KR101426307B1 - Composition Comprising Extract of Daphne genkwa as Active Ingradient - Google Patents
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- KR101426307B1 KR101426307B1 KR1020110031614A KR20110031614A KR101426307B1 KR 101426307 B1 KR101426307 B1 KR 101426307B1 KR 1020110031614 A KR1020110031614 A KR 1020110031614A KR 20110031614 A KR20110031614 A KR 20110031614A KR 101426307 B1 KR101426307 B1 KR 101426307B1
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Abstract
본 발명은 팥꽃나무의 줄기 및 뿌리를 유기용매로 추출하여 수득한 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물, 상기 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 또는 개선효과를 나타내는 식품 첨가물 및 상기 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 활성화 조성물에 관한 것이다. 본 발명의 팥꽃나무 추출물은 별다른 부작용을 나타내지 않으면서도, Nurr1을 활성화시켜서, 이에 의하여 유발되는 파킨슨병, 류마티스 관절염, 정신분열증, 조울증 등의 다양한 Nurr1 기능장애에 의해 유발되는 질환을 예방 또는 치료할 수 있으므로, 다양한 질환의 보다 안전한 치료에 널리 활용될 수 있을 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of diseases caused by Nurr1 dysfunction which comprises an extract of Aspergillus oryzae as an active ingredient obtained by extracting stem and roots of an Asahi bean blossom with an organic solvent, Which is effective for the prevention or amelioration of diseases caused by Nurr1 dysfunction. The present invention also relates to a Nurr1 activating composition comprising the above-mentioned bean floret extract as an active ingredient. The present invention can prevent or treat diseases caused by various Nurr1 dysfunctions such as Parkinson's disease, rheumatoid arthritis, schizophrenia and bipolar disorder caused by activating Nurr1 without showing any adverse side effects , May be widely used for safer treatment of various diseases.
Description
본 발명은 팥꽃나무 추출물을 포함하는 조성물에 관한 것으로, 보다 구체적으로 본 발명은 팥꽃나무의 줄기 및 뿌리를 유기용매로 추출하여 수득한 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물, 상기 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 또는 개선효과를 나타내는 식품 첨가물 및 상기 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 활성화 조성물에 관한 것이다.
The present invention relates to a composition comprising an extract of Aspergillus oryzae. More specifically, the present invention relates to a composition comprising an extract of Aspergillus oryzae, obtained by extracting the stem and root of an adzuki bean flower with an organic solvent, as an active ingredient, A pharmaceutical composition for preventing or treating diseases, a food additive exhibiting an effect of preventing or ameliorating a disease caused by Nurr1 dysfunction including the above-mentioned red bean flour extract as an active ingredient, and Nurr1 activated ≪ / RTI >
신경퇴행성 질환은 신경 세포가 퇴화하고, 기능을 잃고, 그리고 종종 사멸하는 경우의 증상들과 관련된다. 이들은 주로 진행성이기 때문에, 신경퇴행성 질환의 결과는 종종 대단히 파괴적이다. 신경퇴행성 질환을 가진 환자들은 인지(cognitive) 또는 운동(motor) 능력에 있어서의 극심한 퇴화를 겪을 수 있다. 결과적으로, 그들의 삶의 질 및 삶에 대한 기대는 현저히 감소될 수 있다. 인간에게 있어서, 이들 질환은 알츠하이머병(Alzheimer's Disease), 파킨슨병(Parkinsons's Disease), 루게릭병(amyotrophic lateral sclerosis), 헌팅턴병(Huntington's Disease), 전측두엽 치매(Fronto-Temporal Dementia), 및 피질-기저핵 퇴행증(Cortico Basal Degeneration) 및 다른 질병들을 포함한다.
Neurodegenerative diseases are associated with symptoms of neuronal degeneration, loss of function, and often death. Because they are primarily progressive, the consequences of neurodegenerative diseases are often very devastating. Patients with neurodegenerative diseases may experience extreme degeneration in cognitive or motor ability. As a result, their quality of life and their expectations for life can be significantly reduced. For humans, these diseases include Alzheimer ' s Disease, Parkinsons ' s Disease, amyotrophic lateral sclerosis, Huntington's Disease, Fronto-Temporal Dementia, Cortico Basal Degeneration and other diseases.
한편, 상당수의 신경퇴행성 질환에는 Nurr1(Nuclear receptor related 1)이 관련된 것으로 알려져 있다. 상기 Nurr1은 NR4A2(nuclear receptor subfamily 4, group A, member 2)라고도 알려져 있는 핵수용체 관련 1 단백질을 의미하며, 이는 사람의 NR4A2 유전자에 의해 암호화되는 것으로 알려져 있다. 비록, 상기 Nurr1 단백질은 고아 핵 수용체로서, 아직까지는 상기 단백질에 대한 리간드가 규명되어 있지 않지만, 상기 Nurr1은 세포내 전사인자의 핵수용체 패밀리에 속하는 단백질로서, 뇌에서 도파민 시스템(dopaminergic system)을 유지하는 핵심적인 역할을 수행함이 규명되었다. 상기 Nurr1 또는 NR4A2 유전자에 이상이 발생하면, 도파민 시스템의 기능이 손상되어 파킨슨병을 유발시킬 뿐만 아니라, 류마티스 관절염, 정신분열증, 조울증 등의 광범위한 염증성 및 신경성 질환의 원인이 되는 것으로 알려져 있다.On the other hand, a number of neurodegenerative diseases are known to involve Nurr1 (Nuclear receptor related 1). The Nurr1 refers to a nuclear receptor-related protein, also known as NR4A2 (
상기 Nurr1의 기능장애에 의하여 유발되는 대표적인 신경퇴행성 질환인 파킨슨병은 근육 운동을 통제하는 뇌 신경 세포에 영향을 미치는 만성 진행성 신경 질환으로서, 중뇌의 흑질(substantia nigra) 부위에 신경전달물질인 도파민을 만들어 내는 세포가 갑자기 손상되거나, 퇴화되거나 또는 그 수가 크게 감소할 경우에 발생하는데, 상기 도파민은 신체의 운동을 용이하게 하기 위해 세포 사이에서 신호를 전달하기 위한 중요한 화학물질이기 때문에, 전형적으로 나타나는 떨림증(tremor), 경직(rigidity), 운동완서(bradykinesia), 자세의 불안정(postural instability) 및 언어능력 손상과 같은 운동성 질환증상이 야기된다. 이처럼 도파민 생성 세포가 손상되는 원인은 명확히 밝혀져 있지 않으나, 뇌의 동맥경화증, 일산화탄소 중독, 약물, 부갑상선 기능저하증 등에 의한 대사성, 외상성 뇌염 후유증 등이 관여하는 것으로 연구되고 있다. Parkinson's disease, which is a representative neurodegenerative disease caused by dysfunction of Nurr1, is a chronic progressive neurological disease that affects the brain nerve cell that regulates muscle movement. It is a neurodegenerative disorder in which the neurotransmitter dopamine This occurs when the cells that make up are suddenly damaged, degenerated or the number of them is greatly reduced. Because the dopamine is an important chemical for transferring signals between cells to facilitate movement of the body, such as tremor, rigidity, bradykinesia, postural instability, and impaired language ability. The cause of dopaminergic cell damage is not clear yet, but it has been studied that it involves metabolic diseases such as cerebral arteriosclerosis, carbon monoxide poisoning, drugs, hypoparathyroidism, and traumatic encephalopathy complications.
이같은 파킨슨병의 치료를 위한 약물로서, 엘도파(l-dopa) 제제, 도파민 수용체 작용제, 항콜린 약제, 엘데프릴(Eldepryl=depreyl) 등이 알려져 있으며, 이들 약물들 대부분은 원인적인 치료가 아니라 증상을 조절하는 역할을 하는 것이며, 따라서 꾸준하게 지속적인 약물의 복용을 필요로 한다. 그러나, 이러한 약물들의 장기 투여는 약물 부작용의 문제점을 야기하게 된다. 예를 들어, 항콜린 약제들은 자율신경계 이상이나 정신기능의 이상 등이 나타날 수 있어 고령의 환자들에게 지속적으로 투여하는 것에 한계가 있다. 또한, 엘도파 제제의 경우 장기간 동안의 복용에 따라 점차적으로 효과가 떨어지고, 몸이 뒤틀리고 손이나 발이 저절로 움직이는 이상운동이 생기는 등의 부작용이 발생하게 된다.As drugs for the treatment of Parkinson's disease, there are known l-dopa drugs, dopamine receptor agonists, anticholinergic drugs, and Eldepryl = depreyl. Most of these drugs are not causal treatment, And therefore requires continuous and continuous drug use. However, the long-term administration of these drugs causes problems of drug side effects. For example, anticholinergic agents may have autonomic nervous system abnormalities or mental dysfunctions, which limits the continuous administration to older patients. In addition, in the case of the eldopa agent, side effects such as a gradual decrease in the effect due to long-term use, twisting of the body, abnormal movement in which the hands or feet move spontaneously occur, and the like.
이러한 부작용을 방지하기 위하여, 천연물로부터 유래한 파킨슨병의 치료제를 개발하려는 노력이 활발히 진행되고 있다. 예를 들어, 특허공개 제2001-0081188호에는 신경보호작용을 갖는 황금(Scutellariae Radix) 추출물을 유효성분으로 포함하는 파킨슨병 및 노인성치매를 포함하는 뇌질환 등의 신경계질환의 예방 및 치료용 조성물이 개시되어 있고, 특허공개 제2004-0012396호에는 백강잠 101A(Beauveria bassiana 101A)의 추출물을 포함하는 파킨슨병 및 중풍과 같은 퇴행성뇌질환 치료용 조성물이 개시되어 있으며, 특허공개 제2004-0029072호에는 웽구앙구오(wenguanguo) 껍질로부터 얻은 추출물을 포함하는 파킨슨병 치료용 약학 조성물이 개시되어 있고, 특허공개 제2010-0060123호에는 생강 추출물 또는 쇼가올을 포함하는 파킨슨 질환의 예방 또는 치료용 약학 조성물이 개시되어 있으며, 특허공개 제2010-0060949호에는 복숭아 잎 추출물을 유효 성분으로 포함하는 파킨슨병 등의 질환의 예방 및 치료에 사용되는 신경세포 보호용 조성물이 개시되어 있고, 특허공개 제2011-0013466호에는 포도씨 추출물 또는 이로부터 유래되는 하나 이상의 화합물을 유효성분으로 포함하는 파킨슨병 치료용 약학 조성물이 개시되어 있다. 그러나, 이들 천연물로부터 유래된 성분은 부작용이 없는 대신 파킨슨병의 치료효율이 낮다는 단점이 있었다.
In order to prevent such side effects, efforts to develop a therapeutic agent for Parkinson's disease derived from natural products have been actively conducted. For example, Japanese Patent Application Laid-Open No. 2001-0081188 discloses a composition for prevention and treatment of neurological diseases such as Parkinson's disease comprising senescent protective action of Scutellariae Radix as an active ingredient and brain diseases including senile dementia And Patent Document No. 2004-0012396 discloses a composition for treating degenerative brain diseases such as Parkinson's disease and stroke including an extract of Beauveria bassiana 101A. In Patent Publication No. 2004-0029072, Discloses a pharmaceutical composition for treating Parkinson's disease comprising an extract obtained from a wenguanguo skin, and Patent Application No. 2010-0060123 discloses a pharmaceutical composition for preventing or treating Parkinson's disease comprising ginger extract or showol And Patent Literature No. 2010-0060949 discloses a method for preventing and treating diseases such as Parkinson's disease including peach leaf extract as an active ingredient The nerve cell protective composition is disclosed for use in, and Patent Application Publication No. 2011-0013466 discloses is a pharmaceutical composition for treating Parkinson's Disease disclosed comprising at least one compound derived from grape seed extract or an active ingredient therefrom. However, the components derived from these natural products have a disadvantage in that the treatment efficiency of Parkinson's disease is low, without side effects.
이에, 본 발명자들은 팥꽃나무(Daphne genkwa)의 줄기 및 뿌리로부터 유래된 추출물이 천연물로부터 유래되어 부작용이 없으면서도, Nurr1을 활성화시킴으로써, 도파민성 신경세포의 분화, 성장 및 유지를 증진시키고, 그 결과 Nurr1 기능장애에 의해 유발되는 파킨슨병을 비롯한 다양한 질환의 치료효과가 우수함을 확인하고, 본 발명을 완성하게 되었다.
Thus, the present inventors have found that the extract derived from the stem and root of red bean flower (Daphne genkwa) is derived from a natural product, thereby enhancing the differentiation, growth and maintenance of dopaminergic neurons by activating Nurr1 without side effects, It has been confirmed that the therapeutic effect of various diseases including Parkinson's disease induced by Nurr1 dysfunction is excellent, and the present invention has been completed.
본 발명의 주된 목적은 팥꽃나무 추출물을 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.The main object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases caused by Nurr1 dysfunction, which comprises an extract of Aspergillus oryzae.
본 발명의 다른 목적은 상기 팥꽃나무 추출물을 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 또는 개선효과를 나타내는 식품 첨가물을 제공하는 것이다.Another object of the present invention is to provide a food additive exhibiting the effect of preventing or ameliorating a disease caused by Nurr1 dysfunction including the above-mentioned bean curd tree extract.
본 발명의 또 다른 목적은 상기 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1을 활성화시키기 위한 조성물을 제공하는 것이다.
Yet another object of the present invention is to provide a composition for activating Nurr1 comprising the above-mentioned bean curd tree extract as an active ingredient.
상기 목적을 달성하기 위한 본 발명의 일 실시양태에 의하면, 본 발명은 Nurr1 기능장애에 의해 유발되는 질환의 예방 및 치료효과를 나타낼 수 있는 팥꽃나무(Daphne genkwa)의 줄기 및 뿌리로부터 유래된 추출물에 관한 것이다.
According to one embodiment of the present invention, there is provided a method for preventing or treating diseases caused by Nurr1 dysfunction, comprising the steps of: extracting stem and root-derived extracts of Daphne genkwa .
본 발명자들은 부작용이 없으면서도, Nurr1 기능장애에 의해 유발되는 파킨슨병을 비롯한 다양한 질환을 예방 또는 치료하는 효과가 우수한 천연물 유래의 성분을 규명하기 위하여, 다양한 천연물로부터 수득한 다양한 형태의 추출물을 대상으로 하여 연구를 수행한 결과, 팥꽃나무(Daphne genkwa)로부터 수득한 추출물이 Nurr1 활성도를 증가시킬 수 있음을 확인하였다(도 1).
The inventors of the present invention have conducted studies on various kinds of extracts obtained from various natural products in order to identify the components derived from natural products which are excellent in preventing or treating various diseases including Parkinson's disease caused by Nurr1 dysfunction without side effects As a result, it was confirmed that the extract obtained from Daffne genkwa can increase Nurr1 activity (Fig. 1).
본 발명의 용어 "팥꽃나무(Daphne genkwa)"는 쌍떡잎식물 도금양목 팥꽃나무과의 낙엽관목을 의미하는데, 조기꽃나무·이팥나무라고도 하며, 주로 바닷가 근처에서 성장하고, 독성을 띠며, 한의학에서는 이뇨, 수종, 신장염 등의 증상을 치료하는데 사용한다.The term " Daphne genkwa "of the present invention means a deciduous shrub of a deciduous broad-leaved tree planted with a dicotyledonous plant. The term " Daphne genkwa " , And nephritis.
본 발명의 용어 "팥꽃나무 추출물"은 팥꽃나무로부터 수득한 추출물을 의미하는데, 바람직하게는 팥꽃나무의 줄기 또는 뿌리로 부터 수득한 추출물을 의미하고, 바람직하게는 팥꽃나무의 줄기 또는 뿌리를 유기용매 추출하여 수득한 추출물을 의미하며, 보다 바람직하게는 팥꽃나무의 줄기 또는 뿌리를 C1 내지 C5의 저급 알킬알콜로 추출하여 수득한 추출물을 의미한다.
The term " red bean berry leaf extract "of the present invention refers to an extract obtained from a red bean flower tree, preferably an extract obtained from the stem or root of red bean flower tree. Preferably, Refers to an extract obtained by extracting stem or root of red bean flower with CI to C5 lower alkyl alcohol.
또한, 본 발명자들은 상기 팥꽃나무 추출물은 신경세포를 사멸시키는 것으로 알려진 화합물(예를 들어, 6-OHDA 등)에 의한 신경세포 손상을 예방하는 효과를 나타냄을 확인하였다(도 2).In addition, the inventors of the present invention have confirmed that the above-mentioned bean curd tree extract has an effect of preventing neuronal damage by a compound known to kill neurons (for example, 6-OHDA) (FIG. 2).
뿐만 아니라, 본 발명자들은 랫트 뇌의 도파민성 신경세포를 사멸시키고, 상기 팥꽃나무 추출물을 사료에 혼합하여 급이시킨 결과, 사멸된 도파민성 신경세포에 의해 손상된 신경기능이 서서히 개선됨을 확인할 수 있었다(도 3).
In addition, the present inventors have found that the dopaminergic neurons in the rat brain are killed, and the bean curd tree extract is mixed with the feed, and the neuronal functions damaged by the killed dopaminergic neurons are gradually improved 3).
이처럼, 본 발명의 팥꽃나무 추출물은 Nurr1 활성도를 증가시킴으로써, Nurr1 기능장애에 의해 유발되는 다양한 질환, 즉 Nurr1의 활성에 의하여 직접적으로 영향을 받는 도파민성 신경세포의 손상에 의하여 유발되는 다양한 질환의 예방 또는 치료에 효과를 나타낸다. 이때, Nurr1 기능장애에 의해 유발되는 질환은 특별히 이에 제한되지 않으나, 파킨슨병, 류마티스 관절염, 정신분열증, 조울증 등을 포함한다.
As described above, the present invention provides a method for preventing various diseases caused by Nurr1 dysfunction, that is, various diseases caused by damage of dopaminergic neurons directly affected by the activity of Nurr1 by increasing Nurr1 activity Or treatment. The diseases caused by Nurr1 dysfunction include, but are not limited to, Parkinson's disease, rheumatoid arthritis, schizophrenia, bipolar disorder and the like.
본 발명의 다른 실시양태에 의하면, 본 발명은 상기 팥꽃나무 추출물을 유효성분으로 포함하고 약학적으로 허용가능한 담체를 포함하는 Nurr1 기능장애에 의해 유발되는 질환의 예방 및 치료용 약학 조성물에 관한 것이다.
According to another embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing and treating diseases caused by Nurr1 dysfunction, which comprises the above-mentioned bean curd tree extract as an active ingredient and contains a pharmaceutically acceptable carrier.
본 발명에서 용어, "약학적으로 허용가능한 담체"란 생물체를 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 말한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다.
As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate the organism and does not interfere with the biological activity and properties of the administered compound. Examples of the pharmaceutical carrier which is acceptable for the composition to be formulated into a liquid solution include sterilized and sterile water suitable for the living body such as saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added.
본 발명의 또 다른 실시양태에 의하면, 본 발명은 상기 팥꽃나무 추출물을 이용하여 Nurr1 기능장애에 의해 유발되는 질환을 치료하는 방법에 관한 것이다.
According to another embodiment of the present invention, the present invention relates to a method for treating a disease caused by Nurr1 dysfunction using the above-mentioned bean curd tree extract.
상기 방법은 치료를 필요로 하는 개체에 상기 약학적 조성물을 투여하는 단계를 포함하는 Nurr1 기능장애에 의해 유발되는 질환을 치료하는 방법일 수 있으며, 이때, 사용되는 팥꽃나무 추출물, 담체 및 Nurr1 기능장애에 의해 유발되는 질환은 상기에서 설명한 바와 동일하다.The method may be a method of treating a disease caused by Nurr1 dysfunction including the step of administering the pharmaceutical composition to an individual in need of treatment. In this case, the method for treating a disease caused by Nurr1 dysfunction, Are the same as those described above.
상기 조성물은 약학적으로 유효한 양으로 단일 또는 다중 투여될 수 있다. 이때, 조성물은 액제, 산제, 에어로졸, 캡슐제, 장용피 정제 또는 캡슐제 또는 좌제의 형태로 투여할 수 있다. 투여 경로는 복강내 투여, 정맥내 투여, 근육내 투여, 피하내 투여, 내피 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여 등을 포함하지만, 이에 제한되지는 않는다. 그러나 경구 투여시, 천연물로부터 유래된 상기 팥꽃나무 추출물은 소화로 인하여 손실될 수 있기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화 되어야 한다. 또한, 제약 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다. 또한, 본 발명의 Nurr1 기능장애에 의해 유발되는 질환 치료용 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다.The composition may be administered in single or multiple doses in a pharmaceutically effective amount. At this time, the composition may be administered in the form of a liquid preparation, a powder, an aerosol, a capsule, an intravaginal tablet, a capsule, or a suppository. Routes of administration include, but are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, endothelial, oral, topical, intranasal, intrarectal, and the like. However, the orally administered composition should be formulated so as to be coated with an active agent or protected from decomposition at the top, since the red bean berry extract derived from a natural product may be lost due to digestion during oral administration. In addition, the pharmaceutical composition may be administered by any device capable of transferring the active substance to the target cell. In addition, the composition for treating diseases caused by the Nurr1 dysfunction of the present invention 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.
본 발명의 상기 팥꽃나무 추출물을 포함하는 조성물은 약제학적으로 유효한 양으로 투여한다. "약제학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.
The composition comprising the red bean berry extract of the present invention is administered in a pharmaceutically effective amount. "Pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable for medical treatment or prophylaxis, and the effective dosage level will depend on a variety of factors including the severity of the disease, The composition of the present invention can be used in combination with the composition of the present invention, including drugs used in combination with the composition of the present invention, and other medical fields including, for example, body weight, health, sex, sensitivity of the patient to the drug, May be determined according to well known factors.
본 발명의 또 다른 실시양태에 의하면, 본 발명은 팥꽃나무 추출물을 유효성분으로 함유하는 Nurr1 기능장애에 의해 유발되는 질환 개선용 식품 첨가물에 관한 것이다.According to another embodiment of the present invention, the present invention relates to a food additive for improving disease induced by Nurr1 dysfunction, which comprises an extract of Aspergillus oryzae as an active ingredient.
본 발명의 팥꽃나무 추출물은 천연물로부터 유래되어 안전성이 이미 확인되었으므로, 평소의 식습관에 따라 장기간 동안 상식할 경우, 파킨슨병을 포함하는 다양한 Nurr1 기능장애에 의해 유발되는 질환을 예방함은 물론 발병된 상기 질환의 증상을 개선시키는 효과를 나타낼 수 있다.Since the bean curd extract of the present invention is derived from a natural product and its safety has already been confirmed, it is possible to prevent diseases caused by various Nurr1 dysfunctions including Parkinson's disease, It may have an effect of improving symptoms of the disease.
본 발명의 상기 팥꽃나무 추출물을 식품 첨가물로 사용하는 경우, 식품 또는 음료에 상기 팥꽃나무 추출물을 그대로 첨가하거나 또는 다른 식품 첨가물과 함께 조합하여 사용할 수 있다. 본 발명의 식품 첨가물을 식품 또는 음료의 제조시에 첨가할 경우, 이의 첨가량은 특별히 이에 제한되지 않으나, 최종적인 식품의 중량에 대하여 1 내지 5 중량%, 바람직하게는 1 내지 3 중량%의 첨가량으로 첨가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When the bean curd tree extract of the present invention is used as a food additive, the bean curd tree extract may be added to the food or beverage as it is or in combination with other food additives. When the food additive of the present invention is added at the time of the production of a food or beverage, the addition amount thereof is not particularly limited, but may be in the range of 1 to 5% by weight, preferably 1 to 3% by weight, Can be added. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range .
아을러, 상기 식품 또는 음료의 종류는 특별히 이제 제한되지 않으나, 통상적인 의미에서의 식품 또는 음료를 모두 포함하고, 바람직하게는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 포함한다.In addition, the above food or drink is not particularly limited, but includes food or beverage in a conventional sense, preferably meat, sausage, bread, chocolates, candies, snacks, confectionery, pizza, ramen, Other noodles, gums, dairy products including ice cream, various soups, drinks, tea, drinks, alcoholic beverages and vitamin complexes.
이때, 본 발명의 팥꽃나무 추출물을 포함하는 식품 첨가물을 식품에 첨가할 경우에는, 여러가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜 등의 보조성분과 함께 첨가될 수 있고, 상기 보조성분의 함량은 특별히 이에 제한되지 않으나, 최종적인 식품의 중량에 대하여 0.01 내지 0.1 중량%임이 바람직하다.At this time, when the food additive containing the red bean berry extract of the present invention is added to foods, it is possible to use various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and its salts, , a pH adjusting agent, a stabilizer, a preservative, glycerin, and an alcohol. The content of the auxiliary component is not particularly limited, but is preferably 0.01 to 0.1% by weight based on the final weight of the food .
또한, 본 발명의 팥꽃나무 추출물을 포함하는 식품 첨가물을 음료에 첨가할 경우에는, 통상의 음료와 같이 여러 가지 감미제 또는 천연 탄수화물 등을 추가 성분으로 포함할 수 있다. 이때, 상기 감미제는 특별히 이에 제한되지 않으나, 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있고, 상기 천연 탄수화물은 특별히 이에 제한되지 않으나, 단당류(예를 들어, 포도당, 과당 등), 이당류(예를 들어, 말토스, 슈크로스 등), 다당류(예를 들어, 덱스트린, 사이클로덱스트린 등), 또는 당알콜(예를 들어, 자일리톨, 소르비톨, 에리트리톨 등) 등을 사용할 수 있으며, 상기 천연 탄수화물의 함량은 특별히 이에 제한되지 않으나, 최종 음료제품 100㎖당 약 0.01 내지 0.04g, 바람직하게는 약 0.02 내지 0.03g의 비율로 포함됨이 바람직하다.
In addition, when the food additive containing the red bean berry extract of the present invention is added to beverages, it may contain various sweeteners or natural carbohydrates as an additional ingredient such as ordinary beverages. The sweetener may be a natural sweetening agent such as tau Martin or stevia extract or a synthetic sweetening agent such as saccharine or aspartame. The natural carbohydrate is not limited to monosaccharides (E.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), polysaccharides (e.g., dextrin, cyclodextrin, etc.), or sugar alcohols (e.g., xylitol, sorbitol, erythritol ). The content of the natural carbohydrate is not particularly limited, but it is preferably about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the final beverage product.
본 발명의 또 다른 실시양태에 의하면, 본 발명은 팥꽃나무 추출물을 유효성분으로 포함하는 Nurr1 활성화 조성물에 관한 것이다. Nurr1 단백질은 고아 핵 수용체로서, 상기 Nurr1은 뇌에서 도파민 시스템(dopaminergic system)을 유지하는 핵심적인 역할을 수행함이 규명되었으나, 아직까지 상기 단백질에 대한 리간드가 규명되어 있지 않다.
According to another embodiment of the present invention, the present invention relates to a Nurr1 activating composition comprising an extract of Aspergillus oryzae as an active ingredient. The Nurr1 protein is an orphan nuclear receptor. It has been shown that Nurr1 plays a key role in maintaining the dopaminergic system in the brain, but the ligand for the protein has not yet been identified.
상기 조성물은 상술한 팥꽃나무 추출물을 포함하여, 부작용 없이 Nurr1을 활성화시킬 수 있으므로, Nurr1과 관련된 각종 연구에 광범위하게 활용될 수 있을 것이다.
The above composition, including the above-mentioned red bean berry extract, can activate Nurr1 without side effects, so that it can be widely used in various studies related to Nurr1.
본 발명의 팥꽃나무 추출물은 별다른 부작용을 나타내지 않으면서도, Nurr1을 활성화시켜서, 이에 의하여 유발되는 파킨슨병, 류마티스 관절염, 정신분열증, 조울증 등의 다양한 Nurr1 기능장애에 의해 유발되는 질환을 예방 또는 치료할 수 있으므로, 다양한 질환의 보다 안전한 치료에 널리 활용될 수 있을 것이다.
The present invention can prevent or treat diseases caused by various Nurr1 dysfunctions such as Parkinson's disease, rheumatoid arthritis, schizophrenia and bipolar disorder caused by activating Nurr1 without showing any adverse side effects , May be widely used for safer treatment of various diseases.
도 1은 팥꽃나무 추출물의 농도에 따른 Nurr1 활성도의 변화를 루시퍼라제 분석을 통하여 나타낸 그래프이다.
도 2는 6-OHDA에 의해 유도되는 신경세포 사멸효과에 대한 팥꽃나무 추출물의 농도에 따른 효과를 나타내는 그래프이다.
도 3은 도파민성 신경세포가 사멸된 랫트에 대한 팥꽃나무 추출물의 효과를 스텝테스트를 통하여 확인한 결과를 나타내는 그래프이다.FIG. 1 is a graph showing the change in Nurr1 activity according to the concentration of the red bean curd extract obtained through analysis of luciferase.
FIG. 2 is a graph showing the effects of 6-OHDA-induced neuronal apoptosis on the concentration of red bean flour extract.
FIG. 3 is a graph showing the results of a step test to examine the effect of a red bean flour extract on rats in which dopaminergic neurons were killed.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예Example
1: One:
팥꽃나무Red bean flower
추출물의 제조 Preparation of extract
팥꽃나무(Daphne genkwa)의 줄기 1,260.93g과 뿌리 1,487.17g을 세절한 다음, 13ℓ 메탄올에 4시간 동안 침지하고, 여과하여 고형분과 1차 액상성분을 분리하였다. 상기 분리된 고형분을 다시 13ℓ 메탄올에 4시간 동안 침지하고, 여과하여 2차 액상성분을 수득하였다. 상기 수득한 1차 액상성분과 2차 액상성분을 혼합하고, 상기 혼합물을 감압하에서 농축시킨 다음, 잔사를 동결건조하여 172.71g의 팥꽃나무 추출물을 제조하였다.
1,260.93 g of the stem of Daphne genkwa and 1,487.17 g of the root were dipped in 13 L of methanol for 4 hours and then separated into solid and primary liquid components. The separated solids were again dipped in 13 L methanol for 4 hours and filtered to obtain a second liquid component. The obtained primary liquid component and secondary liquid component were mixed, and the mixture was concentrated under reduced pressure, and then the residue was lyophilized to obtain 172.71 g of red bean berry extract.
실시예Example
2: 2:
Nurr1Nurr1
활성도에 대한 About activity
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
GAL4 유전자가 결합할 수 있는 염기서열(5'-CTCGGAGGACAGTACTCCG-3', 서열번호 1)이 8번 반복된 유전자를 리포터 유전자인 루시퍼라제에 결합시킨 벡터를 합성한 후, Nurr1-LBD를 함유한 DNA와 베타-갈락토시다제를 갖고 있는 DNA 등 3종의 플라스미드 DNA를 BE(2)C 세포에 트렌스펙션한 뒤 6시간 후, 팥꽃나무 추출물을 1 내지 200ppm의 농도로 처리하였다. 이렇게 처리한 세포를 20시간 동안 37℃, 5% CO2 배양기에서 배양한 후, 루시퍼라제 분석을 수행하였다(도 1). 도 1은 팥꽃나무 추출물의 농도에 따른 Nurr1 활성도의 변화를 루시퍼라제 분석을 통하여 나타낸 그래프이다. 도 1에서 보듯이, BE(2)C 세포에서 팥꽃나무 추출물에 의해 Nurr1의 활성도가 증가됨을 알 수 있었다.
A vector obtained by ligating a gene in which a GAL4 gene can bind (5'-CTCGGAGGACAGTACTCCG-3 ', SEQ ID NO: 1) 8 times to a reporter gene, luciferase, was synthesized and then DNA containing Nurr1-LBD And beta-galactosidase were transferred to BE (2) C cells for 6 hours, and then treated with a concentration of 1 to 200 ppm. The cells thus treated were cultured in a 5% CO2 incubator at 37 ° C for 20 hours, and then subjected to luciferase analysis (FIG. 1). FIG. 1 is a graph showing the change in Nurr1 activity according to the concentration of the red bean curd extract obtained through analysis of luciferase. As shown in Fig. 1, the activity of Nurr1 was increased by BE (2) C cells.
실시예Example
3: 3:
SHSH
--
SY5YSY5Y
세포에 대한 For cells
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
신경세포인 SH-SY5Y 세포를 5 x 105세포수/웰 로 24-웰 플레이트에 분주하고, 24시간 동안 CO2 배양기에서 배양하였다. 상기 배양된 세포에 세포사멸을 유도하는 6-OHDA(50μM)를 단독으로 또는 서로 다른 농도(5 내지 20ppm)의 팥꽃나무 추출물와 함께 처리하고, 다시 24시간동안 37℃, 5% CO2 배양기에서 배양하였다. 24시간 경과 후, MTT 용액을 1㎎/㎖의 농도로 각 웰에 처리하고, 1시간동안 5% CO2 배양기에 보관한 다음, MTT 추출용액(extraction solution)을 가하였다. 이어, 37℃에서 24시간 동한 보관하고, 570nm에서 흡광도를 측정하였다(도 2). 도 2는 6-OHDA에 의해 유도되는 신경세포 사멸효과에 대한 팥꽃나무 추출물의 농도에 따른 효과를 나타내는 그래프이다. 도 2에서 보듯이, 6-OHDA에 의해 유도되는 신경세포 사멸이 팥꽃나무 추출물에 의해 저해됨을 확인할 수 있었다.
Nerve cells in SH-SY5Y cells were cultured at 5 x 10 5 cells / well and dispensed to a 24-well plate, CO 2 incubator for 24 hours. The cultured cells were treated with 6-OHDA (50 μM), which induces apoptosis, alone or in combination with different concentrations (5-20 ppm) of red bean berry extract and cultured for 24 hours at 37 ° C. in a 5% CO 2 incubator Respectively. After 24 hours, the MTT solution was treated at a concentration of 1 mg / ml in each well, stored in a 5% CO 2 incubator for 1 hour, and MTT extraction solution was added. Then, the sample was stored at 37 DEG C for 24 hours, and absorbance was measured at 570 nm (FIG. 2). FIG. 2 is a graph showing the effects of 6-OHDA-induced neuronal apoptosis on the concentration of red bean flour extract. As shown in FIG. 2, it was confirmed that the neuronal cell death induced by 6-OHDA was inhibited by the red bean curd extract.
실시예Example
4: 신경세포를 손상시킨 4: Damaged neurons
랫트에In rats
대한 About
팥꽃나무Red bean flower
추출물의 효과 Effect of extract
6주령 SD 랫트(코아텍 사)의 중뇌의 흑질 부위에 존재하는 도파민성신경세포를 특이적으로 사멸시키기 위하여, 뇌의 AP(-4.3), ML(-1.8), DV(-8.2) 부위와 AP(-5.0), ML(-1.8), DV(-8.2) 부위에 주입용 키트(stereotaxic tool)를 이용하여 6-OHDA(1㎍/㎕)을 1㎕/min 속도로 4㎍을 직접 주입하였다. 이때, 데시프라민(desipramine)을 25㎎/kg의 용량으로 상기 6-OHDA 투여 30분 전에 투여함으로써, 도파민성 신경세포 이외의 세포사를 억제시켰다. (-4.3), ML (-1.8), and DV (-8.2) regions of the brain and AP (-4.3), and the DV (-8.2) region in order to specifically kill the dopaminergic neurons in the middle cerebral blood zone of
그런 다음, 팥꽃나무 추출물의 1일 투여량이 500㎎/kg이 되도록 상기 추출물이 혼합된 사료를 상기 랫트에게 2주일간 급이시켰다. 이때, 대조군으로는 상기 추출물이 혼합되지 않은 먹이를 급이시킨 랫트를 사용하였다. Then, the mixture containing the above extract was fed to the rats for 2 weeks so that the daily dose of the red bean berry extract was 500 mg / kg. At this time, as a control group, rats to which the extract had not been mixed were used.
약물학적 시험의 오차를 보강하기 위한 비 약물학적 검사 방법인 스텝테스트(Stepping test)를 수행하였다. 구체적으로, 길이 90 cm의 탁자위에서 손으로는 쥐의 세 다리를 제어한 상태에서 탁자면 위를 15초 동안 이동시키며 제어되지 않은 쪽의 다리가 탁자표면을 딛는 수를 각 다리별로 3회 반복하여 측정하였다. 상기 스텝테스트의 측정시점은 6-OHDA를 주입하기 3일전, 6-OHDA 주입 후 2주, 4주 및 6주가 경과된 시점이었다(도 3).Stepping test, a non - pharmacological test method, was performed to reinforce the error of pharmacological test. Specifically, on the table with a length of 90 cm, the hands were allowed to move on the table surface for 15 seconds while the three legs of the mouse were being controlled, and the number of legs on the untreated side of the table surface was repeated three times for each leg Respectively. Measurement of the step test was performed 3 days before the injection of 6-OHDA and 2, 4 and 6 weeks after the 6-OHDA injection (FIG. 3).
도 3은 도파민성 신경세포가 사멸된 랫트에 대한 팥꽃나무 추출물의 효과를 스텝테스트를 통하여 확인한 결과를 나타내는 그래프이다. 도 3에서 보듯이, 팥꽃나무 추출물이 투여된 랫트는 투여되지 않은 랫트에 비하여 스텝의 수가 증가함을 알 수 있었다.FIG. 3 is a graph showing the results of a step test to examine the effect of a red bean flour extract on rats in which dopaminergic neurons were killed. As shown in Fig. 3, it was found that the number of steps increased in the rats to which the red bean flour extract was administered compared to the untreated rats.
<110> Korea Research Institute of Bioscience and Biotechnology <120> Composition Comprising Extract of Daphne genkwa as Active Ingradient <130> PA110247/KR <160> 1 <170> KopatentIn 1.71 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> GAL4 gene <400> 1 ctcggaggac agtactccg 19 <110> Korea Research Institute of Bioscience and Biotechnology <120> Composition Comprising Extract of Daphne genkwa as Active Ingradient <130> PA110247 / KR <160> 1 <170> Kopatentin 1.71 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> GAL4 gene <400> 1 ctcggaggac agtactccg 19
Claims (7)
A pharmaceutical composition for the prophylaxis or treatment of rheumatoid arthritis, which is a disease caused by Nurr1 dysfunction comprising an extract of Daphne genkwa as an active ingredient.
상기 팥꽃나무 추출물은 팥꽃나무의 줄기 또는 뿌리의 추출물인 조성물.
The method according to claim 1,
Wherein said red bean berry extract is an extract of stem or root of bean bloom.
상기 팥꽃나무 추출물은 팥꽃나무의 줄기 또는 뿌리의 C1 내지 C5의 저급 알킬알콜 추출물인 조성물.
3. The method of claim 2,
Wherein said red bean berry extract is a lower alkyl alcohol extract of C1 to C5 in the stem or root of red bean flower.
상기 C1 내지 C5의 저급 알킬알콜은 메탄올인 조성물.
The method of claim 3,
Wherein the C1 to C5 lower alkyl alcohol is methanol.
A functional food additive exhibiting the effect of preventing or ameliorating rheumatoid arthritis, which is a disease caused by Nurr1 dysfunction, which comprises an extract of Asahiri mushroom as an active ingredient.
A composition for increasing the activity of a Nurr1 protein in vitro, comprising an extract of Aspergillus oryzae as an active ingredient.
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