KR20210060983A - Locusta Migratoria ethanol extract for inhibiting osteoclast differentiation and uses therof - Google Patents
Locusta Migratoria ethanol extract for inhibiting osteoclast differentiation and uses therof Download PDFInfo
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- KR20210060983A KR20210060983A KR1020190148669A KR20190148669A KR20210060983A KR 20210060983 A KR20210060983 A KR 20210060983A KR 1020190148669 A KR1020190148669 A KR 1020190148669A KR 20190148669 A KR20190148669 A KR 20190148669A KR 20210060983 A KR20210060983 A KR 20210060983A
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- ethanol extract
- pulmuchi
- bone
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- osteoclast differentiation
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/306—Foods, ingredients or supplements having a functional effect on health having an effect on bone mass, e.g. osteoporosis prevention
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Abstract
Description
본 발명은 파골세포 분화 억제용 풀무치 에탄올 추출물 및 이의 용도에 관한 것이다.The present invention relates to an ethanol extract of fulmuchi for inhibiting osteoclast differentiation and a use thereof.
골조직은 골 재형성(bone remodeling) 과정을 통해 골 항상성(skeletal homeostasis)을 유지하며 골량(bone mass)은 노화된 골을 흡수하는 파골세포(osteoclast)와 뼈기질을 합성하고 채우는 조골세포(osteoblast)의 상반된 작용에 의해 결정된다. 파골세포와 조골세포 활성 간의 균형은 뼈의 항상성 유지를 위해 중요하며, 뼈의 항상성에서 파골세포의 활성 또는 수 증가는 골다공증, 파젯 병, 류마티스 관절염 및 치주 질환과 같은 뼈 질환에서 골질량 감소의 원인이 된다. 골 대사 불균형으로 인한 골질환의 예방 또는 치료 측면에서 젊은 때부터 골질량을 높이는 것이 상당히 중요하며, 뼈의 건강을 유지하는 것은 성별이나 연령과 관계없이 중요한 문제이다.Bone tissue maintains skeletal homeostasis through bone remodeling, and bone mass is osteoblast that synthesizes and fills bone matrix and osteoclast that absorbs aged bone. It is determined by the opposing actions of The balance between osteoclast and osteoblast activity is important for maintaining bone homeostasis, and an increase in the activity or number of osteoclasts in bone homeostasis is the cause of bone mass loss in bone diseases such as osteoporosis, Paget's disease, rheumatoid arthritis and periodontal disease. do. In terms of preventing or treating bone diseases caused by bone metabolic imbalance, it is very important to increase bone mass from a young age, and maintaining bone health is an important issue regardless of sex or age.
이에, 최근 가장 흔한 골질환인 골다공증의 예방 및 치료를 위해서도 골형성 증가 및 골조직 재생능력에 미치는 영향 등에 대한 연구가 활발하게 이루어지고 있다. 골다공증은 세계적으로 가장 흔한 뼈 질환으로 골질량 감소와 골절 위험 증가와 관련이 있다. 골다공증 환자는 골밀도가 낮아져 뼈의 미세 구조가 약화되는 특징을 가지고 있어서 병리학적인 골절을 경험할 가능성이 크다. 골다공증의 주요 원인은 파골세포 수가 증가하여 골 흡수가 증가하는 것과 관련이 깊다. 파골세포는 여러 단핵전구체의 융합으로 형성된 TRAP(tartrate-resistant acid phosphatase) 양성 다핵세포로서 뼈의 재흡수를 담당하며, 오래되거나 약해진 뼈를 제거하거나 혈중 미네랄의 항성성을 유지한다.Accordingly, for the prevention and treatment of osteoporosis, which is the most common bone disease in recent years, studies on the effect of increasing bone formation and regeneration of bone tissue have been actively conducted. Osteoporosis is the world's most common bone disease and is associated with decreased bone mass and increased risk of fractures. Osteoporosis patients have a characteristic that the bone density is lowered and the microstructure of the bone is weakened, so they are more likely to experience pathological fractures. The main cause of osteoporosis is deeply related to increased bone resorption due to an increase in the number of osteoclasts. Osteoclasts are TRAP (tartrate-resistant acid phosphatase)-positive multinuclear cells formed by the fusion of several mononuclear precursors and are responsible for bone resorption, removing old or weakened bones, or maintaining the stellar nature of minerals in the blood.
파골세포의 분화는 두 개의 사이토카인인 M-CSF(macrophage colony stimulating factor)와 RANKL(receptor activator of nuclear factor-κ(NF-κ)에 의해 조절된다. 면역세포/조골세포에서 생성되는 M-CSF는 파골세포 전구세포에서 RANK 발현 및 파골세포의 생존 신호를 유도하며, 조골세포/활성 T 세포에 의해 분비되는 RANKL는 파골세포의 수용체 RANK와 결합하여 MAPK(mitogen-activated protein kinase) 및 NFATc1의 활성화를 유도한다. 상기 NFATc1은 파골세포 형성의 핵심 전사 인자로서 TRAP, cathepsin K, DC-STAMP(dendritic cell-specific transmembrane protein)와 같은 파골세포 분화 및 활성화 인자의 발현을 조절한다.The differentiation of osteoclasts is regulated by two cytokines, macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κ (NF-κ), which are two cytokines. Induces RANK expression and osteoclast survival signals in osteoclast progenitor cells, and RANKL secreted by osteoblasts/active T cells binds to the osteoclast receptor RANK to activate MAPK (mitogen-activated protein kinase) and NFATc1. The NFATc1 is a key transcription factor for osteoclast formation and regulates the expression of osteoclast differentiation and activation factors such as TRAP, cathepsin K, and DC-STAMP (dendritic cell-specific transmembrane protein).
한편, 현재 지구상에 존재하는 곤충은 130만 종으로 알려져 있으나 그에 비해 곤충을 이용한 소재 개발은 미비한 실정이다. 과거 동의보감, 본초강목을 통해 다양한 효능이 보고되었으며, 극한 외부 환경 조건에서 살아가는 곤충의 특성상 체내에 기능성을 가진 2차 대사산물을 함유하고 있을 것으로 추정되고 있다. 뿐만 아니라 미래 인구 증가에 따른 식량 부족에 대한 대안으로써 식용곤충이 각광받고 있으며, 현재 국내에 7종의 식용곤충이 일반식품으로 식품공전에 등록되어 있다. 최근에는 다양한 곤충 유래의 생리활성 물질에 대한 연구가 활발히 진행되고 있으며 곤충의 기능성 연구를 통해 식용 및 약용으로 곤충의 이용이 증가할 것으로 사료된다.Meanwhile, 1.3 million species of insects currently exist on the planet, but compared to that, the development of materials using insects is insufficient. In the past, various effects have been reported through Donguibogam and Bonchogangmok, and it is estimated that the insects living in extreme external environmental conditions contain functional secondary metabolites in the body. In addition, edible insects are in the spotlight as an alternative to food shortages due to future population growth, and 7 kinds of edible insects are currently registered in the Food Code as general foods in Korea. Recently, studies on bioactive substances derived from various insects have been actively conducted, and the use of insects for edible and medicinal purposes is expected to increase through functional studies of insects.
이 중, 풀무치(Locusta migratoria)는 메뚜기목(Orthoptera) 메뚜기과(Acrididae)의 곤충으로 우리나라를 포함하여 아시아, 아프리카, 오스트레일리아, 유럽 등 전세계적으로 분포한다. 크기는 4-6 cm 정도이고, 하루에 100 km를 이동할 수 있을 정도로 이동성이 강한 것으로 알려져 있다. 풀무치는 사료용, 식·약용 등으로 사용되는 유용한 곤충 종 중 하나로 다양한 목적으로의 연구를 위하여 실험실에서 흔하게 사육되고 있고, 체코, 폴란드, 터키 등 유럽 국가에서는 수출용으로 사육되고 있다. 현재까지 풀무치를 이용한 연구로는 집단형 풀무치에 대한 방제 연구, 국내 풀무치의 계통 분석, 풀무치 유래 펩타이드 및 GST의 구조 및 기능 분석 등이 진행되었으나 풀무치 추출물의 파골세포 분화 억제에 미치는 영향에 대하여는 아직까지 보고된 바가 없고, 이에 대한 연구는 미미한 실정이다. Of these, Locusta migratoria ) is an insect of the Orthoptera family Acrididae and is distributed worldwide including Korea, Asia, Africa, Australia, and Europe. It is about 4-6 cm in size and is known to be highly mobile enough to travel 100 km per day. Bellows are one of the useful insect species used for feed, food and medicinal purposes, and are commonly bred in laboratories for research for various purposes, and are bred for export in European countries such as the Czech Republic, Poland, and Turkey. Until now, studies using pulmuchi have included control studies on group-type vellum, systematic analysis of domestic pulmuchi, and structural and functional analysis of Pulmuchi-derived peptides and GSTs. However, the effect of Pulmuchi extract on the inhibition of osteoclast differentiation has yet to be investigated. There are no reports, and research on this is insignificant.
이에, 본 발명자들은 골소실로 인한 골질환의 효과적인 예방과 치료를 가능하게 하는 곤충 유래의 새로운 신약 후보물질을 연구하던 중, 풀무치 에탄올 추출물이 파골세포의 분화를 억제하는 효과가 우수함을 확인하여 본 발명을 완성하였다.Accordingly, the present inventors were studying a new drug candidate derived from insects that enables effective prevention and treatment of bone diseases due to bone loss, while confirming that Pulmuchi ethanol extract has an excellent effect of inhibiting the differentiation of osteoclasts. The invention was completed.
따라서 본 발명의 목적은 풀무치 에탄올 추출물을 포함하는 파골세포 분화 억제용 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a composition for inhibiting osteoclast differentiation comprising an ethanol extract of pulmuchi.
본 발명의 또 다른 목적은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 치료용 약학적 조성물, 골질환 예방 또는 개선용 식품 조성물, 골질환 예방 또는 개선용 의약외품 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating bone diseases, a food composition for preventing or improving bone disease, and a quasi-drug composition for preventing or improving bone disease, including an ethanol extract of fulmuchi.
본 발명의 또 다른 목적은 풀무치 에탄올 추출물을 함유하는 시험관 내(in vitro) 파골세포 분화 억제용 시약 조성물을 제공하는 것이다.Another object of the present invention is to provide a reagent composition for inhibiting osteoclast differentiation in vitro, containing an ethanol extract of fulmuchichi.
상기 목적을 달성하기 위하여, 본 발명은 풀무치 에탄올 추출물을 포함하는 파골세포 분화 억제용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for inhibiting osteoclast differentiation comprising an ethanol extract of pulmuchi.
또한, 본 발명은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases comprising an ethanol extract of pulmuchi.
또한, 본 발명은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving bone diseases comprising an ethanol extract of pulmuchi.
또한, 본 발명은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 개선용 의약외품 조성물을 제공한다.In addition, the present invention provides a quasi-drug composition for preventing or improving bone diseases comprising an ethanol extract of pulmuchi.
또한, 본 발명은 풀무치 에탄올 추출물을 함유하는 시험관 내(in vitro) 파골세포 분화 억제용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for inhibiting osteoclast differentiation in vitro (in vitro) containing the ethanol extract of Pulmuchi.
본 발명은 파골세포 분화를 억제하는 풀무치 에탄올 추출물을 유효성분으로 포함하여, 천연물로 세포독성을 나타내지 않으면서도 파골세포 분화 활성을 현저하게 억제시킬 수 있어 골형성 촉진, 골소실 또는 골 대사 불균형으로 인한 골질환의 효과적인 예방 및 치료를 위한 약학적 조성물 또는 건강기능식품으로 유용하게 사용될 수 있을 것으로 기대된다. The present invention contains an ethanol extract of vellumchi, which inhibits osteoclast differentiation, as an active ingredient, and can significantly inhibit osteoclast differentiation activity without exhibiting cytotoxicity as a natural product, thereby promoting bone formation, bone loss or bone metabolic imbalance. It is expected to be useful as a pharmaceutical composition or health functional food for effective prevention and treatment of bone diseases.
도 1은 풀무치 에탄올 추출물(Locusta Migratoria Extract, LME) 농도(100, 500, 1000, 2000 μg/mL)에 따른 세포독성 확인 결과를 나타낸 도이다.
도 2는 RANKL(100 ng/mL)를 처리한 파골세포에 대하여, 농도(0, 100, 500, 1000, 2000 μg/mL)별 풀무치 에탄올 추출물(Locusta Migratoria Extract, LME) 처리에 따른 TRAP 활성 변화를 확인한 도이다.
도 3은 RANKL(100 ng/mL)를 처리한 파골세포에 대하여, 농도(0, 100, 500, 1000, 2000 μg/mL)별 풀무치 에탄올 추출물(Locusta Migratoria Extract, LME) 처리에 따른 파골세포 분화 관련 유전자(TRAP, RANK, NFATc1 및 CathepsinK) 발현 변화를 확인한 도이다.
도 4는 RANKL(100 ng/mL)를 처리한 파골세포에 대하여, 농도(0, 100, 500, 1000, 2000 μg/mL)별 풀무치 에탄올 추출물(Locusta Migratoria Extract, LME) 처리에 따른 파골세포 분화 관련 단백질(NFATc1 및 c-Src) 발현 변화를 확인한 도이다.
도 5는 RANKL(100 ng/mL)를 처리한 파골세포에 대하여, 농도(0, 100, 500, 1000, 2000 μg/mL)별 풀무치 에탄올 추출물(Locusta Migratoria Extract, LME) 처리에 따른 파골세포 분화 관련 시그널링 단백질 발현 변화를 확인한 도이다. Figure 1 is a diagram showing the results of cytotoxicity check according to the concentration (100, 500, 1000, 2000 μg / mL) of pulmuchi ethanol extract (Locusta Migratoria Extract, LME).
Figure 2 shows the change in TRAP activity according to the treatment of pulmuchi ethanol extract (Locusta Migratoria Extract, LME) by concentration (0, 100, 500, 1000, 2000 μg/mL) for osteoclasts treated with RANKL (100 ng/mL) This is a confirmed degree.
Figure 3 is for osteoclasts treated with RANKL (100 ng/mL), differentiation of osteoclasts according to pulmuchi ethanol extract (Locusta Migratoria Extract, LME) treatment by concentration (0, 100, 500, 1000, 2000 μg/mL) This is a diagram confirming the changes in the expression of related genes (TRAP, RANK, NFATc1 and CathepsinK).
Figure 4 is for osteoclasts treated with RANKL (100 ng/mL), differentiation of osteoclasts according to pulmuchi ethanol extract (Locusta Migratoria Extract, LME) treatment by concentration (0, 100, 500, 1000, 2000 μg/mL) This is a diagram confirming the changes in the expression of related proteins (NFATc1 and c-Src).
Figure 5 is for osteoclasts treated with RANKL (100 ng/mL), differentiation of osteoclasts according to pulmuchi ethanol extract (Locusta Migratoria Extract, LME) treatment by concentration (0, 100, 500, 1000, 2000 μg/mL) This is a diagram confirming the change in the expression of related signaling proteins.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는 것이다.Terms that are not otherwise defined in the present specification have the meanings commonly used in the technical field to which the present invention pertains.
본 발명은 풀무치 에탄올 추출물을 포함하는 파골세포 분화 억제용 조성물을 제공한다.The present invention provides a composition for inhibiting osteoclast differentiation comprising an ethanol extract of pulmuchi.
상기 풀무치 에탄올 추출물은 에탄올을 사용하여 풀무치로부터 추출하여 수득한 추출물을 의미한다. 본 발명은 일 실시예에서 상기 풀무치 에탄올 추출물이 현저한 파골세포 분화 억제 효과가 있음을 확인하였다.The ethanol extract of Pulmuchi refers to an extract obtained by extracting from Pulmuchi using ethanol. In one embodiment of the present invention, it was confirmed that the ethanol extract of pulmuchi had a remarkable inhibitory effect on osteoclast differentiation.
상기 풀무치 에탄올 추출물은 건조 중량의 약 2 내지 20배, 구체적으로는, 약 3 내지 5배에 달하는 부피의 에탄올을 용출 용매로써 사용하는 것이 바람직하다. 상기 에탄올은 50 내지 100%(농도) 에탄올일 수 있으며, 바람직하게는 70% 에탄올일 수 있으나, 이에 제한되지 않는다. 상기 추출 온도는 20 내지 100℃, 예를 들어 실온일 수 있고, 추출 기간은 약 12시간 내지 4일 동안 이루어질 수 있으나 이에 제한되지 않는다. 추출방법으로는 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등을 사용하여 추출할 수 있으며 파골세포 억제 활성이 있는 물질을 추출하는 방법이라면 제한없이 이용될 수 있다. It is preferable to use ethanol in a volume of about 2 to 20 times, specifically, about 3 to 5 times of the dry weight of the ethanol extract, as an elution solvent. The ethanol may be 50 to 100% (concentration) ethanol, preferably 70% ethanol, but is not limited thereto. The extraction temperature may be 20 to 100° C., for example, room temperature, and the extraction period may be about 12 hours to 4 days, but is not limited thereto. The extraction method may be extracted using hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction, and any method of extracting a substance having an osteoclast inhibitory activity may be used without limitation.
본 발명의 일 실시예에서는, 풀무치 동결건조 분말을 70% 에탄올과 10%(v/v)가 되게 혼합한 후, 초음파 처리하여 30분간 실온에서 방치한 뒤 에탄올 추출액을 회수하고 감압증류하여 풀무치 에탄올 추출물을 수득하였다. In one embodiment of the present invention, after mixing the lyophilized velvet powder to be 70% ethanol and 10% (v/v), sonicated and allowed to stand at room temperature for 30 minutes, the ethanol extract was recovered and distilled under reduced pressure to obtain velvet ethanol. An extract was obtained.
본 발명에 있어서, 상기 풀무치 에탄올 추출물은 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 또는 이들의 조정제물 또는 정제물을 모두 포함한다.In the present invention, the ethanol extract of Pulmuchi includes both an extract, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, or a prepared product or purified product thereof.
본 발명에 있어서, 상기 풀무치 에탄올 추출물은 파골세포에서 TRAP, RANK, NFATc1 및 카텝신(Cathepsin) K로 이루어진 군으로부터 선택되는 하나 이상 유전자의 발현을 감소시키는 것을 특징으로 한다.In the present invention, the ethanol extract of vellum is characterized in that it reduces the expression of one or more genes selected from the group consisting of TRAP, RANK, NFATc1 and cathepsin K in osteoclasts.
또한, 본 발명에 있어서, 상기 풀무치 에탄올 추출물은 파골세포에서 NFATc1 또는 c-Src 단백질의 발현을 감소시키는 것을 특징으로 한다.In addition, in the present invention, the ethanol extract of vellum is characterized in that it reduces the expression of NFATc1 or c-Src protein in osteoclasts.
본 발명의 일 실시예에 따르면, 본 발명의 풀무치 에탄올 추출물은 파골세포 분화 관련 유전자(TRAP, RANK, NFATc1 및 카텝신 K) 및 파골세포 분화 관련 단백질(NFATc1 및 c-Src)의 발현을 현저히 감소시키며, 상기 결과를 통해 골질환의 예방 및 치료가 가능함을 확인하였다.According to an embodiment of the present invention, the ethanol extract of Pulmuchi of the present invention significantly reduces the expression of osteoclast differentiation-related genes (TRAP, RANK, NFATc1 and cathepsin K) and osteoclast differentiation-related proteins (NFATc1 and c-Src). And, through the above results, it was confirmed that the prevention and treatment of bone diseases is possible.
또한, 본 발명은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases comprising an ethanol extract of pulmuchi.
본 발명에 있어서, 상기 풀무치 에탄올 추출물은 파골세포 분화 활성을 억제하는 것을 특징으로 하며, 본 발명의 일 실시예에서는 본 발명의 풀무치 에탄올 추출물이 파골세포 분화와 관련된 RAP, RANK, NFATc1 및 CathepsinK의 유전자 발현을 감소시키고, 골세포 분화와 관련된 NFATc1 및 c-Src 단백질 발현을 감소시킴을 확인하여, 상기 추출물이 골질환 예방 또는 치료용도로 사용될 수 있음을 확인하였다.In the present invention, the ethanol extract of vellum is characterized in that it inhibits osteoclast differentiation activity, and in one embodiment of the present invention, the ethanol extract of velumichi of the present invention is a gene of RAP, RANK, NFATc1 and CathepsinK related to osteoclast differentiation It was confirmed that the expression was reduced and the expression of NFATc1 and c-Src proteins related to bone cell differentiation was reduced, and thus it was confirmed that the extract can be used for the prevention or treatment of bone diseases.
본 발명에 있어서, 용어 “골질환”은 골형성과 골흡수의 균형이 깨짐으로써 발병하는 모든 골 관련 질환을 제한 없이 포함하며, 예를 들어 골다공증(osteoporosis), 불유합(non-union) 골절, 골괴사증(osteonecrosis), 골연화증(osteomalacia), 골결손, 골감소증(osteopenia), 골위축(bone atrophy), 골관절염(osteoarthritis), 치주질환(periodontal disease), 무혈성 대퇴골괴사(Avascular necrosis of the Femoral Head)로 이루어진 군으로부터 선택되는 어느 하나일 수 있고, 바람직하게는 골다공증인 것을 특징으로 할 수 있다.In the present invention, the term "bone disease" includes, without limitation, all bone-related diseases caused by a loss of balance between bone formation and bone resorption, for example, osteoporosis, non-union fracture, bone Consist of osteonecrosis, osteomalacia, bone defect, osteopenia, bone atrophy, osteoarthritis, periodontal disease, avascular necrosis of the femoral head. It may be any one selected from the group, preferably it may be characterized in that osteoporosis.
본 발명에 있어서, 상기 약학적 조성물은 골형성의 촉진 또는 골질환의 예방 또는 치료를 목적으로 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.In the present invention, the pharmaceutical composition may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of promoting bone formation or preventing or treating bone diseases.
본 발명에 따른 조성물은 약학적으로 허용 가능한 담체를 포함하여 약학적 조성물로 제제화될 수 있으며, 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화될 수 있다.The composition according to the present invention may be formulated as a pharmaceutical composition including a pharmaceutically acceptable carrier, and oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. according to a conventional method , It can be formulated in the form of external preparations, suppositories, and sterile injectable solutions.
상기 약학적으로 허용가능한 담체는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 포함한다. 또한, 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함한다. 경구용 고형 제제는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 포함할 수 있으며, 마그네슘 스테아레이트, 탈크 같은 윤활제 등을 포함할 수 있다. 경구용 액상 제제는 현탁제, 내용액제, 유제, 시럽제 등을 포함하며, 물, 리퀴드 파라핀 등의 희석제, 습윤제, 감미제, 방향제, 보존제 등을 포함할 수 있다. 비경구용 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제를 포함하며, 비수성 용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르류 등을 포함한다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로 젤라틴 등이 사용될 수 있다.The pharmaceutically acceptable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants are included. Oral solid preparations include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one or more excipients, such as starch, calcium carbonate, sucrose, or lactose. ), gelatin, and the like, and may include a lubricant such as magnesium stearate and talc. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweetening agents, fragrances, preservatives, and the like. Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, ethyl And injectable esters such as oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycero gelatin, and the like may be used.
본 발명에 따른 약학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있으며, 바람직하게는 경구 투여이다.The pharmaceutical composition according to the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., preferably oral administration to be.
상기 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 상기 약학적 조성물의 1일 투여량은 0.1 내지 300 ㎎/㎏/일 또는 약 0.5 내지 50 ㎎/㎏/일 또는 약 1 내지 10 ㎎/㎏/일의 투여량이 일반적으로 충분하다.The suitable dosage of the pharmaceutical composition varies depending on factors such as formulation method, mode of administration, age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate and response sensitivity of the patient, and is usually A skilled practitioner can readily determine and prescribe a dosage effective for the desired treatment or prophylaxis. The daily dosage of the pharmaceutical composition is generally sufficient in a dosage of 0.1 to 300 mg/kg/day or about 0.5 to 50 mg/kg/day or about 1 to 10 mg/kg/day.
또한, 본 발명은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving bone diseases comprising an ethanol extract of pulmuchi.
본 발명에 따른 조성물이 식품용으로 사용되는 경우, 상기 식품 조성물은 건강기능식품으로서 그 자체로 제형화를 거쳐 사용되거나, 건강기능식품의 첨가물로서 다른 건강기능식품에 포함될 수 있다.When the composition according to the present invention is used for food, the food composition may be used after being formulated as a health functional food, or may be included in other health functional foods as an additive of a health functional food.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 수프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and all health functional foods in the usual sense are included.
본 발명의 식품 조성물은 식품 또는 식품 첨가물의 제조에 사용되는 통상의 성분들, 구체적으로, 향미제; 천연 탄수화물로서 포도당, 과당과 같은 모노사카라이드, 말토오스, 수크로오스와 같은 디사카라이드 및 덱스트린, 사이클로덱스트린과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제; 영양제; 비타민; 전해질; 착색제; 유기산; 보호성 콜로이드 증점제; pH 조절제; 안정화제; 방부제; 글리세린; 알코올; 탄산 음료에 사용되는 탄산화제 등을 포함할 수 있다.The food composition of the present invention includes conventional ingredients, specifically, flavoring agents used in the preparation of foods or food additives; As natural carbohydrates, monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, and synthetic sweeteners such as saccharin and aspartame; Nutrients; vitamin; Electrolytes; coloring agent; Organic acids; Protective colloidal thickeners; pH adjuster; Stabilizers; antiseptic; glycerin; Alcohol; Carbonating agents used in carbonated beverages may be included.
본 발명에 있어서, 상기 식품 조성물 또는 건강기능식품은 골형성, 골강화 또는 성장발육 촉진을 목적으로 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.In the present invention, the food composition or health functional food may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of bone formation, bone strengthening, or promotion of growth and development.
본 발명에서, 용어 "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 유효성분의 혼합양은 사용 목적 (예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.In the present invention, the term "health functional food" refers to a food manufactured and processed using raw materials or ingredients having useful functions for the human body according to the Health Functional Food Act No.6727, and with respect to the structure and function of the human body It refers to ingestion for the purpose of controlling or obtaining beneficial effects for health purposes such as physiological effects. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
본 발명에 따른 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안정청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food according to the present invention may contain ordinary food additives, and the suitability as the "food additive" is determined according to the general rules of the food additive code approved by the Food and Drug Administration and the general test method, etc., unless otherwise specified. It is judged according to the standards and standards for the relevant item.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다.Items listed in the "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigments, licorice extract, crystalline cellulose, high color pigments, and guar gum, Mixed preparations, such as a sodium L-glutamate preparation, an alkali additive for noodles, a preservative preparation, and a tar color preparation, etc. are mentioned.
예를 들어, 정제 형태의 건강기능식품은 풀무치 에탄올 추출물을 부형제, 결합제, 붕해제 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다.For example, for health functional foods in the form of tablets, a mixture of vellumchi ethanol extract with an excipient, a binder, a disintegrant, and other additives is granulated by a conventional method, and then a lubricant is added thereto and compression molding, or the mixture is directly It can be compression molded.
또한, 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.In addition, the health functional food in the form of a tablet may contain a mating agent or the like, if necessary, and may be coated with a suitable coating agent if necessary.
캅셀 형태의 건강기능식품 중 경질캅셀제는 통상의 경질캅셀에 풀무치 에탄올 추출물을 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캅셀제는 풀무치 에탄올 추출물을 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캅셀기제에 충진하여 제조할 수 있다. 상기 연질캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.Among the capsule-type health functional foods, hard capsules can be prepared by filling a conventional hard capsule with a mixture of velvet ethanol extract with an additive such as an excipient, or a granular or skinned product thereof, and the soft capsule is a velvet ethanol extract. It can be prepared by filling a mixture with an additive such as an excipient in a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
환 형태의 건강기능식품은 풀무치 에탄올 추출물과 부형제, 결합제, 붕해제 등과의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다.Ring-shaped health functional foods can be prepared by molding a mixture of velvet ethanol extract and excipients, binders, disintegrants, etc. by appropriate methods, and if necessary, the skins may be coated with white sugar or other suitable skin-forming agents, or starch, talc, or a suitable substance. It can also be rejoicing.
과립형태의 건강기능식품은 상기 풀무치 에탄올 추출물과 부형제, 결합제, 붕해제 등과의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The health functional food in the form of granules can be prepared in a granular form by a suitable method of a mixture of the ethanol extract, excipients, binders, disintegrants, and the like of velumucci, and may contain flavoring agents, flavoring agents, and the like, if necessary.
본 발명의 상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함한다.The definitions of terms for the excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, and the like of the present invention are described in documents known in the art and include those having the same or similar functions.
또한, 본 발명은 풀무치 에탄올 추출물을 포함하는 골질환 예방 또는 개선용 의약외품 조성물을 제공한다.In addition, the present invention provides a quasi-drug composition for preventing or improving bone diseases comprising an ethanol extract of pulmuchi.
본 발명에서 용어, "의약외품"은 사람이나 동물의 질병을 치료, 경감, 처치 또는 예방할 목적으로 사용되는 섬유, 고무제품 또는 이와 유사한 것, 인체에 대한 작용이 약하거나 인체에 직접 작용하지 아니며, 기구 또는 기계가 아닌 것과 이와 유사한 것, 감염 예방을 위하여 살균, 살충 및 이와 유사한 용도로 사용되는 제제 중 하나에 해당하는 물품으로서, 사람이나 동물의 질병을 진단, 치료, 경감, 처치 또는 예방할 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것 및 사람이나 동물의 구조와 기능에 약리학적 영향을 줄 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것을 제외한 물품을 의미하며, 피부 외용제 및 개인위생용품도 포함한다.In the present invention, the term "quasi-drug" refers to fibers, rubber products, or the like, which are used for the purpose of treating, alleviating, treating or preventing diseases of humans or animals. Or non-machine and similar, as an article corresponding to one of the preparations used for sterilization, insecticide, and similar purposes to prevent infection, and used for the purpose of diagnosing, treating, alleviating, treating or preventing diseases of humans or animals. It refers to items that are not instruments, machines, or devices among the items that are used, and items that are not instruments, machines or devices among items used for the purpose of pharmacologically affecting the structure and function of humans or animals, and are for external use for skin and personal hygiene. Includes supplies.
본 발명의 풀무치 에탄올 추출물을 골질환 예방 또는 개선을 목적으로 의약외품 조성물에 첨가할 경우, 상기 추출물을 그대로 첨가하거나 다른 분획물이나 다른 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합량은 사용 목적에 따라 적합하게 결정할 수 있다.When the ethanol extract of the present invention is added to a quasi-drug composition for the purpose of preventing or improving bone disease, the extract may be added as it is or may be used with other fractions or other quasi-drug components, and may be appropriately used according to a conventional method. . The mixing amount of the active ingredient can be appropriately determined according to the intended use.
또한, 본 발명은 풀무치 에탄올 추출물을 함유하는 시험관 내(in vitro) 파골세포 분화 억제용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for inhibiting osteoclast differentiation in vitro (in vitro) containing the ethanol extract of Pulmuchi.
본 발명의 풀무치 에탄올 추출물은 시험관 내(in vitro)에서 파골세포의 분화를 억제하는 것을 특징으로 하는 파골세포 분화 억제용 시약 조성물로 활용할 수 있다.The ethanol extract of Pulmuchi of the present invention can be used as a reagent composition for inhibiting osteoclast differentiation, characterized in that it inhibits the differentiation of osteoclasts in vitro.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example 1. 실험 준비 1. Preparation for experiment
풀무치(Locusta migratoria)는 국립농업과학원 곤충산업과에서 실내 계대 사육한 해남 6세대를 사용하였다. 실험 곤충은 밀을 먹이로 사용하였으며 30℃65% R.H., 9L/15D, 1,800 Lux의 조건에서 사육하였다. 풀무치 추출물은 상기 풀무치를 동결건조 한 후 분말화 하여 Baek 등(J. Life Sci. 2017, 27, 1269-1275.)의 방법에 따라 추출하였다. 구체적으로, 풀무치 동결건조 분말을 70% 에탄올의 10%(v/v)가 되게 혼합하여 초음파 처리(250 J, 10초, 2회)한 후 30분간 실온에서 방치하였다. 혼합액의 상등액을 걸러 원심농축기(EYELA, Tokyo, Japan)를 이용하여 완전히 건조한 후 사용 전까지 -20℃에서 냉동보관하였다. 상기 과정을 통해 수득한 풀무치 추출물을 LME로 명명하였다. Locusta migratoria ) used 6 generations of Haenam, which were sub-bred indoors by the Department of Insect Industry, National Academy of Agricultural Sciences. The experimental insects used wheat as food and were reared under the conditions of 30℃65% RH, 9L/15D, and 1,800 Lux. Pulmuchi extract was lyophilized, powdered, and extracted according to the method of Baek et al. (J. Life Sci. 2017, 27, 1269-1275.). Specifically, the lyophilized velvet powder was mixed to a concentration of 10% (v/v) of 70% ethanol, subjected to ultrasonic treatment (250 J, 10 seconds, twice), and left at room temperature for 30 minutes. The supernatant of the mixed solution was filtered and completely dried using a centrifugal concentrator (EYELA, Tokyo, Japan), and then stored frozen at -20°C until use. The extract obtained through the above process was named LME.
파골세포(마우스 대식세포주 유래 Raw264.7)는 ATCC에서 구입하였으며 10% FBS (fetal bovine serum) (Hyclone, Logan, UT, USA)와 1× 페니실린-스트렙토마이신 (Hyclone)이 첨가된 DMEM 배지(Dulbecco's Modified Eagle Medium) (Hyclone)를 사용하여 배양하였고 세포는 37℃, 5% CO2의 배양조건을 유지하였다. 세포가 충분히 성장하는 2-3일 간격으로 계대 배양하며 실험을 진행하였다.Osteoclasts (Raw264.7 derived from a mouse macrophage line) were purchased from ATCC, and 10% FBS (fetal bovine serum) (Hyclone, Logan, UT, USA) and 1× penicillin-streptomycin (Hyclone) were added to DMEM medium (Dulbecco's). Modified Eagle Medium) (Hyclone) was used to culture the cells, and the culture conditions were maintained at 37°C and 5% CO 2. The experiment was carried out by subculturing at intervals of 2-3 days in which cells are sufficiently grown.
실시예Example 2. 풀무치 에탄올 추출물의 세포독성 확인 2. Confirmation of Cytotoxicity of Ethanol Extract of Pulmuchi
본 발명에 따른 풀무치 에탄올 추출물이 Raw264.7 세포의 증식 및 독성에 미치는 영향을 확인하기 위하여 세포 독성 실험을 수행하였다. 구체적으로, Raw264.7 세포를 96-웰 플레이트에 5.0 × 103 cells/웰로 분주하여 세포밀도(confluence)가 약 80%에 도달할 때까지 10% FBS가 들어있는 배지에서 약 24시간 동안 배양하였다. 그 후 풀무치 에탄올 추출물을 농도(100, 500, 1000, 2000 μg/mL)에 따라 처리하고 24시간 및 48시간 동안 추가 배양한 후 MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) 시약을 사용하여 세포 생존율을 측정하였다. 그 결과를 도 1에 나타내었다.Cytotoxicity experiments were performed to confirm the effect of the ethanol extract of vellumchi according to the present invention on the proliferation and toxicity of Raw264.7 cells. Specifically, Raw264.7 cells were distributed in a 96-well plate at 5.0 × 10 3 cells/well and cultured in a medium containing 10% FBS for about 24 hours until the cell density (confluence) reached about 80%. . Thereafter, the ethanol extract of Pulmuchi was treated according to the concentration (100, 500, 1000, 2000 μg/mL), and after further incubation for 24 hours and 48 hours, MTS(3-(4,5-dimethylthiazol-2-yl)-5 Cell viability was measured using -(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) reagent. The results are shown in FIG. 1.
도 1에 나타낸 바와 같이, 본 발명의 풀무치 에탄올 추출물은 2000 μg/mL까지 Raw264.7 세포 독성을 유발하지 않음을 확인하였다. As shown in Fig. 1, it was confirmed that the ethanol extract of vellumchi of the present invention did not cause Raw264.7 cytotoxicity up to 2000 μg/mL.
실시예Example 3. 풀무치 에탄올 추출물이 파골세포의 분화에 미치는 영향 관찰 3. Observation of the effect of ethanol extract of Pulmuchi on the differentiation of osteoclasts
3-1. TRAP 활성 측정3-1. TRAP activity measurement
파골세포는 분화가 진행되면서 단핵의 전 파골세포를 형성하지만, 세포가 융합되면서 다핵의 성숙 파골세포를 형성하게 되고 이는 골 표면에 부착하여 골을 흡수하는 작용을 한다. 파골세포는 TRAP와 칼시토닌 수용체를 가지며, 산 생성이 활발한 특징을 가져, 파골세포의 표지 인자로 널리 사용되고 있다. 이에, Raw 264.7 세포를 이용하여 TRAP 염색을 하고 TRAP 활성 변화를 측정하였다. 구체적으로, Raw 264.7 세포를 5 × 104 cells/ml로 조정하여 96-웰 플레이트에 분주하여 24시간 배양하였다. 배지를 제거하고 DMEM 배지에 분화 인자인 RANKL 100 ng/mL와 시료로써 본 발명의 풀무치 에탄올 추출물을 농도 별로(0, 100, 500, 1000, 2000 μg/mL) 처리하여 4일간 배양하였다. 이후 배지를 제거하고 PBS로 세척한 후 고정 용액(시트레이트 용액 + 아세톤 + 포름알데히드)으로 세포를 고정한 뒤, 기질 용액으로 1.36 mg/ml 4-니트로페닐 포스페이트 디소듐 염(4-nitrophenyl phosphate disodium salt), 10 mM 타르타르산(tartrate)을 포함하는 50 mM 시트레이트 완충용액(pH 4.6)을 제조하여 고정한 세포에 분주하였다. 37℃, 5% CO2 배양기에서 30분간 반응 후 효소 반응액을 0.1 N NaOH로 반응을 중지시키고 ELISA 리더로 405 nm에서 흡광도를 측정하였다. TRAP 활성은 시료의 흡광도를 대조군에 대한 백분율로 표시하였다. 그 결과를 도 2에 나타내었다.The osteoclasts form mononuclear whole osteoclasts as the differentiation progresses, but as the cells fuse, they form multinuclear mature osteoclasts, which attach to the bone surface and absorb bone. Osteoclasts have TRAP and calcitonin receptors, and are active in acid production, and are widely used as markers of osteoclasts. Thus, TRAP staining was performed using Raw 264.7 cells and the change in TRAP activity was measured. Specifically, Raw 264.7 cells were adjusted to 5 × 10 4 cells/ml, dispensed into a 96-well plate, and cultured for 24 hours. After removing the medium, 100 ng/mL of RANKL, a differentiation factor, and the ethanol extract of the present invention as a sample were treated in DMEM medium at different concentrations (0, 100, 500, 1000, 2000 μg/mL), and cultured for 4 days. After removing the medium, washing with PBS, fixing the cells with a fixing solution (citrate solution + acetone + formaldehyde), and then using 1.36 mg/ml 4-nitrophenyl phosphate disodium salt as a substrate solution. ), 50 mM citrate buffer solution (pH 4.6) containing 10 mM tartaric acid (tartrate) was prepared and dispensed to the fixed cells. After reacting for 30 minutes in an incubator at 37° C., 5% CO 2 , the reaction solution was stopped with 0.1 N NaOH, and the absorbance was measured at 405 nm with an ELISA reader. TRAP activity was expressed as a percentage of the absorbance of the sample relative to the control. The results are shown in FIG. 2.
도 2에 나타낸 바와 같이, RANKL에 의해 증가된 TRAP 활성이 본 발명의 풀무치 에탄올 추출물 처리에 의해 농도의존적으로 감소함을 확인하였다. 상기 결과를 통해, 본 발명의 풀무치 에탄올 추출물은 파골세포의 분화를 효과적으로 억제함을 확인하였다. As shown in Fig. 2, it was confirmed that the TRAP activity increased by RANKL was decreased in a concentration-dependent manner by the treatment of the ethanol extract of pulmuchi of the present invention. Through the above results, it was confirmed that the ethanol extract of pulmuchi of the present invention effectively inhibits the differentiation of osteoclasts.
3-2. 파골세포 분화 관련 유전자 발현 측정3-2. Measurement of gene expression related to osteoclast differentiation
본 발명에 따른 풀무치 에탄올 추출물이 파골세포 분화 유전자 마커인 TRAP, RANK, NFATc1 및 CathepsinK의 발현에 미치는 영향을 확인하였다. 구체적으로, Raw 264.7 세포를 1 x 104 cells/웰의 농도로 48-웰 플레이트에 시딩하고, 100 ng/mL RANKL과 시료로써 본 발명의 풀무치 에탄올 추출물을 농도 별로(0, 100, 500, 1000, 2000 μg/mL) 처리하여 5일 동안 37℃ 배양기에서 배양하였다. 배양 완료된 세포를 회수하고 RNA를 추출하여 RT-PCR을 수행하였다. 그 결과를 도 3에 나타내었다.It was confirmed the effect of the ethanol extract of Pulmuchi according to the present invention on the expression of osteoclast differentiation gene markers TRAP, RANK, NFATc1 and CathepsinK. Specifically, Raw 264.7 cells were seeded in a 48-well plate at a concentration of 1 x 10 4 cells/well, and 100 ng/mL RANKL and the ethanol extract of the present invention as a sample were prepared by concentration (0, 100, 500, 1000). , 2000 μg/mL) and cultured in an incubator at 37° C. for 5 days. The cultured cells were recovered, RNA was extracted, and RT-PCR was performed. The results are shown in FIG. 3.
도 3에 나타낸 바와 같이, RANKL 처리에 의해 증가된 TRAP, RANK, NFATc1 및 CathepsinK의 유전자 발현이 본 발명의 풀무치 에탄올 추출물을 처리함에 따라 감소함을 확인하였다. TRAP, NFATc1 및 CathepsinK의 경우 풀무치 에탄올 추출물 처리에 의해 발현량이 농도의존적으로 감소하였다. 상기 결과를 통해, 본 발명의 풀무치 에탄올 추출물은 파골세포의 분화를 효과적으로 억제함을 확인하였다.As shown in Figure 3, it was confirmed that the gene expression of TRAP, RANK, NFATc1 and CathepsinK increased by the RANKL treatment decreased as the ethanol extract of the present invention was treated. In the case of TRAP, NFATc1, and CathepsinK, the expression levels were decreased in a concentration-dependent manner by treatment with ethanol extract of Pulmuchi. Through the above results, it was confirmed that the ethanol extract of pulmuchi of the present invention effectively inhibits the differentiation of osteoclasts.
3-3. 파골세포 분화 관련 단백질 발현 측정3-3. Measurement of protein expression related to osteoclast differentiation
본 발명에 따른 풀무치 에탄올 추출물이 파골세포 분화와 관련된 NFATc1 및 c-Src 단백질 발현에 미치는 영향을 확인하였다. 구체적으로, Raw 264.7 세포를 1 x 104 cells/웰의 농도로 48-웰 플레이트에 시딩하고, 100 ng/mL RANKL과 시료로써 본 발명의 풀무치 에탄올 추출물을 농도 별로(0, 100, 500, 1000, 2000 μg/mL) 처리하여 5일 동안 37℃ 배양기에서 배양하였다. 배양완료된 세포를 회수하고 단백질을 추출하여 웨스턴 블랏을 수행하였다. 그 결과를 도 4에 나타내었다.It was confirmed the effect of the ethanol extract of Pulmuchi according to the present invention on the expression of NFATc1 and c-Src proteins related to osteoclast differentiation. Specifically, Raw 264.7 cells were seeded in a 48-well plate at a concentration of 1 x 10 4 cells/well, and 100 ng/mL RANKL and the ethanol extract of the present invention as a sample were prepared by concentration (0, 100, 500, 1000). , 2000 μg/mL) and cultured in an incubator at 37° C. for 5 days. The cultured cells were recovered, proteins were extracted, and Western blot was performed. The results are shown in FIG. 4.
도 4에 나타낸 바와 같이, RANKL 처리 시 증가한 NFATc1 및 c-Src 단백질 발현량이 본 발명의 풀무치 에탄올 추출물 처리에 의해 감소함을 확인하였다. NFATc1의 경우 풀무치 에탄올 추출물 처리에 의해 단백질 발현량이 농도의존적으로 감소하였다. 상기 결과를 통해, 본 발명의 풀무치 에탄올 추출물은 파골세포의 분화를 효과적으로 억제함을 확인하였다.As shown in FIG. 4, it was confirmed that the amount of NFATc1 and c-Src protein expression increased during RANKL treatment was decreased by the treatment with the ethanol extract of Pulmuchi of the present invention. In the case of NFATc1, the protein expression level was decreased in a concentration-dependent manner by the treatment with ethanol extract of Pulmuchi. Through the above results, it was confirmed that the ethanol extract of pulmuchi of the present invention effectively inhibits the differentiation of osteoclasts.
3-4. 파골세포 분화 관련 3-4. Related to osteoclast differentiation 시그널링Signaling 단백질 발현 측정 Protein expression measurement
본 발명에 따른 풀무치 에탄올 추출물이 파골세포 분화와 관련된 MAPK 신호전달 관련 단백질(ERK, JNK) 및 NF-κ신호전달인자의 발현에 미치는 영향을 확인하였다. 구체적으로, 100 ng/mL RANKL과 농도별 풀무치 에탄올 추출물(0, 100, 500, 1000, 2000 μg/mL) 처리에 따른 MAPK 신호전달경로 및 NF-κ 신호전달경로 관련 단백질의 활성화를 확인하기 위하여, ERK(extracellular signal-regulated protein kinase) 단백질, JNK(Jun-N-terminal kinase) 단백질, p-38 및 IκB 단백질의 인산화를 각각 관찰하였다. 그 결과를 도 5에 나타내었다.The effect of the ethanol extract of pulmuchi according to the present invention on the expression of MAPK signaling related proteins (ERK, JNK) and NF-κ signaling factors related to osteoclast differentiation was confirmed. Specifically, in order to confirm the activation of proteins related to the MAPK signaling pathway and the NF-κ signaling pathway by treatment with 100 ng/mL RANKL and Pulmuchi ethanol extract (0, 100, 500, 1000, 2000 μg/mL) by concentration , Phosphorylation of extracellular signal-regulated protein kinase (ERK) protein, Jun-N-terminal kinase (JNK) protein, p-38 and IκB protein was observed, respectively. The results are shown in FIG. 5.
도 5에 나타낸 바와 같이, 본 발명의 풀무치 에탄올 추출물은 ERK, JNK 및 IκB 활성의 감소를 유발함을 확인하였다. 상기 결과를 통해, 본 발명의 풀무치 에탄올 추출물은 파골세포 분화의 신호전달과정을 억제할 수 있음을 확인하였다.As shown in Figure 5, it was confirmed that the ethanol extract of pulmuchi of the present invention induces a decrease in ERK, JNK and IκB activities. Through the above results, it was confirmed that the ethanol extract of pulmuchi of the present invention can inhibit the signal transduction process of osteoclast differentiation.
따라서, 파골세포 분화를 억제하는 풀무치 에탄올 추출물을 유효성분으로 포함하여, 천연물로 세포독성을 나타내지 않으면서도 파골세포 분화 활성을 현저하게 억제시킬 수 있어 골형성 촉진, 골소실 또는 골 대사 불균형으로 인한 골질환의 효과적인 예방 및 치료를 위한 약학적 조성물 또는 건강기능식품으로 유용하게 사용될 수 있다.Therefore, by including velumucci ethanol extract that inhibits osteoclast differentiation as an active ingredient, it can significantly inhibit osteoclast differentiation activity without showing cytotoxicity as a natural product, thereby promoting bone formation, bone loss, or bone due to bone metabolism imbalance. It can be usefully used as a pharmaceutical composition or health functional food for effective prevention and treatment of diseases.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is clear that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto. Accordingly, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.
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| KR100835214B1 (en) * | 2006-09-01 | 2008-06-09 | 재단법인 제주하이테크산업진흥원 | Anomala albopilosa extracts having anti-oxidant activity and bone metabolism factor inhibition activity |
| JP2015047076A (en) * | 2013-08-29 | 2015-03-16 | 独立行政法人産業技術総合研究所 | Cell culture substrate, method for differentiation-inducing of osteoblasts using the same and method for producing osteoblasts |
| KR20160041110A (en) * | 2014-10-06 | 2016-04-18 | 대한민국(농촌진흥청장) | Composition for Prevention or Treatment of Rheumatoid Arthritis Comprising extract suspension of Tenebrio molitor |
| KR101806474B1 (en) * | 2016-10-25 | 2017-12-07 | 순천향대학교 산학협력단 | A composition for improving, preventing and treating of bone diseases comprising Tenebrio molitor extract |
| KR102185436B1 (en) * | 2018-10-25 | 2020-12-01 | 대한민국 | Composition comprising Locusta migratoria extract for promoting osteoblast differentiation |
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| KR100835214B1 (en) * | 2006-09-01 | 2008-06-09 | 재단법인 제주하이테크산업진흥원 | Anomala albopilosa extracts having anti-oxidant activity and bone metabolism factor inhibition activity |
| JP2015047076A (en) * | 2013-08-29 | 2015-03-16 | 独立行政法人産業技術総合研究所 | Cell culture substrate, method for differentiation-inducing of osteoblasts using the same and method for producing osteoblasts |
| KR20160041110A (en) * | 2014-10-06 | 2016-04-18 | 대한민국(농촌진흥청장) | Composition for Prevention or Treatment of Rheumatoid Arthritis Comprising extract suspension of Tenebrio molitor |
| KR101806474B1 (en) * | 2016-10-25 | 2017-12-07 | 순천향대학교 산학협력단 | A composition for improving, preventing and treating of bone diseases comprising Tenebrio molitor extract |
| KR102185436B1 (en) * | 2018-10-25 | 2020-12-01 | 대한민국 | Composition comprising Locusta migratoria extract for promoting osteoblast differentiation |
Non-Patent Citations (1)
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| 풀무치 에탄올 추출물이 MG-63 조골세포 분화에 미치는 영향, 한국생명과학회 생명과학회지 28(12), 2018.12, 1448-1454. |
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