KR20170129636A - A composition comprising peiminine for preventing and treating atopic dermatitis - Google Patents
A composition comprising peiminine for preventing and treating atopic dermatitis Download PDFInfo
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- KR20170129636A KR20170129636A KR1020170061218A KR20170061218A KR20170129636A KR 20170129636 A KR20170129636 A KR 20170129636A KR 1020170061218 A KR1020170061218 A KR 1020170061218A KR 20170061218 A KR20170061218 A KR 20170061218A KR 20170129636 A KR20170129636 A KR 20170129636A
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- KR
- South Korea
- Prior art keywords
- atopic dermatitis
- composition
- pemiminin
- mast cells
- acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Abstract
Description
본 발명은 페이미닌을 포함하는 아토피 피부염의 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prevention and treatment of atopic dermatitis including peymenin.
아토피 피부염은 심한 소양성, 재발성을 지니는 급성 습진과 만성 피부염으로 주로 영유아에서 발생한다. 연령의 증가에 따라 90%에서 자연치유의 경과를 보이지만 사춘기 성인에서 지속되거나 초발하기도 하고, 소아에서 10-20%, 성인에서 1-3%의 이환율을 보이며, 최근 심한 성인형 아토피 피부염 환자가 증가하고 있다고 보고된 바 있다. 또한 최근 보고에 따르면 선진국에서는 아토피 피부염 증가 추세가 둔화되거나 정점에 이르렀다고 하지만, 한국의 경우 대기오염, 주거환경의 변화, 식품 유해인자에 의한 항원노출의 증가 등으로 인해 아토피 피부염이 증가추세인 것으로 추정된다고 보고되고 있다. Atopic dermatitis is characterized by acute eczema and chronic dermatitis, which are very benign and recurrent, mostly occurring in infants and young children. As the age increases, natural healing progresses at 90%, but it is persistent or early on in adolescents, 10-20% in children and 1-3% in adults, and recent adult adolescent atopic dermatitis It is reported that According to recent reports, the trend of atopic dermatitis in developed countries has slowed or peaked, but in Korea, atopic dermatitis is increasing due to air pollution, changes in residential environment, and increased exposure of food to harmful factors It is reported to be estimated.
아토피 피부염은 유전적 소인, 피부장벽 기능의 이상, 면역학적 이상 및 환경적인 요인이 복합적으로 관여하여 발생하는 것으로 추정된다. 아토피 피부염의 발생기전은 아직 명확하게 밝혀지지 않았으나, 피부 안의 염증반응(INSIDE)과 피부 바깥의 장벽 기능 이상(OUTSIDE)이 중요한 두 축을 이루면서 상호작용을 하는 것으로 보인다. It is presumed that atopic dermatitis is caused by a complex involvement of genetic predisposition, abnormal skin barrier function, immunological abnormality, and environmental factors. The pathogenesis of atopic dermatitis has not been elucidated yet. However, it seems that the inflammation reaction (INSIDE) inside the skin and the OUTSIDE outside the skin have two important axes and interact with each other.
즉, 알레르겐 등의 외부항원이 아토피 피부염 환자의 손상된 피부장벽을 통해 피부에 도달하게 되고 이로 인한 알레르기 염증 반응이 일어나게 된다. 아토피 피부염의 발생과 관련하여 피부 안팎의 작용이 그 선후에 관해 논란을 빚어 왔으며, 최근에는 피부장벽의 필라그린(fillagrin)에 대한 연구가 두드러지면서 피부장벽 기능 이상이 먼저(OUTSIDE/INSIDE)라는 주장과 함께 피부장벽에 대한 중요성이 대두되고 있다. 그러나 아토피 피부염의 치료에 대한 평가지표로서의 접근을 위해서는 염증반응으로 나타나는 면역학적 이상(INSIDE)에 대한 이해가 동반되어야 한다.That is, external antigens such as allergens reach the skin through the damaged skin barrier of atopic dermatitis patients, resulting in an allergic inflammatory reaction. It has been argued that the action of the inside and the outside of the skin in relation to the occurrence of atopic dermatitis has been controversial about its future, and recently, the research on the fillagrin of the skin barrier has become prominent, and the skin barrier function abnormality is first stated (OUTSIDE / INSIDE) And the importance of skin barrier is emerging. However, as an evaluation index for the treatment of atopic dermatitis, an understanding of the immunological abnormality (INSIDE) as an inflammatory reaction must be accompanied.
본 발명자들은 아토피 피부염을 야기하는 비만세포의 알레르기 유발 물질 분비를 효과적으로 차단하는 물질을 개발하고자 노력한 결과, 페이미닌의 항-아토피 효과를 규명하고 본 발명을 완성하였다.The present inventors have made efforts to develop a substance that effectively inhibits the secretion of allergen-inducing substances in mast cells causing atopic dermatitis. As a result, they have confirmed the anti-atopic effect of pemiminin and completed the present invention.
본 발명은 전술한 종래기술의 문제점을 해결하기 위하여 항-아토피 효능을 가지는 화합물을 제공하는 것을 목적으로 한다. DISCLOSURE Technical Problem The present invention aims to provide a compound having an anti-atopic effect in order to solve the problems of the prior art described above.
또한, 본 발명은 상기 화합물을 포함하는 아토피 피부염의 예방 및 치료용 약학 조성물을 제공하는 것을 목적으로 한다. It is another object of the present invention to provide a pharmaceutical composition for preventing and treating atopic dermatitis comprising the above-mentioned compounds.
또한, 본 발명은 상기 화합물을 포함하는 아토피 피부염의 예방 및 개선용 식품 조성물을 제공하는 것을 목적으로 한다.It is another object of the present invention to provide a food composition for prevention and improvement of atopic dermatitis comprising the above-mentioned compounds.
본 발명의 일 측면에 따르면, 페이미닌(peiminine) 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 아토피 피부염의 예방 및 치료용 약학 조성물이 제공된다. According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing and treating atopic dermatitis comprising peiminine or a pharmaceutically acceptable salt thereof as an active ingredient.
일 실시예에 있어서, 상기 조성물은 알레르기성 염증 반응을 억제할 수 있다.In one embodiment, the composition is capable of inhibiting an allergic inflammatory response.
일 실시예에 있어서, 상기 조성물은 MAPK 인산화(MAPKs phosphorylation) 및 NF-kB 신호 전달 경로(NF-kB signal pathway)를 억제할 수 있다. In one embodiment, the composition may inhibit MAPK phosphorylation and the NF-kB signal pathway.
일 실시예에 있어서, 상기 조성물은 히스타민 방출을 억제할 수 있다. In one embodiment, the composition can inhibit histamine release.
일 실시예에 있어서, 상기 조성물은 피부조직 내 호산구 및 비만세포의 침윤을 감소시킬 수 있다.In one embodiment, the composition can reduce the infiltration of eosinophils and mast cells in the dermal tissue.
일 실시예에 있어서, 상기 조성물은 표피 및 진피의 두께를 감소시킬 수 있다.In one embodiment, the composition can reduce the thickness of the epidermis and dermis.
본 발명의 다른 측면에 따르면, 페이미닌(peiminine) 또는 그의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 아토피 피부염의 예방 및 개선용 식품 조성물이 제공된다. According to another aspect of the present invention, there is provided a food composition for preventing and improving atopic dermatitis comprising peiminine or a pharmaceutically acceptable salt thereof as an active ingredient.
일 실시예에 있어서, 상기 조성물은 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 구성된 군에서 선택된 어느 하나의 제형으로 제조될 수 있다. In one embodiment, the composition may be prepared in any one of formulations selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and circles.
본 발명에 따르면, 상기 페이미닌을 함유하는 조성물은 비만세포에 의해 매개되는 알레르기성 염증 반응을 효과적으로 억제하므로 아토피 피부염의 예방 및 치료 효과가 우수하다. According to the present invention, the composition containing the peymenin effectively inhibits the allergic inflammatory response mediated by mast cells, so that the effect of preventing and treating atopic dermatitis is excellent.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.It should be understood that the effects of the present invention are not limited to the effects described above, but include all effects that can be deduced from the description of the invention or the composition of the invention set forth in the claims.
도 1은 인간 비만세포(HMC-1)에서 페이미닌의 세포 독성을 평가한 것이다. 배양액의 광학밀도는 분광광도계로 490 nm에서 측정하였다.
도 2는 PMACI에 의해 자극된 인간 비만세포에서 페이미닌 처리에 따른 전염증성 사이토카인(IL-6, IL-8, TNF-a)의 수준을 측정한 것이다. ELISA 분석을 통해 (A) IL-6 (B) IL-8 (C) TNF-a의 수준을 측정하였다.
도 3은 PMACI에 의해 자극된 인간 비만세포에서 염증성 사이토카인 mRNA의 발현 수준을 측정한 것이다. (A) 세포는 PMACI 자극 이전 10, 25, 50 mg/mL 농도의 페이미닌 및 100nM의 덱사메사손을 사전 처리하였다. Image J를 통해 (B) IL-6 (C) IL-8 (D) TNF-a (E) IL-1β의 mRNA 발현 수준을 측정하였다.
도 4는 인간 비만세포에서 PMACI에 의해 활성화된 MAPKs의 수준을 측정한 것이다. (A) 인간 비만세포는 페이미닌 사전 처리 후, MAPK 활성화를 위해 PMACI로 30분간 자극하였다. Image J를 통해 (B) P-ERK (C) P-JNK (D) P-P38의 mRNA 발현 수준을 측정하였다.
도 5는 인간 비만세포에서 PMACI에 의해 활성화된 NF-kB p65의 수준을 측정한 것이다. (A) 인간 비만세포는 페이미닌 사전 처리 후, PMACI와 함께 2시간 동안 배양하여 자극하였다. Image J를 통해 (B) p-IkB-a (C) NF-kB의 mRNA 발현 수준을 측정하였다.
도 6은 compound 48/80에 의해 자극된 인간 비만세포에서 페이미닌 처리에 따른 히스타민 방출 수준을 측정한 것이다. (A) 정상적인 인간 비만세포를 나타낸다. (B) compound 48/80 자극에 의해 탈과립된 인간 비만세포를 나타낸다. (C-E) 농도별 페이미닌(10 내지 50 mg/mL)을 처리한 인간 비만세포를 나타낸다. (F) 100nM 농도의 덱사메사손을 처리한 인간 비만세포를 나타낸다. (G) compound 48/80 자극에 의해 탈과립된 인간 비만세포에서 페이미닌 처리에 따른 히스타민 방출 수준을 측정한 것이다.
도 7은 마우스 모델에서 페이미닌 처리에 따른 PCA(passive cutaneous anaphylaxis) 반응을 측정한 것이다.
도 8은 DNCB(2,4-dinitrochlorobenzene)에 의해 아토피 피부염이 유도된 마우스 모델에서 페이미닌 처리에 따른 진피 및 표피의 두께를 측정한 것이다. (A) H&E 염색법으로 표피 및 진피의 두께를 측정하였다(배율 : 100´, 기준자 : 200㎛). (B) 표피의 두께를 측정한 것이다. (C) 진피의 두께를 측정한 것이다.
도 9는 DNCB에 의해 아토피 피부염이 유도된 마우스 모델에서 페이미닌 처리에 따른 호산구의 침윤 정도를 측정한 것이다. (A) H&E 염색법으로 피부 병변에서 호산구의 침윤을 측정하였다(배율 : 400´ 및 1000´, 기준자 : 50㎛ 및 20㎛). (B) 호산구 세포의 숫자를 정량한 것이다.
도 10은 DNCB에 의해 아토피 피부염이 유도된 마우스 모델에서 페이미닌 처리에 따른 비만세포의 침윤 정도를 측정한 것이다. (A) 톨루이딘블루 염색법으로 피부 병변에서 비만세포의 침윤을 측정하였다(배율 : 400´ 및 1000´, 기준자 : 200㎛ 및 50㎛). (B) 비만세포의 숫자를 정량한 것이다.
도 11은 은 DNCB에 의해 아토피 피부염이 유도된 마우스 모델에서 혈청 내 IgE 수준을 측정한 것이다.
도 12는 DNCB에 의해 아토피 피부염이 유도된 마우스 모델에서 혈청 내 IgE, IL-6, IL-4, 및 TNF-α의 수준을 측정한 것이다.
도 13은 DNCB에 의해 아토피 피부염이 유도된 마우스 모델에서 NF-κB 단백질의 발현을 측정한 것이다.
도 14는 DNCB에 의해 아토피 피부염이 유도된 마우스 모델에서 MAPK 단백질의 발현을 측정한 것이다.
도 15는 RAW264.7 세포에서 TNF-α, COX-2, 및 IL-1β mRNA의 발현 수준을 측정한 것이다.Fig. 1 is an evaluation of the cytotoxicity of peymenin in human mast cell (HMC-1). The optical density of the culture was measured with a spectrophotometer at 490 nm.
FIG. 2 is a graph showing levels of proinflammatory cytokines (IL-6, IL-8, TNF-a) according to treatment with peminin in human mast cells stimulated by PMACI. The level of IL-6 (B) IL-8 (C) TNF-a was measured by ELISA analysis.
Figure 3 is a measurement of the level of expression of inflammatory cytokine mRNA in human mast cells stimulated by PMACI. (A) cells were pretreated with 10, 25, and 50 mg / mL of pemiminin and 100 nM dexamethasone prior to PMACI stimulation. The level of mRNA expression of IL-6 (C) IL-8 (D) TNF-a (E) IL-
Figure 4 shows the levels of PMACI-activated MAPKs in human mast cells. (A) Human mast cells were stimulated with PMACI for 30 min to activate MAPK after pretreatment with pemimin. MRNA expression levels of (B) P-ERK (C) P-JNK (D) P-
Figure 5 is a graph showing the level of PMACI-activated NF-kB p65 in human mast cells. (A) Human mast cells were stimulated by pretreatment with pemimin and then with PMACI for 2 hours. (B) p-IkB-a (C) NF-kB mRNA expression levels were measured through Image J.
Figure 6 is a histamine release level measured by pemimin treatment in human mast cells stimulated by compound 48/80. (A) Represents normal human mast cell. (B) human mast cells degranulated by compound 48/80 stimulation. (10 to 50 mg / mL) per concentration (CE) concentration of human mast cells. (F) human mast cells treated with dexamethasone at a concentration of 100 nM. (G) The histamine release level was measured by treatment with pemiminin in human mast cells degranulated by compound 48/80 stimulation.
FIG. 7 is a graph showing a PCA (passive cutaneous anaphylaxis) response according to a treatment with a peymenin in a mouse model.
FIG. 8 is a photograph of dermis and epidermal thickness measured by treatment with pemimin in a mouse model in which atopic dermatitis was induced by DNCB (2,4-dinitrochlorobenzene). (A) The thickness of epidermis and dermis was measured by H & E staining (magnification: 100 ', reference: 200 μm). (B) The thickness of the epidermis was measured. (C) The thickness of the dermis is measured.
FIG. 9 is a graph showing the degree of infiltration of eosinophils according to treatment with peminizin in a mouse model in which atopic dermatitis was induced by DNCB. (A) The infiltration of eosinophils in skin lesions was measured by H & E staining (magnification: 400 'and 1000', reference: 50 μm and 20 μm). (B) the number of eosinophils.
10 is a graph showing the degree of infiltration of mast cells according to treatment with pemimin in a mouse model in which atopic dermatitis was induced by DNCB. (A) Infiltration of mast cells in skin lesions was measured by toluidine blue staining (magnification: 400 'and 1000', reference standard: 200 μm and 50 μm). (B) the number of mast cells.
FIG. 11 shows serum IgE levels in a mouse model in which atopic dermatitis was induced by silver DNCB.
FIG. 12 shows the levels of IgE, IL-6, IL-4, and TNF-a in serum in a mouse model in which atopic dermatitis was induced by DNCB.
Fig. 13 shows the expression of NF-κB protein in a mouse model in which atopic dermatitis was induced by DNCB.
14 shows the expression of MAPK protein in a mouse model in which atopic dermatitis was induced by DNCB.
FIG. 15 shows the expression levels of TNF-a, COX-2, and IL-1 beta mRNA in RAW 264.7 cells.
본 명세서에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.As used herein, the terminology used herein is intended to encompass all commonly used generic terms that may be considered while considering the functionality of the present invention, but this may vary depending upon the intent or circumstance of the skilled artisan, the emergence of new technology, and the like. Also, in certain cases, there may be a term selected arbitrarily by the applicant, in which case the meaning thereof will be described in detail in the description of the corresponding invention. Therefore, the term used in the present invention should be defined based on the meaning of the term, not on the name of a simple term, but on the entire contents of the present invention.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the contextual meaning of the related art and are to be interpreted as either ideal or overly formal in the sense of the present application Do not.
수치 범위는 상기 범위에 정의된 수치를 포함한다. 본 명세서에 걸쳐 주어진 모든 최대의 수치 제한은 낮은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 낮은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 최소의 수치 제한은 더 높은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 높은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 수치 제한은 더 좁은 수치 제한이 명확히 쓰여져 있는 것처럼, 더 넓은 수치 범위 내의 더 좋은 모든 수치 범위를 포함할 것이다.The numerical range includes numerical values defined in the above range. All numerical limitations of all the maximum numerical values given throughout this specification include all lower numerical limitations as the lower numerical limitations are explicitly stated. All the minimum numerical limitations given throughout this specification include all higher numerical limitations as the higher numerical limitations are explicitly stated. All numerical limitations given throughout this specification will include any better numerical range within a broader numerical range, as narrower numerical limitations are explicitly stated.
이하, 본 발명의 실시예를 상세히 기술하나, 하기 실시예에 의해 본 발명이 한정되지 아니함은 자명하다.Hereinafter, embodiments of the present invention will be described in detail, but it should be apparent that the present invention is not limited by the following examples.
본 발명의 일 측면은 페이미닌(peiminine) 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 아토피 피부염의 예방 및 치료용 약학 조성물을 제공한다. One aspect of the present invention provides a pharmaceutical composition for preventing and treating atopic dermatitis comprising peiminine or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 페이미닌은 하기 화학식 1로 표시되는 화합물로서 천연 공급원에서 분리할 수 있으나 이에 한정되지 않고, 당해 기술 분야에 공지된 방법으로 화학적으로 합성하거나, 시판되는 물질을 사용할 수 있다.The above-mentioned pemiminin is a compound represented by the following general formula (1), but it can be isolated from a natural source, but it is not limited thereto, and may be chemically synthesized by a method known in the art or a commercially available substance may be used.
[화학식 1][Chemical Formula 1]
상기 화합물은 전통 약재로서 널리 사용된 바 있는 패모( Fritillaria ussuriensis)의 주요 화합물로서, Osnovanine; RADDEANINE; PEIMINE(RG), Fritillarine; Cevan-6-one, 3, 20-dihydroxy-, (3β, 5α)- 또는 3beta, 20-Dihydroxy-5alpha-cevan-6-one로 호칭될 수 있다. The compounds as the major compounds of paemo (Fritillaria ussuriensis) with a widely used as a traditional medicine bar, Osnovanine; RADDEANINE; PEIMINE (RG), Fritillarine; Cevan-6-one, 3, 20-dihydroxy-, (3β, 5α) - or 3beta, 20-Dihydroxy-5alpha-cevan-6-one.
상기 패모는 기침을 억제하고 중추신경 계통, 특히 호흡과 핏줄 운동 중추에 작용하여 호흡 및 맥박을 완화시키는 것으로 알려져 다양한 폐질환의 치료 용도로서 사용된 바 있다. 상기 패모의 다양한 생리 효과에도 불구하고 상기 페이미닌이 아토피 피부염과 관련된 신호 경로에 직접적으로 작용하는 항-아토피 효과가 있음은 알려진 바 없다. It has been known to inhibit coughing and to act on the central nervous system, particularly respiration and the vital muscles, to alleviate respiration and pulse, and has been used for the treatment of various pulmonary diseases. Despite the diverse physiological effects of this remnant, it is not known that the pemiminin has an anti-atopic effect that acts directly on the signal pathway associated with atopic dermatitis.
상기 “유효성분으로 포함하는”은 투여하고자 하는 개체에 대한 치료적 또는 예방적 효과를 제공하기에 충분한 페이미닌을 포함하는 것을 의미하며, 페이미닌은 인체에 대한 독성이 없으므로 당업자가 다양한 변수를 고려하여 양적 상한을 적절히 조정할 수 있다. As used herein, the phrase " comprising as an active ingredient " means to include a sufficient amount of peymenin to provide a therapeutic or prophylactic effect on the individual to be administered. Peymanin is not toxic to the human body, The quantitative upper limit can be appropriately adjusted.
상기 “예방”은 동물의 병리학적 현상의 발생 빈도 또는 정도를 감소시키는 모든 행위를 의미한다. 예방은 완전할 수 있으며 또는 부분적일 수도 있다. 이 경우에는 특정 개체에 발병된 아토피 피부염이 상기 조성물을 사용하지 않은 경우와 비교하여 감소하는 현상을 의미할 수 있다. Said " prevention " means any action which reduces the frequency or degree of occurrence of the pathological phenomenon of an animal. Prevention can be complete or partial. In this case, it may mean that the atopic dermatitis developed in a specific subject is reduced as compared with the case where the composition is not used.
상기 “치료”는 치료하고자 하는 대상 또는 세포의 천연 과정을 변경시키기 위하여 임상적으로 개입하는 모든 행위를 의미하며, 임상 병리 상태가 진행되는 동안 또는 이를 예방하기 위하여 수행될 수 있다. 목적하는 치료 효과는 질병의 발생 또는 재발을 예방하거나, 증상을 완화시키거나, 질병에 따른 모든 직접 또는 간접적인 병리학적 결과를 저하시키거나, 전이를 예방하거나, 질병 진행 속도를 감소시키거나, 질병 상태를 경감 또는 일시적 완화시키거나, 예후를 개선시키는 것을 포함할 수 있다.The term " treatment " means any act that is clinically intervened to alter the natural course of the subject or cell to be treated, and may be performed during or during the course of the clinical pathology. The desired therapeutic effect may be to prevent the occurrence or recurrence of the disease, to alleviate the symptoms, to reduce all direct or indirect pathological consequences of the disease, to prevent metastasis, to reduce the rate of disease progression, Relieving or temporarily alleviating the condition, or improving the prognosis.
상기 염은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 사용될 수 있다. 상기 산 부가염은 통상의 방법, 예컨대 화합물을 과량의 산 수용액에 용해시키고, 수혼화성 유기 용매(예컨대, 메탄올, 에탄올, 아세톤 또는 아세토니트릴)로 침전시켜 제조할 수 있다. 또한, 동 몰량의 화합물 및 물 중의 산 또는 알코올(예컨대, 글리콜 모노메틸 에테르)을 가열하고, 상기 혼합물을 증발시켜 건조시키거나 석출된 염을 흡인 여과할 수 있다. The salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. The acid addition salt can be prepared by a conventional method, for example, by dissolving the compound in an excess amount of an aqueous acid solution and precipitating with a water-miscible organic solvent (for example, methanol, ethanol, acetone or acetonitrile). Further, the same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated, the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.
상기 유리산은 유기산 및 무기산이 사용될 수 있다. 예컨대, 상기 무기산은 염산, 브롬산, 황산, 또는 인산일 수 있으며, 상기 유기산은 구연산(Citric acid), 초산, 젖산, 주석산(Tartaric acid), 말레인산, 푸마르산(Fumaric acid), 포름산, 프로피온산(Propionic acid), 옥살산, 트리플루오로아세트산, 벤조산, 글루콘산, 메탄설폰산, 글리콜산, 숙신산(Succinic acid), 4-톨루엔설폰산, 벤젠설폰산, 살리실산, 니코틴산, 이소니코틴산, 피콜린산, 글루탐산 또는 아스파르트산일 수 있으나, 이에 한정되는 것은 아니다. The free acid may be an organic acid or an inorganic acid. For example, the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, or phosphoric acid. The organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, wherein the organic acid is selected from the group consisting of acetic acid, acetic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4- toluenesulfonic acid, benzenesulfonic acid, salicylic acid, nicotinic acid, isonicotinic acid, Or aspartic acid, but is not limited thereto.
상기 조성물은 비만세포(mast cell)가 매개하는 알레르기성 염증 반응을 억제할 수 있다. The composition may inhibit allergic inflammatory responses mediated by mast cells.
상기 비만세포는 모든 포유 동물 조직에 있으며, 염증 및 자가 면역 질환의 발병 기전에 중요한 역할을 한다(Heger et al., 2014). 상기 비만세포는 생명을 위협하는 아나필락시스, 알레르기성 비염, 아토피성 피부염과 같은 알레르기성 반응의 초기 단계 또는 후기 단계 염증 반응 중에 효과기 세포(effector cells)로서 기능할 수 있다(El-Agamy, 2012).The mast cells are present in all mammalian tissues and play an important role in the pathogenesis of inflammation and autoimmune diseases (Heger et al., 2014). The mast cells may function as effector cells during early or late stage inflammatory reactions of allergic reactions such as life-threatening anaphylaxis, allergic rhinitis, and atopic dermatitis (El-Agamy, 2012).
활성화되어 탈과립(degranulation)된 비만세포는 사이토카인(cytokines) 및 케모카인(chemokines)을 생성할 수 있다. 상기 비만세포에 의해 방출되는 사이토카인은 상주 세포(resident cells)에 의한 염증유발 사이토카인(proinflammatory cytokine)의 생성을 증대시킬 수 있다.Activated and degranulated mast cells can produce cytokines and chemokines. The cytokine released by the mast cells may increase the production of proinflammatory cytokines by resident cells.
특히, 방출된 히스타민은 혈관(vessel) 투과성(permeabilization)을 증대시켜 염증 조직으로 호산구(eosinophils), 호중구(neutrophils), 및 대식세포의 이동을 촉진할 수 있다. 따라서, 비만세포의 활성화 및 탈과립은 상기 염증 반응을 증대 및 지속시킬 수 있다(Galli and Tsai, 2012).In particular, released histamine increases vessel permeabilization and can promote the migration of eosinophils, neutrophils, and macrophages into inflammatory tissues. Thus, activation and degranulation of mast cells can increase and sustain the inflammatory response (Galli and Tsai, 2012).
따라서 상기 조성물은 상기 비만세포의 활성화 및 탈과립화를 저해하므로 상기 비만세포에 의해 매개되는 알레르기성 염증 반응을 효과적으로 억제할 수 있다. Therefore, the composition inhibits the activation and degranulation of the mast cell, thereby effectively suppressing the allergic inflammation mediated by the mast cell.
구체적으로 상기 조성물은 비만세포의 MAPK 인산화(MAPKs phosphorylation) 및 NF-kB 신호 전달 경로(NF-kB signal pathway)를 억제할 수 있고, 상기 비만세포의 히스타민 방출을 억제하여 알레르기성 염증 반응을 완화 또는 제거할 수 있다. Specifically, the composition can inhibit MAPK phosphorylation and NF-kB signal pathway of mast cells and inhibit histamine release of mast cells to alleviate or prevent allergic inflammation. Can be removed.
염증성 사이토카인의 발현은 NF-kB 및 MAPKs의 신호 전달(transductions)에 의존한다. 상기 비만세포는 PMACI의 자극에 의해 MAPKs 및 NF-kB 신호가 활성화되고, 이로 인해 다량의 사이토카인 및 케모카인, 부착분자(adhesion molecule), 염증 매개물질(inflammatory mediator), 매트릭스 분해 효소(matrix degrading enzyme)의 과량 발현 및 방출을 야기할 수 있다. The expression of inflammatory cytokines depends on the transduction of NF-kB and MAPKs. In the mast cells, MAPKs and NF-kB signals are activated by the stimulation of PMACI, and thus a large amount of cytokines and chemokines, adhesion molecules, inflammatory mediators, matrix degrading enzymes ) ≪ / RTI >
MAPKs는 중요한 NF-kB 활성화 인자이다. 상기 NF-kB는 세포 외 신호-조절 키나아제(ERK), P38, 및 c-Jun N-말단 키나아제(JNK)와 같은 MAPK 패밀리 멤버에 의해 활성화될 수 있다(Han et al., 2013).MAPKs are important NF-kB activating factors. The NF-kB can be activated by MAPK family members such as extracellular signal-regulated kinase (ERK), P38, and c-Jun N-terminal kinase (JNK) (Han et al., 2013).
신호전달 반응에 의해서 비만세포가 활성화되면 세포질 내 칼슘 농도가 상승하고 비만세포의 탈과립이 유도되어 과립 내의 히스타민, 프로스타글란딘, 류코트리엔, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-13 등의 사이토카인을 분비하며, 분비된 염증성 사이토카인은 혈관 확장이나 투과성의 항진, 신경종말의 자극, 점액 분비의 항진, 평활근의 수축 등 조기 알레르기 반응을 촉진할 수 있다(Meltzer, E. O. et al, 2000).When mast cells are activated by signal transduction, intracellular calcium concentration is elevated, and degranulation of mast cells is induced. Thus, histamine, prostaglandin, leukotrienes, TNF-α, IL-1β, IL- 6, and IL-13, and secreted inflammatory cytokines can promote early allergic responses such as vasodilation and hyperpermeability, stimulation of nerve endings, exacerbation of mucus secretion, and smooth muscle contraction (Meltzer , EO et al, 2000).
상기 페이미닌은 TNF-α, IL-4, IL-6, IL-10 등 알레르기 염증 반응에 관여하는 사이토카인의 생성을 억제하며, 사이토카인의 전사인자인 NF-kB 및 상기 NF-kB의 활성화에 관여하는 MAPK(ERK, JNK 및 p-38)을 효과적으로 저해하므로 아토피 피부염의 예방 및 치료 효과가 우수하다. The pemiminin inhibits the production of cytokines involved in allergic inflammatory reactions such as TNF-a, IL-4, IL-6 and IL-10 and inhibits cytokine transcription factors NF-kB and NF- And effectively inhibits MAPK (ERK, JNK, and p-38) involved in activation. Thus, the prevention and treatment effect of atopic dermatitis is excellent.
한편, 상기 조성물은 약학 조성물의 제조에 사용되는 담체, 부형제 및 희석제를 더 포함할 수 있다. On the other hand, the composition may further comprise a carrier, an excipient, and a diluent used in the production of the pharmaceutical composition.
상기 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유를 들 수 있으나, 이에 한정되는 것은 아니다. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, But are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
또한, 상기 조성물은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화 하여 사용할 수 있다. In addition, the composition may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like, external preparation, suppository and sterilized injection solution.
상기 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 페이미닌과 적어도 하나 이상의 부형제, 예컨대, 전분, 칼슘카보네이트, 수크로오스, 락토오스, 또는 젤라틴 등을 혼합하여 조제할 수 있다. 상기 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제가 사용될 수도 있다. Such solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which are prepared by mixing the above-mentioned pemiminin with at least one excipient such as starch, calcium carbonate, sucrose, lactose, And the like can be mixed and prepared. In addition to the above excipients, lubricants such as magnesium stearate and talc may also be used.
상기 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 사용될 수 있으며, 단순희석제인 물, 리퀴드 파라핀 외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions, syrups, and the like. In addition to water and liquid paraffin which are simple diluents, various excipients such as wetting agents, sweeteners, have.
상기 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 사용될 수 있다. 상기 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르가 사용될 수 있다. 상기 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴이 사용될 수 있다. The preparation for parenteral administration may be a sterilized aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, or a suppository. Examples of the non-aqueous solvent and suspensions may include injectable esters such as propylene glycol, polyethylene glycol, vegetable oil such as olive oil and ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, and glycerogelatin.
상기 페이미닌을 유효성분으로 포함하는 약학적 조성물은 약제학적으로 유효한 양이 대상체에 투여될 수 있다. 상기 “유효한 양”은 의학적 치료에 적용 가능한 합리적인 수혜 또는 위험 비율로 질환을 치료하기에 충분한 양을 의미한다. 상기 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. A pharmaceutical composition containing the above-mentioned pemiminin as an active ingredient can be administered to a subject in a pharmaceutically effective amount. Said " effective amount " means an amount sufficient to treat the disease at a reasonable benefit or risk rate applicable to medical treatment. The efficacious dose level will depend on factors such as the type of disease of the patient, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, Can be determined accordingly.
상기 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며 단일 또는 다중 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 바람직하며, 이는 당업자에 의해 용이하게 결정될 수 있다. The pharmaceutical composition may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is desirable to administer an amount that allows for all of the above factors to be maximally effected in a minimal amount without side effects, which can be readily determined by one skilled in the art.
본 발명의 다른 측면은 페이미닌(peiminine) 또는 그의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 아토피 피부염의 예방 및 개선용 식품 조성물을 제공한다. Another aspect of the present invention provides a food composition for preventing and improving atopic dermatitis comprising peiminine or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 식품 조성물은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등 모든 형태의 식품 조성물을 포함할 수 있다. 상기 유형의 식품 조성물은 당해 기술 분야에 공지된 통상적인 방법에 따라 제조될 수 있다. The food composition may comprise any form of food composition, such as functional food, nutritional supplement, health food and food additives. Food compositions of this type may be prepared according to conventional methods known in the art.
일 실시예에 있어서, 상기 식품 조성물은 건강기능식품 형태로 제공될 수 있다. 상기 건강기능식품은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, 상기 기능성은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 의미한다. In one embodiment, the food composition may be provided in the form of a health functional food. The health functional food refers to a food prepared and processed by using a raw material or a component having a useful function in the human body according to the Health Functional Food Act No. 6727. The functional property refers to the nutrient ≪ / RTI > or physiological effects, and the like.
상기 식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 식품 첨가물은 다른 규정이 없는 한 식품의약품 안정청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 적합성 여부를 판단할 수 있다. 상기 식품 첨가물 공전에 기재된 품목은 예컨대 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류를 들 수 있다.The above food composition may contain conventional food additives and, unless otherwise specified, conform to the standards and standards of the relevant items in accordance with the general provisions of the Food Additives Ordinance approved by the Korea Food & Can be determined. The food additives described in the above-mentioned Food Additives Code include chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as persimmon extract, licorice extract, crystalline cellulose, high- A preservative formulation, a tar coloring agent, and the like.
상기 식품 조성물은 아토피성 피부염 예방 또는 개선을 위한 식품 및 음료 등에 다양하게 이용될 수 있으며, 예컨대, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성 보조 식품, 식품 첨가제 등에 사용될 수 있다. The food composition can be variously used for foods and beverages for prevention or improvement of atopic dermatitis and can be used for various foods, beverages, gums, tea, vitamin complex, health functional supplement, food additive and the like.
또한, 상기 식품 조성물은 알레르기 관련 질환 예방 또는 개선을 목적으로 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군에서 선택된 어느 하나의 제형으로 제조 및 가공될 수 있다. In addition, the food composition may be manufactured and processed into any one form selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and rings for the purpose of preventing or improving allergy-related diseases.
구체적으로 상기 정제 형태의 식품 조성물은 페이미닌, 부형제, 결합제, 붕해제 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 후, 활택제 등을 넣어 압축 성형하거나, 상기 혼합물을 직접 압축 성형하여 제조할 수 있다. 또한, 상기 정제 형태의 건강기능식품은 필요에 따라 고미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.Specifically, the food composition in tablet form may be prepared by granulating a mixture of peymenin, excipient, binder, disintegrant, and other additives by a conventional method, compression-molding the mixture by a lubricant or the like, . In addition, the health functional food of the tablet form may contain a starch or the like as needed, and may be sieved with a suitable skin care agent if necessary.
상기 캅셀 형태의 식품 조성물 중 경질캅셀제는 통상의 경질캅셀에 페이미닌 및 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캅셀제는 페이미닌 및 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캅셀기제에 충진하여 제조할 수 있다. 상기 연질캅셀제는 필요에 따라 글리세린 또는 솔비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.The hard capsule of the capsule type food composition can be prepared by filling a normal hard capsule with a mixture with an additive such as pemimin and an excipient, or a granulate thereof or a granulated product thereof. An excipient or the like may be filled in a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
상기 환 형태의 식품 조성물은 페이미닌 놀렌산, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다.The food composition in the form of a ring can be prepared by molding a mixture of pemimininoleic acid, an excipient, a binder, a disintegrant and the like in an appropriate manner. If necessary, the food composition may be mixed with saccharide or other suitable agent, It may also be an objectionable substance.
상기 과립 형태의 식품 조성물은 페이미닌, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 고미제 등을 함유할 수 있다. 상기 부형제, 결합제, 붕해제, 활택제, 고미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함할 수 있다. The granular food composition may be prepared by granulating a mixture of pemimin, an excipient, a binder, a disintegrant and the like in a suitable manner, and may contain a flavoring agent, a starch, and the like, if necessary. The definitions of the above excipients, binders, disintegrants, lubricants, antiseptics, flavors and the like are described in documents known in the art, and the functions and the like may be the same or similar.
이하 실시예를 통해, 본 발명을 더욱 상술하나 하기 실시예에 의해 본 발명이 제한되지 아니함은 자명하다.The present invention will be further described with reference to the following examples, but it should be apparent that the present invention is not limited by the following examples.
실험예Experimental Example 1 : 세포 독성 시험 1: Cytotoxicity test
본 발명자들은 페이미닌의 세포 생존에 대한 영향을 분석하고자 MTS 분석을 수행하였다. 인간 비만세포(human mast cell; HMC-1)에 1, 10, 25, 50, 100mg/mL 농도의 페이미닌을 각각 처리하였다. The present inventors conducted an MTS analysis to analyze the effect of pemiminin on cell survival. Human mast cells (HMC-1) were treated with 1, 10, 25, 50, and 100 mg / mL of pemiminin, respectively.
세포 독성을 시험하고자 항염 글루코코르티코이드(Glucocorticoid)인 1, 10, 및 100nM 농도의 덱사메사손(dexamethasone)을 양성 대조군으로 이용하였다. To test cytotoxicity, dexamethasone at a concentration of 1, 10, and 100 nM, a glucocorticoid, was used as a positive control.
상기 덱사메사손은 인간 백혈병성 비만세포에서 IL-6, IL-8, TNF-a, IL-3 및 GM-CSF(granulocyte-macrophage colony-stimulating factor)의 발현을 감소시키는 것으로 보고된 바 있다. The dexamethasone has been reported to reduce the expression of IL-6, IL-8, TNF-a, IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in human leukemic mast cells.
시험 결과 페이미닌 및 덱사메사손은 세포 독성이 확인되지 않았으며, 50mg/mL 농도의 페이미닌이 최적의 농도로 사용되었다(도 1).As a result, no cytotoxicity was observed for the pemiminin and dexamethasone, and the optimum concentration of pemiminin at a concentration of 50 mg / mL was used (FIG. 1).
실험예Experimental Example 2 : 사이토카인 방출 억제 활성 시험 2: Test for inhibiting cytokine release
페이미닌이 칼슘 이온 운반체 A23187(PMACI)에 의해 유도된 IL-6, IL-8 및 TNF-a의 생산을 저해할 수 있는지 평가하고자 HMC-1 세포에 페이미닌을 사전 처리하였다. 비만세포는 IL-6 및 IL-8와 같은 염증성 사이토카인의 생산을 매개하므로 염증 반응에서 중요한 역할을 한다. HEM-1 cells were pretreated with pemimin in order to evaluate whether the pemiminin could inhibit the production of IL-6, IL-8 and TNF-a induced by the calcium ion carrier A23187 (PMACI). Mast cells play an important role in the inflammatory response because they mediate the production of inflammatory cytokines such as IL-6 and IL-8.
IL-6은 비만세포에서 방출되고, 충분한 양이 생산될 때 전신 급성기반응(systemic acute phase reaction)을 촉진한다. IL-6 is released from mast cells and promotes the systemic acute phase reaction when a sufficient amount is produced.
TNF-a는 알레르겐 노출에 따라 수분 내에 히스타민 및 다른 알레르기성 매개자와 함께 방출되고, 비만세포 및 T 세포를 활성화한다. 또한, TNF-a는 IL-8 방출에 의한 호중구(neutrophils)의 이동을 유도한다. IL-8는 급성기반응과 연관되고, 림프구 및 호중구의 주화성인자(chemotactic factor)로서 기능한다. TNF-a is released with histamine and other allergenic mediators within minutes in response to allergen exposure and activates mast cells and T cells. In addition, TNF-a induces the migration of neutrophils by IL-8 release. IL-8 is associated with acute phase response and functions as a chemotactic factor for lymphocytes and neutrophils.
페이미닌은 비만세포에서 PMACI에 의해 유도된 IL-6, IL-8 및 TNF-a의 발현을 감소시켰다(도 2). Pemiminin reduced the expression of PMACI-induced IL-6, IL-8 and TNF-a in mast cells (Figure 2).
특히, 10, 25, 50 mg/mL 농도의 페이미닌 및 덱사메사손은 IL-6의 발현을 현저히 감소시켰다. 또한, 50 mg/mL 농도의 페이미닌 및 덱사메사손은 IL-8의 발현을 현저히 감소시켰으며, 10, 25, 50 mg/mL 농도의 페이미닌 및 덱사메사손은 TNF-a을 현저히 억제하였다. In particular, the 10, 25, and 50 mg / mL concentrations of pemimin and dexamethasone significantly reduced the expression of IL-6. Pemimin and dexamethasone at a concentration of 50 mg / mL markedly decreased the expression of IL-8, and the concentrations of 10, 25 and 50 mg / mL of pemimin and dexamethasone significantly increased TNF-a Respectively.
즉, 상기 결과는 페이미닌이 염증성 사이토카인의 발현을 조절할 수 있음을 시사한다. That is, the above results suggest that pemiminin can regulate the expression of inflammatory cytokines.
실험예Experimental Example 3 : 사이토카인 3: cytokine mRNAmRNA 발현량 측정 시험 Expression measurement test
페이미닌이 전염증성 사이토카인(proinflammatory cytokine) mRNA 생산에 영향을 미치는지 분석하고자 PMACI 처리(6시간) 전에 페이미닌을 사전 처리하고 RT-PCR을 수행하였다.To investigate whether pemiminin affects the production of proinflammatory cytokine mRNA, pre-treatment with pemimin was performed before PMACI treatment (6 hours) and RT-PCR was performed.
페이미닌을 사전 처리했을 때 PMACI에 의해 증대된 IL-6, IL-8, TNF-a 및 IL-1β의 발현은 현저히 감소하였다(도 3).The expression of IL-6, IL-8, TNF-a and IL-1β increased by PMACI was markedly reduced upon pretreatment with pemiminin (FIG. 3).
50 mg/mL 농도의 페이미닌 및 덱사메사손은 IL-6의 발현을 현저히 감소시켰다. 25, 50 mg/mL 농도의 페이미닌 및 덱사메사손은 PMACI에 의해 유도된 IL-8 발현을 현저히 억제하였다. 50 mg/mL 농도의 페이미닌 및 덱사메사손은 IL-1β의 발현을 현저히 감소시켰다. 50 mg/mL 농도의 페이미닌은 TNF-a의 발현을 현저히 감소시켰다. Pemiminin and dexamethasone at concentrations of 50 mg / mL significantly reduced the expression of IL-6. 25 and 50 mg / mL of pemimin and dexamethasone significantly inhibited PMACI-induced IL-8 expression. Pemiminin and dexamethasone at a concentration of 50 mg / mL markedly decreased IL-1β expression. Pemiminin at a concentration of 50 mg / mL markedly decreased the expression of TNF-a.
IL-1β는 IL-1 군에 속하며 사이토카인 네트워크의 활성화에 있어 중요한 역할을 수행한다. IL-1에 의해 유도된 염증 활성은 IL-6 발현과 관련된다. IL-1β belongs to the IL-1 family and plays an important role in the activation of the cytokine network. IL-1-induced inflammatory activity is associated with IL-6 expression.
실험예Experimental Example 4 : 4 : PMACI에To PMACI 의해 자극된 Stimulated by MAPKMAPK 활성화 억제 시험 Activation inhibition test
ERK(extracellular signal-regulated kinase), P38, 및 JNK(c-Jun N-terminal kinase)와 같은 MAPK는 사이토카인의 발현과 연관된 신호 전달에 있어서 중요한 역할을 수행하는 것으로 보고된 바 있다. MAPKs such as ERK (extracellular signal-regulated kinase), P38, and JNK (c-Jun N-terminal kinase) have been reported to play an important role in signal transduction associated with the expression of cytokines.
세포질 또는 세포핵에서 전사인자는 MAPK의 활성화에 따라 인산화되고, 표적 유전자의 발현을 촉발시켜 생체 반응을 결과한다. In the cytoplasm or nucleus, transcription factors are phosphorylated upon activation of the MAPK and trigger the expression of the target gene, resulting in a vital response.
페이미닌은 P-ERK 및 P-JNK의 발현을 현저히 억제하였으나, P-P38에 영향을 미치지 않았다(도 4).Peminin significantly inhibited the expression of P-ERK and P-JNK, but did not affect P-P38 (FIG. 4).
상기 결과는 페이미닌이 비만세포에서 사이토카인의 발현을 억제시킴으로써 항-알레르기 효과를 보유할 수 있음을 시사한다. 즉, 페이미닌은 염증성 사이토카인의 생산과 연관된 비만세포에서 ERK 및 JNK의 인산화를 차단시켜 염증성 반응을 감소시킬 수 있다.The results suggest that pemiminin may have an anti-allergic effect by inhibiting the expression of cytokines in mast cells. That is, pemiminin can reduce the inflammatory response by blocking the phosphorylation of ERK and JNK in mast cells associated with the production of inflammatory cytokines.
실험예Experimental Example 5 : 5: PMACI에To PMACI 의해 자극된 of Stimulated by NFNF -- kBkB 활성화 억제 시험 Activation inhibition test
HMC-1 세포에서 페이미닌의 NF-kB의 활성화 및 IkB-a의 분해에 대한 영향을 확인하고자 웨스턴 블랏을 수행하였다.Western blotting was performed in HMC-1 cells to determine the effect of the pemiminin on NF-kB activation and degradation of IkB-a.
NF-kB는 TNF-a, IL-6 및 IL-8와 같은 사이토카인 유전자의 발현을 제어함으로써 염증성 반응에서 중추적 역할을 수행한다. 전사인자인 NF-kB는 알레르기성 염증에서 사이토카인 유전자를 조절한다. NF-kB 활성화에서 저해 단백질 IkB-a의 인산화 및 분해는 필수적이다.NF-kB plays a pivotal role in the inflammatory response by controlling the expression of cytokine genes such as TNF-a, IL-6 and IL-8. The transcription factor NF-kB regulates the cytokine gene in allergic inflammation. Phosphorylation and degradation of the inhibitory protein IkB-a is essential in NF-kB activation.
페이미닌은 IkB-a의 분해를 억제하여 NF-kB의 핵 내 이동을 저해하였으며, 이를 통해 HMC-1 세포에서 TNF-a, IL-6, IL-1β 및 IL-8의 발현을 억제할 수 있다. Peminin inhibited the nuclear translocation of NF-kB by inhibiting the degradation of IkB-a, thereby inhibiting the expression of TNF-a, IL-6, IL-1β and IL-8 in HMC-1 cells .
In vivo에서 급성 알레르기 반응에 앞서 비만세포에서 히스타민이 방출되며, 모세혈관 투과성이 증대된다. Prior to an acute allergic response in vivo In the histamine is released from mast cells, it is increased capillary permeability.
페이미닌(25, 50 mg/mL)은 세포기질(cytosol)에서 농도의존적으로 IkB-a의 분해를 억제하였다. 한편, 덱사메사손은 세포기질에서 IkB-a의 분해를 억제하였으며, 페이미닌(50 mg/mL)은 NF-kB 활성화를 현저히 감소시켰다(도 5).Pemiminin (25, 50 mg / mL) inhibited the degradation of IkB-a in a concentration-dependent manner in the cytosol. On the other hand, dexamethasone inhibited the degradation of IkB-a in cell matrix, and pemiminin (50 mg / mL) markedly reduced NF-kB activation (Fig. 5).
실험예Experimental Example 6 : 히스타민 방출 억제 시험 6: Histamine release inhibition test
HMC-1 세포에서 페이미닌의 히스타민 방출에 대한 효과를 분석하고자 compound 48/80에 의한 세포 활성화를 측정하였다. Cell activation by compound 48/80 was measured in HMC-1 cells in order to analyze the effect of pemiminin on histamine release.
히스타민은 아나필락시스(anaphylaxis) 및 아토피성 피부염(atopic dermatitis)과 같은 알레르기성 반응을 유도한다. 히스타민은 IL-6 및 IL-8을 포함하는 사이토카인 및 케모카인의 발현 및 분비를 제어하는 중요한 역할을 수행하는 것으로 보고되었다. Histamine induces an allergic reaction such as anaphylaxis and atopic dermatitis. Histamine has been reported to play an important role in controlling the expression and secretion of cytokines and chemokines including IL-6 and IL-8.
50 mg/mL 농도의 페이미닌은 compound 48/80에 의한 히스타민 방출을 억제하였으며, 덱사메사손 역시 히스타민 방출을 현저하게 감소시켰다(도 6).Pemiminin at 50 mg / mL inhibited histamine release by compound 48/80, and dexamethasone also significantly reduced histamine release (FIG. 6).
상기 결과는 페이미닌이 compound 48/80에 의한 HMC-1 세포 탈과립 반응에서 히스타민의 수준을 감소시키는 항-알레르기 효과를 보유하고 있음을 시사한다. These results suggest that the pemiminin possesses an anti-allergic effect that reduces histamine levels in the HMC-1 cell degranulation reaction by compound 48/80.
실험예Experimental Example 7 : 7: IgEIgE -매개의 - mediated PCAPCA 반응 억제 시험 Reaction inhibition test
In vivo에서 페이미닌의 알레르기 반응에 대한 효과를 분석하고자 PCA 마우스 모델을 구축하였다. A PCA mouse model was constructed to analyze the effects of peymenin on allergic responses in vivo .
PCA 반응은 급성과민증을 위한 유용한 실험 모델로서, in vivo에서 아나필락시스(anaphylaxis)를 측정할 때 사용된다. The PCA reaction is a useful experimental model for acute hypersensitivity and is used to measure anaphylaxis in vivo .
페이미닌은 마우스의 경구 투여에 따라 IgE-매개의 PCA 반응에 대한 항-알레르기 효과를 나타내었다. Pemiminin showed an anti-allergic effect on the IgE-mediated PCA response upon oral administration of mice.
1, 5 mg/mL 농도의 페이미닌은 반응 면적 및 염색의 양적인 측면에서 PCA 반응을 현저히 억제하였다(도 7). 또한, 1 mg/mL 농도의 덱사메사손은 PCA 반응 면적 및 염색의 양을 현저히 감소시켰다. The 1, 5 mg / mL concentration of the pemiminin significantly inhibited the PCA reaction in terms of the reaction area and the amount of staining (Fig. 7). In addition, dexamethasone at a concentration of 1 mg / mL significantly reduced the area of PCA reaction and the amount of staining.
즉, 상기 결과는 페이미닌이 in vivo에서 IgE 활성을 조절하고, 아나필락시스를 감소시킬 수 있음을 시사한다. That is, the above results suggest that pemiminin can regulate IgE activity in vivo and reduce anaphylaxis.
실험예Experimental Example 8 : 아토피 피부염 억제 효과 시험 8: Atopic dermatitis inhibitory effect test
In vivo에서 페이미닌의 아토피 피부염에 대한 억제 효과를 분석하고자, 생후 7주령된 암컷 BALB/c 마우스를 대상으로 아토피 피부염 모델을 구축하였다. DNCB(2,4-dinitrochlorobenzene)를 일정 조건에 따라 마우스에 처리하여 아토피 피부염을 유발하였다. In vivo in Tenerife we were already established atopic dermatitis models aimed at suppressing To analyze the effect of age 7 week-old female BALB / c mice for non-atopic dermatitis. DNCB (2,4-dinitrochlorobenzene) was treated with mice under certain conditions to induce atopic dermatitis.
적응 기간이 끝난 마우스는 아토피성 피부염을 유발하지 않은 양성 대조군, 아토피성 피부염을 유발시킨 음성 대조군, 아토피성 피부염을 유발시킨 후 1mg/kg의 페이미닌을 도포한 실험군(PMN-Low) 및 5mg/kg의 페이미닌을 도포한 실험군(PMN-High)으로 8마리씩 분류하였다.At the end of the adaptation period, mice were divided into a positive control group that did not induce atopic dermatitis, a negative control group that caused atopic dermatitis, an atopic dermatitis-induced group (PMN-Low) and 1 mg / / kg of pemiminin (PMN-High).
상기 대조군 및 실험군을 대상으로 피부조직에 호산구(eosinophil) 세포 및 부종을 식별하는 H&E(hematoxyline and eosin) 염색과 비만세포를 식별하는 톨루이딘블루(toluidine blue) 염색을 하고 조직 내 비만세포의 침윤을 관찰하였다.The control and experimental groups were subjected to hematoxyline and eosin (H & E) staining to identify eosinophil cells and edema in the skin tissue, and toluidine blue staining to identify mast cells and to observe the infiltration of mast cells in the tissues Respectively.
H&E 염색을 한 대조군의 피부 조직은 표피 및 진피의 두께가 부종으로 인해 유의하게 증가하였고 호산구의 침윤이 확인(표피 : 516%, 진피 : 250%, 호산구 : 597%)되었다(도 8).The epidermis and dermis thickness were significantly increased due to edema and the eosinophil infiltration was confirmed (epidermis: 516%, dermis: 250%, eosinophil: 597%) in the H & E-stained control tissue.
반면, 페이미닌을 처리한 실험군은 대조군과 비교하여 표피 및 진피의 두께와 호산구의 침윤이 유의적으로 감소(PMN-Low 표피 : 154 %, PMN-High 표피 : 167 %, PMN-Low 진피 : 119 %, PMN-High 진피 : 128 %, PMN-Low 호산구 : 177 %, PMN-High 호산구 : 219 %)하였다(도 9).On the other hand, in the experimental group treated with pemiminin, epidermal and dermal thicknesses and eosinophil infiltration were significantly reduced (PMN-Low skin: 154%, PMN-High skin: 167%, PMN-Low dermis: 119%, PMN-High dermis: 128%, PMN-Low eosinophil: 177%, PMN-High eosinophil: 219%).
또한, 톨루이딘블루로 염색된 대조군의 피부 조직은 비만세포의 침윤이 관찰되었다(비만세포: 582 %). 반면, 페이미닌을 처리한 실험군은 대조군과 비교하여 비만세포의 침윤이 유의적으로 감소(PMN-Low 비만세포 : 122%, PMN-High 비만세포 : 147%)하였다(도 10). In addition, the skin tissue of the control group stained with toluidine blue showed infiltration of mast cells (mast cells: 582%). On the other hand, in the experimental group treated with pemiminin, mast cell infiltration was significantly decreased (PMN-Low mast cell: 122%, PMN-High mast cell: 147%) as compared with the control group (FIG.
혈액과 병변 조직에서 호산구의 증가는 아토피 질환의 특징적인 양상이다. 호산구의 활성은 과립구-대식구 집락 자극인자(granulocyte-macrophage colony stimulating factors, GM-CSF), IL-5, eotaxin에 의해 유도되며, 활성화된 호산구는 다양한 화학물질을 방출하여 염증 반응과 조직 손상을 유발한다. The increase of eosinophils in blood and lesion tissues is a characteristic aspect of atopic disease. Activation of eosinophils is induced by granulocyte-macrophage colony stimulating factors (GM-CSF), IL-5 and eotaxin. Activated eosinophils release a variety of chemicals, causing inflammatory reactions and tissue damage do.
급성 또는 만성병변의 빠른 악화에서 피부조직의 호산구 증가와 해면화 정도가 연관성이 있음이 밝혀지기도 하였다. 본 실험에서는 페이미닌 투여가 DNCB 유도된 아토피 피부염 모델의 피부 조직에 미치는 영향과 호산구 침윤 억제를 보기 위해 H&E 염색을 실시하였고, 그 결과 대조군에 비해 PMN-High군과 PMN-Low군 모두에서 호산구의 조직 내 침윤이 유의하게 감소가 관찰되었다. It has been shown that the rapid increase of eosinophilia in the skin tissue and the degree of spongenization are related to the rapid deterioration of acute or chronic lesions. In this study, H & E staining was performed to examine the effect of peymenin administration on skin tissue and inhibition of eosinophil infiltration in DNCB-induced atopic dermatitis model. As a result, eosinophil counts in both PMN-High and PMN- Was significantly decreased.
상기 결과는 페이미닌이 호산구의 조직 내 침윤을 감소시킬 수 있음을 시사하며, 이로써 염증반응 및 해면화 등을 억제하여 병변을 호전시킬 수 있다.These results suggest that peymenin may reduce the infiltration of eosinophils into the tissues, thereby inhibiting the inflammatory reaction and sponge formation, thereby improving the lesion.
실험예Experimental Example 9 : 아토피 피부염 모델의 혈청 내 사이토카인 측정 시험 9: Measurement of serum cytokines in atopic dermatitis models
실험예 8에서 구축된 아토피 피부염 모델의 혈청 내 사이토카인 수준을 측정하고자 ELISA assay를 수행하였다. The ELISA assay was performed to measure the serum cytokine levels of the atopic dermatitis model constructed in Experimental Example 8.
페이미닌 투여에 따른 사이토카인 생성량의 변화를 확인하기 위해 대표적 면역학적 지표인 IgE 값을 분석하고 하기 표 1에 나타내었다.In order to confirm the change of cytokine production according to the administration of pemimin, IgE value which is a representative immunological index was analyzed and shown in Table 1 below.
페이미닌을 처리한 실험군은 음성 대조군과 비교하여 IgE 발현이 현저하게 감소(PMN-Low : 121 %, PMN-High : 136 %)하였으며(도 11), 상기 결과는 페이미닌이 IgE 활성을 조절하고 항-알레르기 효과를 보유하고 있음을 시사한다. In the experimental group treated with pemiminin, the expression of IgE was markedly reduced (PMN-Low: 121%, PMN-High: 136%) compared with the negative control (Fig. 11) And have anti-allergic effects.
실험예Experimental Example 10 : 아토피 피부염 모델의 혈청 내 사이토카인 생성량 시험 10: Production of cytokines in serum of atopic dermatitis model
실험예 8의 아토피 피부염 모델에서 페이미닌 투여가 사이토카인의 생성량의 변화를 확인하기 위해 대표적인 면역학적 지표인 IgE 및 IL-4, IL-6, TNF-α 수치를 추가적으로 확인하였다(도 12). In order to confirm the change of cytokine production in the atopic dermatitis model of Experimental Example 8, the addition of pemiminin further confirmed IgE and IL-4, IL-6 and TNF-alpha levels which are typical immunological indicators (Fig. 12) .
IgE 수치는 정상군 456.87 ± 46.91 ng/ml, 대조군 11467.79 ± 1057.35 ng/ml, PMN-Low군 9449.09 ± 1565.16 ng/ml, PMN-High군 8405.77 ± 866.13 ng/ml로 대조군에 비해 실험군(High군)의 IgE 발현이 유의하게 감소하였다(Low : 82%, High : 73%). The IgE levels were significantly higher in the experimental group (High group) than in the control group (456.87 ± 46.91 ng / ml in the normal group, 11467.79 ± 1057.35 ng / ml in the control group, 9449.09 ± 1565.16 ng / ml in the PMN-Low group and 8405.77 ± 866.13 ng / ml in the PMN- (Low: 82%, High: 73%), respectively.
IL-4 수치는 정상군 0.26 ± 0.06 pg/ml, 대조군 0.79 ± 0.09 pg/ml, PMN-Low군 0.2 ± 0.03 pg/ml, PMN-High군 0.21 ± 0.04 pg/ml로 대조군에 비해 실험군(Low군과 High군 모두)의 IL-4 발현이 유의하게 감소하였다(Low : 25%, High : 26%). The IL-4 levels were 0.26 ± 0.06 pg / ml in the normal group, 0.79 ± 0.09 pg / ml in the control group, 0.2 ± 0.03 pg / ml in the PMN-Low group and 0.21 ± 0.04 pg / ml in the PMN- (Low: 25%, High: 26%), respectively.
IL-6 수치는 정상군 2.38 ± 0.26 pg/ml, 대조군 107.79 ± 17.43 pg/ml, PMN-Low군 34.12 ± 17.43 pg/ml, PMN-High군 73.33 ± 12.76 pg/ml로 대조군에 비해 실험군(Low군)의 IL-6 발현이 감소하였다(Low : 31%, High : 68%). The IL-6 levels were 2.38 ± 0.26 pg / ml in the normal group, 107.79 ± 17.43 pg / ml in the control group, 34.12 ± 17.43 pg / ml in the PMN-Low group and 73.33 ± 12.76 pg / ml in the PMN- (Low: 31%, high: 68%).
TNF-α 수치는 정상군 3.00 ± 0.16 pg/ml, 대조군 4.71 ± 0.35 pg/ml, PMN-Low군 2.97 ± 0.17 pg/ml, PMN-High군 2.32 ± 0.51 pg/ml로 대조군에 비해 실험군(Low군과 High군 모두)의 TNF-α 발현이 유의하게 감소하였다(Low : 63%, High : 49%).The TNF-α level was 3.00 ± 0.16 pg / ml in the normal group, 4.71 ± 0.35 pg / ml in the control group, 2.97 ± 0.17 pg / ml in the PMN-Low group and 2.32 ± 0.51 pg / ml in the PMN- (Low: 63%, high: 49%).
실험예Experimental Example 11 : 아토피 피부염 모델의 11: Atopic dermatitis model NFNF -- κB의KB 활성 시험 Activity test
실험예 8의 아토피 피부염 모델에서 페이미닌 투여가 염증 유발 유전자를 조절하는 핵 내 NF-κB의 단백질 발현에 미치는 영향을 확인하고자 western blot을 수행하였다(도 13).In the atopic dermatitis model of Experimental Example 8, western blotting was performed to confirm the effect of the pemiminin administration on the protein expression of NF-κB in the nucleus which regulates the inflammation-inducing gene (FIG. 13).
DNCB 유도된 대조군에서 NF-κB 발현 농도는 정상군에 비해 증가하였으며, 실험군(High군)에서는 대조군에 비해 감소하였다(PMN-Low : 91%, High : 65%).In the DNCB-induced control group, the NF-κB expression level was increased compared to the normal group and decreased in the experimental group (PMN-Low: 91%, High: 65%) compared with the control group.
실험예Experimental Example 12 : 아토피 피부염 모델의 12: Atopic dermatitis model MAPKMAPK 활성 시험 Activity test
실험예 8의 아토피 피부염 모델에서 NF-κB의 활성화 과정에 관계되는 MAP kinase 인산화를 추가로 확인하였다(도 14).MAP kinase phosphorylation related to the activation of NF-κB was further confirmed in the atopic dermatitis model of Experimental Example 8 (FIG. 14).
정상군에 비해 DNCB 유도된 대조군에서 phosphor-ERK1/2, -JNK, -P38의 활성이 증가하였으며, 실험군에서는 DNCB 유도된 대조군에 비해 P-ERK(PMN-Low : 82%, High : 56%) Low, High 순으로 억제하였으며, P-JNK(PMN-Low: 114%, High : 81%), P-P38(PMN-Low : 110%, High : 55%)는 High에서만 억제하였다. ERK1 / 2, -JNK, and -P38 were increased in the DNCB-induced control group compared with the normal control group. P-ERK (PMN-Low: 82%, High: 56% (PMN-Low: 114%, High: 81%) and P-P38 (PMN-Low: 110%, High: 55%) were suppressed only at High.
실험예Experimental Example 13 : 사이토카인 13: cytokine mRNAmRNA 발현량 측정 시험( Expression amount measurement test ( RAW2643RAW2643 .7 세포).7 cells)
페이미닌 투여가 염증성 세포인 RAW2643.7 세포에 미치는 영향을 확인하고자 mRNA 활성을 평가하였다(도 15).MRNA activity was evaluated to confirm the effect of the pemiminin administration on inflammatory cell RAW2643.7 cells (Fig. 15).
TNF-α, COX-2, 및 IL-1β의 mRNA 발현을 측정하기 위해 PCR을 실시하였다. Raw264.7 세포에 농도를 달리한 페이미닌(10, 25, 50 μg), 자극제 LPS (Lipopolysaccharides, 1 μg/ml)를 처리하여 37℃에서 6시간 동안 반응 시켰다.PCR was performed to measure mRNA expression of TNF-a, COX-2, and IL-1 ?. Raw264.7 cells were treated with different concentrations of pemiminin (10, 25, and 50 μg) and stimulant LPS (Lipopolysaccharides, 1 μg / ml) for reaction at 37 ° C for 6 hours.
배지 상층액을 제거한 후 trizol lysis buffer를 well에 1 ml씩 분주하여 세포에서 RNA를 추출 하였다. 추출한 RNA는 Nano-Drop을 이용하여 RNA량을 측정 하였다. 측정된 RNA는 역전사 키트를 사용하여 제조사의 프로토콜에 따라 total RNA (2 μg)로부터 cDNA를 제조 한 후 Taq 중합 효소를 이용하여 PCR로 증폭시켰다. PCR은 마우스 TNF-α, COX-2 그리고 IL-1β 프라이머를 이용하여 수행 되였다. cDNA sample은 1.2% agarose gel을 이용하여 분리하고, SYBR green 염색하고, NαBI를 사용하여 측정하였다.After removal of the supernatant, 1 ml of trizol lysis buffer was added to each well and RNA was extracted from the cells. The amount of extracted RNA was measured using nano-drop. The measured RNA was amplified by PCR using Taq polymerase after preparing cDNA from total RNA (2 μg) according to the manufacturer's protocol using a reverse kits kit. PCR was carried out using mouse TNF-α, COX-2 and IL-1β primers. cDNA samples were isolated using 1.2% agarose gel, stained SYBR green, and measured using NαBI.
실험결과 페이미닌이 LPS로 유도된 염증성 사이토카인인 TNF-α의 mRNA 발현을 농도 의존적으로 유의하게 감소시켰다. 또한 COX-2의 mRNA 발현 또한 고농도에서 유의하게 억제시켰으며, IL-1β에서는 1 μg/mL과 100 μg/mL 농도에서 사이토카인을 유의하게 억제시켰다.As a result, pemiminin significantly reduced mRNA expression of TNF-α, an inflammatory cytokine induced by LPS, in a concentration-dependent manner. In addition, COX-2 mRNA expression was also significantly inhibited at high concentrations, and IL-1β significantly inhibited cytokine concentrations at 1 μg / mL and 100 μg / mL.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is defined by the appended claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included within the scope of the present invention.
Claims (8)
알레르기성 염증 반응을 억제하는 약학 조성물.The method according to claim 1,
A pharmaceutical composition for inhibiting an allergic inflammatory response.
MAPK 인산화(MAPKs phosphorylation) 및 NF-kB 신호 전달 경로(NF-kB signal pathway)를 억제하는 약학 조성물.The method according to claim 1,
MAPK phosphorylation and the NF-kB signaling pathway.
히스타민 방출을 억제하는 약학 조성물.The method according to claim 1,
A pharmaceutical composition for inhibiting histamine release.
피부조직 내 호산구 및 비만세포의 침윤을 감소시키는 약학 조성물.The method according to claim 1,
A pharmaceutical composition for reducing infiltration of eosinophils and mast cells in dermal tissue.
표피 및 진피의 두께를 감소시키는 약학 조성물.6. The method of claim 5,
A pharmaceutical composition for reducing the thickness of epidermis and dermis.
정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 구성된 군에서 선택된 어느 하나의 제형으로 제조된 식품 조성물.
8. The method of claim 7,
Wherein the composition is in the form of a tablet, a granule, a powder, a capsule, a liquid solution and a ring.
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| KR101984579B1 (en) | 2017-11-29 | 2019-06-07 | 김좌진 | Composition for Treating Atopic Dermatitis |
| KR20200040402A (en) * | 2018-10-10 | 2020-04-20 | 경희대학교 산학협력단 | A composition for preventing or terating atopic dermatitis comprising lycopi herba extract as an active ingredient |
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| KR20200040402A (en) * | 2018-10-10 | 2020-04-20 | 경희대학교 산학협력단 | A composition for preventing or terating atopic dermatitis comprising lycopi herba extract as an active ingredient |
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