ ASM981 (Pimecrolimus; Pimecrolimus; Grassberger et al , ( 1999) Br. J. Dermatology 141: 264-273). On the other hand, steroids and antihistamines, which are used as treatments for atopic dermatitis, have the effect of temporarily relieving the symptoms, but skin thinning and osteoporosis in patients with long-term use of external or oral steroid hormones. In children, it is clinically problematic due to local and systemic side effects such as growth inhibition. Therefore, there is a need for the development of a new atopic therapeutic agent having a superior effect on the treatment of atopy, but less side effects.
이에 본 발명자들은 새로운 아토피 피부염 치료제에 관하여 연구하던 중 탄닌산과 퀘르세틴을 동시에 도포하는 경우 아토피 피부염 치료효과가 우수한 것을 발견하여 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by discovering an excellent atopic dermatitis treatment effect when tannin acid and quercetin are simultaneously applied while studying a new atopic dermatitis treatment agent.
따라서 본 발명의 목적은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating atopic dermatitis, which contains tannic acid and quercetin as active ingredients.
또한 본 발명의 다른 목적은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving atopic dermatitis, containing tannic acid and quercetin as active ingredients.
또한 본 발명의 다른 목적은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 개선용 화장료 조성물을 제공하는 것이다.Another object of the present invention to provide a cosmetic composition for preventing or improving atopic dermatitis, containing tannic acid and quercetin as an active ingredient.
상기와 같은 목적을 달성하기 위하여, 본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating atopic dermatitis containing tannic acid and quercetin as an active ingredient.
본 발명의 다른 목적을 달성하기 위하여, 본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 개선용 식품 조성물을 제공한다.In order to achieve another object of the present invention, the present invention provides a food composition for preventing or improving atopic dermatitis containing tannic acid and quercetin as an active ingredient.
본 발명의 다른 목적을 달성하기 위하여, 본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 개선용 화장료 조성물을 제공한다.In order to achieve another object of the present invention, the present invention provides a cosmetic composition for preventing or improving atopic dermatitis, containing tannic acid and quercetin as an active ingredient.
이하 본 발명의 내용을 보다 상세히 설명하기로 한다.Hereinafter, the present invention will be described in more detail.
본 발명의 탄닌산은 오배자 또는 Quercus infectoria Olivier의 어리고 작은 가지와 Quercus L.(Fam. Fagaceae)의 유사 종; Tara(Caesalpinia spinosa)의 꼬투리(콩, 평지등의); 여러 옻나무 종(Rhus semialata, R. coriaria, R. galabra, and R. typhia을 포함)의 오배자의 생성물을 용매 추출하여 얻는다. 탄닌산은 물, 아세톤과 알코올에 매우 잘 녹으며 순수한 알코올에는 미량 용해된다. 클로로포름, 에테르, 용매헥산에는 부분적으로 불용이다. 탄닌산은 청징제, 방향제, 향미증진제, 향미보조제, pH조절제, boiler water additive 등에 사용된다. (미국 FCC 규격기준).Tannic acid of the present invention may be selected from the group consisting of the young and small twigs of the genus Magnus or Quercus infectoria Olivier and similar species of Quercus L. (Fam. Fagaceae); Pods of Tara (Caesalpinia spinosa) (beans, rape, etc.); Obtained by solvent extraction of the gall bladder from several Sumac species (including Rhus semialata, R. coriaria, R. galabra, and R. typhia). Tannic acid is very soluble in water, acetone and alcohol, and is very soluble in pure alcohol. Partially insoluble in chloroform, ether and solvent hexane. Tannic acid is used in clarifiers, fragrances, flavor enhancers, flavor aids, pH adjusters, and boiler water additives. (US FCC standard).
퀘르세틴(Quercetin)은 후라보노이드계 일종으로, 일반적으로 퀘르세틴의 배당체 형태로 야채와 과실에 널리 분포해있다. Quercetin is a family of flavonoids, usually a glycoside of quercetin, widely distributed in vegetables and fruits.
본 발명의 탄닌산과 퀘르세틴은 식물에서 추출할 수 있으며 또는 정제된 것 을 구입하여 사용할 수 있다. Tannic acid and quercetin of the present invention can be extracted from plants or can be purchased and used purified.
본 발명의 탄닌산 및 퀘르세틴 혼합 조성물은 혈관내피 세포 성장 인자(VEGF) 발현을 억제하는 활성이 우수하다. VEGF는 내피세포에 특이적인 유사분열촉진제로서 신생혈관형성에 주역할을 하는 물질이다.Tannin acid and quercetin mixed composition of the present invention is excellent in inhibiting vascular endothelial cell growth factor (VEGF) expression. VEGF is a mitotic promoter specific for endothelial cells and plays a role in angiogenesis.
본 발명의 일실시예에서는 인간 케라티노사이트 세포주에 TNF-α를 처리하여 VEGF의 발현을 증가시킨 후 본 발명의 탄닌산 및 퀘르세틴 혼합조성물을 투여하여 그 발현 변화를 측정하였다. 그 결과 탄닌산과 퀘르세틴을 각각 투여한 경우보다 이를 혼합하여 동시에 투여하는 경우 VEGF 발현을 억제하는 효과가 매우 우수한 것을 확인하였다(실시예 1 참조).In one embodiment of the present invention treated with TNF-α to the human keratinocyte cell line to increase the expression of VEGF and then administered the tannin acid and quercetin mixed composition of the present invention to measure the expression change. As a result, it was confirmed that the effect of inhibiting the expression of VEGF is very excellent when mixed and administered at the same time than when administered tannin acid and quercetin (see Example 1).
본 발명의 탄닌산 및 퀘르세틴 혼합 조성물은 또한 TSLP 및 TARC 발현을 억제하는 활성이 우수하다.The tannic acid and quercetin mixed compositions of the present invention are also excellent in inhibiting TSLP and TARC expression.
흉선간질성림프구신생인자(TSLP, thymic stromal lymphopoietin)는 Th2 사이토카인을 유도하며, 알레르기 반응, IgE 생산 및 eosinophia에 관련이 있다.Thymic stromal lymphopoietin (TSLP) induces Th2 cytokines and is involved in allergic reactions, IgE production and eosinophia.
TARC(Thymus and activation regulated chemokine)는 아토피 피부염성 피부병변에서 과잉생산 되는 것으로 알려진 사이토카인이며 대표적인 Th2 케모카인이다.Thymus and activation regulated chemokine (TARC) is a cytokine known to be overproduced in atopic dermatitis and is a representative Th2 chemokine.
본 발명의 일실시예에서는 아토피 피부염의 주요 기작인 Th2 극성 이상증의 원인인 TSLP와 TARC의 발현을 본 발명의 탄닌산 및 퀘르세틴의 혼합조성물이 조절 하는지 여부를 관찰하였다.In one embodiment of the present invention it was observed whether the mixed composition of the tannin acid and quercetin of the present invention regulates the expression of TSLP and TARC, which is the cause of Th2 polarity disorder, which is the main mechanism of atopic dermatitis.
인간 케라티노사이트 세포주의 TSLP와 TARC의 발현을 증가시킨 후 본 발명의 조성물을 처리한 결과 본 발명의 탄닌산 및 퀘르세틴 혼합 조성물은 효과적으로 TSLP와 TARC의 발현을 억제하는 것을 확인하였다(실시예 2 참조). After increasing the expression of TSLP and TARC in the human keratinocyte cell line, the tannin acid and quercetin mixed composition of the present invention was found to effectively inhibit the expression of TSLP and TARC (see Example 2). .
이와 같이 본 발명의 탄닌산 및 퀘르세틴의 혼합 조성물은 아토피성 피부염 치료 효과가 우수함을 특징으로 한다.As described above, the mixed composition of tannic acid and quercetin of the present invention is characterized by excellent atopic dermatitis therapeutic effect.
본 발명의 조성물의 아토피성 피부염 치료 효과는 동물 실험을 통하여서도 입증 되었다. 본 발명의 일실시예에서는 Nc/Nga 생쥐에 집먼지 진드기 알러지원을 이용하여 아토피 피부염을 유발하고 본 발명의 조성물을 도포하여 그 치료 효과를 관찰하였다.The therapeutic effect of atopic dermatitis of the compositions of the present invention has also been demonstrated through animal experiments. In one embodiment of the present invention, atopic dermatitis was induced using house dust mite allergen to Nc / Nga mice, and the composition of the present invention was applied to observe the therapeutic effect.
실험대상 생쥐의 피부를 외관 관찰한 결과 본 발명의 조성물을 도포한 생쥐는 대조군에 비하여 아토피 피부염 병변이 확실히 호전된 것을 확인하였으며, 그 병변 피부조직을 채취하여 현미경 관찰을 한 결과에서도 침습, 부풀어오름, 홍반, 부종 및 미란이 억제 되며 표피 상층부의 염증이 감소되는 것을 확인하여 피부 변경 개선효과가 탁월한 것을 확인하였다(실시예 3-1 참조).As a result of observing the skin of the test subjects, the mice coated with the composition of the present invention confirmed that the atopic dermatitis lesion was definitely improved compared to the control group, and the invasive and swelling resulted from the microscopic observation of the lesion skin tissue. , Erythema, edema and erosion is suppressed and the inflammation of the upper epidermal layer is reduced to confirm that the skin change improvement effect is excellent (see Example 3-1).
또한 혈관신생과 연관된 CD31의 발현을 면역조직학적 분석을 통하여 측정한 결과 본 발명의 조성물을 투여한 군의 경우 CD31의 발현이 억제되는 것을 확인하여 본 발명의 조성물은 혈관 신생 억제 효과가 뛰어난 것을 확인하였다(실시예 3-2 참 조).In addition, as a result of measuring the expression of CD31 associated with angiogenesis through immunohistochemical analysis, it was confirmed that the expression of CD31 was suppressed in the group administered with the composition of the present invention. (See Example 3-2).
본 발명의 조성물에 함유되는 탄닌산과 퀘르세틴의 비율은 아토피성 피부염 예방 또는 치료 효과를 보이는 한 특별히 제한되지 아니하나 바람직하게는 탄닌산과 퀘르세틴의 중량비율이 20:1 내지 1:1로 함유되며 더욱 바람직하게는 10:1 내지 5:1로 함유될 수 있으며 가장 바람직하게는 10:1로 함유될 수 있다.The ratio of tannic acid and quercetin contained in the composition of the present invention is not particularly limited as long as it shows the effect of preventing or treating atopic dermatitis. Preferably, the weight ratio of tannic acid and quercetin is contained in a ratio of 20: 1 to 1: 1, more preferably. Preferably from 10: 1 to 5: 1 and most preferably from 10: 1.
따라서 본 발명에서는 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물을 제공한다.Therefore, the present invention provides a pharmaceutical composition for preventing or treating atopic dermatitis, containing tannic acid and quercetin as active ingredients.
상기 약학적 조성물의 경우에는 본 발명의 탄닌산 또는 퀘르세틴, 또는 그들의 약학적으로 허용 가능한 염을 단독으로 포함하거나 또는 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. The pharmaceutical composition may include tannic acid or quercetin of the present invention, or a pharmaceutically acceptable salt thereof, or may further include one or more pharmaceutically acceptable carriers, excipients or diluents.
상기에서 "약학적으로 허용되는 염" 이란 의학적 판단의 범위 내에서 과다한 독성, 자극, 알레르기 반응 등의 유발 없이 사람 및 하등 동물의 조직과 접촉하여 사용하기에 적합한 염을 의미한다. 상기 약학적으로 허용되는 염의 종류는 당 분야에 잘 알려져 있다. 예를 들면 문헌에 약학적으로 허용되는 염에 대해 상세히 기술되어 있다(S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66:1). As used herein, “pharmaceutically acceptable salts” means salts suitable for use in contact with tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc. within the scope of medical judgment. Kinds of such pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail in the literature (SM Berge et al., J. Pharmaceutical Sciences , 1977, 66: 1).
상기 약학적 조성물을 포유동물에 투여하는 방법으로는 특별히 한정되지 않으며 예를 들면, 경구 또는 비경구적으로 투여할 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나, 피하 내, 정맥 내, 근육 내 또는 복강 내 투여할 수 있다. 바람직하게는 본 발명의 약학적 조성물은 경구 투여될 수 있다.The method of administering the pharmaceutical composition to a mammal is not particularly limited and may be administered orally or parenterally, for example. Parenteral administration methods include, but are not limited to, subcutaneous, intravenous, intramuscular or intraperitoneal administration. Preferably the pharmaceutical composition of the present invention may be administered orally.
상기 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다. The pharmaceutical composition may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.
경구 투여용 제제의 경우에 본 발명의 조성물은 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 슬러리제, 현탁액 등으로 당업계에 공지된 방법을 이용하여 제형화될 수 있다. 예를 들어, 경구용 제제는 활성 성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. 적합한 부형제의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다. 나아가, 상기 약학 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In the case of a preparation for oral administration, the composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a liquid, a gel, a syrup, a slurry, . For example, oral formulations can obtain tablets or dragees by combining the active ingredients with solid excipients and then grinding them, adding suitable auxiliaries and processing them into granule mixtures. Examples of suitable excipients include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, including starch, corn starch, wheat starch, rice starch and potato starch, etc. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
비경구 투여용 제제의 경우에는 주사제, 크림제, 로션제, 외용 연고제, 오일제, 보습제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다.Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.
본 발명의 약학적 조성물의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 본 발명의 약학적 조성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있다. 바람직하게 본 발명의 조성물의 바람직한 전체 용량은 1일당 환자 체중 1㎏ 당 0.01㎍ 내지 500mg, 가장 바람직하게는 0.1㎍ 내지 100mg일 수 있다. 그러나 상기 조성물의 용량은 약학적 조성물의 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율 등 다양한 요인들을 고려하여 환자에 가한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당 분야의 통상적인 지식을 가진 자라면 상기 조성물을 아토피성 피부염의 예방 또는 치료제로서의 특정한 용도에 따른 적절한 유효 투여량을 결정할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다.The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol which is administered in multiple doses for a long time. . In the pharmaceutical composition of the present invention, the content of the active ingredient may be varied depending on the degree of the disease. Preferably the preferred total dose of the composition of the present invention may be 0.01 μg to 500 mg, most preferably 0.1 μg to 100 mg per kg of patient body weight per day. However, the dose of the composition is determined in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate as well as the route and frequency of treatment of the pharmaceutical composition is determined In view of this, one of ordinary skill in the art will be able to determine the appropriate effective dosage for the particular use of the composition as a prophylactic or therapeutic agent for atopic dermatitis. The pharmaceutical composition according to the present invention is not particularly limited to the formulation, administration route and administration method as long as the effect of the present invention is exhibited.
또한 본 발명의 조성물은 식품 조성물의 형태로 제공될 수 있다.The composition of the present invention may also be provided in the form of a food composition.
본 발명의 식품 조성물은 아토피 피부염성 피부변병을 개선하는 효과가 있다.The food composition of the present invention has the effect of improving atopic dermatitis skin lesions.
본 발명의 식품 조성물은 기능성 식품(functional food), 영양 보조 제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형의 식품 조성물은 당 업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다.The food composition of the present invention includes all forms such as functional foods, nutritional supplements, health foods and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
예를 들면, 건강식품으로는 본 발명의 조성물을 차, 주스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. For example, as a health food, the composition of the present invention may be prepared in the form of tea, juice and drink for drinking, or may be ingested by granulation, encapsulation and powdering.
또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마아말레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지콘비이프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치이즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 조성물을 첨가하여 제조할 수 있다.In addition, functional foods include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruit, canned foods, jams, marmalade, etc.), fish, meat and processed foods (e.g. ham, sausage cornebipe) Breads and noodles (e.g. udon, soba noodles, ramen, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, syrups, dairy products (e.g. butter, cheese), edible vegetable oils, margarine, vegetable protein , Retort foods, frozen foods, various seasonings (e.g., miso, soy sauce, sauce, etc.) may be added to the composition of the present invention.
본 발명의 식품 조성물 중 본 발명의 탄닌산 및 퀘르세틴 혼합 조성물의 바람직한 함유량으로는 이에 한정되지 않지만 바람직하게는 최종적으로 제조된 식품 중 0.01 내지 50 중량%이다.The preferred content of the tannic acid and quercetin mixed composition of the present invention in the food composition of the present invention is not limited thereto, but is preferably 0.01 to 50% by weight in the finally prepared food.
또한, 본 발명의 조성물을 식품 첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.In addition, in order to use the composition of the present invention in the form of a food additive, it can be prepared in powder or concentrate form.
또한 본 발명의 조성물은 화장료 조성물의 형태로 제공될 수 있다.In addition, the composition of the present invention may be provided in the form of a cosmetic composition.
상기 본 발명의 화장료 조성물은 탄닌산 및 퀘르세틴을 유효성분으로 함유하며 피부학적으로 허용 가능한 부형제와 함께 기초 화장품 조성물(화장수, 크림, 에센스, 클렌징 폼 및 클렌징 워터와 같은 세안제, 팩, 보디오일), 색조 화장품 조성물(화운데이션, 립스틱, 마스카라, 메이크업 베이스), 두발 제품 조성물(샴푸, 린스, 헤어컨디셔너, 헤어젤) 및 비누 등의 형태로 제조될 수 있다.The cosmetic composition of the present invention contains tannic acid and quercetin as an active ingredient, and together with a dermatologically acceptable excipient, a basic cosmetic composition (washing agent such as cosmetic water, cream, essence, cleansing foam and cleansing water, pack, body oil), color tone Cosmetic compositions (foundation, lipstick, mascara, makeup base), hair product compositions (shampoos, rinses, hair conditioners, hair gels), soaps and the like.
상기 부형제로는 이에 한정되지는 않으나 예를 들어, 피부연화제, 피부 침투 증강제, 착색제, 방향제, 유화제, 농화제 및 용매를 포함할 수 있다. 또한, 향료, 색소, 살균제, 산화방지제, 방부제 및 보습제 등을 추가로 포함할 수 있으며, 물성개선을 목적으로 점증제, 무기염류, 합성 고분자 물질 등을 포함할 수 있다. 예를 들면, 본 발명의 화장료 조성물로 세안제 및 비누를 제조하는 경우에는 통상의 세안제 및 비누 베이스에 탄닌산 및 퀘르세틴을 첨가하여 용이하게 제조할 수 있다. 크림을 제조하는 경우에는 일반적인 수중유적형(O/W)의 크림베이스에 탄닌산 및 퀘르세틴을 첨가하여 제조할 수 있다. 여기에 향료, 킬레이트제, 색소, 산화방지제, 방부제 등과 물성개선을 목적으로 한 단백질, 미네랄, 비타민 등 합성 또는 천연소재를 추가로 첨가할 수 있다.Such excipients include, but are not limited to, emollients, skin penetration enhancers, colorants, perfumes, emulsifiers, thickeners and solvents. In addition, fragrances, pigments, fungicides, antioxidants, preservatives and moisturizing agents may be further included, and may include thickeners, inorganic salts, synthetic polymer materials and the like for the purpose of improving the properties. For example, when the face wash and the soap are manufactured with the cosmetic composition of the present invention, tannin acid and quercetin can be easily prepared by adding the face wash and the soap base. In the case of making the cream, it can be prepared by adding tannic acid and quercetin to the cream base of the general oil-in-water type (O / W). To this, synthetic or natural materials, such as proteins, minerals, vitamins, etc., for the purpose of improving physical properties, such as flavors, chelating agents, pigments, antioxidants, and preservatives, may be added.
본 발명의 화장료 조성물에 함유되는 탄닌산 및 퀘르세틴의 혼합 조성물의 함량은 이에 한정되지 않지만 전체 조성물 총중량에 대하여 0.001 내지 10 중량%인 것이 바람직하고, 0.01 내지 5 중량%인 것이 더욱 바람직하다. 상기 함량이 0.001중량% 미만에서는 목적하는 효과를 기대할 수 없고, 10중량% 초과에서는 안전성 또는 제형상의 제조에 어려움이 있을 수 있다.Although the content of the mixed composition of tannic acid and quercetin contained in the cosmetic composition of the present invention is not limited thereto, it is preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight based on the total weight of the composition. If the content is less than 0.001% by weight can not be expected the desired effect, more than 10% by weight may be difficult to manufacture safety or formulation.
이상 살펴본 바와 같이, 본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물, 식품 조성물 또는 화장료 조성물을 제공한다. 본 발명의 조성물은 아토피성 피부염의 병변을 개선시키며, 혈관신생을 억제하여 아토피 피부염의 진행을 막아 아토피 피부염 예방 또는 치료 효과가 있어, 아토피 피부염 치료제 개발 또는 아토피 환자를 위한 기능성 식품 또는 화장품 개발에 효과적으로 이용될 수 있다.As described above, the present invention provides a pharmaceutical composition, food composition or cosmetic composition for preventing or treating atopic dermatitis containing tannic acid and quercetin as an active ingredient. The composition of the present invention improves the lesions of atopic dermatitis, inhibits angiogenesis and prevents the progression of atopic dermatitis, thereby preventing or treating atopic dermatitis, and effectively developing a therapeutic agent for atopic dermatitis or developing functional foods or cosmetics for atopic dermatitis. Can be used.
이하, 본 발명을 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.
<실시예 1>≪ Example 1 >
탄닌산과 퀘르세틴의 TNF-α 유도성 VEGF 발현 억제Inhibition of TNF-α-induced VEGF Expression by Tannic Acid and Quercetin
<1-1> 탄닌산과 퀘르세틴의 VEGF 발현억제<1-1> VEGF Expression Inhibition of Tannic Acid and Quercetin
혈관신생은 친-혈관신생 인자와 항-혈관신생 인자의 벨런싱으로 조절된다. 혈관내피 세포 성장 인자(VEGF, human vascular endothelial growth factor)는 대 표적인 친-혈관신생 인자이며 TNF-α에 의하여 그 발현이 증가한다. 탄닌산과 퀘르세틴의 VEGF 발현 억제 효능을 알아보기 위하여 HaCaT 세포(인간 케라티노사이트 세포주)를 실험에 사용하였다. 세포는 Dulbecco’s modified Eagle’s media (DMEM) 에 10% 불활화 우태아혈청(FBS), 100 mg/ml 페니실린 및 100 mg/ml 스트렙토마이신을 첨가하여, 37℃에서 5% CO2 존재하에 배양하였다. Angiogenesis is regulated by balancing pro-angiogenic and anti-angiogenic factors. Human vascular endothelial growth factor (VEGF) is a representative pro-angiogenic factor and its expression is increased by TNF-α. HaCaT cells (human keratinocyte cell line) were used in experiments to investigate the inhibitory effects of tannic acid and quercetin on VEGF expression. Cells were incubated in Dulbecco's modified Eagle's media (DMEM) with 10% inactivated fetal bovine serum (FBS), 100 mg / ml penicillin and 100 mg / ml streptomycin in the presence of 5% CO 2 at 37 ° C.
HaCaT 세포주를 TNF-α (50ng/ml)의 존재 또는 부재하에 1시간 경과시킨 후 0, 10, 25, 및 50 μM의 탄닌산과 0, 1, 5, 및 10 μM의 퀘르세틴으로 6시간 처리하였다. 세포들을 각각 수획하여 총 RNA를 트리졸 용액(Invitrogen)으로 분리하고 cDNA를 합성하였다. cDNA와 하기의 프라이머들을 이용하여 Real time PCR 분석으로 VEGF mRNA를 확인하였다. 결과는 VEGF mRNA와 β-actin mRNA의 발현 비율로 표시하였다.HaCaT cell lines were treated for 1 hour with or without TNF-α (50 ng / ml) and then treated with 0, 10, 25, and 50 μM tannic acid and 0, 1, 5, and 10 μM quercetin for 6 hours. The cells were harvested individually to separate total RNA into Trizol solution (Invitrogen) and cDNA was synthesized. VEGF mRNA was confirmed by real time PCR analysis using cDNA and the following primers. The results were expressed as the expression ratio of VEGF mRNA and β-actin mRNA.
서열번호 1: VEGF-sense 5’-AGGCCGAGAAGGAGAAGCTGTTG-3’SEQ ID NO: VEGF-sense 5'-AGGCCGAGAAGGAGAAGCTGTTG-3 '
서열번호 2: VEGF-antisense 5’-TGGCCACCTCTTTGCTCTGCTC-3’ SEQ ID NO: VEGF-antisense 5'-TGGCCACCTCTTTGCTCTGCTC-3 '
서열번호 3: beta-actin-sense 5’-TCACCCACACTGTGCCCATCTACG-3’SEQ ID NO: beta-actin-sense 5'-TCACCCACACTGTGCCCATCTACG-3 '
서열번호 4: beta-actin-antisense 5’-CAGCGGAACCGCTCATTGCCAATG-3’ SEQ ID NO: beta-actin-antisense 5'-CAGCGGAACCGCTCATTGCCAATG-3 '
그 결과 도 1에서 보는바와 같이 TNF-α 처리로 인하여 VEGF 발현이 5배 상승하였고, 이 효과는 탄닌산과 퀘르세틴의 처리에 의해 감소하는 것을 확인하였다. 이는 케라티노사이트 세포에 있어서, 탄닌산과 퀘르세틴의 처리가 특이적으로 VEGF mRNA 수준을 조절하며, 이것은 혈관신생과 관련된 염증의 억제에 주요한 역할을 한다는 것을 시사한다.As a result, as shown in FIG. 1, VEGF expression was increased by 5 times due to TNF-α treatment, and this effect was confirmed to be reduced by treatment with tannic acid and quercetin. This suggests that in keratinocyte cells, the treatment of tannic acid and quercetin specifically regulates VEGF mRNA levels, which play a major role in the inhibition of inflammation associated with angiogenesis.
<1-2> 탄닌산 및 퀘르세틴 동시 처리시 VEGF 발현 억제 효과<1-2> Inhibitory Effect of Tannin Acid and Quercetin on VEGF Expression
탄닌산(25μM)과 퀘르세틴(5μM)의 복합 효과를 알아보고자, 이들 화합물을 개별적으로 또는 복합적으로 투여하고 PCR 및 ELISA를 통하여 VEGF 발현수준을 조사하였다.To evaluate the combined effects of tannic acid (25 μM) and quercetin (5 μM), these compounds were administered individually or in combination and VEGF expression levels were examined by PCR and ELISA.
HaCaT 세포주를 TNF-α (50ng/ml)로 1시간동안 전처리하고 25 μM의 탄닌산과 5 μM의 퀘르세틴으로 각각 또는 함께 6시간 동안 처리하였다. 세포를 이후 수획하여, 총 RNA를 분리하고, cDNA를 합성하였다. RT-PCR 분석으로 VEGF mRNA를 확인하고, Real time PCR 분석으로 HaCaT 세포주에서 VEGF mRNA 발현을 확인하였다. 결과는 VEGF mRNA와 β-actin mRNA의 발현 비율로 표시하였다.HaCaT cell lines were pretreated with TNF-α (50 ng / ml) for 1 hour and treated with 25 μM tannic acid and 5 μM quercetin, respectively or together for 6 hours. The cells were then harvested to isolate total RNA and synthesize cDNA. VEGF mRNA was confirmed by RT-PCR analysis, and VEGF mRNA expression was confirmed in HaCaT cell line by real time PCR analysis. The results were expressed as the expression ratio of VEGF mRNA and β-actin mRNA.
발현되는 VEGF의 양의 변화를 직접 측정하기 위하여 HaCaT 세포주 및 인간 초대배양 케라티노사이트를 TNF- α (50ng/ml)의 존재 또는 부재하에 1시간 경과시킨 후 25 μM의 탄닌산과 5 μM의 퀘르세틴으로 각각 또는 함께 6시간 처리하였다. 이후 상층액을 취하여 VEGF의 양을 인간 VEGF-specific ELISA 키트(human VEGF ELISA kit, Raybiotech, 미국)를 사용하여 키트에 제공된 방법에 따라 조사하였다. 도 3은 3회의 실험을 반복한 결과중 대표적인 실험결과이다. 데이터는 평균값 ± SD로 표시되었다. In order to directly measure the change in the amount of VEGF expressed, HaCaT cell line and human supercultured keratinocytes were subjected to 1 hr in the presence or absence of TNF-α (50 ng / ml), followed by 25 μM tannic acid and 5 μM quercetin. Six hours each or together. The supernatant was then taken and the amount of VEGF was investigated using the human VEGF-specific ELISA kit (Raybiotech, USA) according to the method provided in the kit. Figure 3 is a representative experimental results of the results of repeating three experiments. Data is expressed as mean value ± SD.
그 결과 도 2 또는 도 3에서 보는 바와 같이 탄닌산과 퀘르세틴을 함께 처리한 것이 각각을 처리한 것보다 더욱 강력한 효과를 나타내는 것을 확인하였다. 이는 탄닌산과 퀘르세틴의 복합투여가 케라티노사이트에 있어서 VEGF 억제제로서 강력한 역할을 함을 시사한다.As a result, as shown in Fig. 2 or 3, it was confirmed that tannin acid and quercetin were treated together more powerfully than each treatment. This suggests that the combination of tannic acid and quercetin plays a powerful role as a VEGF inhibitor in keratinocytes.
<실시예 2><Example 2>
탄닌산과 퀘르세틴의 Th2 극성 이상증 완화 효과Tannin Acid and Quercetin Alleviate Th2 Polarity
아토피 피부염은 염증성 Th2 극성 이상증으로 특징지어진다(Howell et al., (2007) Curr Opin Allergy Clin Immunol 7:413-417). 따라서 본 발명자들은 thymic stromal lymphopoietin(TSLP)이 아토피 피부염에 있어서 탄닌산과 퀘르세틴의 치료효과와 상관성이 있는지 조사하였다. TSLP는 Thymus and activation regulated chemokine(TARC)을 포함한 Th2 사이토카인을 유도하며, 알레르기 반응, IgE 생산 및 eosinophia에 관련이 있다. Atopic dermatitis is characterized by inflammatory Th2 polar dysplasia (Howell et al. , (2007) Curr Opin Allergy Clin Immunol 7: 413-417). Therefore, the present inventors investigated whether thymic stromal lymphopoietin (TSLP) correlated with the therapeutic effect of tannin and quercetin in atopic dermatitis. TSLP induces Th2 cytokines, including Thymus and activation regulated chemokine (TARC), and is involved in allergic reactions, IgE production and eosinophia.
본 발명자들은 ELISA를 이용하여 TNF-α가 촉진된 인간 케라티노사이트에서 TSLP의 분비를 측정하였고, We measured the secretion of TSLP in TNF-α-promoted human keratinocytes using ELISA,
HaCaT 세포 및 초대배양 인간 케라티노사이트를 TNF- α (50ng/ml) 존재 또는 부재로 1시간동안 전처리한 후 25μM의 탄닌산 및 5μM의 퀘르세틴을 각각 또는 조합으로 24시간동안 처리하였다. 이후 상층액을 취하여 TSLP의 양을 인간 TSLP-specific ELISA키트(human TSLP ELISA kit, R&D system, 미국)를 사용하여 키트에 제공된 방법에 따라 조사하였다. 결과는 평균값 ± SD로 표시되었다. HaCaT cells and supercultured human keratinocytes were pretreated for 1 hour with or without TNF-α (50 ng / ml) and then treated with 25 μM tannic acid and 5 μM quercetin, respectively or in combination for 24 hours. The supernatant was then taken and the amount of TSLP was investigated using the human TSLP-specific ELISA kit (human TSLP ELISA kit, R & D system, USA) according to the method provided in the kit. The results are expressed as mean ± SD.
그 결과 도 4에서 보는 바와 같이 탄닌산과 퀘르세틴의 처리가 TNF-α 유도성 TSLP 발현을 억제함을 확인하였다.As a result, it was confirmed that the treatment of tannic acid and quercetin inhibited TNF-α-induced TSLP expression as shown in FIG. 4.
아토피 피부염에 있어서 탄닌산과 퀘르세틴의 기작을 더 자세히 설명하고자, 본 발명자들은 TARC에 중점을 두었다. TARC는 아토피 피부염성 피부병변에서 과잉생산되는 것으로 알려진 사이토카인이다(Zheng et al., (2003) J Dermatol 30:26-32). 그러나 아토피 피부염 관련 모델에서 탄닌산과 퀘르세틴에 의한 TARC 발현조절은 아직 잘 알려져 있지 않다. TARC 발현에 있어서 탄닌산과 퀘르세틴의 효과를 인간 케라티노사이트로 실험하였다. TNF-α를 포함한 다양한 친-염증성 사이토카인들의 생산수준이 아토피 피부염에서 증가되며, 이것이 케라티노사이트에서 TARC 생산을 유도한다는 것은 보고된 바 있다(Maeda et al., (2009) Vet Immunol Immunopathol. 131(3-4):298-302). 따라서 HaCaT 세포를 탄닌산과 퀘르세틴으로 처리하기 전에 TNF-α로 1시간동안 전처리하고, TARC 단백질의 발현수준을 ELISA로 조사하였다.To explain in more detail the mechanism of tannic acid and quercetin in atopic dermatitis, we focused on TARC. TARC is a cytokine known to be overproduced in atopic dermatitis (Zheng et al. , (2003) J Dermatol 30: 26-32). However, the regulation of TARC expression by tannic acid and quercetin in atopic dermatitis related models is not well known. The effects of tannic acid and quercetin on TARC expression were tested with human keratinocytes. It has been reported that production levels of various pro-inflammatory cytokines, including TNF-α, are increased in atopic dermatitis, which induces TARC production in keratinocytes (Maeda et al. , (2009) Vet Immunol Immunopathol. 131 (3-4): 298-302). Therefore, HaCaT cells were pretreated with TNF-α for 1 hour before treatment with tannic acid and quercetin, and the expression level of TARC protein was examined by ELISA.
HaCaT 세포 및 초대배양 인간 케라티노사이트를 TNF-α (50ng/ml) 존재 또는 부재로 1시간동안 전처리한 후 25μM의 탄닌산 및 5μM의 퀘르세틴을 각각 또는 조합으로 24시간동안 처리하였다. 이후 상층액을 취하여 TARC의 양을 인간 TARC-specific ELISA키트(human TARC ELISA kit, R&D systems, 미국)를 사용하여 키트에 제공된 방법에 따라 조사하였다. 결과는 3회 반복실험 중의 대표실험값이다. 데이터는 평균값 ± SD로 표시되었다. HaCaT cells and supercultured human keratinocytes were pretreated for 1 hour with or without TNF-α (50 ng / ml) and then treated with 25 μM tannic acid and 5 μM quercetin, respectively or in combination for 24 hours. The supernatant was then taken and the amount of TARC was investigated using the human TARC-specific ELISA kit (human TARC ELISA kit, R & D systems, USA) according to the method provided in the kit. The results are representative experimental values from three replicates. Data is expressed as mean value ± SD.
그 결과 도 5에서 보는바와 같이 TNF-α 유도성 TARC의 단백질 발현수준은 HaCaT 세포에 있어서 탄닌산과 퀘르세틴 처리 이후에 감소됨을 확인하였다. As a result, as shown in Figure 5, the protein expression level of TNF-α-induced TARC was confirmed to be reduced after tannin acid and quercetin treatment in HaCaT cells.
상기 결과로 탄닌산과 퀘르세틴이 HaCaT 세포에 있어서 TARC를 감소시킴을 알 수 있었다.The results showed that tannic acid and quercetin reduced TARC in HaCaT cells.
<실시예 3><Example 3>
동물 모델에서의 탄닌산과 퀘르세틴의 아토피성 피부염 치료 효과Treatment of Atopic Dermatitis with Tannic Acid and Quercetin in Animal Models
<3-1> 탄닌산과 퀘르세틴의 아토피 피부염성 피부병변 개선효과<3-1> Effects of Tannic Acid and Quercetin on Atopic Dermatitis
본 발명자들은 이후 탄닌산과 퀘르세틴의 복합 도포가 in vivo 상으로도 치료효과가 있는지를 Nc/Nga 생쥐에 아토피 피부염을 유발하여 알아보았다. 5주령 암컷 NC/Nga 생쥐를 SCL 사(일본)에서 구입하였다. 생쥐들을 다음의 3 개의 군으로 나누었다: 건강한 정상군(음성 대조군), 아토피 피부염 대조군(아토피 피부염을 유도하였으나, 치료기간동안 인산완충용액 만을 투여 받는 군), 탄닌산과 퀘르세틴 공동처리 그룹(아토피 피부염을 유발시킨 후 탄닌산 및 퀘르세틴을 병변에 도포하는 군). The inventors then examined whether the combined application of tannic acid and quercetin has a therapeutic effect even in vivo by inducing atopic dermatitis in Nc / Nga mice. Five-week-old female NC / Nga mice were purchased from SCL Corporation (Japan). Mice were divided into three groups: healthy normal (negative control), atopic dermatitis control group (induced atopic dermatitis but receiving only phosphate buffer solution during treatment), tannin acid and quercetin co-treatment group (atopic dermatitis Tannic acid and quercetin applied to the lesion after induction).
아토피 피부염은 집먼지 진드기 알러지원을 3주간 3차례 귀 피부부위에 도포 함으로서 유도하였다.Atopic dermatitis was induced by applying dust mite allergen to the ear skin area three times for three weeks.
이후 0.5ml 탄닌산(25mM)과 퀘르세틴(2.5mM)을 3주간 주 5회씩 중증 아토피 피부염이 발생된 부위에 도포하였다. 대조군 동물은 인산완충용액을 도포하였다.Then 0.5ml tannic acid (25mM) and quercetin (2.5mM) was applied to the site of severe atopic dermatitis five times a week for three weeks. Control animals were applied with phosphate buffer solution.
치료 3주후, 피부염의 중증도는 3명의 피부학자들에 의해 평가되었다. 아토피 피부염 점수는 홍반/출혈, 흉터/건조, 부종 및 찰과상/미란을 기준으로 평가하였다. 각 요소는 0(정상), 1(가벼움), 2(중간), 3(심함)으로 기록되었다. 4개 요소의 점수로 아토피 점수가 매겨졌다.Three weeks after treatment, the severity of dermatitis was assessed by three dermatologists. Atopic dermatitis scores were evaluated based on erythema / bleeding, scar / dry, edema and abrasion / erosion. Each element was recorded as 0 (normal), 1 (light), 2 (medium), 3 (severe). Atopic scores were scored with four elements.
이후 실험을 위하여 생쥐를 희생하고, 심장채혈로 ELISA용 혈액을 채취하였다. After that, the mice were sacrificed for experiments, and blood for ELISA was collected by heart blood collection.
조직관찰을 위하여 대조군 및 실험군의 아토피성 병변 피부조직을 채취하여 10%(w/v)의 중성 완충 포르말린이 포함된 용액에 고정시키고 25% 수크로즈 용액에 침지하였다. 시료들을 frozen medium에 포매하고 8um의 두께로 냉동절편을 제작하였다. 상기 절편을 헤마톡실린과 에오신(H&E)으로 염색하고 광학현미경에서 조직학적 관찰을 하였다. 디지털 영상을 현미경(CH30; Olympus, Tokyo, Japan)에 연결된 고해상도 디지털 카메라(C3040-AD6; Olympus, Tokyo, Japan)로부터 얻었다.For histological observation, atopic lesion skin tissues of control and experimental groups were taken, fixed in a solution containing 10% (w / v) neutral buffered formalin and immersed in 25% sucrose solution. Samples were embedded in frozen medium and frozen sections were prepared to a thickness of 8 μm. The sections were stained with hematoxylin and eosin (H & E) and examined histologically on an optical microscope. Digital images were obtained from a high resolution digital camera (C3040-AD6; Olympus, Tokyo, Japan) connected to a microscope (CH30; Olympus, Tokyo, Japan).
그 결과 도 6B에서 보는 바와 같이, 아토피 피부염 유발후 탄닌산/퀘르세틴의 도포가 아토피 점수를 감소시킴을 확인하였다. As a result, as shown in Figure 6B, it was confirmed that the application of tannic acid / quercetin after atopic dermatitis reduced the atopic score.
또한 도 6A에서 보는 바와 같이, 탄닌산 및 퀘르세틴을 치료받은 군에서 확연히 증상의 개선이 보였다. 아토피 피부염 대조군과 비교하여 탄닌산 및 퀘르세틴 을 치료받은 Nc/Nga 생쥐는 침습, 부풀어오름, 홍반, 부종 및 미란의 억제를 보였다. 광학현미경으로 조직을 관찰한 결과에서도 건강한 정상군에서는 특별한 변화를 관찰할 수 없었다. 대조적으로, 아토피 피부염 대조군은 귀의 두께가 두꺼워지고 표피 상층부의 백혈구 염증이 증진된 것을 볼 수 있었다. 흥미롭게도 아토피 피부염 대조군과 비교하여 탄닌산과 퀘르세틴 처리 그룹은 귀 및 표피 두께 및 백혈구 염증의 명백한 감소를 보였다. In addition, as shown in FIG. 6A, the symptoms of the tannin acid and quercetin were significantly improved. Nc / Nga mice treated with tannic acid and quercetin showed inhibition of invasion, swelling, erythema, edema and erosion compared to the atopic dermatitis control group. Even when the tissues were observed under the light microscope, no special changes were observed in the healthy normal group. In contrast, the atopic dermatitis control group was found to have thickened ear thickness and increased leukocyte inflammation in the upper epidermis. Interestingly, the tannic acid and quercetin treated groups showed a clear reduction in ear and epidermal thickness and leukocyte inflammation compared to the atopic dermatitis control group.
이로서 탄닌산과 퀘르세틴이 아토피 증상완화를 초래하며 아토피 피부염의 치료효과가 우수함을 알 수 있다.This suggests that tannic acid and quercetin can alleviate atopic symptoms and have excellent therapeutic effects for atopic dermatitis.
<3-2> 탄닌산과 퀘르세틴의 아토피 피부염성 피부병변의 혈관신생 억제효과<3-2> Anti-angiogenic Effects of Tannic Acid and Quercetin on Atopic Dermatitis
혈관신생은 아토피 피부염과 같은 알레르기 관련 질환에 있어서 결정적인 요소이다. in vivo상에서 혈관신생에 있어 탄닌산과 퀘르세틴의 효과를 연구하고자, 본 발명자들은 탄닌산과 퀘르세틴을 아토피 피부염성 병변에 3주간 도포한 후 vascularization을 관찰하였다. 상기에 언급한 바와 같이, 본 발명자들은 인간 케라티노사이트에 있어서 처리하지 않은 군과 대비하여 탄닌산과 퀘르세틴을 처리한 군에서 VEGF 발현 수준이 확연히 감소함을 관찰하였다(실시예 1-2참조). 따라서 본 발명자들은 아토피 피부염성 피부병에의 탄닌산과 퀘르세틴 치료가 in vivo 상에서 혈관신생에 효과가 있다고 추론하였다. 이 추론을 확립하기 위해 본 발명자들은 CD31의 면역조직 염색을 실시하였다. CD31-매개성 내피 세포-세포간 상호작용은 혈관신생과 연관되어 있고 관(vessel)을 검출할 때 일반적으로 사용되는 마커이다(Saban et al., (2007) BMC Cancer 7:219). 아토피 피부염 유도성 혈관신생에 있어서 탄닌산과 퀘르세틴의 억제효과(A) 탄닌산(25mM)/퀘르세틴(2.5mM)의 존재 또는 부재하에 아토피 피부염 유발 Nc/Nga 생쥐를 3주간 치료한 후 면역조직학적 분석을 실시하였다. 혈관신생 수준은 CD31(적색)로 검출하였다.Angiogenesis is a decisive factor in allergic diseases such as atopic dermatitis. In order to study the effects of tannic acid and quercetin on angiogenesis in vivo, the present inventors observed vascularization after applying tannic acid and quercetin to atopic dermatitis for 3 weeks. As mentioned above, the inventors observed a significant decrease in VEGF expression levels in the tannin acid and quercetin treated groups as compared to the untreated group in human keratinocytes (see Example 1-2). Therefore, the present inventors deduced that tannin acid and quercetin treatment in atopic dermatitis are effective on angiogenesis in vivo. To establish this inference, we performed immunohistostaining of CD31. CD31-mediated endothelial cell-cell interactions are associated markers of angiogenesis and are commonly used markers for detecting vessels (Saban et al. , (2007) BMC Cancer 7: 219). Inhibitory Effect of Tannic Acid and Quercetin on Atopic Dermatitis-induced Angiogenesis (A) Immunohistologic analysis after 3 weeks of treatment of atopic dermatitis-induced Nc / Nga mice with or without tannic acid (25 mM) / quercetin (2.5 mM) Was carried out. Angiogenesis levels were detected with CD31 (red).
CD31 발현을 확인하는 면역조직염색은 실시예 3-1에서 제조한 냉동절편을 사용하여 다음과 같이 수행하였다. 시료를 실온에서 건조하고 4℃의 차가운 아세톤으로 고정하였다. 고정된 시료는 렛트 항-생쥐 CD 31 항체(rat anti-mouse CD31 antibody, BD Pharmingen) 로 1시간동안 습실(wet chamber)에 반응시켰다. 이후, 이들을 바이오티닐레이티드 염소 항-렛트 IgG 항체(biotinylated goat anti-rat IgG antibody, Sigma, 미국)에 30분 동안 동일조건에서 반응시켰다. 최종적으로 조직을 포스파테이즈-콘쥬게이티드 스트렙트아비딘(phosphatase-conjugated streptavidin)과 반응시켰다. 표지된 세포들은 혼합된 기질용액(fast red, naphtha, and levamisole; Sigma, 미국)을 사용하여 가시화 하였다. 면역조직염색결과는 염색농도 정량화를 이용하여 수치화 하였으며, imagePro Plus 3.0(Media Cybernetics LP, Silver Spring, 미국) 프로그램을 사용하여서 CD31이 양성 염색된 부분만을 수치화하였다.Immunohistochemical staining to confirm the expression of CD31 was performed using the frozen sections prepared in Example 3-1 as follows. Samples were dried at room temperature and fixed with cold acetone at 4 ° C. The immobilized samples were reacted in a wet chamber for 1 hour with a rat anti-mouse CD31 antibody (BD Pharmingen). Then, they were reacted with biotinylated goat anti-rat IgG antibody (Sigma, USA) for 30 minutes under the same conditions. Finally, the tissue was reacted with phosphatase-conjugated streptavidin. Labeled cells were visualized using mixed substrate solution (fast red, naphtha, and levamisole; Sigma, USA). Immunohistologic staining results were quantified using staining concentration quantification, and only the areas where CD31 was positively stained using the imagePro Plus 3.0 (Media Cybernetics LP, Silver Spring, USA) program.
그 결과 도 7에서 보는 바와 같이 탄닌산과 퀘르세틴 처리군(n=10)의 CD31 발현수준은 아토피 피부염 대조군(n=10)과 비교하였을 때 확연히 낮았다. 탄닌산과 퀘르세틴 처리군(n=10)은 음성 대조군(n=10)과 유사한 정도의 CD31 발현패턴을 보 였다. 이미지 분석에 의한 CD31양성염색 정량분석결과에서도 탄닌산과 퀘르세틴 처리군에서의 CD31의 발현은 아토피 피부염 대조군과 비교하여 확연히 낮은 것으로 나타났다. As a result, as shown in Figure 7, the tannin acid and quercetin treated group (n = 10) CD31 expression level was significantly lower than the atopic dermatitis control group (n = 10). Tannin acid and quercetin treatment group (n = 10) showed a CD31 expression pattern similar to the negative control (n = 10). In the quantitative analysis of CD31 positive staining by image analysis, the expression of CD31 in tannic acid and quercetin-treated group was significantly lower than that of atopic dermatitis control group.
상기 결과에 의하여 탄닌산과 퀘르세틴이 혈관신생(neoangiogenesis)의 억제를 이끌어내고, 이는 또한 아토피 피부염성 피부병변의 염증수준을 감소시키는 것을 확인하였다.The results confirm that tannic acid and quercetin lead to inhibition of neoangiogenesis, which also reduces the inflammation level of atopic dermatitis.
<3-3> 동물 모델에서 탄닌산과 퀘르세틴의 Th2 극성 이상증 완화 효과<3-3> Effects of Tannic Acid and Quercetin on Th2 Polarity Abnormalities
혈청내 IgE의 수치상승은 아토피 피부염의 특성중 하나이다(Park et al., (2007) J Biochem Mol Biol 40:486-493). 따라서 본 발명자들은 탄닌산과 퀘르세틴이 또한 아토피 피부염이 유도된 Nc/Nga 생쥐에서 in vivo상으로 TARC 발현을 조절하는지 여부와 탄닌산과 퀘르세틴을 도포에 의해 혈청내 IgE가 감소하는지 여부를 ELISA로 조사하였다.Elevated levels of IgE in serum are one of the characteristics of atopic dermatitis (Park et al., (2007) J Biochem Mol Biol 40: 486-493). Therefore, the present inventors investigated by ELISA whether tannic acid and quercetin also regulate TARC expression in vivo in atopic dermatitis-induced Nc / Nga mice and by applying tannic acid and quercetin.
혈청은 실시예 3-1의 3주간의 처치가 끝난 생쥐에서 채취하였다. 에버틴(15ul/g)으로 마취시킨 Nc/Nga 생쥐로부터 심장 채혈하여 혈액을 채취하여 응고시켜 혈청을 수획하고, 12,000g로 10분간 원심분리하였다. 혈청내 IgE 및 TARC 농도는 ELISA 키트(mouse TARC ELISA kits, BD bioscience, 미국; mouse IgE ELISA kit, SHIBAYGI, 일본)를 사용하여 키트에 제공된 방법에 따라 측정하였다.Serum was collected from mice treated after 3 weeks of Example 3-1. Blood was collected from the Nc / Nga mice anesthetized with Evertin (15 ul / g), blood was collected and coagulated to collect serum, and centrifuged at 12,000 g for 10 minutes. Serum IgE and TARC concentrations were measured using ELISA kits (mouse TARC ELISA kits, BD bioscience, USA; mouse IgE ELISA kit, SHIBAYGI, Japan) according to the methods provided in the kits.
그 결과 도 8에서 보는 바와 같이 TARC의 발현은 정상군과 대조할 때, 아토 피 피부염 대조군에서 상승되었다. 상승된 TARC 수치는 탄닌산과 퀘르세틴 처리에 의해 감소되는 것을 확인하였는데, 이는 in vitro 결과(도 5 참조)와 일치하는 결과이다.As a result, as shown in FIG. 8, the expression of TARC was elevated in the atopic dermatitis control group as compared with the normal group. Elevated TARC levels were found to be decreased by tannic acid and quercetin treatment, which is consistent with in vitro results (see FIG. 5).
또한 IgE 수치를 측정한 결과 아토피 피부염 대조군은 건강한 대조군보다 3.5배 가량 IgE 수치가 높았다. 그러나 상승된 혈청내 IgE 수치는 탄닌산과 퀘르세틴 처리에 의해 50% 이상 확연히 감소되었다. 이로서 탄닌산/퀘르세틴의 도포가 아토피 피부염을 보이는 생쥐에 있어서 혈청내 IgE 수치를 감소시키는 것을 확인하였다.In addition, as a result of measuring the IgE level, the atopic dermatitis control group was 3.5 times higher than the healthy control group. However, elevated serum IgE levels were significantly reduced by more than 50% by tannin and quercetin treatment. It was confirmed that the application of tannic acid / quercetin reduced serum IgE levels in mice showing atopic dermatitis.
따라서 살펴본 바와 같이, 본 발명은 탄닌산 및 퀘르세틴을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 약학적 조성물, 식품 조성물 또는 화장료 조성물을 제공한다. 본 발명의 조성물은 아토피성 피부염의 병변을 개선시키며, 혈관신생을 억제하여 아토피 피부염의 진행을 막아 아토피 피부염 예방 또는 치료 효과가 있어, 아토피 피부염 치료제 개발 또는 아토피 환자를 위한 기능성 식품 또는 화장품 개발에 효과적으로 이용될 수 있어 산업상 이용 가능성이 크다.Therefore, as described above, the present invention provides a pharmaceutical composition, food composition or cosmetic composition for preventing or treating atopic dermatitis containing tannic acid and quercetin as an active ingredient. The composition of the present invention improves the lesions of atopic dermatitis, inhibits angiogenesis and prevents the progression of atopic dermatitis, thereby preventing or treating atopic dermatitis, and effectively developing a therapeutic agent for atopic dermatitis or developing functional foods or cosmetics for atopic dermatitis. As it can be used, it is likely to be used industrially.
도 1은 TNF-α에 의하여 증가된 VEGF의 발현이 본 발명의 탄닌산 또는 퀘르세틴에 의하여 억제되는지 여부를 real time PCR로 측정한 결과 그래프이다(TA: 탄닌산, Quercetin: 퀘르세틴, TNF-α: TNF-α(50ng/ml), 표시된 농도: 탄닌산 또는 퀘르세틴 투여농도(uM), (-)control: 음성대조군)1 is a graph of the result of measuring by real time PCR whether the expression of VEGF increased by TNF-α is inhibited by tannin or quercetin of the present invention (TA: tannic acid, Quercetin: quercetin, TNF-α: TNF- α (50 ng / ml), indicated concentration: tannic acid or quercetin dose (uM), (-) control: negative control)
도 2는 TNF-α에 의하여 증가된 VEGF의 발현이 본 발명의 탄닌산 또는 퀘르세틴 단독 투여시보다 동시 투여시 더욱 억제되는지 여부를 알아본 결과이다. 도 2A는 RT-PCR로 mRNA의 양을 측정한 결과이며, 도 2B는 real time PCR로 측정한 결과 그래프이다(TA: 탄닌산(25uM), Quercetin: 퀘르세틴(5uM), TNF-α: TNF-α(50ng/ml)).Figure 2 is a result of examining whether the expression of VEGF increased by TNF-α is more inhibited when simultaneous administration than tannin or quercetin of the present invention alone. Figure 2A is the result of measuring the amount of mRNA by RT-PCR, Figure 2B is a graph of the result measured by real time PCR (TA: tannic acid (25uM), Quercetin: quercetin (5uM), TNF-α: TNF-α (50 ng / ml)).
도 3은 TNF-α에 의하여 증가된 VEGF의 발현이 본 발명의 탄닌산 또는 퀘르세틴 단독 투여시보다 동시 투여시 더욱 억제되는지 여부를 ELISA로 VEGF의 양을 측정하여 알아본 결과이다(TA: 탄닌산(25uM), Quercetin: 퀘르세틴(5uM), TNF-α: TNF-α(50ng/ml), HaCaT: 인간 케라티노사이트 세포주, Primary: 인간 초대배양 케라티노사이트).3 is a result of measuring the amount of VEGF by the ELISA whether the expression of VEGF increased by TNF-α is more inhibited at the same time than tannin or quercetin alone administration of the present invention (TA: tannin acid (25uM ), Quercetin: quercetin (5 uM), TNF-α: TNF-α (50 ng / ml), HaCaT: human keratinocyte cell line, Primary: human supercultured keratinocytes).
도 4는 TNF-α에 의하여 증가된 TSLP의 발현이 본 발명의 탄닌산 또는 퀘르세틴 단독 투여시보다 동시 투여시 더욱 억제되는지 여부를 ELISA로 TSLP의 양을 측정하여 알아본 결과이다(TA: 탄닌산(25uM), Quercetin: 퀘르세틴(5uM), TNF-α: TNF-α(50ng/ml), HaCaT: 인간 케라티노사이트 세포주, Primary: 인간 초대배양 케라티노사이트).4 is a result obtained by measuring the amount of TSLP by ELISA to determine whether the expression of TSLP increased by TNF-α is more inhibited at the same time than tannin or quercetin alone (TA: tannin acid (25 uM). ), Quercetin: quercetin (5 uM), TNF-α: TNF-α (50 ng / ml), HaCaT: human keratinocyte cell line, Primary: human supercultured keratinocytes).
도 5는 TNF-α에 의하여 증가된 TARC의 발현이 본 발명의 탄닌산 또는 퀘르세틴 단독 투여시보다 동시 투여시 더욱 억제되는지 여부를 ELISA로 TARC의 양을 측정하여 알아본 결과이다(TA: 탄닌산(25uM), Quercetin: 퀘르세틴(5uM), TNF-α: TNF-α(50ng/ml), HaCaT: 인간 케라티노사이트 세포주, Primary: 인간 초대배양 케라티노사이트).5 is a result obtained by measuring the amount of TARC by ELISA to determine whether the expression of TARC increased by TNF-α is more inhibited at the same time than tannin or quercetin alone (TA: tannin acid (25 uM) ), Quercetin: quercetin (5 uM), TNF-α: TNF-α (50 ng / ml), HaCaT: human keratinocyte cell line, Primary: human supercultured keratinocytes).
도 6은 Nc/Nga 생쥐를 이용한 아토피 피부염 모델에서 탄닌산 및 퀘르세틴 혼합 조성물에 의한 아토피 피부염 치료 효과를 관찰한 결과이다. 도 6A는 아토피 피부염을 일으킨 생쥐의 외관 사진 및 현미경으로 관찰한 조직 사진이다. 도 6B는 피부염 점수 그래프이다((-)control: 음성대조군, AD control: 양성대조군, TA/Quercetin: 탄닌산(25mM) 및 퀘르세틴(2.5mM) 투여군).Figure 6 is a result of observing the effect of atopic dermatitis treatment by tannic acid and quercetin mixed composition in atopic dermatitis model using Nc / Nga mice. Figure 6A is a photomicrograph of the appearance of the mice causing atopic dermatitis and tissue photographs observed under a microscope. FIG. 6B is a graph of dermatitis score ((-) control: negative control, AD control: positive control, TA / Quercetin: tannic acid (25 mM) and quercetin (2.5 mM) administration group).
도 7은 Nc/Nga 생쥐를 이용한 아토피 피부염 모델에서 탄닌산 및 퀘르세틴 혼합 조성물에 의한 혈관신생억제 효과를 관찰한 결과이다. 도 7A는 실험 대상 생쥐에서 CD31의 발현여부를 면역조직염색을 통하여 관찰한 현미경 사진이며 도 7B는 이미지 분석을 통하여 CD31의 상대적 농도를 측정한 결과 그래프 이다((-)control: 음성대조군, AD control: 양성대조군, TA/Quercetin: 탄닌산(25mM) 및 퀘르세틴(2.5mM) 투여군). Figure 7 is the result of observing the angiogenesis inhibitory effect by tannin acid and quercetin mixed composition in atopic dermatitis model using Nc / Nga mice. FIG. 7A is a micrograph of the expression of CD31 in the mice tested by immunohistostaining. FIG. 7B is a graph of the relative concentration of CD31 measured through image analysis ((-) control: negative control, AD control. : Positive control group, TA / Quercetin: tannic acid (25 mM) and quercetin (2.5 mM) administration group).
도 8은 Nc/Nga 생쥐를 이용한 아토피 피부염 모델에서 탄닌산 및 퀘르세틴 혼합 조성물에 의한 혈액내 TARC와 IgE의 농도를 ELISA로 측정한 결과 그래프이다((-)control: 음성대조군, AD control: 양성대조군, TA/Quercetin: 탄닌산(25mM) 및 퀘르세틴(2.5mM) 투여군).Figure 8 is a graph of the results of measuring the concentration of TARC and IgE in the blood by tannin acid and quercetin mixed composition in the atopic dermatitis model using Nc / Nga mice by ELISA ((-) control: negative control, AD control: positive control, TA / Quercetin: tannic acid (25 mM) and quercetin (2.5 mM) administration groups).
<110> Industry-Academic Cooperation Foundation, Sookmyung Women's University <120> Composition for preventing, improving or treating atopyic dermatitis comprising tannic acid and quercetin as an active ingredient <160> 4 <170> KopatentIn 1.71 <210> 1 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> VEGF-sense: Froward primer for VEGF <400> 1 aggccgagaa ggagaagctg ttg 23 <210> 2 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> VEGF-antisense: Reverse primer for VEFG <400> 2 tggccacctc tttgctctgc tc 22 <210> 3 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> beta-actin-sense: Forward primer for beta-actin <400> 3 tcacccacac tgtgcccatc tacg 24 <210> 4 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> beta-actin-antisense: Reverse primer for beta-actin <400> 4 cagcggaacc gctcattgcc aatg 24 <110> Industry-Academic Cooperation Foundation, Sookmyung Women's University <120> Composition for preventing, improving or treating atopyic dermatitis comprising tannic acid and quercetin as an active ingredient <160> 4 <170> Kopatentin 1.71 <210> 1 <211> 23 <212> DNA <213> Artificial Sequence <220> 223 VEGF-sense: Froward primer for VEGF <400> 1 aggccgagaa ggagaagctg ttg 23 <210> 2 <211> 22 <212> DNA <213> Artificial Sequence <220> 223 VEGF-antisense: Reverse primer for VEFG <400> 2 tggccacctc tttgctctgc tc 22 <210> 3 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> beta-actin-sense: Forward primer for beta-actin <400> 3 tcacccacac tgtgcccatc tacg 24 <210> 4 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> beta-actin-antisense: Reverse primer for beta-actin <400> 4 cagcggaacc gctcattgcc aatg 24
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