KR101384330B1 - A pharmaceutical composition comprising daumone for anti-inflammation - Google Patents
A pharmaceutical composition comprising daumone for anti-inflammation Download PDFInfo
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- KR101384330B1 KR101384330B1 KR1020120005242A KR20120005242A KR101384330B1 KR 101384330 B1 KR101384330 B1 KR 101384330B1 KR 1020120005242 A KR1020120005242 A KR 1020120005242A KR 20120005242 A KR20120005242 A KR 20120005242A KR 101384330 B1 KR101384330 B1 KR 101384330B1
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- Prior art keywords
- inflammatory
- daumone
- present
- active ingredient
- chronic
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Abstract
본 발명은 다우몬(Dauer-Inducing Pheromone, Daumone)을 유효성분으로 함유하는 염증성 질환의 예방 및 치료용 약학적 조성물에 관한 것으로, 더욱 구체적으로는 다우몬은 마우스 모델에서 노화로 인해 증가한 염증성 사이토카인인 F4/80, ICAM-1, IL-6, iNOS, MCP-1, TNF-α 및 VCAM-1들을 억제하며, LPS로 유발한 급성 염증 반응에 의한 간 손상 정도를 감소시키고 염증성 사이토카인인 IL-6를 억제하는 활성을 가짐으로써 만성 및 급성 염증성 질환의 예방 및 치료용 약학적 조성물, 건강식품, 항염증용 피부 외용제, 및 항염증용 화장료 조성물의 유효성분으로 유용하게 사용될 수 있다.The present invention relates to a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing Dauone (Dauer-Inducing Pheromone, Daumone) as an active ingredient, and more specifically, Daumon is an inflammatory cytokine F4 increased due to aging in a mouse model. / 80, inhibits ICAM-1, IL-6, iNOS, MCP-1, TNF-α and VCAM-1, reduces liver damage caused by LPS-induced acute inflammatory response and IL-6, an inflammatory cytokine By having the activity of inhibiting can be usefully used as an active ingredient of the pharmaceutical composition for the prevention and treatment of chronic and acute inflammatory diseases, health foods, anti-inflammatory skin external preparations, and anti-inflammatory cosmetic composition.
Description
본 발명은 다우몬(Dauer-Inducing Pheromone, Daumone)을 유효성분으로 함유하는 만성 또는 급성 염증성 질환의 예방 및 치료용 약학적 조성물 및 건강식품에 관한 것이다.
The present invention relates to a pharmaceutical composition and health food for the prevention and treatment of chronic or acute inflammatory diseases containing Dauone (Dauer-Inducing Pheromone, Daumone) as an active ingredient.
염증(inflammation)이란 외부 감염원(박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발물질)의 침입에 의하여 형성되는 농양의 병리적 상태를 뜻한다. 구체적으로, 외부 세균이 특정 조직에 침입하여 증식을 하게 되면 생체의 백혈구가 이를 인지하여 증식된 외부 세균을 활발히 공격하게 되는데, 이 과정 중 발생하는 백혈구의 사해가 균에 의하여 침입받은 조직에 축적됨과 동시에 백혈구에 의하여 사멸된 침입균의 세포 파괴물이 침입받은 조직 내로 융해되어 농양이 형성된다. 염증에 의한 농양의 치료는 소염작용을 통하여 촉진될 수 있는데, 소염작용이란 항균제를 이용하여 침입균의 증식을 억제하거나 농양 중에 축적된 이물질들을 탐식하는 대식세포(macrophage)를 활성화하여 상기 이물질들을 소화 및 배설하는 대식세포의 기능을 항진시키는 등의 염증치료 촉진작용이다. 일반적으로 염증반응은 생체의 세포나 조직에 기질적 변화를 가져오는 침습으로 인한 손상을 수복 및 재생하기 위한 생체방어 반응과정이고, 이 반응과정에는 국소의 혈관, 체액의 각종 조직세포 및 면역세포 등이 작용한다. 정상적으로 외부 침입균에 의하여 유도되는 염증반응은 생체를 보호하기 위한 이러한 방어 메커니즘은 생존에 필수적이다. 그러나, 시간적 또는 공간적으로 부적합한 염증성 반응은 자가면역 질환, 천식 또는 죽상경화증 같은 명백히 백혈구 성분에 의한 것들뿐 아니라 관절염 또는 알츠하이머 질환 같은 전통적으로 백혈구와 관련되지 않는다고 여겨지는 질환을 포함하여, 넓은 범위의 질병에 큰 역할을 한다. 이러한 염증질환에서 백혈구는 항체가 숙주 단백질을 부주의하게 인지하는 자가면역반응, 또는 영구 세포 사멸체, 세포 외 콜레스테롤 침착물, 또는 폐 안의 입자상 물질과 같은 축적된 조직 손상과 같은 부적합한 촉발에 의해 조직으로 모여들게 된다. 이와 같은 질병은 모여든 백혈구가 촉발자를 처리할 수 없고 (예를 들면, 백혈구는 자가 항원을 발현하는 모든 숙주 세포를 제거 또는 사멸하거나 또는 그 세포에 대해 지나치게 큰 입자들을 함입시킬 수 없다), 따라서 종종 만성화가 되고 계속해서 염증성 사이토카인을 방출하여 추가의 백혈구를 불필요한 장소로 보내 만성 염증이 된다. 이와 같은 염증반응을 통해, 동맥경화, 비만, 인슐린저항성, 류마티스 관절염, 사구체 신염, 암 진행 등과 같은 만성 진행성 질환이 발생하며, 노화의 진행에서도 주된 역할을 한다고 보고된바 있다(Jung KJ et al., Inflamm Res, 58:143, 2009). Inflammation refers to the pathological condition of an abscess formed by the invasion of external infectious agents (bacteria, fungi, viruses, various types of allergens). Specifically, when the external bacteria invade specific tissues and proliferate, the white blood cells of the living body recognize this, and actively attack the multiplying external bacteria. The dead sea of white blood cells generated during this process accumulates in the tissues invaded by the bacteria. At the same time, cell destruction of invading bacteria killed by leukocytes is fused into the invaded tissue to form an abscess. Inflammation of the abscess can be promoted through anti-inflammatory action, which is used to inhibit the growth of invading bacteria using antibacterial agents or to activate macrophage (macrophage) that feeds on foreign substances accumulated in the abscess to digest the foreign substances. And promotes inflammation, such as promoting the function of the macrophages to excrete. In general, an inflammatory reaction is a biodefense reaction process for repairing and regenerating damage caused by an invasion that causes organic changes in cells or tissues of a living body, and this reaction process includes local blood vessels, various tissue cells of body fluids and immune cells, etc. This works. Inflammatory responses normally induced by external invading bacteria are essential for survival. However, a wide range of diseases, including temporally or spatially inadequate inflammatory responses, including those caused by apparently white blood cell components such as autoimmune diseases, asthma or atherosclerosis, as well as diseases traditionally not associated with leukocytes such as arthritis or Alzheimer's disease Plays a big role in In these inflammatory diseases, leukocytes may enter the tissue by inadequate triggers such as autoimmune reactions in which the antibody inadvertently recognizes the host protein, or accumulated tissue damage such as permanent cell death bodies, extracellular cholesterol deposits, or particulate matter in the lungs. Gathered. Such a disease is such that the collected white blood cells cannot process the trigger (for example, white blood cells cannot remove or kill all host cells expressing autoantigens or incorporate too large particles into the cells). It often becomes chronic and continues to release inflammatory cytokines, sending additional white blood cells to unnecessary places for chronic inflammation. Through these inflammatory reactions, chronic progressive diseases such as arteriosclerosis, obesity, insulin resistance, rheumatoid arthritis, glomerulonephritis, and cancer progression occur, and it has been reported to play a major role in the progression of aging (Jung KJ et al. , Inflamm Res, 58: 143, 2009).
급성 염증 반응을 유발하는 리포폴리사카라이드(lipopolysaccharide, LPS)는 외부로 분비되는 박테리아 톡신(toxin)이며, 일산화질소(NO), 사이토카인 (cytokine), 종양괴사인자(TNF-α), 프로스타글란딘 E2(prostaglandin E2) 및 염증반응을 촉진하는 아이코사노이드(eicosanoid) 조절물질을 포함하는 여러 가지의 염증조절물질을 분비하게 한다(Chen YC, et al., Biochem. Pharmacol., 61, 1417-1427, 2001). 혈관근육세포(smooth muscle cells), 대식세포(macropharge), 간세포(hepatocyte) 및 성상세포(astrocyte)는 염증 사이토카인과 리포폴리사카라이드 등에 반응하여 유도되어지며, 일산화질소 합성효소의 활성화는 다양한 염증질환의 질병에서 중요한 역할을 하는, 많은 양의 일산화질소 형성을 촉진한다. 또한, COX-2 및 유도성 일산화질소 합성효소뿐만 아니라, 인터루킨-1, 인터루킨-2, 인터루킨-6 및 종양괴사인자 같은 여러 가지의 염증 전사인자들이 포함된다(Csaba Szabo, et al., Nature Reviews Drug Discovery, 6, 662-680. 2007). 특히, 일산화질소(nitric Oxide; NO)를 발생시키는 효소인 일산화질소 합성효소(nitric oxide synthase; NOS) 및 프로스타글란딘(prostaglandin)의 생합성과 관련된 효소들은 염증 반응을 매개하는데 있어서 중요한 역할을 하고 있는 것으로 알려져 있으며, L-아르기닌(L-Arginine)으로부터 NO를 생성시키는 효소인 NOS, 또는 아라키돈산(Arachidonic acid)으로부터 프로스타글란딘류를 합성하는데 관련된 효소인 시클로옥시게나제(cyclooxygenase; COX)는 염증을 차단하는데 있어서 주된 목표가 되고 있다. 최근의 연구 결과에 따르면, NOS는 몇 가지 종류가 존재하는데 뇌에 존재하는 뇌 일산화질소 합성효소(brain NOS; bNOS), 신경계에 존재하는 신경 일산화질소 합성효소(neuronal NOS; nNOS) 및 혈관계에 존재하는 내피 일산화질소 합성효소(endothelial NOS; eNOS) 등은 체내에 항상 일정수준으로 발현되고 있으며, 이들에 의해 소량 생성되는 NO는 신경전달이나 혈관확장을 유도하는 등 정상적인 신체의 항상성 유지에 중요한 역할을 하는데 반하여, 각종 사이토카인(cytokines)이나 외부 자극물질에 의해 유도되는 iNOS(induced NOS)에 의해 급격히 과량 발생되는 NO는 세포독성이나 각종 염증반응을 일으키는 것으로 알려져 있으며, 만성 염증은 iNOS 활성의 증가와 관련 있다는 연구가 있다(Jon O. Lundberg, et al., Nature Reviews Drug Discovery, 2008).
Lipopolysaccharide (LPS), which causes an acute inflammatory response, is an externally secreted bacterial toxin (NO), cytokine (cytokine), tumor necrosis factor (TNF-α), and prostaglandin E2 secrete a variety of inflammatory modulators, including prostaglandin E2 and eicosanoid modulators that promote inflammatory responses (Chen YC, et al., Biochem. Pharmacol., 61, 1417-1427, 2001). Smooth muscle cells, macrophages, hepatocytes, and astrocytes are induced in response to inflammatory cytokines and lipopolysaccharides. Promotes the formation of large amounts of nitric oxide, which plays an important role in the disease of the disease. In addition to COX-2 and inducible nitric oxide synthase, various inflammatory transcription factors such as interleukin-1, interleukin-2, interleukin-6 and tumor necrosis factor are included (Csaba Szabo, et al., Nature Reviews Drug Discovery, 6, 662-680. 2007). In particular, enzymes associated with the biosynthesis of nitric oxide synthase (NOS) and prostaglandin, enzymes that generate nitric oxide (NO), are known to play an important role in mediating the inflammatory response. In addition, NOS, an enzyme that generates NO from L-Arginine, or cyclooxygenase (COX), an enzyme involved in synthesizing prostaglandins from arachidonic acid, is used to block inflammation. It becomes the main goal. Recent studies show that there are several types of NOS: brain NOS (bNOS) in the brain, neuronal NOS (nNOS) in the nervous system, and in the vascular system. Endothelial nitric oxide synthase (endothelial NOS; eNOS) is always expressed at a certain level in the body, and a small amount of NO produced by them plays an important role in maintaining normal homeostasis, such as inducing neurotransmission and vasodilation. On the other hand, NO, which is excessively generated by iNOS (induced NOS) induced by various cytokines or external stimulants, is known to cause cytotoxicity and various inflammatory reactions. Chronic inflammation is associated with an increase in iNOS activity. There is a study (Jon O. Lundberg, et al., Nature Reviews Drug Discovery, 2008).
이와 같은 염증을 치료하는 것은 수십 년간 전 세계 제약 업계의 가장 중요한 목표였고 수많은 유용한 치료법이 개발되어왔다. 그 예는 코르티코스테로이드(프레드니솔론, 메틸프레드니솔론, 덱사메타손, 베타메타손, 플루티카손 등을 포함하여 코티솔의 효과를 모의하도록 고안된 다양한 범위의 천연, 반합성 및 합성 제제), 사이클로옥시게나아제 억제제(인도메타신, 설파살라진 및 아스피린 같이 비선택성 또는 콕스-1(cox-1) 선택성 및 더 최근의 셀레콕시브 같은 콕스-2(cox-2) 선택성, 류코트리엔 차단제(몬테루카스트 같은) 및 TNF 수용체 융합 단백질과 같은 항-TNF(탈리도마이드 같은 저분자 TNF-α 합성 억제제뿐만 아니라 인플릭시마브(RemicadeTM) 및 아달리무마브(HumiraTm)를 포함하는 개량 모노클로날 중화 항체, 에타너셉트 '45nbrelTM)를 포함한다.
Treating these inflammations has been the most important goal of the global pharmaceutical industry for decades and numerous useful therapies have been developed. Examples include corticosteroids (a wide range of natural, semisynthetic and synthetic agents designed to simulate the effects of cortisol, including prednisolone, methylprednisolone, dexamethasone, betamethasone, fluticasone, etc.), cyclooxygenase inhibitors (indometacin, Non-selective or cox-1 selectivity, such as sulfasalazine and aspirin and more recent cox-2 selectivity, such as celecoxib, anti-TNF such as leukotriene blockers (such as montelukast) and TNF receptor fusion proteins (Including low molecular weight TNF-α synthesis inhibitors such as thalidomide, as well as improved monoclonal neutralizing antibodies, etanercept '45nbrel ™), including Infliximab (Remicade ™) and adalimumab (HumiraTm).
다우몬(Dauer-Inducing Pheromone, Daumone)은 인간 단백질과 약 70%정도의 유사성를 갖고 있으며 유전자의 상동성도 약 40%에 이를 만큼 인간의 질병 연구에 매우 좋은 실험동물인 예쁜꼬마선충(Caenorhabditis elegans)에서, 먹이가 고갈되고 환경이 나빠지거나 개체 밀도가 높아지면제 2 유충기의 휴면에 들어가도록 유도하는 노화조절 물질로 보고된바 있으나(Young-Ki Paik, et al., Nature 433, 541-545, 2005), 아직까지 다우몬의 항염증 효과에 대해서는 밝혀진 바가 없다.
Dauer-Inducing Pheromone (Daumone) has about 70% similarity to human protein and its homology is about 40%. In the Caenorhabditis elegans, an experimental animal that is very good for human disease research, Depletion of food, deterioration of the environment, or high population density have been reported as aging regulators that induce
이에, 본 발명자들은 다우몬(Dauer-Inducing Pheromone, Daumone)이 염증 반응에 미치는 효과를 연구한 결과, 노화에 동반된 만성 염증 반응에서 중요한 염증성 사이토카인들을 억제함을 확인하였으며, 세균의 감염시 발생하는 LPS에 의해 유도되는 급성 염증 반응을 억제함을 확인하였으므로, 이를 통해 본 발명의 다우몬(Dauer-Inducing Pheromone, Daumone)이 동맥경화, 비만, 류마티스 관절염, 사구체 신염, 암 진행과 같은 만성 진행성 염증 질환 또는 급성 염증 반응을 억제하기 위한 염증성 질환의 예방 및 치료용 조성물, 예방 및 개선용 건강식품의 유효성분으로 유용하게 사용될 수 있음을 밝힘으로써, 본 발명을 완성하였다.
Accordingly, the present inventors have studied the effects of Dauer-Daumon (Dauer-Inducing Pheromone, Daumone) on the inflammatory response, and confirmed that it inhibits the important inflammatory cytokines in the chronic inflammatory response accompanying aging, which occurs during bacterial infection Since it was confirmed that it suppresses the acute inflammatory response induced by LPS, through this, Dauer-Inducing Pheromone, Daumone of the present invention is a chronic progressive inflammatory disease such as atherosclerosis, obesity, rheumatoid arthritis, glomerulonephritis, cancer progression or The present invention has been completed by revealing that it can be usefully used as an active ingredient for the prevention and treatment of inflammatory diseases for inhibiting an acute inflammatory response, and for the prevention and improvement of health foods.
본 발명의 목적은, 다우몬(Dauer-Inducing Pheromone, Daumone)을 유효성분으로 함유하는 염증성 질환의 예방 및 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing Daumon (Dauer-Inducing Pheromone, Daumone) as an active ingredient.
또한, 본 발명의 목적은, 약학적으로 유효한 양의 다우몬을 염증성 질환에 걸린 인간을 제외한 포유류에 투여하는 단계를 포함하는 염증성 질환의 치료 방법을 제공하는 것이다.It is also an object of the present invention to provide a method for treating an inflammatory disease comprising administering a pharmaceutically effective amount of damon to a mammal, except for a human suffering from an inflammatory disease.
또한, 본 발명의 목적은, 약학적으로 유효한 양의 다우몬을 염증성 질환에 걸린 인간을 제외한 포유류에 투여하는 단계를 포함하는 염증성 질환의 예방 방법을 제공하는 것이다.It is also an object of the present invention to provide a method for preventing an inflammatory disease comprising administering a pharmaceutically effective amount of daumone to a mammal, except for a human suffering from an inflammatory disease.
또한, 본 발명의 목적은, 다우몬을 유효성분으로 함유하는 염증성 질환의 예방 및 개선용 건강식품을 제공하는 것이다.It is also an object of the present invention to provide a health food for the prevention and improvement of inflammatory diseases containing Daumone as an active ingredient.
또한, 본 발명의 목적은, 다우몬을 유효성분으로 함유하는 항염증용 피부 외용제를 제공하는 것이다.It is also an object of the present invention to provide an anti-inflammatory skin external preparation containing damon as an active ingredient.
아울러, 본 발명의 목적은, 다우몬을 유효성분으로 함유하는 항염증용 화장료 조성물을 제공하는 것이다.
In addition, an object of the present invention is to provide an anti-inflammatory cosmetic composition containing Daumone as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 다우몬(Dauer-Inducing Pheromone, Daumone)을 유효성분으로 함유하는 염증성 질환의 예방 및 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing Daumon (Dauer-Inducing Pheromone, Daumone) as an active ingredient.
또한, 상기 목적을 달성하기 위하여, 본 발명은 약학적으로 유효한 양의 다우몬을 염증성 질환에 걸린 인간을 제외한 포유류에 투여하는 단계를 포함하는 염증성 질환의 치료 방법을 제공한다.In addition, in order to achieve the above object, the present invention provides a method of treating inflammatory diseases comprising administering a pharmaceutically effective amount of Daumone to a mammal, except for humans with inflammatory diseases.
또한, 상기 목적을 달성하기 위하여, 본 발명은 약학적으로 유효한 양의 다우몬을 염증성 질환에 걸린 인간을 제외한 포유류에 투여하는 단계를 포함하는 염증성 질환의 예방 방법을 제공한다.In addition, in order to achieve the above object, the present invention provides a method of preventing inflammatory diseases comprising administering a pharmaceutically effective amount of daumone to a mammal except for humans with inflammatory diseases.
또한, 상기 목적을 달성하기 위하여, 본 발명은 다우몬을 유효성분으로 함유하는 염증성 질환의 예방 및 개선용 건강식품을 제공한다.In addition, in order to achieve the above object, the present invention provides a health food for the prevention and improvement of inflammatory diseases containing Daumone as an active ingredient.
또한, 상기 목적을 달성하기 위하여, 본 발명은 다우몬을 유효성분으로 함유하는 항염증용 피부 외용제를 제공한다.In addition, to achieve the above object, the present invention provides an anti-inflammatory skin external preparation containing Damon as an active ingredient.
아울러, 상기 목적을 달성하기 위하여, 다우몬을 유효성분으로 함유하는 항염증용 화장료 조성물을 제공한다.
In addition, in order to achieve the above object, it provides an anti-inflammatory cosmetic composition containing Doumon as an active ingredient.
본 발명의 다우몬은, 마우스 모델에서 노화로 인해 증가한 염증성 사이토카인인 F4/80, ICAM-1, IL-6, iNOS, MCP-1, TNF-α 및 VCAM-1들을 억제하며, LPS로 유발한 급성 염증 반응에 의한 간 손상 정도를 감소시키고 염증성 사이토카인인 IL-6를 억제하여, 만성 또는 급성 염증성 질환의 예방 및 치료용 약학적 조성물, 및 건강식품의 유효성분으로 유용하게 사용될 수 있다.
Damon of the present invention inhibits inflammatory cytokines F4 / 80, ICAM-1, IL-6, iNOS, MCP-1, TNF-α and VCAM-1, which are increased due to aging in a mouse model and induced by LPS. By reducing the degree of liver damage caused by an acute inflammatory response and inhibiting the inflammatory cytokine IL-6, it can be usefully used as an active ingredient in the pharmaceutical composition for the prevention and treatment of chronic or acute inflammatory diseases, and health foods.
도 1은 만성 염증 모델 마우스에서 몸무게 및 간 무게를 측정한 그래프이다;
A: 몸무게;
B: 몸무게로 보정한 간 무게; 및
Mean±SE, *p<0.05 vs. Young.
도 2a는 만성 염증 모델 마우스의 간에서의 ICAM-1의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 2b는 만성 염증 모델 마우스의 간에서의 VCAM-1의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 2c는 만성 염증 모델 마우스의 간에서의 TNF-α의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 2d는 만성 염증 모델 마우스의 간에서의 MCP-1의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 2e는 만성 염증 모델 마우스의 간에서의 iNOS의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 2f는 만성 염증 모델 마우스의 간에서의 IL-6의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 2g는 만성 염증 모델 마우스의 간에서의 F4/80의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 3a는 LPS로 급성 염증 반응을 일으킨 마우스의 몸무게를 측정한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 3b는 LPS로 급성 염증 반응을 일으킨 마우스의 간 손상 지표인 AST 및 ALT를 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).
도 3c는 LPS로 급성 염증 반응을 일으킨 마우스의 간에서의 IL-6의 mRNA의 발현량을 Real Time RT qPCR로 확인한 그래프이다(Mean±SE, *p<0.05 vs. Young, †p<0.05 vs. old).1 is a graph of weight and liver weight in chronic inflammation model mice;
A: weight;
B: liver weight corrected for weight; And
Mean ± SE, * p <0.05 vs. Young.
Figure 2a is a graph confirming the expression level of ICAM-1 mRNA in the liver of chronic inflammation model mouse by Real Time RT qPCR (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 2b is a graph confirming the expression level of VCAM-1 mRNA in the liver of chronic inflammation model mouse by Real Time RT qPCR (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 2c is a graph confirming the expression level of TNF-α mRNA in the liver of chronic inflammation model mouse by Real Time RT qPCR (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 2d is a graph confirming the expression of MCP-1 mRNA in the liver of chronic inflammation model mouse by Real Time RT qPCR (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 2e is a graph confirming the expression level of iNOS mRNA in the liver of chronic inflammation model mouse by Real Time RT qPCR (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 2f is a graph confirming the expression of IL-6 mRNA in the liver of chronic inflammation model mouse by Real Time RT qPCR (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 2g is a graph confirming the expression level of the mRNA of F4 / 80 mRNA in the liver of chronic inflammation model mouse (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 3a is a graph measuring the weight of the mice that caused an acute inflammatory response with LPS (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 3b is a graph confirming the liver damage indicators AST and ALT in mice that caused an acute inflammatory response with LPS (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
Figure 3c is a graph confirming the expression of IL-6 mRNA in the liver of the mouse acute inflammatory response with LPS (Mean ± SE, * p <0.05 vs. Young, † p <0.05 vs. old).
이하, 본 발명을 상세히 설명한다.
Hereinafter, the present invention will be described in detail.
본 발명은 다우몬(Dauer-Inducing Pheromone, Daumone)을 유효성분으로 함유하는 염증성 질환의 예방 및 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing Daumon (Dauer-Inducing Pheromone, Daumone) as an active ingredient.
상기 다우몬은 하기 [화학식 1]의 구조를 가지는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The damon is preferably one having a structure of the following [Formula 1], but is not limited thereto.
상기 염증성 질환은 만성 염증성 질환인 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The inflammatory disease is preferably a chronic inflammatory disease, but is not limited thereto.
상기 만성 염증성 질환은 노화, 동맥경화, 만성 신질환, 관절염, 천식, 대사성 증후군, 비만, 치매, 치주염 및 암 등 만성 퇴행성 염증 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The chronic inflammatory disease is preferably selected from the group consisting of chronic degenerative inflammatory diseases such as aging, arteriosclerosis, chronic kidney disease, arthritis, asthma, metabolic syndrome, obesity, dementia, periodontitis and cancer, but is not limited thereto. .
상기 염증성 질환은 급성 염증성 질환인 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The inflammatory disease is preferably an acute inflammatory disease, but is not limited thereto.
상기 급성 염증성 질환은 복막염, 위염, 장염, 간염, 췌장염, 비염 등 세균 감염에 의한 박테리아 톡신(LPS)에 의해 유발되는 염증성 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.
The acute inflammatory disease is preferably selected from the group consisting of inflammatory diseases caused by bacterial toxin (LPS) caused by bacterial infections such as peritonitis, gastritis, enteritis, hepatitis, pancreatitis and rhinitis, but is not limited thereto. .
본 발명의 구체적인 실시예에서, 본 발명자들은 다우몬이 노화로 인해 유발되는 만성 염증 반응에 미치는 영향을 알아보기 위하여, 24 개월령이 된 마우스에게 다우몬을 투여한 후, 간을 적출해 염증성 사이트카인(cytokine)인 F4/80, ICAM-1(including intercellular adhesion molecule), IL-6(interleukin-6), iNOS(inducible nitric oxide synthase), MCP-1(monocyte chemotactic protein), TNF-α(tumor necrosis factor) 및 VCAM-1(vascular cell adhesion molecule)의 mRNA 발현을 확인한 결과, 다우몬에 의해 발현량이 감소함을 확인하였다(도 2 참조). In a specific embodiment of the present invention, the inventors of the present invention, in order to determine the effect of damon on the chronic inflammatory response induced by aging, after administration of damon to a 24-month-old mouse, the liver was extracted and inflammatory cytokines (cytokine) ) F4 / 80, including intercellular adhesion molecule (IMC-1), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), monocyte chemotactic protein (MCP-1), and tumor necrosis factor (TNF-α) And as a result of confirming the mRNA expression of VCAM-1 (vascular cell adhesion molecule), it was confirmed that the expression amount is reduced by Daum (see Fig. 2).
또한, 본 발명의 또 다른 구체적인 실시예에서, 본 발명자들은 다우몬이 급성 염증 반응에 미치는 영향을 알아보기 위하여, 세균이 분비하는 톡신인 LPS로 염증반응을 유도한 후, 마우스의 몸무게를 측정하고 간 손상 지표 및 염증성 사이토카인의 발현량을 확인한 결과, LPS에 의해 몸무게가 유의적으로 감소하였으며, LPS에 의해 증가한 간 손상 지표인 AST 및 ALT가 다우몬에 의해 감소하였다. 또한, LPS에 의해 증가한 염증성 사이토카인 IL-6의 mRNA 발현량이 다우몬에 의해 감소함을 확인하였다(도 3 참조).In addition, in another specific embodiment of the present invention, the present inventors induce the inflammatory response with LPS, a toxin produced by bacteria, to determine the effect of Damon on the acute inflammatory response, and then measure the weight of the mouse and liver As a result of confirming the damage index and the expression level of inflammatory cytokines, weight was significantly decreased by LPS, and AST and ALT, which were increased by LPS, were decreased by Daum. In addition, it was confirmed that the mRNA expression level of inflammatory cytokine IL-6 increased by LPS was reduced by Daum (see FIG. 3).
따라서, 본 발명의 다우몬이 노화에 동반된 만성 염증을 억제하고 LPS로 유도된 급성 염증 반응 및 간 손상을 억제하는 효과를 가지므로, 염증성 질환의 예방 및 치료용 약학적 조성물의 유효성분으로 유용하게 사용될 수 있음을 알 수 있다.
Therefore, since the daumone of the present invention has the effect of inhibiting chronic inflammation accompanying aging and inhibiting acute inflammatory response and liver damage induced by LPS, it is useful as an active ingredient of a pharmaceutical composition for preventing and treating inflammatory diseases. It can be seen that it can be used.
본 발명의 다우몬은 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약제학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약제학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.Doumon of the present invention may further comprise a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additives are starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose , Mannitol, malt, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, opiodry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate , Sucrose, dextrose, sorbitol, talc and the like can be used. The pharmaceutically acceptable additives according to the present invention are preferably included in the composition in an amount of 0.1 to 90 parts by weight, but are not limited thereto.
즉, 본 발명의 조성물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 다우몬 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(Calcium carbonate), 수크로스(Sucrose), 락토오스(Lactose) 또는 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결 건조 제제, 좌제가 포함될 수 있다. 비수성 용제, 현탁 용제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.That is, the composition of the present invention can be administered in various formulations of oral and parenteral administration at the time of actual clinical administration. In the case of formulation, a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, . ≪ / RTI > Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate and sucrose in the Daumone composition. ), Lactose (Lactose) or gelatin can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate talc may also be used. Oral liquid preparations include suspensions, solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.
본 발명의 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여할 수 있으며, 비경구 투여시 피부 외용 또는 복강내 주사, 직장내 주사, 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식을 선택하는 것이 바람직하다. 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다.The composition of the present invention may be administered orally or parenterally according to a desired method, and externally or intraperitoneally, rectally, subcutaneously, intravenously, intramuscularly or intrathoracically It is preferable to select. The dosage varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
본 발명의 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도에 따라 그 범위가 다양하며, 일일 투여량은 다우몬의 양을 기준으로 0.0001 내지 100 ㎎/㎏이고, 바람직하게는 0.001 내지 10 ㎎/㎏이며, 하루 1 내지 6 회 투여될 수 있다.
The dosage of the composition of the present invention varies depending on the weight, age, sex, health status, diet, time of administration, administration method, excretion rate and severity of the disease of the patient, the daily dosage is based on the amount of Damon 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, and may be administered 1 to 6 times a day.
또한, 본 발명은 약학적으로 유효한 양의 다우몬을 염증성 질환에 걸린 인간을 제외한 포유류에 투여하는 단계를 포함하는 염증성 질환의 치료 방법을 제공한다.
The present invention also provides a method of treating an inflammatory disease comprising administering a pharmaceutically effective amount of Damon to a mammal, except for a human suffering from an inflammatory disease.
또한, 본 발명은 약학적으로 유효한 양의 다우몬을 염증성 질환에 걸린 인간을 제외한 포유류에 투여하는 단계를 포함하는 염증성 질환의 예방 방법을 제공한다.The present invention also provides a method for preventing inflammatory disease, comprising administering a pharmaceutically effective amount of daumone to a mammal, except for a human suffering from an inflammatory disease.
상기 염증성 질환은 만성 염증성 질환인 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The inflammatory disease is preferably a chronic inflammatory disease, but is not limited thereto.
상기 만성 염증성 질환은 노화, 동맥경화, 만성 신질환, 관절염, 천식, 대사성 증후군, 비만, 치매, 치주염 및 암 등 만성 퇴행성 염증 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The chronic inflammatory disease is preferably selected from the group consisting of chronic degenerative inflammatory diseases such as aging, arteriosclerosis, chronic kidney disease, arthritis, asthma, metabolic syndrome, obesity, dementia, periodontitis and cancer, but is not limited thereto. .
상기 염증성 질환은 급성 염증성 질환인 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The inflammatory disease is preferably an acute inflammatory disease, but is not limited thereto.
상기 급성 염증성 질환은 복막염, 위염, 장염, 간염, 췌장염, 비염 등 세균 감염에 의한 박테리아 톡신(LPS)에 의해 유발되는 염증성 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The acute inflammatory disease is preferably selected from the group consisting of inflammatory diseases caused by bacterial toxin (LPS) caused by bacterial infections such as peritonitis, gastritis, enteritis, hepatitis, pancreatitis and rhinitis, but is not limited thereto. .
상기 약학적으로 유효한 양이란 0.0001 내지 100 ㎎/㎏이고, 바람직하게는 0.001 내지 10 ㎎/㎏이며, 이에 제한되는 것은 아니다. 투여량은 특정 환자의 체중, 연령, 성별, 건강상태, 식이, 투여기간, 투여방법, 제거율, 질환의 중증도 등에 따라 변화될 수 있다. The pharmaceutically effective amount is 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, but is not limited thereto. The dose may vary depending on the weight, age, sex, health condition, diet, administration period, method of administration, rate of elimination, severity of disease, and the like of a particular patient.
상기 개체는 척추동물이고 바람직하게는 포유동물이며, 그보다 바람직하게는 쥐, 토끼, 기니아피크, 햄스터, 개, 고양이와 같은 실험동물이고, 가장 바람직하게는 침팬지, 고릴라와 같은 유인원류 동물이다. The subject is a vertebrate animal, preferably a mammal, more preferably an experimental animal such as a mouse, a rabbit, a guinea pig, a hamster, a dog or a cat, and most preferably an ape-like animal such as a chimpanzee or a gorilla.
상기 투여 방법은 경구 또는 비경구 투여할 수 있으며, 비경구 투여시 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내 주사, 자궁내 경막 주사, 뇌혈관내(intracerebroventricular) 주사 또는 흉부내 주사에 의해 투여될 수 있다.
The method of administration may be administered orally or parenterally, and during parenteral administration, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrauterine dural injection, intracerebroventricular injection or intrathoracic injection It can be administered by injection.
또한, 본 발명은 다우몬을 유효성분으로 함유하는 염증성 질환의 예방 및 개선용 건강식품을 제공한다.In addition, the present invention provides a health food for the prevention and improvement of inflammatory diseases containing Daumone as an active ingredient.
상기 염증성 질환은 만성 염증성 질환인 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The inflammatory disease is preferably a chronic inflammatory disease, but is not limited thereto.
상기 만성 염증성 질환은 노화, 동맥경화, 만성 신질환, 관절염, 천식, 대사성 증후군, 비만, 치매, 치주염 및 암 등 만성 퇴행성 염증 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The chronic inflammatory disease is preferably selected from the group consisting of chronic degenerative inflammatory diseases such as aging, arteriosclerosis, chronic kidney disease, arthritis, asthma, metabolic syndrome, obesity, dementia, periodontitis and cancer, but is not limited thereto. .
상기 염증성 질환은 급성 염증성 질환인 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.The inflammatory disease is preferably an acute inflammatory disease, but is not limited thereto.
상기 급성 염증성 질환은 복막염, 위염, 장염, 간염, 췌장염, 비염 등 세균 감염에 의한 박테리아 톡신(LPS)에 의해 유발되는 염증성 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 것이 바람직하나, 이에 한정되지 않는다.
The acute inflammatory disease is preferably selected from the group consisting of inflammatory diseases caused by bacterial toxin (LPS) caused by bacterial infections such as peritonitis, gastritis, enteritis, hepatitis, pancreatitis and rhinitis, but is not limited thereto. .
본 발명의 구체적인 실시예에서, 본 발명자들은 다우몬이 노화에 동반된 만성 염증 반응 및 LPS에 의해 유도된 급성 염증 반응을 억제함을 확인함으로써, 본 발명의 다우몬이 염증성 질환의 예방 및 개선용 건강식품의 유효성분으로 유용하게 사용될 수 있음을 알 수 있다.
In a specific embodiment of the present invention, the inventors confirmed that Damon suppresses the chronic inflammatory response accompanied by aging and the acute inflammatory response induced by LPS, so that the Damon of the present invention prevents and improves inflammatory diseases. It can be seen that it can be usefully used as an effective ingredient of.
본 발명의 건강식품은 다우몬을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. The health food of the present invention may be added as it is or may be used together with other food or food ingredients, and may be appropriately used according to conventional methods.
상기 건강식품의 종류에는 특별한 제한은 없다. 상기 다우몬을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the health food. Examples of foods to which the taumon may be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, drinks, tea, drink, Alcoholic beverages and vitamin complexes, etc., includes all of the health food in the conventional sense.
본 발명의 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 0.01 내지 0.04 g, 바람직하게는 약 0.02 내지 0.03 g 이다.The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 건강식품은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above, the health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, , A carbonating agent used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명은 다우몬을 유효성분으로 함유하는 항염증용 피부 외용제를 제공한다.
The present invention also provides an anti-inflammatory skin external preparation containing Damon as an active ingredient.
아울러, 본 발명은 다우몬을 유효성분으로 함유하는 항염증용 화장료 조성물을 제공한다.
In addition, the present invention provides an anti-inflammatory cosmetic composition containing Daumone as an active ingredient.
본 발명의 구체적인 실시예에서, 본 발명자들은 다우몬이 노화에 동반된 만성 염증 반응 및 LPS에 의해 유도된 급성 염증 반응을 억제함을 확인함으로써, 본 발명의 다우몬이 항염증용 피부 외용제 및 항염증용 화장료 조성물의 유효성분으로 유용하게 사용될 수 있음을 알 수 있다.
In a specific embodiment of the present invention, the inventors confirm that Damon inhibits the chronic inflammatory response accompanied by aging and the acute inflammatory response induced by LPS, so that the Damon of the present invention is used for anti-inflammatory skin external preparations and anti-inflammatory It can be seen that it can be usefully used as an active ingredient of the cosmetic composition.
본 발명의 다우몬을 유효성분으로 함유하는 화장료 조성물은 수용성 비타민, 유용성 비타민, 고분자 펩티드, 고분자 다당 및 스핑고 지질로 이루어진 군에서 선택된 조성물을 포함할 수 있으며, 상기 성분과 더불어 필요에 따라 통상 화장료 조성물에 배합되는 유지 성분, 보습제, 에몰리엔트제, 계면 활성제, 유기 및 무기 안료 유기 분체, 자외선 흡수제, 방부제, 살균제, 산화 방지제, 식물 추출물, pH 조정제, 알콜, 색소, 향료, 혈행 촉진제, 냉감제, 제한(制汗)제, 정제수 등의 다른 성분을 배합할 수 있다. 또한, 본 발명의 화장료 조성물은 통상 화장료 조성물이 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어 유액, 크림, 화장수, 팩, 파운데이션, 로션, 미용액, 모발화장료 등이 될 수 있다.The cosmetic composition containing the daumone of the present invention as an active ingredient may include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, and sphingolipids. Fats and oils, moisturizers, emollients, surfactants, organic and inorganic pigments organic powders, UV absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, blood circulation accelerators Other components, such as a restriction | limiting agent and purified water, can be mix | blended. In addition, the cosmetic composition of the present invention may be prepared in any formulation in which the cosmetic composition is usually prepared, and may be, for example, an emulsion, a cream, a lotion, a pack, a foundation, a lotion, a cosmetic liquid, a hair cosmetic, and the like.
또한, 본 발명의 피부를 위한 다우몬을 유효성분으로 함유하는 화장료 조성물은 스킨로션, 스킨소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스쳐 로션, 영양로션, 맛사지크림, 영양크림, 모이스처크림, 핸드크림, 파운데이션, 에센스, 영양에센스, 팩, 비누, 클렌징폼, 클렌징로션, 클렌징크림, 바디로션 및 바디클린저의 제형이 포함될 수 있다. 본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물섬유, 식물섬유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있고, 본 발명의 제형이 용액 또는 유탁액의 경우에는 담체 성분으로서 용매, 용매화제 또는 유탁화제가 해당되는데, 예를 들어, 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 포함될 수 있다. 본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다. 본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산디에탄올아미드, 식물성 유, 리놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.
In addition, the cosmetic composition containing Doumon for the skin of the present invention as an active ingredient skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand Formulations of creams, foundations, essences, nutritional essences, packs, soaps, cleansing foams, cleansing lotions, cleansing creams, body lotions and body cleansers. When the formulation of the present invention is a paste, cream or gel, animal carriers, vegetable fibers, waxes, paraffins, starches, tracantes, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide, etc. may be used as carrier components. In the case of the solution or emulsion of the present invention, a solvent, a solvating agent or an emulsifying agent may be used as a carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzo Fatty acid esters of ate, propylene glycol, 1,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan. When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used. When the formulation of the present invention is a surfactant-containing cleansing, the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide. Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
이하, 본 발명을 실시예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to examples.
단, 하기 실시예는 본 발명을 구체적으로 예시하는 것일 뿐, 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.
However, the following examples are only illustrative of the present invention in detail, and the content of the present invention is not limited by the examples.
<< 실시예Example 1> 만성 염증 반응에 대한 다우몬( 1> Damon for Chronic Inflammatory Response daumone)daumone) 의 항염증 효과 확인Anti-inflammatory effects
<1-1> 만성 염증 마우스 모델 및 시료 준비<1-1> Chronic Inflammatory Mouse Model and Sample Preparation
본 발명자들은 만성 염증에서 다우몬(daumone)의 효과를 확인하기 위하여 만성 염증 마우스 모델을 수립하고 각 군의 간 무게를 보정하여 시료를 준비하였다.In order to confirm the effect of daumone in chronic inflammation, the present inventors established a chronic inflammation mouse model and prepared samples by correcting liver weight of each group.
구체적으로, 중앙실험동물(Japan SLC, Inc., 일본)에서 구입한 6 개월령 수컷 C57BL/6 마우스를 온도 23±1 ℃, 습도 45 내지 65%인 SPF 동물실에서 12시간 light/dark 사이클로 사육하였고, 자유롭게 물과 먹이를 섭취할 수 있도록 하였다. 6 개월령 마우스가 24 개월령이 되었을 때, 무작위로 10 마리를 선택하여 노화군(old), 2 mg/kg의 다우몬(daumone) 투여군(Old+2) 및 20 mg/kg의 다우몬(daumone) 투여군을 투여한 노화군(Old+20)으로 하였다(다우몬(daumone)은 Nature. 2005 Feb 3;433(7025):541-5.의 합성 방법으로 합성하였다). 대조군으로서 9 주령 마우스를 무작위로 10 마리를 선택하여 어린 대조군(young) 및 20 mg/kg의 다우몬(daumone)을 투여한 어린 대조군(Young+20)으로 하였다. 다우몬(daumone)은 마우스의 몸무게 g당 0.01 ml 식수에 희석하여 다우몬(daumone) 투여군인 Young+20, Old+2 및 Old+20군에 위관영양법(oral gavage)으로 매일 동일 시간에 투여하였다. 대조군인 Young와 Old군에는 식수를 몸무게 g당 0.01 ml 투여하였다. 투여 5 주 후, 몸무게를 측정하였으며, 마취(Urethane 1.7 mg/kg) 후 복대동맥(abdominal aorta)을 통해 0.1% 디에틸파이로카르본산(diethylpyrocarbonate)이 함유된 PBS로 관류(perfusion)한 후, 희생하였다. 그 후, 간을 취하여 무게를 잰 후 곧바로 -70 ℃에 보관하였다.Specifically, 6-month-old male C57BL / 6 mice purchased from a central laboratory animal (Japan SLC, Inc., Japan) were bred in a 12 hour light / dark cycle in an SPF animal room with a temperature of 23 ± 1 ° C. and a humidity of 45-65%. In addition, water and food can be taken freely. At the age of 6 months of age at 24 months of age, 10 randomly selected mice were treated with aging (old), 2 mg / kg daumone dose (Old + 2) and 20 mg / kg daumone dose. The aging group (Old + 20) was administered (daumone was synthesized by the synthesis method of Nature. 2005
아울러, 실험결과의 측정치는 “평균(mean)±표준오차(standard error)”로 나타내었고, 각 군 간의 통계학적인 비교는 분산 분석(ANOVA)과 Fisher's 최소유의차 검증법(least significant difference)으로 검정하였으며, P 값이 0.05 미만인 값에서만 의미가 있는 것으로 판정하였다.In addition, the measured results were expressed as “mean ± standard error”, and the statistical comparison between each group was tested by ANOVA and Fisher's least significant difference. It was determined that only the value of P value less than 0.05 was significant.
그 결과, 24 개월령 마우스(Old)가 9 주령 마우스(Young)에 비해 몸무게가 유의하게 증가하였으며(도 1A), 이를 이용하여 간 무게를 보정한 군들 사이에 차이가 없음을 확인하였다(도 1B).
As a result, the weight of the 24 month old mouse (Old) was significantly increased compared to the 9-week old mouse (Young) (Fig. 1A), it was confirmed that there is no difference between the groups of the liver weight correction using this (Fig. 1B) .
<1-2> 만성 염증에서 다우몬에 의한 간 염증성 사이토카인 발현 억제 확인<1-2> Confirmation of Dowmon Inhibition of Hepatic Inflammatory Cytokine Expression in Chronic Inflammation
본 발명자들은 상기 <실시예 1-1>에서 준비한 만성 염증 마우스 모델의 간 시료에서 염증성 사이토카인의 mRNA 발현 정도를 Real-Time RT qPCR로 확인하였다.The present inventors confirmed the mRNA expression level of inflammatory cytokines in liver samples of the chronic inflammatory mouse model prepared in Example 1-1 using Real-Time RT qPCR.
구체적으로, 상기 <실시예 1-1>에서 무게를 잰 간에서 총 RNA를 Trizol(Invitrogen, Carlsbad, CA, USA)을 사용하여 분리하였다. 분광광도계를 이용하여 260 nm에서 분리한 RNA의 농도를 측정하였고, 260 nm와 280 nm에서 측정한 흡광도의 비율로 RNA 순도를 평가하였다. 상기 분리한 RNA 1 ㎍을 High Capacity cDNA Reverse Transcription Kit(Applied Biosystems, Carlsbad, CA, USA)를 사용하여 역전사 반응을 수행하였으며, 이 후, 대조군인 18S와 염증성 사이토카인(cytokine)인 F4/80, ICAM-1(including intercellular adhesion molecule), IL-6(interleukin-6), iNOS(inducible nitric oxide synthase), MCP-1(monocyte chemotactic protein), TNF-α(tumor necrosis factor) 및 VCAM-1(vascular cell adhesion molecule)의 mRNA 발현을 하기 표 1의 각각의 primer(바이오니아, 대전, 한국)와 SYBR Green System(7300 Real-Time PCR System, Applied Biosystems)을 사용하여 확인하였다. Specifically, total RNA was separated from liver weighed in Example 1-1 using Trizol (Invitrogen, Carlsbad, CA, USA). The concentration of RNA isolated at 260 nm was measured using a spectrophotometer, and RNA purity was evaluated by the ratio of absorbance measured at 260 nm and 280 nm. 1 ㎍ of the isolated RNA was subjected to reverse transcription using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Carlsbad, Calif., USA), after which, the control group 18S and the inflammatory cytokine (F4 / 80), ICAM-1 (including intercellular adhesion molecule), IL-6 (interleukin-6), iNOS (inducible nitric oxide synthase), MCP-1 (monocyte chemotactic protein), TNF-α (tumor necrosis factor) and VCAM-1 (vascular mRNA expression of the cell adhesion molecule) was confirmed using the primers of each of Table 1 (Bionia, Daejeon, Korea) and SYBR Green System (7300 Real-Time PCR System, Applied Biosystems).
아울러, 실험결과의 측정치는 “평균(mean)±표준오차(standard error)”로 나타내었고, 각 군 간의 통계학적인 비교는 분산 분석(ANOVA)과 Fisher's 최소유의차 검증법(least significant difference)으로 검정하였으며, P 값이 0.05 미만인 값에서만 의미가 있는 것으로 판정하였다.In addition, the measured results were expressed as “mean ± standard error”, and the statistical comparison between each group was tested by ANOVA and Fisher's least significant difference. It was determined that only the value of P value less than 0.05 was significant.
18S
267
F4 / 80
123
ICAM-1
137
IL-6
159
iNOS
71
MCP-1
127
TNF-α
206
VCAM-1
118
그 결과, Old 군의 간에서 염증성 사이토카인인 ICAM-1(도 2a), VCAM-1(도 2b), TNF-α(도 2c), MCP-1(도 2d), iNOS(도 2e), IL-6(도 2f), 및 F4/80(도 2g)의 mRNA가 Young 군에 비해 유의하게 증가하였으며, 다우몬(daumone) 투여 시 ICAM-1, TNF-α, MCP-1, iNOS, IL-6, 및 F4/80의 mRNA가 old 군에 비해 유의미하게 감소하였다. As a result, ICAM-1 (FIG. 2A), VCAM-1 (FIG. 2B), TNF-α (FIG. 2C), MCP-1 (FIG. 2D), iNOS (FIG. 2E), which are inflammatory cytokines in the liver of the Old group, MRNAs of IL-6 (FIG. 2F) and F4 / 80 (FIG. 2G) were significantly increased compared to the Young group, and ICAM-1, TNF-α, MCP-1, iNOS and IL- were administered when daumone was administered. MRNAs at 6, and F4 / 80 were significantly reduced compared to the old group.
따라서, 노화에 동반되는 만성 염증에 대한 다우몬(daumone)의 항염증 효과를 확인할 수 있었다.
Thus, the anti-inflammatory effect of daumone (daumone) on chronic inflammation accompanying aging was confirmed.
<< 실시예Example 2> 급성 염증 반응에 대한 다우몬의 항염증 효과 확인 2> Confirm the anti-inflammatory effect of Damon on the acute inflammatory response
<2-1> 급성 염증 마우스의 몸무게 측정 및 시료 준비<2-1> Weight Measurement and Sample Preparation of Acute Inflammatory Mice
본 발명자들은 급성 염증에서 다우몬(daumone)의 항염증 효과를 확인하기 위하여 염증 유발 물질을 마우스 모델에 투여하여 시료를 준비하였다.The present inventors prepared a sample by administering an inflammation-inducing substance to a mouse model to confirm the anti-inflammatory effect of daumone in acute inflammation.
구체적으로, 중앙실험동물(Japan SLC, Inc., 일본)에서 구입한 6 주령 수컷 C57BL/6 마우스를 군당 5마리씩 나누어 0.9% NaCl을 복강 투여한 군, 다우몬(daumone)을 0.5 mg/kg 복강 투여한 군, 다우몬(daumone)을 1 mg/kg 복강 투여한 군 및 0.9% NaCl을 10 일간 투여한 대조군으로 나누었다. 복강 투여 10일 후, 대조군을 제외한 세 군에 10 mg/kg 염증 유발 물질로 잘 알려진 리포폴리사카라이드(lipopolysaccharide, LPS)LPS를 단 회 복강 투여하였다. LPS투여 7 시간 후에 몸무게를 측정하였으며, 마취(Urethane 1.7 mg/kg)하여 혈액을 취하고 복대동맥(abdominal aorta)을 통해 0.1% 디에틸파이로카르본산(diethylpyrocarbonate)이 함유된 PBS로 관류(perfusion)한 후, 희생하였다. 그 후, 간을 취하여 곧바로 -70 ℃에 보관하였다.Specifically, a group of 6-week-old male C57BL / 6 mice purchased from a central laboratory animal (Japan SLC, Inc., Japan) divided by 5 per group and intraperitoneally administered 0.9% NaCl, and 0.5 mg / kg intraperitoneally administered daumone One group, the daumone administered 1 mg / kg intraperitoneally and the control group administered 0.9% NaCl for 10 days. Ten days after the intraperitoneal administration, three groups except the control group received a single intraperitoneal administration of lipopolysaccharide (LPS) LPS, a well known 10 mg / kg inflammatory agent. Weight was measured 7 hours after LPS administration, anesthetized (1.7 mg / kg of urethane), blood was taken, and perfused with PBS containing 0.1% diethylpyrocarbonate through abdominal aorta. And then sacrificed. Thereafter, the livers were taken and immediately stored at -70 ° C.
아울러, 실험결과의 측정치는 “평균(mean)±표준오차(standard error)”로 나타내었고, 각 군 간의 통계학적인 비교는 분산 분석(ANOVA)과 Fisher's 최소유의차 검증법(least significant difference)으로 검정하였으며, P 값이 0.05 미만인 값에서만 의미가 있는 것으로 판정하였다.In addition, the measured results were expressed as “mean ± standard error”, and the statistical comparison between each group was tested by ANOVA and Fisher's least significant difference. It was determined that only the value of P value less than 0.05 was significant.
그 결과, LPS 투여 7시간 후, LPS 투여 군의 몸무게가 감소하였다(도 3a).
As a result, after 7 hours of LPS administration, the weight of the LPS administration group was decreased (FIG. 3A).
<2-2> 급성 염증에서 다우몬에 의한 간 손상지표 확인<2-2> Identification of Liver Injury Indicators by Daum in Acute Inflammation
본 발명자들은 상기 <실시예 2-1>에서 수득한 급성 염증 유도 마우스의 혈액에서 간 손상지표를 확인하였다.The present inventors confirmed the liver damage index in the blood of the acute inflammation-induced mouse obtained in Example 2-1.
구체적으로, 간 손상의 지표인 AST 및 ALT를 확인하기 위하여, 상기 <실시예 2-1>에서 수득한 급성 염증 유도 마우스의 혈액을 3000 rpm에서 20분 동안 원심분리 한 후 상층액을 취하였다. 혈액의 상층액을 Wako 시약(Wako pure chemical industries,Ltd., Tokyo, Japan)으로 Hitachi 7600 자동화학분석기(Hitachi, Tokyo, Japan)를 이용하여 UV without P5P법으로 측정하였다.Specifically, in order to confirm AST and ALT as indicators of liver damage, the blood of the acute inflammation-induced mouse obtained in Example 2-1 was centrifuged at 3000 rpm for 20 minutes, and then the supernatant was taken. The supernatant of blood was measured by UV without P5P method using a Hitachi 7600 automated analyzer (Hitachi, Tokyo, Japan) with Wako reagent (Wako pure chemical industries, Ltd., Tokyo, Japan).
그 결과, 다우몬(daumone)을 투여한 군의 간 손상 지표인 AST 및 ALT가 유의적으로 감소함을 확인하였다(도 3b).
As a result, it was confirmed that AST and ALT, which are indicators of liver damage, of the group administered with daumone were significantly reduced (FIG. 3B).
<2-3> 급성 염증에서 다우몬에 의한 염증성 사이토카인 발현 억제 확인<2-3> Inhibition of Inflammatory Cytokine Expression by Daum in Acute Inflammation
본 발명자들은 상기 <실시예 2-1>에서 준비한 급성 염증 마우스의 간 시료에서의 염증성 사이토카인인 IL-6의 mRNA 발현 정도를 Real-Time RT qPCR로 확인하였다.The present inventors confirmed the mRNA expression level of inflammatory cytokine IL-6 in liver samples of the acute inflammatory mouse prepared in <Example 2-1> by Real-Time RT qPCR.
구체적으로, 상기 <실시예 2-1>에서 수득한 간에서 총 RNA를 Trizol(Invitrogen, Carlsbad, CA, USA)을 사용하여 분리하였다. 분광광도계를 이용하여 260 nm에서 분리한 RNA의 농도를 측정하였고, 260 nm와 280 nm에서 측정한 흡광도의 비율로 RNA 순도를 평가하였다. 상기 분리한 RNA 1 ㎍을 High Capacity cDNA Reverse Transcription Kit(Applied Biosystems, Carlsbad, CA, USA)를 사용하여 역전사 반응을 수행하였으며, 이 후, 대조군인 18S 및 염증성 사이토카인(cytokine)인 IL-6(interleukin-6)의 mRNA 발현을 상기 표 1의 각각의 primer(바이오니아, 대전, 한국)와 SYBR Green System(7300 Real-Time PCR System, Applied Biosystems)을 사용하여 확인하였다. Specifically, total RNA was isolated from the liver obtained in Example 2-1 using Trizol (Invitrogen, Carlsbad, CA, USA). The concentration of RNA isolated at 260 nm was measured using a spectrophotometer, and RNA purity was evaluated by the ratio of absorbance measured at 260 nm and 280 nm. 1 μg of the isolated RNA was subjected to reverse transcription using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Carlsbad, Calif., USA), followed by control of 18-6 and IL-6, an inflammatory cytokine (cytokine). mRNA expression of interleukin-6) was confirmed using the primers of each of Table 1 (Bionia, Daejeon, Korea) and SYBR Green System (7300 Real-Time PCR System, Applied Biosystems).
아울러, 실험결과의 측정치는 “평균(mean)±표준오차(standard error)”로 나타내었고, 각 군 간의 통계학적인 비교는 분산 분석(ANOVA)과 Fisher's 최소유의차 검증법(least significant difference)으로 검정하였으며, P 값이 0.05 미만인 값에서만 의미가 있는 것으로 판정하였다.In addition, the measured results were expressed as “mean ± standard error”, and the statistical comparison between each group was tested by ANOVA and Fisher's least significant difference. It was determined that only the value of P value less than 0.05 was significant.
그 결과, LPS에 의해 증가한 IL-6의 mRNA가 다우몬(daumone) 투여시 유의미하게 감소하였다(도 3c). As a result, the mRNA of IL-6 increased by LPS significantly decreased when daumone was administered (FIG. 3C).
따라서, LPS에 의해 유도되는 급성 염증에 대한 다우몬(daumone)의 항염증 효과를 확인할 수 있었다.
Therefore, the anti-inflammatory effect of daumone on acute inflammation induced by LPS could be confirmed.
서열목록 전자파일 첨부Attach an electronic file to a sequence list
Claims (13)
Pharmaceutical composition for the prevention and treatment of any one inflammatory disease selected from the group consisting of arthritis, periodontitis, peritonitis, gastritis, enteritis, hepatitis, pancreatitis and rhinitis containing Daumon (Dauer-Inducing Pheromone, Daumone) as an active ingredient.
[화학식 1]
[Claim 2] The pharmaceutical composition for preventing and treating inflammatory diseases of claim 1, wherein the daumone has a structure of [Formula 1]:
[Chemical Formula 1]
Health food for the prevention and improvement of any one inflammatory disease selected from the group consisting of arthritis, periodontitis, peritonitis, gastritis, enteritis, hepatitis, pancreatitis and rhinitis containing Damon as an active ingredient.
The method of claim 9, wherein the inflammatory disease is a chronic inflammatory disease, or acute inflammatory disease, characterized in that the health food for the prevention and improvement of inflammatory diseases.
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| KR20050079353A (en) * | 2004-02-05 | 2005-08-10 | 정만길 | 6r-(3,6-dideoxy-l-arabino-hexopyranosyl) heptanoic acid, preparation process for the same and dauer effect thereof |
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