KR101664531B1 - Composition for prevention of depilation and improvement of hair growth comprising Formononetin - Google Patents
Composition for prevention of depilation and improvement of hair growth comprising Formononetin Download PDFInfo
- Publication number
- KR101664531B1 KR101664531B1 KR1020130016046A KR20130016046A KR101664531B1 KR 101664531 B1 KR101664531 B1 KR 101664531B1 KR 1020130016046 A KR1020130016046 A KR 1020130016046A KR 20130016046 A KR20130016046 A KR 20130016046A KR 101664531 B1 KR101664531 B1 KR 101664531B1
- Authority
- KR
- South Korea
- Prior art keywords
- hair
- composition
- hair loss
- formononetin
- pharmaceutically acceptable
- Prior art date
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- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 title claims abstract description 60
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Abstract
본 발명은 포모노네틴(Formononetin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 및 발모촉진용 약제학적 조성물에 관한 것이다. 본 발명의 따른 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 조성물은 탈모에 의해서 발생하는 면역반응 및 세포사멸 반응을 억제하는 것을 통해 모발의 재발모를 촉진하는 효과를 가지며, 상기 면역 반응 및 세포사멸 반응을 억제하는 효과를 통해 애초에 자연적으로 일어나는 탈모를 방지하는 효과를 가짐에 따라, 포모노네틴이 탈모방지 및 발모촉진용 조성물로 널리 사용될 수 있다.The present invention relates to a pharmaceutical composition for preventing hair loss and promoting hair growth comprising Formononetin or a pharmaceutically acceptable salt thereof as an active ingredient. The composition comprising as an active ingredient pomanoneceptin or a pharmaceutically acceptable salt thereof according to the present invention has an effect of promoting hair regrowth through inhibiting the immune reaction and apoptosis caused by hair loss, The effect of inhibiting the immune reaction and the apoptosis reaction is prevented, and pomonoetin can be widely used as a composition for preventing hair loss and promoting hair growth.
Description
본 발명은 포모노네틴(Formononetin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 및 발모촉진용 약제학적 조성물에 관한 것이다.
The present invention relates to a pharmaceutical composition for preventing hair loss and promoting hair growth comprising Formononetin or a pharmaceutically acceptable salt thereof as an active ingredient.
두피로부터 모발이 빠지는 탈모증은 여러 가지 요인에 의해 발생되는 것으로, 유전적인 체질이나 남성 호르몬의 작용과 같은 내적인 요인 또는 일상 생활에서의 정신적인 스트레스, 두피에서의 과산화지질의 축적과 같은 외적인 요인이 있으며, 이러한 요인들이 복잡하게 관여하여 탈모증상을 나타내는 것으로 알려져 있다. 최근에는 남성형 탈모뿐만 아니라 여성들의 비만성 탈모를 비롯하여 젊은 층에서의 탈모가 점차 확산되어가는 추세에 있으며, 이러한 탈모현상을 개선하기 위해 많은 종류의 모발성장 또는 육모제가 시판되고 있다.
Hair loss from the scalp is caused by a number of factors, including external factors such as genetic constitution, internal factors such as male hormone action, mental stress in daily life, and accumulation of lipid peroxidation in the scalp , And these factors are known to exhibit hair loss symptoms due to complicated involvement. In recent years, as well as male hair loss, hair loss in young people including obesity hair loss has been gradually spreading. Many types of hair growth or hair restorers are on the market to improve such hair loss phenomenon.
시판중인 모발성장 또는 육모제에 사용되는 주요 성분으로는 두피에 충분한 혈액을 순환시키기 위한 염화카프로니움, 미녹시딜 및 각종 식물의 추출물 등의 혈관 확장제나 모유두(毛乳頭)에 부착하여 모발을 탈락시키는 남성 호르몬의 작용을 억제하기 위한 에스트로겐, 에스트라지올, 프로게스테론 등의 여성 호르몬제 또는 펜타데칸산, 피나스테라이드 등의 남성 호르몬 활성화 억제제가 있다. 예를 들면, 미국의 식품의약국(FDA)으로부터 탈모치료제로 허가받은 약물은 두 종류로, 바르는 치료제인 미녹시딜은 혈관 확장작용에 의한 것이고 경구용인 프로페시아는 피나스테라이드를 주제로 한 남성 호르몬의 활성화 억제작용에 의해 탈모방지 효과가 우수한 제제로 많이 이용되고 있다. 그러나, 전술한 대부분의 모발성장, 육모제들은 탈모의 방지에는 어느 정도의 효과를 나타내지만 발모와 관련된 효과는 다소 저조한 것으로 보고되고 있다. 즉, 이들 제제는 모근이 활성화 되어있는 부위에서만 효과를 나타내므로 탈모방지 효과는 상당하지만, 장기간의 휴지기 상태에 있는 모발의 성장, 즉 발모효과는 미미하여서 이미 탈모가 진행되어 모낭이 위축된 대머리에는 전혀 효과가 없는 것으로 나타났다.
The main ingredients used in commercially available hair growth or hair restorers include vasodilators such as chloramphenic chloride, minoxidil and various plant extracts for circulating sufficient blood to the scalp, and male hormones that attach to the papilla to remove hair Estradiol, progesterone and the like, or male hormone activation inhibitors such as pentadecanoic acid and finasteride. For example, two drugs approved by the US Food and Drug Administration (FDA) for hair loss treatment are minoxidil, which is a drug for vasodilation, and propecia for oral use, which inhibits the activation of male hormones on the theme of pinasteride Is widely used as a preparation having excellent hair-loss preventive effect. However, most of the hair growth and hair restorers mentioned above have some effect to prevent hair loss, but the effect related to hair growth has been reported to be somewhat poor. In other words, these preparations are effective only in the area where the hair follicles are activated, so that the effect of preventing hair loss is significant, but the growth of the hair in the resting state for a long period of time, that is, hair growth effect is insignificant, It was not effective at all.
두피의 하나 또는 몇 개의 영역에서 모발이 돌연 없어지는 원형 탈모증의 경우에는 면역계의 변조에 의해 모낭이 임파구에 의해 공격을 받아 발육상태가 갑자기 중단되면서 발생하는 것으로 알려져 있다. 이와 관련하여, 일부 과학자들은 대머리를 원형 탈모와 같은 '자가면역질환'의 하나로 보고 있으며 남성호르몬(디하이드로테스토스테론, DHT)이 면역반응을 일으켜 모근을 파괴시킨다는 설을 제시하고 있다. 즉, 탈모증상이 나타난 사람들의 경우 체내에서 백혈구가 모낭을 제거해야하는 외부 단백질로 인식하면서 자기항체를 생성하여 모낭을 공격하게 된다는 것이다. 자기항체가 생성되면 흉선이 위축되어 면역계의 기능이 약화되고 그 결과의 하나로 모낭이 위축되면서 머리카락이 가늘어지고 조밀성이 감소하면서 빠져나가게 된다는 것이다. 또한, 탈모현상을 일으키는 주요 원인의 하나로 피지의 역할도 강조되고 있다. 성장기에 있는 모낭으로부터 두피로 분비된 피지는 활성산소나 자외선조사에 의해 두피 층에 과산화지질을 생성하면서 굳어지는 성질이 있어, 굳어진 피지가 모공을 막아버리므로 모발의 정상적인 성장을 방해하거나 세포구성물의 괴사를 가져와 탈모를 촉진하게 된다는 것이다.
In the case of alopecia areata, hair disappears suddenly in one or several areas of the scalp. It is known that the hair follicle is attacked by lymphocytes due to immune system modulation and abruptly stops developing. In this regard, some scientists see baldness as one of the "autoimmune diseases" such as round hair loss and suggest that the male hormone (dihydrotestosterone, DHT) causes an immune response and destroys the hair follicle. In other words, in the case of people with hair loss symptoms, white blood cells in the body as an external protein to remove hair follicles, while creating a self-antibody to attack the hair follicles. When the self-antibody is produced, the thymus is atrophied and the function of the immune system is weakened. As a result, hair follicles are shrunken and the hair becomes thinner and the density is reduced, and it is escaped. In addition, the role of sebum is also emphasized as one of the main causes of hair loss. The sebaceous secretion from the hair follicles in the growing stage is induced by active oxygen or ultraviolet rays to produce lipid peroxides in the scalp layer, which hardens, and the hardened sebum blocks the pores, thereby hindering the normal growth of the hair, Necrosis is brought to promote hair loss.
한편, 대머리 부위 조직은 보통의 머리가 있는 부위의 조직에 비하여 5-알파 환원효소의 활성도가 높다는 연구결과가 보고된바 있다. 5-알파 환원효소는 테스토스테론(testosterone)을 디하이드로테스토스테론(dehydrotestosterone, DHT)으로 환원시키는 것으로, 남성의 형질발현에 있어 골격근 증가, 정자 형성 등은 테스토스테론이 관여하고 여드름, 피지증가, 탈모 및 전립선비대증 등은 디하이드로테스토스테론이 해당조직에서 관여하는 것으로 알려져 있다(J. Invest. Dermatol. 1995; 105(2): 209-14). 따라서, 테스토스테론에서 디하이드로테스토스테론의 반응에 관여하는 생체 효소인 5-알파 환원효소의 활성을 저해함으로써 탈모증을 치료하는 약리활성 물질은 찾는 연구가 많이 이루어지고 있다. 현재 5-알파 환원효소 저해제로 피나스테라이드와 같은 화합물이 있으며, 투여용량을 달리하여 전립선 치료제 및 탈모방지제로 사용되고 있다. 피나스테라이드는 편리성과 효능면에서 우수한 약이나 피나스테라이드를 제조하는데 있어 사용되는 시약이 고가이거나 맹독성이어서 제조원가에 부담을 주거나 환경을 오염시키는 문제점이 있다. 특히, 부생성물의 제거가 용이하지 않아 목적산물의 순도가 떨어지거나, 수분에 용이하게 저해되는 시약 또는 활성 유도체를 사용함으로써 대량생산이 어렵다는 문제점이 있을 뿐 아니라 스테로이드 호르몬 자체는 정상적인 생리활성에도 중요한 역할을 하므로 스테로이드 호르몬 생성 자체를 인위적으로 차단할 경우, 여러 종류의 문제점들이 야기될 수 있다.
On the other hand, studies on the activity of 5-alpha-reductase in bald tissue have been reported compared with that of normal hair. The 5-alpha reductase reduces testosterone to dehydrotestosterone (DHT), and increases skeletal muscle and spermatogenesis in male transcripts. Testosterone is involved, and acne, sebum increase, hair loss and enlargement of the prostate Have been known to involve dihydrotestosterone in their tissues (J. Invest. Dermatol. 1995; 105 (2): 209-14). Therefore, many studies have been conducted to find pharmacologically active substances for treating alopecia by inhibiting the activity of 5-alpha reductase, a biosynthetic enzyme involved in the reaction of dihydrootestosterone in testosterone. Currently, there are compounds such as finasteride as a 5-alpha-reductase inhibitor, and they are used as prostate remedy and hair loss preventing agent in different doses. The finasteride is a drug which is superior in terms of convenience and efficacy, and the reagent used in manufacturing the pinasteride is expensive or toxic, which causes a burden on the manufacturing cost or pollutes the environment. Particularly, since the removal of by-products is not easy and the purity of the objective product is lowered or the reagent or the active derivative which is easily inhibited by moisture is used, there is a problem that mass production is difficult, and the steroid hormone itself is also important for the normal physiological activity , And thus, various kinds of problems may be caused when the steroid hormone production itself is artificially blocked.
상기와 같은 배경 하에, 본 발명자들은 탈모방지 및 발모촉진 효과가 우수하면서 안정성이 높아 부작용이 없는 신규한 물질을 연구하던 중, 식물로부터 추출할 수 있는 포모노네틴이 탈모를 유도한 동물모델에서 탈모 방지 효과뿐만 아니라, 발모촉진 효과도 우수함을 확인하여, 포모노네틴이 탈모방지 및 발모촉진용 조성물로 유용하게 사용될 수 있음을 확인함으로써 본 발명을 완성하였다.
Under the above circumstances, the inventors of the present invention have been studying a novel substance which is excellent in the effect of preventing hair loss and promoting hair growth and having high stability and having no side effects, and it has been found that, in an animal model in which hairy- It has been confirmed that pamoonecein can be effectively used as a composition for preventing hair loss and for promoting hair growth, thereby completing the present invention.
본 발명의 목적은 포모노네틴(Formononetin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 약제학적 조성물을 제공하는 것이다. It is an object of the present invention to provide a pharmaceutical composition for preventing hair loss or promoting hair growth comprising Formononetin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 화장료 조성물을 제공하는 것이다.It is still another object of the present invention to provide a cosmetic composition for preventing hair loss or promoting hair growth comprising pomanonethine or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 의약외품 조성물을 제공하는 것이다.It is still another object of the present invention to provide a quasi-drug composition for preventing hair loss or promoting hair growth, comprising as an active ingredient pomonotenine or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 식품 조성물을 제공하는 것이다.
It is still another object of the present invention to provide a food composition for preventing hair loss or promoting hair growth, comprising as an active ingredient pomannotine or a pharmaceutically acceptable salt thereof.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 포모노네틴(Formononetin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 약제학적 조성물을 제공한다.
In one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing hair loss or promoting hair growth comprising Formononetin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 용어, "포모노네틴(Formononetin)"은 O-메틸화 이소플라본으로 붉은 클로버(red clover)등 수많은 식물 및 허브에서 발견되는 화합물이다. 특히, 완두콩, 밤콩과 같은 콩과 식물들에 주로 생기며, 다른 이름으로는 비오카닌 B 으로 불린다. 하기 화학식 1의 구조를 가지고 있다. The term "Formononetin" of the present invention is O-methylated isoflavone, a compound found in numerous plants and herbs such as red clover. In particular, it occurs mainly in beans and plants such as peas and bacon, and is also called Biocanin B in other names. And has a structure represented by the following formula (1).
[화학식 1][Chemical Formula 1]
본 발명에서 상기 포모노네틴은 콩과 식물, 황기, 승마 또는 붉은 클로버 등으로부터 추출하여 수득하거나, 화학적으로 합성하여 제조할 수 있다.In the present invention, the formononetin can be obtained by extracting from soybean plants, Hwanggi, horse riding or red clover, or by chemical synthesis.
상기 추출은 당업계에 공지된 통상적인 용매를 사용하여 수행할 수 있으며, 바람직하게는 에탄올, 메탄올 또는 부탄올을 이용하여 추출할 수 있다. 또한, 상기의 용매 추출물뿐 아니라 추가적인 정제방법을 통하여 얻어진 분획물도 포함할 수 있다. 본원발명의 일실시예에서 포모노네틴은 Sigma-Aldrich에서 제조한 것을 구매하여 사용하였다(Catalog No. 47752-formononetin).The extraction can be carried out using a conventional solvent known in the art, preferably ethanol, methanol or butanol. In addition, the above-mentioned solvent extract as well as fractions obtained through an additional purification method may be included. In one embodiment of the present invention, formononetin was purchased from Sigma-Aldrich and used (Catalog No. 47752-formononetin).
본 발명에 사용된 용어, "약학적으로 허용가능한 염"은 당해 기술분야에서 통상적인 방법에 따라 제조된 염을 의미하며, 이러한 제조방법은 당업자에게 공지되어 있다. 구체적으로, 상기 약학적으로 허용 가능한 염은 약리학적 또는 생리학적으로 허용되는 하기 무기산과 유기산 및 염기로부터 유도된 염을 포함하지만 이것으로 한정되지는 않는다. 적합한 산의 예로는 염산, 브롬산, 황산, 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산, 시트르산, 메탄설폰산, 포름산, 벤조산, 말론산, 나프탈렌-2-설폰산, 벤젠설폰산 등을 포함할 수 있다. 적합한 염기로부터 유도된 염은 알칼리 금속, 예를 들어, 나트륨, 또는 칼륨, 알칼리 토금속, 예를 들어, 마그네슘을 포함할 수 있다.
As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals, such as sodium, or potassium, alkaline earth metals, such as magnesium.
상기 포모노네틴은 총 조성물 중량 대비 0.00001 중량% 내지 30 중량%로 포함할 수 있으며, 바람직하게는 0.0001 중량% 내지 10 중량%로 포함한다. 더 바람직하게는 0.002 중량% 내지 3 중량%이다. 만약, 포모노네틴이 0.00001 중량% 미만이면 효능이 미약한 단점이 있다. 또한, 15 중량%를 초과하는 경우에는 함량의 증가에 따른 효과의 증가는 매우 미약하며, 제형상의 안정성이 확보되지 않는 문제점이 발생할 수 있다.
The formononetin may be contained in an amount of 0.00001% by weight to 30% by weight, preferably 0.0001% by weight to 10% by weight, based on the total weight of the composition. More preferably 0.002 wt% to 3 wt%. If the content of pomonotethene is less than 0.00001% by weight, the efficacy is weak. On the other hand, if it exceeds 15% by weight, the increase in the effect of the increase of the content is very weak and the stability of the shape can not be secured.
본 발명의 조성물은 투여를 위하여, 상기 기재한 유효성분 이외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토오스, 덱트트로오스, 수크로오스, 소르비톨, 만니톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로오스, 폴리비닐피롤리돈, 셀룰로오스, 물, 시럽, 메틸 셀룰로오스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 스테아르산 마그네슘 및 미네랄 오일을 들 수 있다.
The composition of the present invention may contain, for administration, a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-described effective ingredients. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, Cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 조성물은 각각 통상의 방법에 따라 제형화하여 사용할 수 있다. 상세하게는, 제형화할 경우 통상 사용하는 윤활제, 습윤제, 향미제, 유화제, 현탁제, 보존제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.
Each of the compositions of the present invention can be formulated according to a conventional method. Specifically, when formulated, it can be prepared using a diluent or excipient such as a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, a surfactant and the like which are usually used.
바람직하게, 본 발명의 조성물은 모발 또는 두피에 직접 도포 또는 산포하는 등의 방법에 의해 사용될 수 있다. 본 발명의 조성물이 적용되는 모발이란, 머리의 모근 및 모낭, 머리카락 및 속눈썹과 겉눈썹, 수염, 겨드랑이, 음모, 신체 전반에 모근 및 모낭이 있는 모든 부위를 포함한다.
Preferably, the composition of the present invention can be used by a method such as direct application or spreading on hair or scalp. The hair to which the composition of the present invention is applied includes hair follicles and hair follicles, hair and eyelashes and eyelashes, beard, armpits, pubic hair, hair follicles and hair follicles.
본 발명의 조성물의 적합한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 포모노네틴의 일일 투여량은 성인 기준으로 1.0 ㎖ 내지 3.0 ㎖이며, 필요에 따라 일일 1회 내지 5회 도포하여 투여할 수 있다.
Suitable doses of the compositions of the present invention will vary with the condition and weight of the patient, the severity of the disease, the form of the drug, and the time, but may be suitably selected by those skilled in the art. The daily dose of pomonotenine is 1.0 ml to 3.0 ml on an adult basis, and may be administered once to five times a day, if necessary.
본 발명의 구체적인 실시예에 따르면, 탈모를 유도한 쥐에 본 발명의 유효성분인 포모노네틴을 처리한 경우에는 농도 의존적으로 모발이 발모하는 것을 확인하였다(실시예 1 및 도 1). 또한, 조직학적으로는 포모노네틴 처리에 의해 파괴되었던 모근과 모간이 재건되는 것을 확인할 수 있었으며, 이에 따라 퇴행기에 도입되던 모낭이 성장기에 접어드는 현상을 확인할 수 있었다(실시예 2 및 도 2).
According to a specific example of the present invention, it was confirmed that hair treated with formononetin, an effective ingredient of the present invention, in hair loss-inducing rats was hairy in a concentration-dependent manner (Example 1 and Fig. 1). In addition, it was confirmed that the hair follicle and the moraine which were destroyed by the pomonotin treatment were reconstructed histologically, and thus the hair follicle introduced into the retrograde period was observed to enter the growth period (Example 2 and Fig. 2).
본 발명의 또 다른 구체적인 실시예에서는, 쥐를 동물 모델로 한 실험에서 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 처리군의 등피부조직에서 면역 및 세포사멸 관련 현상에 포모노네틴이 미치는 영향을 확인하였다. In another specific example of the present invention, in an experiment using an animal as an animal model, it was found that when formononetin was added to the immune and cell death-related phenomena in the normal skin and hair loss induction group, .
구체적으로는, 탈모가 일어난 피부에서 T림프구 활성화와 관련된 사이토카인 IL-8과 TNF-β의 mRNA 발현이 증가하는데 비하여, 포모노네틴을 처리하는 경우에 농도의존적으로 상기 두 유전자의 mRNA 발현이 감소되는 것을 확인하였으며(실시예 3 및 도 3), 단백질 수준에서는 면역 관련 사이토카인인 TNF-α, TNF-β, IL-1β, 4, 6, 및 8 수준이 감소하며, 전-면역반응 관련 사이토카인과 관련된 전사인자 NF-κB 및 p-IκB-α의 수준이 감소하였다(실시예 5, 실시예 7-1 내지 실시예 7-2 및 도 4 내지 도 6).Specifically, mRNA expression of cytokines IL-8 and TNF-β associated with T lymphocyte activation is increased in hair loss-treated skin, whereas mRNA expression of the two genes is decreased in a concentration-dependent manner when pomonoetin is treated (TNF-alpha, TNF-beta, IL-1 beta, 4, 6, and 8 levels were decreased at the protein level, and the levels of pro-immune response-related cytokines The levels of the transcription factors NF-kB and p-IkB-a associated with cyne were reduced (Example 5, Examples 7-1 to 7-2 and Figures 4 to 6).
또한, 포모노네틴의 처리가 세포생존 및 사멸과 관련된 3개의 MAP kinase들(p38, SAPK/JNK 및 ERK)의 활성화에 미치는 영향을 확인한 결과, 포모노네틴을 처리한 모든 군에서 정상군에 가까운 정도로 완벽히 회복(감소)되는 것을 확인하였다. 또한, SAPK/JNK pathway의 하위인자인 c-Jun의 활성도 감소하였다(실시예 7-3 내지 실시예 7-5 및 도 7 내지 도 9). In addition, the effects of pomanonetin treatment on the activation of three MAP kinases (p38, SAPK / JNK and ERK) related to cell survival and death were examined. As a result, in all the groups treated with pomonotenine, (Reduction) of the total amount of water. In addition, the activity of c-Jun, a sub-factor of the SAPK / JNK pathway, decreased (Examples 7-3 to 7-5 and Figures 7 to 9).
상기 결과에서, 본 발명의 포모노네틴은 탈모를 일으킨 동물 모델에서 뛰어난 발모 촉진 효과를 가지는 것을 확인했으며, 이는 탈모에 의해서 발생하는 면역반응 및 세포사멸 반응을 억제하는 것을 통해 모발의 재발모를 촉진하는 효과를 가지는 것을 확인하였다. 또한, 상기 면역 반응 및 세포사멸 반응을 억제하는 효과를 통해 애초에 자연적으로 일어나는 탈모를 방지하는 효과를 가질 수 있음을 예측할 수 있었다.
From the above results, it was confirmed that the pamo-nonetin of the present invention has an excellent hair growth promoting effect in an animal model of hair loss, which promotes hair regrowth through inhibiting immune reaction and apoptosis caused by hair loss Respectively. In addition, it was predicted that the effect of inhibiting the immune reaction and apoptosis could be prevented by preventing the hair loss which occurs naturally in the beginning.
또 다른 양태로서, 본 발명은 포모노네틴(Formononetin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 조성물을 제공한다. 상기 조성물은 탈모방지 또는/및 발모촉진용 유효성분으로서 포모노네틴만을 포함하는 것으로서, 포모노네틴의 탈모방지/발모 촉진 활성을 방해하지 않는 다른 보조 성분을 추가로 포함할 수 있다.
In another aspect, the present invention provides a composition for preventing hair loss or promoting hair growth comprising Formononetin or a pharmaceutically acceptable salt thereof as an active ingredient. The composition may include other auxiliary components that do not interfere with the hair loss prevention / hair growth promoting activity of pomonoetin, including only formononetin as an active ingredient for preventing hair loss or promoting hair growth.
또한, 본 발명은 분리된 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 탈모방지 또는 발모촉진용 조성물을 제공한다. The present invention also provides a composition for promoting hair loss prevention or hair growth comprising the separated pomanonetin or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 조성물은 포모노네틴이 식물, 이의 추출물 또는 분획물에 포함된 형태가 아닌 분리된 형태로 포함된 것일 수 있다.
The composition may be one containing isolated form of pomono neetin not contained in the plant, its extract or fraction.
또 다른 양태로서, 본 발명은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 화장품 조성물을 제공한다. In another aspect, the present invention provides a cosmetic composition for preventing hair loss or promoting hair growth comprising as an active ingredient pomanoneceptin or a pharmaceutically acceptable salt thereof.
상기 화장료 조성물은 탈모방지 또는 발모촉진용 두피 모발케어 조성물일 수 있다.The cosmetic composition may be a scalp hair care composition for preventing hair loss or promoting hair growth.
본 발명에서 사용하는 용어 "두피 모발케어 조성물"은, 물리적 또는 화학적 요인에 의하여 발생되는 두피 및 모발의 손상을 방지 또는 완화해주는 조성물을 의미한다. 본 발명의 조성물은 샴푸, 린스, 에센스, 영양제, 세럼, 마사지크림, 로션 또는 팩제인 것이 바람직하나, 이에 제한되는 것은 아니다.
As used herein, the term "scalp hair care composition" refers to a composition that prevents or alleviates damage to scalp and hair caused by physical or chemical factors. The composition of the present invention is preferably, but not exclusively, a shampoo, a rinse, an essence, a nutrient, a serum, a massage cream, a lotion or a pack.
또한, 상기 조성물은 각각의 제형에 따라 상기의 필수성분 이외에 통상적으로 이용되는 성분들을 포함할 수 있으며, 예컨대 항산화제, 안정화제, 용해화제, 비타민제, 안료 및 향료와 같은 보조제 및 담체를 들 수 있다.
In addition, the composition may contain components commonly used in addition to the above-mentioned essential components according to the respective formulations, and examples thereof include adjuvants and carriers such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances .
또 다른 양태로서, 본 발명은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 의약외품 조성물을 제공한다.
In still another aspect, the present invention provides a quasi-drug composition for preventing hair loss or promoting hair growth, comprising as an active ingredient pomannotine or a pharmaceutically acceptable salt thereof.
본 발명의 탈모방지 및 발모촉진용 조성물은 화장품 또는 의약외품의 제형으로 사용될 수 있다. 상기 조성물의 제형은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로서 배합할 수 있는 어느 형태의 제형도 가능하다, 바람직하게, 상기 탈모방지 및 발모촉진용 화장품 또는 의약외품의 제형으로 헤어토닉, 헤어크림, 헤어로션, 헤어샴푸, 헤어린스, 헤어컨디셔너, 헤어스프레이, 헤어에어졸, 포마드, 분말, 젤, 헤어팩, 헤어트리트먼트, 눈썹발모제, 속눈썹 발모제, 속눈썹 영양제, 또는 애완동물용 샴푸 및 애완동물용 린스 등과 같이 용액, 솔젤, 에멀젼, 오일, 왁스, 에어졸 등 다양한 형태로 제조될 수 있고, 가발 또는 모자 등의 두피 또는 모발용 기구의 제조나 가공에 사용될 수 도 있으며, 이들로 제한되는 것은 아니다.
The composition for preventing hair loss and promoting hair growth of the present invention can be used as a cosmetic or quasi-drug formulation. The formulation of the composition may be any form of formulation capable of compounding pomonoetin or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, the formulation of the cosmetic or quasi-drug for hair loss prevention and promotion of hair growth, , Hair cream, hair lotion, hair shampoo, hair rinse, hair conditioner, hair spray, hair aerosol, pomade, powder, gel, hair pack, hair treatment, eyebrow hair removal agent, eyelash hair growth agent, eyelash nourishing agent, or pet shampoo and pets It can be manufactured in various forms such as a solution, a sol gel, an emulsion, an oil, a wax, an aerosol such as an animal rinse, and the like, and can be used for manufacturing or processing a scalp or hair appliance such as a wig or a cap, .
또한 상기 탈모방지용 조성물에는 상술한 각종 제형에 따라 또는 최종목적에 적합하게 통상의 탈모방지용 조성물에 배합되는 각종 성분들을 함유할 수 있다. 예를 들면, 샴푸의 제형을 갖는 경우에는 세정 성분인 합성 계면활성제와 방부제, 점증제, 점도 조절제, pH 조절제, 향료, 염료, 모발 컨디셔닝제 및 물 중 어느 하나 이상을 함유할 수 있다. 상기 합성 계면활성제 중 합성 음이온 계면활성제는 알킬 및 알킬 에테르 설페이트로서, 대표적인 예로 라우릴 황산나트륨, 라우릴 황 산암모늄, 라우릴 황산 트리에탄올아민, 폴리옥시에틸렌 라우릴 황산나트륨, 폴리옥시에틸렌 라우릴 황산암모늄 등이 있다. 또한 상기 합성 계면활성제 중 합성 양쪽성 계면활성제는 알킬 베타민 및 알킬 아미도프로필 베타인으로서, 대표적인 예로는 코코디메틸 카복시메틸 베타인, 라우릴디메틸 카복시메틸 베타인, 라우릴 디메틸 알파-카복시에틸 베타인, 세틸 디메틸 카복시메틸 베타인, 코카미도 프로필 베타인 등이 있다. 상기 비이온 계면활성제는 알카놀 아미드 및 아민 옥사이드로서, 라우릴 디에틸 아민옥사이드, 야자유 알킬디메틸 아민옥사이드, 라우린산 디에탄올아미드, 야자유 지방산 디 에탄올아미드, 야자유 지방산 모노에탄올아미드 등이 있다.
In addition, the composition for preventing alopecia may contain various components to be compounded in a conventional anti-hair-loss composition according to the above-described various formulations or for a final purpose. For example, in the case of having a formulation of shampoo, it may contain at least one of a synthetic surfactant, which is a cleaning component, and at least one of preservatives, thickeners, viscosity regulators, pH adjusting agents, perfumes, dyes, hair conditioning agents and water. Examples of the synthetic anionic surfactant in the synthetic surfactant include alkyl and alkyl ether sulfates. Representative examples thereof include sodium lauryl sulfate, ammonium lauryl sulfate, triethanolamine lauryl sulfate, sodium polyoxyethylene lauryl sulfate, polyoxyethylene lauryl sulfate and the like . The synthetic amphoteric surfactants in the synthetic surfactants are alkyl betamines and alkylamidopropyl betaines. Representative examples include cocodimethylcarboxymethylbetaine, lauryldimethylcarboxymethylbetaine, lauryldimethyl alpha-carboxyethylbetaine , Cetyl dimethyl carboxymethyl betaine, and cocamidopropyl betaine. Examples of the nonionic surfactant include alkanolamides and amine oxides such as lauryldiethylamine oxide, palm oil alkyldimethylamine oxide, lauric acid diethanolamide, palm oil fatty acid diethanolamide, palm oil fatty acid monoethanolamide, and the like.
본 발명에서 사용되는 임의 성분으로서는 샴푸로서의 기본적 물성 및 품질을 유지하기 위한 통상적인 임의 성분으로서 당해 분야의 전문가에게 널리 공지되어 있다. 이러한 임의 성분에는 진주박 보조제, 방부제, 점중제 및 점도 조절제, pH 조절제, 향료, 염료, 모발 컨디셔닝제가 포함된다. 예를 들면 에틸렌글리콜 모노스테아레이트, 에틸렌글리콜 디스테아레이트와 같은 진주박 보조제; 파라 옥시안식향산메틸, 메틸클로로 이소치아졸리논과 메틸 이소치아졸 리논의 혼합물과 같은 방부제; 염화나트륨, 염화암모늄, 프로필렌 글리콜과 같은 점증제 및 점도 조절제; 구연산, 인산, 수산화나트륨, 수산화칼륨과 같은 pH 조절제; 폴리쿼터늄-10, 폴리쿼터늄-7, 메틸폴리실록산, 디메티콘코폴리 올, 가수분해 동물단백질과 같은 모발 컨디셔닝제, 수용성 타르와 같은 염료가 사용되며, 또한 향료가 사용될 수 있다.
The optional ingredients used in the present invention are well known to those skilled in the art as conventional optional ingredients for maintaining basic properties and quality as a shampoo. Such optional ingredients include, but are not limited to, pearl wood supplements, preservatives, dyes and viscosity modifiers, pH adjusting agents, perfumes, dyes, and hair conditioning agents. Such as ethylene glycol monostearate and ethylene glycol distearate; Preservatives such as methyl paraoxybenzoate, mixtures of methylchloroisothiazolinone and methyl isothiazolinone; Thickeners and viscosity modifiers such as sodium chloride, ammonium chloride, propylene glycol; PH adjusting agents such as citric acid, phosphoric acid, sodium hydroxide and potassium hydroxide; Hair conditioning agents such as polyquaternium-10, polyquaternium-7, methylpolysiloxane, dimethicone copolyols, hydrolyzed animal proteins, dyes such as water-soluble tar, and perfumes can also be used.
추가로, 본 발명의 탈모방지용 조성물은 그 제형에 달리하여 애완동물용으로 사용할 수 있다. 본 발명의 조성물을 함유하는 샴푸 형태로 제조될 수 있으며, 애완동물의 피부에 자극이 적고 보습력이 탁월한 중성의 세제를 첨가하여 제조할 수 있다. 이때, 본 발명의 성물에 의해 강력한 살충, 항균능력과 탈모 방지 효과를 얻을 수 있다.
In addition, the composition for preventing alopecia of the present invention may be used for pets in a different form of the composition. Can be prepared in the form of a shampoo containing the composition of the present invention and can be prepared by adding a neutral detergent having less irritation to the skin of the pet and excellent in moisture retention. At this time, strong insecticide, antibacterial ability and hair loss prevention effect can be obtained by the art of the present invention.
또한, 상기 조성물은 각각의 제형에 따라 상기의 필수성분 이외에 통상적으로 이용되는 성분들을 포함할 수 있으며, 예컨대 항산화제, 안정화제, 용해화제, 비타민제, 안료 및 향료와 같은 보조제 및 담체를 들 수 있다.
In addition, the composition may contain components commonly used in addition to the above-mentioned essential components according to the respective formulations, and examples thereof include adjuvants and carriers such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances .
또 다른 양태로서, 본 발명은 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 탈모방지 또는 발모촉진용 식품 조성물을 제공한다. 식품 제조 시에 통상적으로 첨가되는 성분은 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드(예를 들어, 포도당, 과당 등), 디사카라이드(예를 들어, 말토스, 슈크로스, 올리고당 등) 및 폴리사카라이드(예를 들어, 덱스트린, 사이클로덱스트린 등)와 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제(예를 들어, 타우마틴, 레바우디오시드 A, 글리시르히진 등과 같은 스테비아 추출물) 및 합성 향미제(예를 들어, 사카린, 아스파르탐 등)를 사용할 수 있다.
In another aspect, the present invention provides a food composition for preventing hair loss or promoting hair growth comprising as an active ingredient pomanoneceptin or a pharmaceutically acceptable salt thereof. Ingredients conventionally added in food manufacture include, for example, proteins, carbohydrates, fats, nutrients, flavoring agents and flavoring agents. Examples of the above-mentioned carbohydrates include monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, oligosaccharides etc.) and polysaccharides (e.g., dextrin, cyclodextrin Etc.), and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (for example, stevia extract such as tau martin, rebaudioside A, glycyrrhizin and the like) and synthetic flavors (for example, saccharin, aspartame, etc.) can be used as flavorings.
본 발명의 따른 포모노네틴 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 조성물은 탈모에 의해서 발생하는 면역반응 및 세포사멸 반응을 억제하는 것을 통해 모발의 재발모를 촉진하는 효과를 가지며, 상기 면역 반응 및 세포사멸 반응을 억제하는 효과를 통해 애초에 자연적으로 일어나는 탈모를 방지하는 효과를 가짐에 따라, 포모노네틴이 탈모방지 및 발모촉진용 조성물로 널리 사용될 수 있다.
The composition comprising as an active ingredient pomanoneceptin or a pharmaceutically acceptable salt thereof according to the present invention has an effect of promoting hair regrowth through inhibiting the immune reaction and apoptosis caused by hair loss, The effect of inhibiting the immune reaction and the apoptosis reaction is prevented, and pomonoetin can be widely used as a composition for preventing hair loss and promoting hair growth.
도 1은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부 및 모발 사진이다.
도 2은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직 단편을 H&E 염색한 사진이다.
도 3은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 TNF-β, IL-8 및 GAPDH의 mRNA 발현량을 역전사 PCR을 통해 확인하는 도면이다.
도 4은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 (A)TNF-α, (B)IL-1β, (C)4, (D)6 및 (E)IFN-γ의 수준을 확인하는 도면이다.
도 5는 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 NF-κB 및 IκB-α 활성을 확인하는 도면이다.
도 6은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 i-Nos 및 Cox-2의 발현을 확인하는 도면이다.
도 7은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 MAP kinase들(p38, SAPK/JNK 및 ERK)의 발현량과 활성화를 의미하는 인산화를 확인하는 도면이다.
도 8은 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 SAPK/JNK pathway의 하위 인자인 c-Jun의 활성을 확인하는 도면이다.
도 9는 쥐를 동물 모델로 하여 정상군과 탈모유도군, 및 탈모유도 후 포모노네틴 농도별 처리군(1 또는 1000 uM)의 탈모유도 후 15일째 등피부조직으로부터 Bcl-2, Bax, p53, capase-3 및 9의 활성을 확인하는 도면이다.Fig. 1 is photographs of skin and hair, such as 15 days after induction of hair loss in normal group and hair loss induction group, and treatment group (1 or 1000 uM) treated with concentration of formononetin after induction of hair loss, using mice as an animal model.
FIG. 2 is a photograph of H & E staining of skin tissue fragments such as 15 days after induction of hair loss in normal group and hair loss induction group and mice treated with formalinonetin concentration (1 or 1000 uM) using mouse as an animal model.
FIG. 3 is a graph showing changes in TNF-.beta. And IL-8 levels from the skin tissues after 15 days of induction of hair loss in normal group and hair loss induction group and in group treated with concentration of formononetin (1 or 1000 uM) And the amount of mRNA expression of GAPDH is confirmed by reverse transcription PCR.
FIG. 4 shows (A) TNF-.alpha., (B), and (B) after 15 days from the induction of hair loss of the normal group and hair loss induction group and the group treated with the concentration of formononetin (1 or 1000 uM) (B) IL-1?, (C) 4, (D) 6 and (E) IFN- ?.
Fig. 5 shows the results of NF-κB and IκB-α (1 μg / ml) from the skin tissues after 15 days of induction of hair loss in the normal group and hair loss induction group and the treatment group of the formononetin concentration Fig.
Fig. 6 is a graph showing changes in i-Nos and Cox-2 from skin tissues after 15 days of induction of hair loss in the normal group and hair loss induction group and in the group treated with the concentration of formononetin (1 or 1000 uM) As shown in Fig.
Fig. 7 shows the results of MAP kinases (p38, SAPK) from the skin tissues after 15 days of induction of hair loss of the treated group (1 or 1000 uM) after induction of hair loss, / JNK and ERK) and phosphorylation which means activation.
Fig. 8 is a graph showing the relationship between the subpopulations of the SAPK / JNK pathway from the skin tissues such as the 15th day after induction of hair loss in the normal group and the hair loss induction group, and the group treated with the formononetin concentration (1 or 1000 uM) Lt; RTI ID = 0.0 > c-Jun < / RTI >
FIG. 9 is a graph showing changes in Bcl-2, Bax, and p53 levels from the skin tissues after 15 days of induction of hair loss in the normal group and the hair loss induction group and in the group treated with the concentration of formononetin (1 or 1000 uM) , < / RTI > capase-3 and 9, respectively.
이하, 하기 실시예에 의하여 본 발명을 보다 상세하게 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들로 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
실시예Example
1. 동물 관리 및 실험 과정 1. Animal Care and Experimental Course
7주차 C57bl/6 암컷(18~20 g)을 삼타코 실험 동물 센터(오산, 경기도, 한국)에서 구입하였다. 등의 피부 색상이 분홍색인 것으로 쉽게 식별이 가능한, 모발 성장 주기가 휴지기(Telegen)에 접어든 쥐를 선택하였다. 기존에 알려진 방법인 탈모(털뽑기)를 통해 성장기(검은색)에 접어드는 것으로 자연적 퇴행기(Catagen)(회색)를 유도하였다. 동물은 22 ± 1 ℃ 및 상대습도 55 ± 10%로 유지되는 층류 방식 무균실에 한 cage당 7마리씩 사육되었으며, 쥐는 경희대학교 동물실험윤리위원회에서 정한 지침 및 실험동물 사육 및 이용에 관한 지침(보건 교육 후생부, NIH; publication #78-23, 1996)에 따라 취급되었다. 포모노네틴은 Sigma-Aldrich에서 제조한 것을 구매하여 사용하였다(Catalog No. 47752-formononetin).
Seven C57bl / 6 females (18-20 g) were purchased from the Samtaco Experimental Animal Center (Osan, Kyonggi-do, Korea). The rats whose hair growth cycle is Telegen, which is easily recognizable as having a skin color of pink, are selected. The natural regenerator (Catagen) (gray) was induced by entering the growing period (black) through hair loss (hair pulling), which is a known method. Animals were housed 7 per cage in a laminar flow clean room maintained at 22 ± 1 ° C and 55 ± 10% relative humidity. The rats were fed with the guidelines set by Kyunghee University's Animal Experimentation Ethics Committee and the Guidelines for the Rehabilitation and Use of Laboratory Animals Ministry of Health and Welfare, NIH; publication # 78-23, 1996). Formononetin was purchased from Sigma-Aldrich (Catalog No. 47752-formononetin).
쥐는 무작위적으로 4개의 군에 7마리씩 배정되었다. Nor(일반 C57BL/6 쥐) 군과 Alopecia(탈모 C57BL/6 쥐) 군들에 담체와 2 종류의 농도(1, 100 μM; 메탄올 용매)인 포모노네틴을 탈모 후 일주일에 5일 국소적으로 처리하였다. 성장기의 유도와 대량의 퇴행기 진행 여부를 2주간 측정하였다. 탈모 후 15일째에, 사진을 찍고 개별 쥐의 등피부조직을 사용시까지 얼린 상태로 유지된 채로 수집하였다.
Rats were randomly assigned to 7 rats in four groups. In the alopecia (alopecia C57BL / 6 mice) and Nor (general C57BL / 6 rats) groups, the carrier and two concentrations (1, 100 μM; methanol solvent) of formononetin were treated topically Respectively. The induction of growth phase and the progression of massive regressions were measured for 2 weeks. On
구체적으로는, 모발 재발모에 포모노네틴이 미치는 영향을 확인하기 위하여, 정상군과 탈모군에 메탄올을 처리하여 모발 소실이 일어난 등쪽 피부에 포모노네틴을 국소적으로 처리하였다. Specifically, in order to examine the effect of hair regrowth moefononetin, the normal group and hair loss group were treated with methanol to treat locally the dorsal skin with hair loss.
그 결과, 포모노네틴을 처리하지 않은 모발 소실이 일어난 쥐는 모발이 소실된 채로 유지되어 있었으며 등피부는 분홍 또는 회색을 보였다. 반면, 포모노네틴을 처리한 경우에는 농도 의존적으로 모발이 재발모하는 것을 확인하였다(도 1). 포모노네틴 처리군에 속한 모든 쥐에서 탈모가 뚜렷하게 개선되었다.
As a result, the mice that had lost the hair without treatment of the pomononetin were kept in a state of disappearing hair and the cheekbones were pink or gray. On the other hand, when pomono neetin was treated, it was confirmed that hair was re-accumulated depending on the concentration (FIG. 1). Hair loss was significantly improved in all mice belonging to the pomonotin treatment group.
실시예Example
2. 모발 성장의 조직학적 실험 2. Histological examination of hair growth
포모노네틴이 모낭(hair follicle), 모근(hair bulbs) 및 모간(hair shafts)에 미치는 영향을 확인하기 위하여, 실시예 1에서 수득한 각 군의 등피부조직을 헤마톡실린 & 에오신(Hematoxylin & Eosin, H&E) 염색을 위해 4% 포름알데하이드로 고정하였다. 파라핀으로 고정된 4-um 두께의 절편들을 에탄올과 증류수로 수화하고 H&E 시약으로 염색하였다. 퍼마운트(자일렌) 한 방울을 유리 막대를 이용하여 기포 없이 슬라이드에 떨어뜨린다. 슬라이드 위에 커버슬립을 부드럽게 얹으면, 퍼마운트는 커버슬립 아래에 퍼지게 되고, 이를 후드에서 하룻밤 동안 말렸다. Leica Application Suute(LAS) 현미경 소프트웨어(Leica Microsystems Inc., IL, USA)가 디지털 이미지를 얻는데 사용되었다. 배율은 x100, x200 및 x400이었다.
In order to examine the effect of pomonotenine on hair follicle, hair bulbs and hair shafts, the dorsal skin tissue of each group obtained in Example 1 was treated with hematoxylin & eosin Eosin, H & E) were fixed with 4% formaldehyde for staining. Paraffin-fixed 4-μm thick sections were hydrated with ethanol and distilled water and stained with H & E reagent. Use a glass rod to drop a droplet of fur mount (xylene) onto the slide without air bubbles. When the cover slip was gently placed on the slide, the fur mount was spread under the cover slip, which was dried in the hood overnight. Leica Application Suute (LAS) microscope software (Leica Microsystems Inc., IL, USA) was used to acquire digital images. The magnifications were x100, x200 and x400.
도 2는 x100, x200 및 x400배 확대된 H&E 염색 단면의 대표적인 모습이다. T림프구 침윤에 영향받은 피부 부위는 모간이 망가져 모낭으로부터 뻗어나가지 못하는 특징을 보인다. 그리고 도면상 모근 주위에 이른바 '벌떼(swam of bees)'라 일컬어지는 높은 T림프구 침윤은 거의 확인되지 않았다. 놀랍도록 작아진 모낭이 피부 상피 표면으로부터 떨어져서 존재했다. 그리고 탈모-영향 피부에서 모근 주변에 몇몇 호산구가 침윤한 모습은 확인되었다. 포모노네틴을 처리한 후에 새로운 모발이 생겨났으며, 빈영양형 퇴행기 모낭이 새로이 길쭉한 성장기 모낭으로 변화하였다. 포모노네틴 처리로 인하여, 모발 및 긴 모간을 포함하는 모낭의 크기를 회복하였다. 특히 100mg/mL의 포모노네틴 처리군에서는 모낭으로부터 피부 표면에까지 곧게 뻗은, 잘 분화된 모간을 보였다.
FIG. 2 is a representative view of the H & E-dyed sections enlarged at x100, x200 and x400 times. The skin area affected by T lymphocyte infiltration is characterized by the loss of the moraine and failure to extend from the hair follicle. There was little evidence of high T lymphocyte infiltration around the hair follicle, so-called 'swam of bees'. There was an amazingly small follicle away from the skin epithelium surface. And some eosinophils infiltrated around the hair follicle in the hair loss-affected skin. After treatment with formononetin, new hair was formed, and an empty nutritional degeneration hair follicle changed into a new elongated growing hair follicle. Due to the pomonotin treatment, the size of hair follicles including hair and long hair was restored. In particular, 100 mg / mL of the pomonotetin-treated group showed well-differentiated moraines extending straight from the hair follicle to the skin surface.
실시예Example
3. 3.
역전사Reverse transcription
PCRPCR
((
ReverseReverse
transcriptiontranscription
polymerase중합체
chainchain
reactionreaction
, ,
RTRT
--
PCRPCR
)을 통한 TNF-β, 및 ), ≪ / RTI > and
ILIL
-8 -8
mRNAmRNA
정량 측정 Quantitative measurement
탈모 영역의 피부조직으로부터 TRIzol 시약(Invitrogen Corp., Carlsbad, CA, USA)을 이용하여 제조자의 지시에 따라 전RNA를 분리하였다. 분리된 전RNA(1ug)를 상업적으로 사용가능한 cDNA 제조키트(Invitrogen Corp., Carlsbad, CA, USA)를 이용하여 cDNA로 역전사하였다. 실험 튜브들을 45℃에서 60 분간 정치한 후, 95℃에서 5분간 정치하였다. 상기 샘플들은 이후 사용시까지 -20℃에서 보관되었다. cDNA는 Taq 합성효소(Promega}와 TNF-β, IL-8 및 GAPDH의 mRNA에 특이적인 프라이머를 통해 증폭되었다. 역전사 PCR(RT-PCR)의 최적 조건은 일반적인 방법을 통해서 확정되었다. TNF-β 및 IL-8은 94℃ 20초, 60℃ 30초, 및 72℃로 2분의 사이클을 35회 반복한 후, 최종 합성을 위해 72℃로 10분간 PCR을 진행하였다. PCR 결과물을 1% 아가로즈 젤에 전기영동하여, GAPDH mRNA를 기준으로 하여 상대적인 mRNA 발현량을 Quantity One 소프트웨어를 이용하여 정량화하였다.
Total RNA was isolated from the skin tissue of the hair loss region according to the manufacturer's instructions using TRIzol reagent (Invitrogen Corp., Carlsbad, Calif., USA). The separated total RNA (1 ug) was reverse transcribed with cDNA using a commercially available cDNA preparation kit (Invitrogen Corp., Carlsbad, Calif., USA). The test tubes were allowed to stand at 45 DEG C for 60 minutes and then at 95 DEG C for 5 minutes. The samples were stored at -20 [deg.] C until further use. cDNA was amplified by primers specific for Taq synthetase (Promega) and TNF-β, IL-8 and GAPDH mRNA. The optimal conditions for reverse transcription PCR (RT-PCR) And IL-8 were repeated 35 times at 94 ° C for 20 seconds, 60 ° C for 30 seconds, and 72 ° C for 2 minutes, and then subjected to PCR for 10 minutes at 72 ° C for final synthesis. The relative amount of mRNA expression on the basis of GAPDH mRNA was quantitated using Quantity One software by electrophoresis on a rose gel.
도 3에 나타난 바와 같이, 탈모가 일어난 피부에서 IL-8과 TNF-β의 mRNA 발현이 증가하는데 비하여, 포모노네틴을 처리하는 경우에 농도의존적으로 상기 두 사이토카인의 발현 증가를 억제하는 것을 확인하였다.
As shown in Fig. 3, mRNA expression of IL-8 and TNF-beta was increased in the skin with hair loss, whereas when pomonoetin was treated, it was confirmed that the expression of the two cytokines was inhibited in a concentration- Respectively.
실시예Example
4. 전, 세포질 및 핵 단백질 수득을 위한 조직 4. Tissues for obtaining pre-, cytoplasmic and nuclear proteins
용해물Melt
제조 Produce
전조직 용해물을 수득하기 위해서, 쥐의 등피부로부터 수득한 500mg(그룹당 7마리) 쥐 조직을 얼음 위에서 단백질 분해효소 저해 cocktail((Roche, Idianapolis, IN)을 포함하는 T-PER 조직 단백질 추출용액 (Pierce, Rockford, IL, USA) 2mL에 균질화하였다. 혼합물은 얼음위에 15분간 정치시킨 후 15초간 볼텍싱하였다. 이러한 과정을 4회 반복하였다. 마지막으로 4℃에서 12,000Xg로 20분간 원심분리하여 상층액을 수득하였으며, 그 후 상기 상층액에 등피부조직으로부터 얻은 전단백질이라고 라벨링하고, 등피부조직의 tumor necrosis factor (TNF)-α, interleukin (IL)-1β, 4, 6 및 IFN-γ 등과 같은 사이토카인과 면역 및 세포사멸 인자의 발현을 확인하였다. 또한, 쥐의 등피부로부터 수득한 또다른 500mg(그룹당 7마리)의 쥐 조직을 얼음 위에서 단백질 분해효소 저해 cocktail을 포함하는 세포질 완충용액 (10 mM HEPES, pH 7.9, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, 0.15% Nonidet P-40, 50 mM β-glycerophosphate, 10 mM NaF 및 5 mM Na3VO4) 2mL에 균질화하였다. 균질물을 얼음 위에서 15분간 정치한 후에 4℃에서 12,000Xg로 30분간 원심분리하였다. 상기 상층액을 세포질 단백질이라고 라벨링하고, 펠렛(핵 포함)은 핵 완충용액(20 mM HEPES, pH 7.9, 400 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0.50% Nonidet P-40, 50 mM β-glycerophosphate, 10 mM NaF 및 5 mM Na3VO4)에 현탁시킨 후, 얼음 위에 15분간 정치하였다. 핵 단백질 분획은 4℃에서 12,000Xg로 30분간 원심분리한 상층액으로 얻었다. 전, 세포질 및 핵 단백질 분획은 사용시까지 -80℃에 보관하였다.
To obtain a whole tissue lysate, 500 mg (7 rats per group) of rat tissues obtained from the dorsal skin of rats were inoculated on ice with T-PER tissue protein extract solution containing protease inhibitor cocktail (Roche, Idianapolis, IN) (Pierce, Rockford, Ill., USA) .The mixture was left on ice for 15 minutes and then vortexed for 15 seconds.This procedure was repeated four times.Finally, the mixture was centrifuged at 12,000 xg for 20 minutes (TNF) -α, interleukin (IL) -1β, 4, 6, and IFN-γ in the dorsal skin tissues were labeled as whole proteins from the dorsal skin tissues in the supernatant, (7 mice per group) obtained from the dorsal skin of rats were infected with the cytoplasmic bundles containing the protease inhibiting cocktail on ice, Solution (10 mM HEPES, pH 7.9, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, 0.15% Nonidet P-40, 50 mM β-glycerophosphate, 10 mM NaF , and 5 mM Na 3 VO 4) 2mL The homogenate was allowed to stand on ice for 15 minutes and then centrifuged at 12,000 xg for 30 minutes at 4 DEG C. The supernatant was labeled as a cytoplasmic protein and the pellet (including nucleus) was dissolved in a nuclear buffer solution (20 mM HEPES, pH 7.9, 400 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0.50% Nonidet P-40, 50 mM β-glycerophosphate, 10 mM NaF and 5 mM Na 3 VO 4 ) The nuclear protein fraction was obtained by centrifugation at 12,000 × g for 30 minutes at 4 ° C. The cytoplasmic and nuclear protein fractions were stored at -80 ° C. until use.
실시예Example
5. 사이토카인 측정을 위한 효소-연결 면역흡착 분석( 5. Enzyme-Linked Immunosorbent Assay for Cytokine Measurement
ELISAELISA
))
T 림프구 침윤에 영향받지 않은 피부 조직 또는 영향받은 피부 조직 단백질에서 사이토카인 생성량을 측정하기 위하여 변형된 ELISA 방법을 이용하였다. 단백질 농도는 단백질 분석 용액(Bio-Rad, Hercules, CA)을 이용하여 측정하였다. 간단하게 말하면, 편평한 96-웰 플레이트(BD Bioscience, San Jose, CA)를 IL-6 and IFN-γ 포획 항체(capture antibody)를 포함하는 코팅 용액으로 4℃에서 하룻밤 동안 코팅시켰다. 그 후, PBS-T 용액(0.05% Tween-20 포함 PBS)로 3회 세척한 후 분석 희석 용액(Assay Diluent buffer, 10% FBS를 포함하는 PBS)로 실온에서 1시간 동안 블라킹하였다. PBS-T로 플레이트를 세척하였다. 샘플과 기준 시료를 웰 3개씩에 처리하고, 실온에서 2시간 동안 정치하였다. 다음으로, 각 웰들을 5번씩 세척한 다음, 탐지 항체(detection antibody)를 각 웰에 처리하고, 상기 플레이트를 실온에서 1시간 동안 정치한다. 상기 플레이트를 7번 세척하였다. 그 다음, TMB 기질 시약(BD Bioscience, San Jose, CA)을 첨가한 다음 암전 상태로 30분간 실온에서 정치시켰다. 본 반응은 정지 용액(2N H2SO4)으로 고정하고, 각 웰의 광학적 세기는 450 nm 필터와 570 nm 필터를 이용하여 ELISA Reader(Molecular Devices, Downingtown, PA)를 통해 측정하였다. 사이토카인 수준은 총 단백질 g 당 pg으로 계산하였다.
A modified ELISA method was used to measure cytokine production from unaffected skin tissue or affected skin tissue proteins by T lymphocyte infiltration. Protein concentration was measured using protein analysis solution (Bio-Rad, Hercules, Calif.). Briefly, flat 96-well plates (BD Bioscience, San Jose, Calif.) Were coated overnight at 4 ° C with coating solutions containing IL-6 and IFN-y capture antibodies. Subsequently, the cells were washed three times with PBS-T solution (PBS containing 0.05% Tween-20) and then blocked with assay diluent buffer (PBS containing 10% FBS) for 1 hour at room temperature. The plates were washed with PBS-T. The sample and the reference sample were treated in three wells and left at room temperature for 2 hours. Next, each well is washed five times, then detection antibody is treated in each well, and the plate is left at room temperature for 1 hour. The plate was washed 7 times. Then, TMB substrate reagent (BD Bioscience, San Jose, Calif.) Was added and allowed to stand at room temperature for 30 minutes in the dark state. The reaction was fixed with stop solution (2N H 2 SO 4 ) and the optical intensities of each well were measured using an ELISA reader (Molecular Devices, Downingtown, PA) using a 450 nm filter and a 570 nm filter. The level of cytokine was calculated as pg per gram of total protein.
포모노네틴이 T림프구 활성화와 관련된 사이토카인 생성에 미치는 영향을 확인하기 위하여, 등피부조직으로부터 얻은 전-용해물을 사용하였다. 기존에 알려진 바와 같이 수개의 T 세포-매개 사이토카인들이 면역반응 과정을 조절한다. 상기 ELISA 실험 결과, 탈모 및 T림프구 침윤 그룹에서 TNF-α, IL-1β, 4, 6, 및 IFN-γ의 수준이 증가되었다. In order to determine the effect of pomonotenine on cytokine production associated with T lymphocyte activation, a pre-dissolved extract from dorsal skin tissue was used. As is known, several T cell-mediated cytokines regulate the immune response process. As a result of the ELISA test, levels of TNF-α, IL-1β, 4, 6, and IFN-γ were increased in the group of hair loss and T lymphocyte infiltration.
실시예 3에 의한 역전사 PCR과 상기 결과를 종합하면, 포모노네틴은 탈모 그룹과 비교하여 TNF-α, TNF-β, IL-1β, 4, 6, 및 8 수준을 감소시켰다. 그러나, IFN-γ의 수준은 포모노네틴 처리 여부에 영향을 받지 않았다(도 4).
By combining the results of the reverse transcription PCR according to Example 3 and the above results, pomonothelin decreased levels of TNF-α, TNF-β, IL-1β, 4, 6, and 8 as compared with the hair loss group. However, the level of IFN-y was not affected by the presence of the pomonoetin treatment (Fig. 4).
실시예Example
6. 웨스턴 블랏팅 분석 6. Western Blot Analysis
β-actin, 유도성 산화질소 합성효소(inducible nitric oxide synthase, i-Nos), cyclooxygenase (Cox)-2, c-Jun, extracellular signal-regulated kinase (ERK), p-ERK, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinases (SAPK/JNK), p-SAPK/JNK, p38, p-p38, Bax, Bcl-2, p53, caspase-3 및 9의 활성화를 전단백질 레벨에서 확인하였다. 또한, NF-κB의 활성은 핵 단백질에서, IκB-α 및 p-IκB-α의 수준은 세포질 단백질에서 분석하였다. 각 단백질 50 μg을 SDS 용액(62.5 mM Tris-HCl, pH 6.8, 2% SDS, 20% glycerol, 1% bromophenol blue 및 10% 2-mercaptoethanol)으로 변성시켰다. 변성된 시료는 10% SDS-polyacrylamide gel에 의해 분리되어 PVDF 막(Bio-Rad, Hercules, CA, USA)에 2시간 동안 이동되었다. 상기 막은 5% 탈지 우유 용액(TBS-T)에 2시간동안 블라킹 된 후, TBS-T 용액에 의해 세척되었다. 이후, 1차 항체(anti-β-actin, -i-Nos, -Cox-2, -c-Jun, -ERK, -p-ERK, -SAPK/JNK, -p-SAPK/JNK, -p38, -p-p38, -Bax, -Bcl-2, -p53, caspase-3, capase-9, -NF-κB, -IκB-α 및 -p-IκB-α; TBS-T 용액에 1:800 비율로 희석; cell signaling, USA)를 처리하여 하룻밤 정치하였다. 세척한 후, 2차 항체(anti-mouse IgG; TBS-T 용액에 1:2000비율로 희석)을 붙였다. 항체가 결합된 단백질은 ECL 탐지 시약 (enhanced chemiluminescence 탐지 시약, Amersham Pharmacia, Piscataway, NJ, USA)으로 시각화하였다. β-actin은 i-Nos, Cox-2, c-Jun, Bax, Bcl-2, p53, caspase-3, 9, NF-κB, IκB-α 및 p-IκB-α의 단백질 수준을 측정하기 위한 내부 대조군(internal loading control)으로 이용하였다. MAP kinase(ERK, JNF, p-38)는 인산화 정도를 측정하기 위한 내부 대조군으로 이용하였다. 상기 밴드의 상대적인 세기는 컴퓨터화된 세기 측정 시스템(computerized densitometry system)을 이용하여 측정하였다.
β-actin, inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox) -2, c-Jun, extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK) / c-Jun N-terminal kinases (SAPK / JNK), p-SAPK / JNK, p38, p-p38, Bax, Bcl-2, p53, caspase-3 and 9 Respectively. In addition, the activity of NF-κB in nuclear proteins, the levels of IκB-α and p-IκB-α were analyzed in cytoplasmic proteins. 50 μg of each protein was denatured with SDS solution (62.5 mM Tris-HCl, pH 6.8, 2% SDS, 20% glycerol, 1% bromophenol blue and 10% 2-mercaptoethanol). The denatured samples were separated by 10% SDS-polyacrylamide gel and transferred to a PVDF membrane (Bio-Rad, Hercules, CA, USA) for 2 h. The membrane was blocked with 5% defatted milk solution (TBS-T) for 2 hours and then washed with TBS-T solution. Then, the primary antibody (anti-β-actin, -iNos, -Cox-2, -c-Jun, -ERK, -p-ERK, -SAPK / JNK, 1: 800 ratio was added to a solution of TBS-T, p-p38, -Bax, -Bcl-2, -p53, caspase-3, capase-9, -NF-κB, -IκB- Cell signaling, USA) and allowed to stand overnight. After washing, secondary antibody (anti-mouse IgG, diluted 1: 2000 in TBS-T solution) was added. Antibody-bound proteins were visualized with ECL detection reagents (enhanced chemiluminescence detection reagent, Amersham Pharmacia, Piscataway, NJ, USA). β-actin was used to measure protein levels of i-Nos, Cox-2, c-Jun, Bax, Bcl-2, p53, caspase-3, 9, NF-κB, IκB-α and p- And used as an internal loading control. MAP kinase (ERK, JNF, p-38) was used as an internal control for measuring the degree of phosphorylation. The relative intensities of the bands were measured using a computerized densitometry system.
실시예Example
7. 7.
포모노네틴에Formononetin
의한 면역 및 세포사멸 관련 인자 활성 측정 Of immune and apoptosis related factors
상시 실시예 6에서 설명한 웨스턴 블랏팅 방법을 통해서, 면역 및 세포사멸 관련 인자들의 발현량 또는 활성(인산화 등)을 확인하였다.
Through the Western blotting method described in Example 6, the expression level or activity (such as phosphorylation) of immunological and apoptosis-related factors was confirmed.
실시예Example
7-1 7-1
포모노네틴의Pomonotenine
NFNF
-κB 및 IκB-α 활성에 미치는 영향-KB and IκB-α
웨스턴 블랏팅을 통하여 많은 전-면역반응 관련 사이토카인과 관련된 것이 알려진 전사인자의 발현량을 측정하였다. 포모노네틴 처리는 핵 단백질 내에서 NF-κB의 발현을 감소시키고 세포질 단백질 내에서 p-IκB-α의 수준을 감소시켰다(도 5). Western blotting was used to measure the expression levels of a number of transcription factors known to be associated with many pro-immune response related cytokines. Formononetin treatment reduced the expression of NF-κB in the nuclear protein and decreased the level of p-IκB-α in the cytoplasmic protein (FIG. 5).
이는 포모노네틴이 NF-κB의 핵 내로의 이동을 막아서 IκB-α의 인산화를 억제한다는 것을 의미한다. 또한, 포모노네틴에 의한 NF-κB의 발현 감소는 세포질 내에서 IκB-α의 분해를 저해한다.
This implies that pomanonetin inhibits the phosphorylation of IκB-α by blocking the migration of NF-κB into the nucleus. In addition, the decreased expression of NF-κB by pomonotetin inhibits the degradation of IκB-α in the cytoplasm.
실시예Example
7-2. 7-2.
포모노네틴의Pomonotenine
i- i-
NosNos
및 And
CoxCox
-2 활성에 미치는 영향-2 activity
NF-κB의 활성은 i-Nos 및 Cox-2의 발현과 관련되어 있음은 기존에 알려져 있다. NF-κB의 저해에 의한 추후 기작을 확인하기 위하여, 전단백질 용해물에서 i-Nos 및 Cox-2의 발현 수준을 측정하였다. 탈모에 의해 증가되었던 i-Nos 및 Cox-2의 발현이 포모노네틴에 의해서 농도 의존적으로 감소하는 것을 확인하였다(도 6).
It is known that the activity of NF-kB is related to the expression of i-Nos and Cox-2. In order to confirm the mechanism by inhibition of NF-κB, i-Nos and Cox-2 expression levels were measured in whole protein lysate. It was confirmed that the expression of i-Nos and Cox-2, which were increased by hair loss, was decreased in a concentration-dependent manner by pomonothelin (FIG. 6).
실시예Example
7-3. 7-3.
포모노네틴의Pomonotenine
MAPMAP
kinasekinase
활성에 미치는 영향 Effect on activity
포모노네틴의 처리가 세포생존 및 사멸과 관련된 3개의 MAP kinase들(p38, SAPK/JNK 및 ERK)의 활성화를 의미하는 인산화를 억제하는지 여부를 확인하였다. T림프구 침윤에 영향받은 피부 영역에서 해당 3 MAP kinase의 증가된 인산화 수준이 포모노네틴 처리에 의해서 감소되는 것을 확인하였다. 포모노네틴을 처리한 모든 군에서 정상군(Alopiecia -, 포모노네틴 -)에 가까운 정도로 완벽히 회복되는 것을 확인하였다(도 7).
Confirming whether the treatment of pomonotenin inhibits phosphorylation, which implies activation of three MAP kinases (p38, SAPK / JNK and ERK) associated with cell survival and death. The increased phosphorylation level of the corresponding 3 MAP kinase in the area of the skin affected by T lymphocyte infiltration was confirmed to be reduced by the treatment with formononetin. It was confirmed that all groups treated with formononetin were completely recovered to a degree close to that of the normal group (Alopiecia -, pomonotenine-) (FIG. 7).
실시예Example
7-4. 7-4.
포모노네틴의Pomonotenine
c- c-
JunJun
활성에 미치는 영향 Effect on activity
SAPK/JNK pathway의 활성화를 추가적으로 확인하기 위해서 SAPK/JNK-관련 인자인 c-Jun에 대해서 분석하였다. 실시예 7-3에서 확인하였듯이 포모노네틴의 처리에 의한 SAPK/JNK의 발현 및 활성 감소와 일치하여, 그 하위인자인 c-Jun의 활성도 감소하였다(도 8).
To further validate the activation of the SAPK / JNK pathway, we analyzed the SAPK / JNK-related factor c-Jun. As shown in Example 7-3, the activity of c-Jun, a sub-factor thereof, decreased in accordance with the decrease in expression and activity of SAPK / JNK by treatment with pomanonethin (FIG. 8).
실시예Example
7-5. 7-5.
포모노네틴의Pomonotenine
세포사멸인자Cell death factor
생성에 미치는 영향 Effect on production
모낭의 퇴행으로 여겨지는 퇴행기에 대한 조절은 케라티노사이트 사멸을 반영한다. 항-세포사멸 Bcl-2와 전세포사멸 Bax 발현 비율은 세포사멸 조정 과정을 대표한다. 사멸형 퇴행기-영향 쥐에서 Bax의 증가만큼이나 Bcl-2의 감소가 확인되었다. 포모노네틴 처리 쥐에서는 상기 두 사멸-관련 인자의 발현이 서로 반대되어 결국 Bcl-2와 Bax 발현 비율이 증가하는 것을 확인하였다. 이에 더하여, p53, capase-3 및 9의 활성이 포모노네틴 처리에 의해서 감소하였다(도 9).
Control of the regressors considered degenerative of hair follicles reflects the keratinocyte death. Anti-apoptotic Bcl-2 and whole cell death Bax expression ratios represent the apoptosis-regulating process. A decrease in Bcl-2 was confirmed as an increase in Bax in the apoptotic retrograde-effected rats. The expression of the two death-related factors in the pomonotin-treated rats were opposite to each other, and the ratio of Bcl-2 and Bax expression was increased. In addition, the activity of p53, capase-3 and 9 was reduced by pomonotine treatment (Fig. 9).
실시예Example
8. 통계학적 분석 8. Statistical analysis
ANOVA(one-way analysis of variance) 및 비모수 검정을 통하여 유의미도를 측정하였다. 모든 분석에서, 통계학적 유의미성의 기준으로 P<0.05을 확인하였다.
One-way analysis of variance (ANOVA) and nonparametric test were used to measure significance. In all analyzes, P <0.05 was determined on the basis of statistical significance.
상기 결과에서, 본 발명의 포모노네틴은 탈모를 일으킨 동물 모델에서 뛰어난 발모 촉진 효과를 가지는 것을 확인했으며, 이는 탈모에 의해서 발생하는 면역반응 및 세포사멸 반응을 억제하는 것을 통해 모발의 재발모를 촉진하는 효과를 가지는 것을 확인하였다. 또한, 상기 면역 반응 및 세포사멸 반응을 억제하는 효과를 통해 애초에 자연적으로 일어나는 탈모를 방지하는 효과를 가질 수 있음도 예측할 수 있다.
From the above results, it was confirmed that the pamo-nonetin of the present invention has an excellent hair growth promoting effect in an animal model of hair loss, which promotes hair regrowth through inhibiting immune reaction and apoptosis caused by hair loss Respectively. In addition, it can be predicted that the effect of inhibiting the immune reaction and the cell death killing effect can be prevented to prevent hair loss naturally occurring in the beginning.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
Claims (8)
A pharmaceutical composition for promoting hair growth of resting alopecia including as an active ingredient formononetin or a pharmaceutically acceptable salt thereof.
2. The composition of claim 1, wherein the formononetin or a pharmaceutically acceptable salt thereof is present in an amount of 0.00001% to 30% by weight relative to the total weight of the composition.
The pharmaceutical composition according to claim 1, wherein the composition is an external preparation for skin.
A composition for accelerating hair growth of resting alopecia comprising only pomonoetin or a pharmaceutically acceptable salt thereof as an active ingredient for promoting hair growth.
Claims: 1. A cosmetic composition for stimulating hair growth of resting alopecia including as an active ingredient, formononetin or a pharmaceutically acceptable salt thereof.
6. The cosmetic composition according to claim 5, wherein the pomononetin or a pharmaceutically acceptable salt thereof is contained in an amount of 0.00001 to 30% by weight based on the total weight of the composition.
A quasi-drug composition for accelerating the hair growth of resting alopecia including as an active ingredient, pomonotenine or a pharmaceutically acceptable salt thereof.
Claims 1. A food composition for promoting the hair growth of resting alopecia areata, comprising as an active ingredient, pomonotenine or a pharmaceutically acceptable salt thereof.
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