KR101544514B1 - Composion for Treating Diabetes Containing Isoprenoid From Phytonchid - Google Patents
Composion for Treating Diabetes Containing Isoprenoid From Phytonchid Download PDFInfo
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- KR101544514B1 KR101544514B1 KR1020150031544A KR20150031544A KR101544514B1 KR 101544514 B1 KR101544514 B1 KR 101544514B1 KR 1020150031544 A KR1020150031544 A KR 1020150031544A KR 20150031544 A KR20150031544 A KR 20150031544A KR 101544514 B1 KR101544514 B1 KR 101544514B1
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- KR
- South Korea
- Prior art keywords
- present
- phytoncide
- acid
- isoprenoid
- ampk
- Prior art date
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Abstract
본 발명은 피톤치드 유래의 이소프레노이드를 유효성분으로 함유하는 당뇨병 치료용 조성물에 관한 것으로, 더욱 자세하게는 피톤치드 유래 성분인 미르센(myrcene), α-카디놀(α-cardinol) 또는 사비넨(sabinene)을 유효성분으로 함유하는 당뇨병 치료용 조성물에 관한 것이다.
본 발명에서는 천연성분인 피톤치드에 함유된 이소프레노이드의 당뇨병 치료효과를 확인하였으며, 본 발명에 따르면 포도당 흡수율과 AMPK 조절능이 뛰어나, 당뇨병 치료효과를 기대할 수 있는 피톤치드 유래 이소프레노이드를 유효성분으로 함유하는 당뇨병 치료제 또는 당뇨병 예방용 건강기능 식품을 제공하는 효과가 있다.The present invention relates to a composition for the treatment of diabetes mellitus comprising isoprenoid derived from phytoncide as an active ingredient and more particularly to a composition for treating diabetes mellitus comprising a phytoncide-derived component myrcene,? -Cardinol or sabinene ) As an active ingredient.
In accordance with the present invention, it has been confirmed that isoprenoid contained in phytoncide, which is a natural ingredient, is effective for treating diabetes. According to the present invention, phytoncide-derived isoprenoid, which is excellent in glucose uptake and AMPK modulating ability, A diabetic therapeutic agent or a diabetic health functional food.
Description
본 발명은 피톤치드 유래의 이소프레노이드를 유효성분으로 함유하는 당뇨병 치료용 조성물에 관한 것으로, 더욱 자세하게는 피톤치드 유래 성분인 미르센(myrcene), α-카디놀(α-cardinol) 또는 사비넨(sabinene)을 유효성분으로 함유하는 당뇨병 치료용 조성물에 관한 것이다.
The present invention relates to a composition for the treatment of diabetes mellitus comprising isoprenoid derived from phytoncide as an active ingredient and more particularly to a composition for treating diabetes mellitus comprising a phytoncide-derived component myrcene,? -Cardinol or sabinene ) As an active ingredient.
피톤치드(phytoncide)란 식물이 해충이나 미생물로부터 자신을 방어하기 위하여 만들어 내는 살균성 물질의 총칭이다. 피톤치드의 주요성분은 이소프레노이드(isoprenoid 또는 terpene) 류 화합물로 이들은 독특한 방향성을 가지며, 심폐기능 강화, 혈관기능 강화, 호흡기 강화 및 피부살균 작용 등 여러가지 산림욕 효과에 가장 크게 기여하는 물질이라고 알려져 있다.Phytoncide (phytoncide) is a generic term for bactericidal substances that plants produce to protect themselves from pests and microorganisms. The major components of phytoncide are isoprenoids (isoprenoid or terpene) -like compounds, which have a unique orientation and are known to be the most important contributors to various forest-fighting effects such as cardiopulmonary strengthening, vascular strengthening, respiratory strengthening and skin sterilization.
이소프레노이드는 다수의 이소프렌(isoprene, C5H8)이 결합하여 이루어진 탄화수소의 일종으로 이소프렌이 2개, 3개 또는 4개인 모노 테르펜, 세스 퀴테르펜, 디테르펜 등이 있으며, 식물은 일반적으로 태양에너지의 광합성작용을 통하여 0.01∼5％ 가량의 테르펜을 합성한다. 일반적으로 이소프레노이드는 수증기 증류법, 압착법 또는 추출법을 통하여 정유(essential oil)의 형태로 얻어진다.Isoprenoid is a kind of hydrocarbon composed of isoprene (C 5 H 8 ) combined with many isotopes, and monoterpene, sesquiterpene, diterpene and the like having 2, 3 or 4 isoprene, Through the photosynthesis of solar energy, about 0.01 to 5% of terpenes are synthesized. In general, isoprenoids are obtained in the form of essential oils via steam distillation, compression or extraction.
피톤치드의 방출량과 그에 함유된 성분은 수목마다 다르며 침엽수는 활엽수에 비해 두배 이상의 피톤치드를 발산하는 것으로 알려져 있다.The amount of phytoncide emitted and its contents vary from tree to tree, and coniferous trees are known to radiate phytoncide more than twice as large as broad-leaved trees.
피톤치드는 인간에게 사용할 경우 스트레스 완화, 항균, 소취 및 유해물질 중화, 진정작용 및 쾌적효과, 알레르기 및 피부질환 개선 그리고 면역기능 증대 등의 효과를 발휘하므로, 오늘날과 같이 각종 오염 및 스트레스에 시달리는 현대인에게는 무엇보다 그 활용이 기대되고 있는 물질이다.Phytoncide is used in humans, and it is effective in relieving stress, neutralizing antioxidants, deodorizing and harmful substances, improving sedative and pleasant effects, improving allergies and skin diseases, and enhancing immune function. Above all, it is a substance that is expected to be used.
그리하여, 이러한 피톤치드의 효과를 인간생활에 적용하고자 하는 노력들이 잇달아 왔으나, 이는 주로 공기정화기, 휘산기와 같은 분야에 한정되어 왔다[실용신안등록 제 280014호, 제 289673호, 제 265617호, 제 216086호, 특허등록 제383911호, 제 375889호]. 또한, 피톤치드의 성분 중 미르센(myrcene)의 경우는 인진쑥 추출물의 성분에도 포함되어 있는 것으로 알려져 있으나, 미르센의 항당뇨 효과에 대하여는 알려져 있지 않디(대한민국 특허공개 10-2005-0092974).Thus, efforts have been made to apply the effect of phytoncide to human life, but this has been limited mainly to such fields as air purifier and vaporizer [Utility Model Registration No. 280014, No. 289673, No. 265617, No. 216086 , Patent No. 383911, No. 375889]. In addition, myrcene among phytoncide components is known to be contained in the components of Artemisia sp. Extract, but the antidiabetic effect of myrcene is not known (Korean Patent Laid-open Publication No. 10-2005-0092974).
이에, 본 발명자들은 피톤치드에 함유된 이소프레노이드에 함유된 성분이 직접적으로 질병치료효과를 가지는지 확인하기 위하여 예의 노력한 결과, 피톤치드에 함유된 이소프레노이드가 근육세포주에서 AMPK 활성을 조절하여 혈당강하효과를 나타내는 것을 확인하고 본 발명을 완성하게 되었다.
Accordingly, the present inventors have made intensive efforts to confirm whether the ingredient contained in the isoprenoid contained in the phytoncide directly has a therapeutic effect on the disease. As a result, it has been found that the isoprenoid contained in the phytoncide regulates the AMPK activity in the muscle cell line, And the present invention has been completed.
본 발명의 목적은 피톤치드 유래 이소프레노이드를 유효성분으로 함유하는 당뇨병 치료용 조성물을 제공하는데 있다.It is an object of the present invention to provide a composition for treating diabetes comprising phytoncide-derived isoprenoid as an active ingredient.
본 발명의 목적은 피톤치드 유래 이소프레노이드를 유효성분으로 함유하는 당뇨병 예방용 건강기능 식품을 제공하는데 있다.
It is an object of the present invention to provide a health functional food for diabetes prevention comprising phytoncide-derived isoprenoid as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 화학식 1로 표시되는 α-카디놀(α- cardinol) 또는 그의 염을 유효성분으로 함유하는 당뇨병 치료용 조성물 또는 당뇨병 예방용 건강기능식품을 제공한다:In order to achieve the above object, the present invention provides a composition for treating diabetes or a diabetic health functional food comprising? -Cardinol or a salt thereof represented by the general formula (1) as an active ingredient:
본 발명은 또한, 화학식 2로 표시되는 사비넨(sabinene) 또는 그의 염을 유효성분으로 함유하는 당뇨병 치료용 조성물 또는 당뇨병 예방용 건강기능식품을 제공한다:The present invention also provides a composition for treating diabetes or a diabetic health functional food comprising sabinene or a salt thereof represented by the general formula (2) as an active ingredient:
본 발명은 또한, 화학식 3으로 표시되는 미르센(myrsene) 또는 그의 염을 유효성분으로 함유하는 당뇨병 치료용 조성물 또는 당뇨병 예방용 건강기능식품을 제공한다:The present invention also provides a composition for treating diabetes mellitus or a dietary supplement health food containing myrsene or a salt thereof as an active ingredient:
본 발명에서는 천연성분인 피톤치드에 함유된 이소프레노이드의 당뇨병 치료효과를 확인하였으며, 본 발명에 따르면 포도당 흡수율과 AMPK 조절능이 뛰어나, 당뇨병 치료효과를 기대할 수 있는 피톤치드 유래 이소프레노이드를 유효성분으로 함유하는 당뇨병 치료제 또는 당뇨병 예방용 건강기능 식품을 제공하는 효과가 있다.
In accordance with the present invention, it has been confirmed that isoprenoid contained in phytoncide, which is a natural ingredient, is effective for treating diabetes. According to the present invention, phytoncide-derived isoprenoid, which is excellent in glucose uptake and AMPK modulating ability, A diabetic therapeutic agent or a diabetic health functional food.
도 1은 피톤치드 유래 13종의 이소프레노이드 처리에 따른 근육세포의 포도당 흡수율을 나타낸 그래프이다.
도 2는 α-카디놀(α-cardinol)의 당조절 효과를 나타낸 것이다.
도 3은 사비넨(sabinene)의 당조절 효과를 나타낸 것이다.
도 4는 미르센(myrcene)의 당조절 효과를 나타낸 것이다.FIG. 1 is a graph showing glucose uptake of muscle cells following treatment with isoprenoid of 13 phytoncide-derived isoprenoids.
Figure 2 shows the tonic effect of alpha-cardinol.
Figure 3 shows the tonic effect of sabinene.
Figure 4 shows the tonic effect of myrcene.
일 관점에서, 본 발명은 화학식 1로 표시되는 α-카디놀(α- cardinol) 또는 그의 염을 유효성분으로 함유하는 당뇨병 치료용 조성물 또는 당뇨병 예방용 건강기능식품에 관한 것이다:In one aspect, the present invention relates to a composition for treating diabetes or a diabetic health functional food containing? -Cardinol or a salt thereof represented by the formula (1) as an active ingredient:
[화학식 1 ][Chemical Formula 1]
α-카디놀(α- cardinol)은 피톤치드 유래의 이소프레노이드의 일종으로, 본 발명의 일양태에 의하면, α-카디놀(α- cardinol)을 10μM 농도로 처리한 근육세포에서 포도당 흡수율이 증가되었으며, 생체내 항상성을 조절하는 주요 단백질인 AMPK의 인산화를 증가시키는 역할을 하는 것을 확인하였다. The α-cardinol is a kind of isoprenoid derived from phytoncide. According to one embodiment of the present invention, the glucose absorption rate is increased in muscle cells treated with α-cardinol at a concentration of 10 μM And increased the phosphorylation of AMPK, a major protein that regulates in vivo homeostasis.
본 발명에서 상기 α-카디놀의 염(salt)으로는 약리학적으로 허용되는 염이라면 특별히 제한되지는 않으며, 상기 약리학적으로 허용되는 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있다. 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산 (아스피린)과 같은 유기산과 함께 약리학적으로 허용 가능한 산의 염을 형성하거나, 또는 소듐, 포타슘 등의 알칼리 금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약리학적으로 허용 가능한 염을 형성할 수 있다.In the present invention, the salt of? -Cadinol is not particularly limited as long as it is a pharmacologically acceptable salt, and the pharmacologically acceptable salt can be prepared by a conventional method in the art. For example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogenphosphate, phosphoric acid and carbonic acid, or salts with inorganic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, Salicylic acid, or an organic acid such as acetylsalicylic acid (aspirin) to form a salt of a pharmacologically acceptable acid, or react with an alkali metal ion such as sodium, potassium or the like to form a metal salt thereof, Ion to form another form of the pharmacologically acceptable salt.
다른 관점에서, 본 발명은 화학식 2로 표시되는 사비넨(sabinene) 또는 그의 염을 유효성분으로 함유하는 당뇨병 치료용 조성물 또는 당뇨병 예방용 건강기능식품에 관한 것이다:In another aspect, the present invention relates to a composition for treating diabetes comprising sabinene or a salt thereof represented by the general formula (2) as an active ingredient, or a health functional food for the prevention of diabetes:
[화학식 2](2)
사비넨(sabinene)은 피톤치드 유래의 이소프레노이드의 일종으로, 본 발명의 일양태에 의하면, 사비넨(sabinene)을 20μM 농도로 처리한 근육세포에서 포도당 흡수율이 증가되었으며, 생체내 항상성을 조절하는 주요 단백질인 AMPK의 인산화를 증가시키는 역할을 하는 것을 확인하였다. Sabinene is a kind of isoprenoid derived from phytoncide. According to one embodiment of the present invention, the absorption rate of glucose in muscle cells treated with sabinene at a concentration of 20 μM is increased, It was confirmed that it plays a role in increasing the phosphorylation of AMPK, a major protein.
본 발명에서 상기 사비넨(sabinene)의 염(salt)으로는 약리학적으로 허용되는 염이라면 특별히 제한되지는 않으며, 상기 약리학적으로 허용되는 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있다. 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산 (아스피린)과 같은 유기산과 함께 약리학적으로 허용 가능한 산의 염을 형성하거나, 또는 소듐, 포타슘 등의 알칼리 금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약리학적으로 허용 가능한 염을 형성할 수 있다.In the present invention, the salt of sabinene is not particularly limited as long as it is a pharmacologically acceptable salt, and the pharmacologically acceptable salt can be prepared by a method common in the art . For example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogenphosphate, phosphoric acid and carbonic acid, or salts with inorganic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, Salicylic acid, or an organic acid such as acetylsalicylic acid (aspirin) to form a salt of a pharmacologically acceptable acid, or react with an alkali metal ion such as sodium, potassium or the like to form a metal salt thereof, Ion to form another form of the pharmacologically acceptable salt.
또 다른 관점에서, 본 발명은 화학식 3으로 표시되는 미르센(myrsene) 또는 그의 염을 유효성분으로 함유하는 당뇨병 치료용 의약조성물 또는 당뇨병 예방용 건강기능식품에 관한 것이다:In another aspect, the present invention relates to a pharmaceutical composition for treating diabetes mellitus or a dietary supplement health food containing myrsene or a salt thereof as an active ingredient,
[화학식 3](3)
미르센(myrsene)은 피톤치드 유래의 이소프레노이드의 일종으로, 본 발명의 일양태에 의하면, 미르센(myrsene)을 10μM 농도로 처리한 근육세포에서 포도당 흡수율이 증가되었으며, 생체내 항상성을 조절하는 주요 단백질인 AMPK의 인산화를 증가시키는 역할을 하는 것을 확인하였다. Myrsene is a kind of isoprenoid derived from phytoncide. According to one embodiment of the present invention, glucose uptake is increased in muscle cells treated with 10 μM myrsene, It was confirmed that it plays a role in increasing the phosphorylation of AMPK, a major protein.
또한, 본 발명에서는 미르센(myrsene)에 의한 당섭취 반응에 p38MAPK와 CaMKK가 중요하게 관여하고 있는 것을 확인하였다.In addition, in the present invention, it was confirmed that p38MAPK and CaMKK are involved in glucose uptake by myrsene.
본 발명에서 상기 미르센(myrsene)의 염(salt)으로는 약리학적으로 허용되는 염이라면 특별히 제한되지는 않으며, 약리학적으로 허용되는 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있다. 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산 (아스피린)과 같은 유기산과 함께 약리학적으로 허용 가능한 산의 염을 형성하거나, 또는 소듐, 포타슘 등의 알칼리 금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약리학적으로 허용 가능한 염을 형성할 수 있다.In the present invention, the salt of myrsene is not particularly limited as long as it is a pharmacologically acceptable salt, and a pharmacologically acceptable salt can be prepared by a conventional method in the art. For example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogenphosphate, phosphoric acid and carbonic acid, or salts with inorganic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, Salicylic acid, or an organic acid such as acetylsalicylic acid (aspirin) to form a salt of a pharmacologically acceptable acid, or react with an alkali metal ion such as sodium, potassium or the like to form a metal salt thereof, Ion to form another form of the pharmacologically acceptable salt.
본 발명의 치료용 조성물은 약제학적으로 허용되는 담체를 추가로 포함할 수 있으며, 약제학적으로 허용되는 담체는 담체, 보조제 및 비히클을 포함하며 총괄적으로 “약제학적으로 허용되는 담체”라고 한다. 본 발명의 의약 조성물에 사용될 수 있는 약제학적으로 허용되는 담체로는 이들로 한정되는 것은 아니지만 이온 교환, 알루미나, 알루미늄 스테아레이트, 레시틴, 혈청 단백질(예, 사람 혈청 알부민), 완충 물질(예, 여러 인산염, 글리신, 소르브산, 칼륨 소르베이트, 포화 식물성 지방산의 부분적인 글리세라이드 혼합물), 물, 염 또는 전해질(예, 프로타민 설페이트, 인산수소이나트륨, 인산수소칼륨, 염화나트륨 및 아연 염), 교질성 실리카, 마그네슘 트리실리케이트, 폴리비닐 피롤리돈, 셀룰로즈-계 기질, 폴리에틸렌 글리콜, 나트륨 카르복시메틸셀룰로즈, 폴리아릴레이트, 왁스, 폴리에틸렌-폴리옥시프로필렌-차단 중합체, 폴리에틸렌 글리콜 및 양모지 등이 포함된다.The therapeutic composition of the present invention may further comprise a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier includes a carrier, adjuvant and vehicle and is collectively referred to as a " pharmaceutically acceptable carrier ". Pharmaceutically acceptable carriers that can be used in the medicinal compositions of the present invention include, but are not limited to, ion exchange, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances Water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicas such as glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, , Magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substrate, polyethylene glycol, sodium carboxymethyl cellulose, polyarylate, wax, polyethylene-polyoxypropylene-barrier polymer, polyethylene glycol and wool.
본 발명에 따른 의약 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 본 발명에서 사용된 용어 “비경구”는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입 기술을 포함한다. The route of administration of the pharmaceutical composition according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, Sublingual or rectal. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
의약 조성물은 멸균 주사용 수성 또는 유성 현탁액으로서 멸균 주사용 제제의 형태일 수 있다. 이 현탁액은 적합한 분산제 또는 습윤제(예, 트윈 80) 및 현탁화제를 사용하여 본 분야에 공지된 기술에 따라 제형될 수 있다. 멸균 주사용 제제는 또한 무독성의 비경구적으로 허용되는 희석제 또는 용매중의 멸균 주사용액 또는 현탁액(예, 1,3-부탄디올중의 용액)일 수 있다. 허용적으로 사용될 수 있는 비히클 및 용매로는 만니톨, 물, 링겔 용액 및 등장성 염화나트륨 용액이 있다. 또한, 멸균 불휘발성 오일이 통상적으로 용매 또는 현탁화 매질로서 사용된다. 이러한 목적을 위해, 합성 모노 또는 디글리세라이드를 포함하여 자극성이 적은 어떠한 불휘발성 오일도 사용할 수 있다. 올레산 및 이의 글리세라이드 유도체와 같은 지방산이 약제학적으로 허용되는 천연 오일(예, 올리브유 또는 피마자유), 특히 이들의 폴리옥시에틸화된 것과 마찬가지로 주사 제제에 유용하다.The pharmaceutical composition may be in the form of a sterile injectable preparation as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e. G., Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Vehicles and solvents that may be used tolerably include mannitol, water, a Ringgel solution and an isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil with low irritation, including synthetic mono- or diglycerides, may be used. Fatty acids such as oleic acid and glyceride derivatives thereof are useful in injection formulations as well as pharmaceutically acceptable natural oils (e.g., olive oil or castor oil), especially those polyoxyethylated.
본 발명의 의약 조성물은 이들로 한정되는 것은 아니지만 캡슐, 정제 및 수성 현탁액 및 용액을 포함하여 경구적으로 허용되는 어떠한 용량형으로도 경구 투여될 수 있다. 경구용 정제의 경우, 흔히 사용되는 담체로는 락토즈 및 옥수수 전분이 포함된다. 마그네슘 스테아레이트와 같은 윤활제가 또한 전형적으로 첨가된다. 캡슐형으로 경구 투여하는 경우 유용한 희석제로는 락토즈 및 건조된 옥수수 전분이 포함된다. 수성 현탁액이 경구 투여될 때 활성 성분은 유화제 및 현탁화제와 배합된다. 필요한 경우, 감미제 및/또는 풍미제 및/또는 착색제가 첨가될 수 있다.The pharmaceutical compositions of the present invention may be orally administered in any dosage form orally acceptable, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When the aqueous suspension is orally administered, the active ingredient is combined with an emulsifying agent and a suspending agent. If desired, sweetening and / or flavoring agents and / or coloring agents may be added.
본 발명의 의약 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다. 이들 조성물은 본 발명의 화합물을 실온에서 고형이지만 직장 온도에서는 액상인 적합한 비자극성 부형제와 혼합하여 제조할 수 있다. 이러한 물질로는 이들로 한정되는 것은 아니지만 코코아 버터, 밀랍 및 폴리에틸렌 글리콜이 포함된다.The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration. These compositions may be prepared by mixing the compounds of the invention with suitable non-polar excipients which are solid at room temperature but liquid at rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
본 발명에 따른 의약 조성물의 경구 투여는 목적하는 치료가 국소 적용으로 접근이 용이한 부위 또는 기관과 관련이 있을 때 특히 유용하다. 피부에 국소적으로 적용하는 경우, 의약 조성물은 담체에 현탁 또는 용해된 활성 성분을 함유한 적합한 연고로 제형되어야 한다. 본 발명의 화합물을 국소 투여하기 위한 담체로는 이들로 한정되는 것은 아니지만 광유, 유동 파라핀, 백색 와셀린, 프로필렌 글리콜, 폴리옥시에틸렌, 폴리옥시프로필렌 화합물, 유화 왁스 및 물이 포함된다. 다른 방도로서, 의약 조성물은 담체에 현탁 또는 용해된 활성 화합물을 함유한 적합한 로션 또는 크림으로 제형될 수 있다. 적합한 담체로는 이들로 한정되는 것은 아니지만 광유, 솔비탄 모노스테아레이트, 폴리솔베이트 60, 세틸 에스테르 왁스, 세테아릴 알코올, 2-옥틸도데카놀, 벤질 알코올 및 물이 포함된다. 본 발명의 의약 조성물은 또한 직장 좌제에 의해 또한 적합한 관장제로 하부 장관으로 국소 적용할 수 있다. 국소 적용된 경피 패치가 또한 본 발명에 포함된다.Oral administration of a pharmaceutical composition according to the present invention is particularly useful when the desired treatment is associated with a site or organ that is accessible by topical application. When topically applied to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in the carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may also be topically applied by rectal suppositories to the lower intestinal tract with a suitable enema. Topically applied transdermal patches are also included in the present invention.
본 발명의 의약 조성물은 비내 에어로졸 또는 흡입에 의해 투여할 수 있다. 이러한 조성물은 약제의 분야에 잘 알려진 기술에 따라 제조하며 벤질 알코올 또는 다른 적합한 보존제, 생체이용율을 증강시키기 위한 흡수 촉진제, 플루오로카본 및/또는 기타 본 분야에 알려진 가용화제 또는 분산제를 사용하여 염수중의 용액으로서 제조할 수 있다.The pharmaceutical composition of the present invention can be administered by inhalation aerosol or by inhalation. Such compositions may be prepared according to techniques well known in the art of pharmacy and may be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art, Solution.
본 발명의 조성물은 통상적인 항염증제와 혼합하거나 매트릭스 메탈로프로테아제 억제제, 리폭시게나제 억제제 및 IL-1β외의 사이토킨의 억제제와 혼합하여 사용할 수 있다. 본 발명의 조성물은 또한 염증과 같은 IL-1 매개된 질환 증세를 예방 또는 퇴치하기 위해 면역조절제(예, 브로피리민, 항-사람 알파 인터페론 항체, IL-2, GM-CSF, 메티오닌 엔케팔린, 인터페론 알파, 디에틸디티오카바메이트, 종양 괴사 인자, 날트렉손 및 rEPO) 또는 프로스타글란딘과 배합하여 투여할 수 있다. 본 발명의 조성물이 다른 치료 제제와 배합하여 투여될 때 이들은 환자에게 순차적으로 또는 동시에 투여될 수 있다. 다른 방도로서, 본 발명에 따른 의약 조성물은 일반식(1)의 화합물과 상기된 다른 치료 또는 예방제와 혼합하여 이루어질 수 있다.The composition of the present invention can be used in combination with a conventional anti-inflammatory agent or in combination with a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor and an inhibitor of cytokines other than IL-1beta. The compositions of the present invention may also be used in combination with immunomodulators (e.g., bropyrimines, anti-human alpha interferon antibodies, IL-2, GM-CSF, methionine enkephalin, interferon Alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) or prostaglandins. When the compositions of the present invention are administered in combination with other therapeutic agents, they may be administered to a patient sequentially or concurrently. Alternatively, the pharmaceutical composition according to the present invention may be prepared by mixing the compound of the general formula (1) with another therapeutic or prophylactic agent as described above.
용어 “치료학적 유효량”은 사람의 경우 상기 증세의 치료에 사용하기 위해 일일당 체중 kg 당 약 0.1 mg 내지 약 100 mg의 용량 수준을 가리킨다. The term " therapeutically effective amount " refers to a dosage level of from about 0.1 mg to about 100 mg per kg of body weight per day for use in the treatment of the condition in humans.
그러나, 특정 환자에 대한 특정 유효량은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 규정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 변할 수 있음은 이해될 것이다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다. It will be understood, however, that the specific effective amount for a particular patient will depend upon a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and severity of the particular disease It will be appreciated that it may vary depending on factors. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.
바람직한 양태로서, 구강내 투여를 위한 의약 조성물은 고체상의 부형제와 함께 활성 성분을 혼합함으로써 제조할 수 있으며 정제 또는 당의정 형태로 제조하기 위해 과립형태로 제조할 수 있다. 적합한 부형제로는 락토스, 수크로스, 만니톨 및 소비톨과 같은 슈가 형태 또는 옥수수, 밀가루, 쌀, 감자 또는 다른 식물로부터 전분, 메틸 셀룰로스, 하이드로시프로필메틸-셀룰로스 또는 나트륨 카복시메틸세룰로스와 같은 세룰로스, 아라빅 검, 타가칸쓰 검을 포함하는 검류와 같은 카보하이드레이트 또는 젤라틴, 콜라겐과 같은 단백질 필러를 사용할 수 있다. 필요한 경우에는, 교차결합된 폴리비닐피롤리돈, 아가 및 알긴산 또는 나트륨 알긴산과 같은 각각의 염 형태의 붕해제 또는 용해제를 첨가할 수 있다.In a preferred embodiment, the pharmaceutical compositions for oral administration can be prepared by mixing the active ingredients together with solid excipients and may be prepared in the form of granules for preparation in the form of tablets or dragees. Suitable excipients include sugars such as lactose, sucrose, mannitol and sorbitol or starches from corn, wheat flour, rice, potato or other plants, cellulose such as methylcellulose, hydrocyclopropylmethylcellulose or sodium carboxymethylcellulose , Arabic gum, carbohydrates such as gum including Tagakans gum, or protein fillers such as gelatin and collagen. If necessary, disintegrating or solubilizing agents in the form of respective salts such as cross-linked polyvinylpyrrolidone, agar and alginic acid or sodium alginic acid may be added.
바람직한 양태로서, 비경구적 투여의 경우 본 발명의 의약 조성물은 수용성 용액으로 제조할 수 있다. 바람직하게는, 한스 용액 (Hank's solution), 링거 용액 (Ringer's solution) 또는 물리적으로 완충된 염수와 같은 물리적으로 적절한 완충용액을 사용할 수 있다. 수용성 주입 (injection) 현탁액은 소디움 카복시메틸 셀루로스, 솔비톨 또는 덱스트란과 같이 현탁액의 점도를 증가시킬 수 있는 기질을 첨가할 수 있다. 덧붙여서, 활성 성분의 현탁액은 적합한 유질의 주입 현탁액 (oily injection suspensions)으로 제조될 수 있다. 적합한 친지성 용매 또는 담체는 참기름과 같은 지방산 또는 에틸 올레이트, 트리글리세라이드 또는 리포솜과 같은 합성 지방산 에스테르를 포함한다. 복수양이온성 비지질 아미노 폴리머(polycationic amino polymers)도 운반체로서 사용될 수 있다. 임의로, 현탁액은 화합물의 용해도를 증가시키고 고농도의 용액을 제조하기 위해 적합한 안정화제 또는 약제를 사용할 수 있다.In a preferred embodiment, for parenteral administration, the pharmaceutical composition of the present invention can be prepared as a water-soluble solution. Preferably, physically suitable buffer solutions such as Hank's solution, Ringer's solution or physically buffered saline can be used. Water-soluble injection suspensions may contain a substrate capable of increasing the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. In addition, suspensions of the active ingredient may be prepared in suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty acids such as sesame oil or synthetic fatty acid esters such as ethyl oleate, triglycerides or liposomes. Polycationic amino polymers can also be used as carriers. Optionally, the suspension may employ a suitable stabilizing agent or agent to increase the solubility of the compound and to produce a high concentration of solution.
본 발명의 건강기능 식품은 당뇨 예방을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 건강기능 식품은, 예를 들어, 각종 식품류, 캔디, 초콜릿, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The health functional food of the present invention can be used variously for medicine, food and beverage for prevention of diabetes. The health functional food of the present invention can be used in the form of powder, granule, tablet, capsule or beverage, for example, various foods, candy, chocolate, beverage, gum, tea, vitamin complex, .
본 발명의 상기 조성물은 당뇨 및 비만 예방을 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 조성물의 양은 일반적으로 본 발명의 건강 기능 식품 조성물은 전체 식품 중량의 0.01 내지 50 중량%, 바람직하게는 0.1 내지 20 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다. The composition of the present invention may be added to foods or beverages for the purpose of preventing diabetes and obesity. At this time, the amount of the composition in food or beverage is generally 0.01 to 50% by weight, preferably 0.1 to 20% by weight, of the total food weight of the health functional food composition of the present invention, and 100% In a proportion of 0.02 to 10 g, preferably 0.3 to 1 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health beverage composition of the present invention has no particular limitation on the liquid ingredient other than the above-mentioned extract as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose, polysaccharides such as maltose, sucrose and the like, such as dextrin, cyclodextrin and the like And sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and aging agents (cheese, chocolate etc.), pectic acid and its salts, , Organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
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 당업게에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예 1: 피톤치드 유래 이소프레노이드의 포도당 흡수 시험Example 1: Glucose uptake test of phytoncide-derived isoprenoid
피톤치드 유래의 이소프레노이드로 알려져 있는 a-cardinol(propranololhydrochloride), hinokitiol(b-thujaplicin), borneol, menthol, Tricyclenee, camphene, sabinene(sabinene hydrate), myrcene, camphore, Thymol(r-cymene-3-ol), cedrol, b-eudesmol 및 globulol를 사용하여, 근육세포의 포도당 흡수 시험을 수행하였다(Sigma Aldrich; Calbiochem).A-cardinol (propranololhydrochloride), hinokitiol (b-thujaplicin), borneol, menthol, Tricyclenee, camphene, sabinene hydrate, myrcene, camphore, thymol (r-cymene-3-ol ), cedrol, b-eudesmol and globulol were used to conduct glucose uptake tests of muscle cells (Sigma Aldrich; Calbiochem).
L6 근육전구세포(ATCC CRL1458) 를 12 웰 플레이트에 분주한 후 2% FBS가 들어 있는 DMEM 배지에서 근육세포로 분화시켰다. 근육세포에 상기 피톤치드 유래 이소프레노이드를 각각 20μM 농도로 처리하고, 37℃에서 1시간 동안 배양한 후, 각 well에 포도당 유도체 2-DOG(2-deoxy-[3H]-D-glucose 100) 100μM을 15분간 처리한 후 PBS 버퍼로 2회 세척 후 건조시켰다. 용해버퍼(Lysis buffer; 0.5N NaOH + 0.5% SDS)를 웰 당 500μL씩 넣어 세포를 용해시킨 후 500μL씩 LSC 바이알에 옮겨 1mL의 cocktail(Ultimagold)과 혼합 후 β-counter로 측정하였다.L6 muscle precursor cells (ATCC CRL1458) were dispensed into 12-well plates and then differentiated into muscle cells in DMEM medium containing 2% FBS. The muscle cells were treated with the above-mentioned phytoncide-derived isoprenoids at a concentration of 20 μM and cultured at 37 ° C. for 1 hour. Then, 2-DOG (2-deoxy- [ 3 H] 100 μM for 15 minutes, washed twice with PBS buffer, and then dried. The cells were lysed by adding 500 μL of lysis buffer (0.5 N NaOH + 0.5% SDS) per well, and transferred to LSC vials in 500 μL each, mixed with 1 mL of cocktail (Ultimagold), and then measured with a β-counter.
그 결과, 도 1에 나타난 바와 같이, 포도당 흡수가 증가되는 경향성을 보이는 물질 5종류(camphene, myrcene, sabinene, alpha-cardinol, borneol) 이 확인되었다.
As a result, as shown in Fig. 1, five kinds of substances (camphene, myrcene, sabinene, alpha-cardinol, borneol) showing tendency to increase glucose uptake were confirmed.
실시예 2: 피톤치드 유래 이소프레노이드가 AMPK 단백질 인산화에 미치는 영향 확인 Example 2: Confirmation of effect of phytoncide-derived isoprenoid on AMPK protein phosphorylation
피톤치드 유래 이소프레노이드에 의해 생체 내 항상성 조절 주요단백질인 AMPK의 인산화가 활성화되어지는지 확인하였다.It was confirmed by phytoncide-derived isoprenoid that the phosphorylation of AMPK, the major protein for regulating the homeostasis in vivo, was activated.
C2C12 근육세포(ATCC CRL1772)와 MCF7 유방암 세포(ATCC HTB-22)에 피톤치드 유래의 이소프레노이드 a-cardinol(propranololhydrochloride), hinokitiol(b-thujaplicin), borneol, menthol, Tricyclenee, camphene, sabinene(sabinene hydrate), myrcene, camphore, Thymol(r-cymene-3-ol), cedrol, b-eudesmol 및 globulol를 각각 10μM 농도로 한시간 동안 처리하고 cell lysate를 취하여, AMPK 인산화 항체를 사용하여 웨스턴 블럿을 수행하였다.The isoprenoids derived from phytoncide, propranololhydrochloride, hinokitiol (b-thujaplicin), borneol, menthol, Tricyclenee, camphene, sabinene (sabinene hydrate) were added to C2C12 muscle cells (ATCC CRL1772) and MCF7 breast cancer cells ), myrcene, camphore, thymol (r-cymene-3-ol), cedrol, b-eudesmol and globulol were each treated at a concentration of 10 μM for one hour and cell lysate was taken and Western blot was performed using AMPK phosphorylated antibody.
그 결과, 표 1에 나타난 바와 같이, 상기 사용한 13개 이소프레노이드를 처리하였을때, 근육세포 또는 유방암 세포에서 AMPK 단백질의 발현이 활성화되는 거을 확인하였다. 이는 피톤치드 유래 이소프레노이드에 의하여 AMPK활성을 조절하여 각 세포에서 생체 내 항상성 유지에 관여할 수 있음을 의미한다. As a result, as shown in Table 1, when the above-mentioned 13 isoprenoids were treated, it was confirmed that the expression of AMPK protein was activated in muscle cells or breast cancer cells. This means that AMPK activity can be regulated by phytoncide-derived isoprenoid, and thus it can participate in the maintenance of homology in vivo in each cell.
Isoprenoid
(▲:강, =:약 및 X: no)
(▲: strong, =: approx. And X: no)
실시예 3: a-cardinol의 혈당조절능력 확인Example 3: Confirmation of the ability of a-cardinol to regulate blood glucose
*3-1: 포도당 섭취능 증가 * 3-1: Increased glucose uptake ability
α-카디놀(α-cardinol)의 혈당조절 능력을 검증하기 위해 분화된 근육세포주를 이용해서 α-카디놀을 처리하여 당 섭취 능력이 증가되는 패턴을 비교, 분석하고, 당뇨 치료제로서의 생물학적 가능성 확인하였다.In order to verify the ability of α-cardinol to regulate blood glucose, α-cardinol was treated with differentiated muscle cell lines to compare and analyze patterns of increased glucose uptake ability. Respectively.
L6 근육전구세포(ATCC CRL1458)를 12 웰 플레이트에 분주한 후 2% FBS가 들어 있는 DMEM 배지에서 근육세포로 분화시켰다. 근육세포에 α-카디놀을 10μM 농도로 60분 처리 후 포도당 유도체 2-DOG(2-deoxy-[3H]-D-glucose 100)를 100μM를 15분간 처리한 후, PBS 버퍼로 2회 세척 후 건조시켰다. Lysis buffer (0.5N NaOH + 0.5% SDS)를 well 당 500μL씩 넣어 세포를 용해시킨 후 450μL씩 LSC 바이알에 옮겨 1mL의 cocktail(Ultimagold, 미국)과 혼합 후 β-counter로 측정하였다.L6 muscle precursor cells (ATCC CRL1458) were dispensed into 12-well plates and then differentiated into muscle cells in DMEM medium containing 2% FBS. The muscle cells were treated with α-cardinol at a concentration of 10 μM for 60 minutes, treated with 100 μM of the glucose derivative 2-DOG (2-deoxy- [ 3 H] -D-glucose 100) for 15 minutes, washed twice with PBS buffer And then dried. Lysis buffer (0.5 N NaOH + 0.5% SDS) was added to 500 μL of each well to dissolve the cells. 450 μL of each solution was transferred to LSC vials, mixed with 1 mL of cocktail (Ultimagold, USA) and then measured by β-counter.
그 결과, 도 2의 A에 나타난 바와 같이, 근육세포의 당 섭취 능력이 α-카디놀 처리에 의해 증가하는 것을 확인하였으며, 이것은 α-카디놀이 당 조절 능력을 가지고 있음을 보여주는 것이다.
As a result, as shown in Fig. 2A, it was confirmed that the sugar-consuming ability of the muscle cells was increased by the? -Cardinol treatment, showing that the? -Cadinol had the ability to regulate the sugar.
3-2: AMPK 활성화3-2: Activation of AMPK
α-카디놀에 의하여, 당 조절 능력을 가지고 있다고 알려진 AMPK,의 활성화 여부를 확인하기 위하여, 칼슘 인식 색소인 Fluo-3를 이용해서 confocal microscope를 이용하여 직접 세포내 칼슘 농도의 변화를 확인하였다.In order to confirm the activation of AMPK, which is known to have the ability to regulate glucose, α-cardinol, a change in intracellular calcium concentration was confirmed using a confocal microscope using Fluo-3, a calcium recognition dye.
C2C12 근육세포(ATCC CRL1772)를 35-mm 디쉬에 분주한 후 하루 동안 10% FBS가 들어 있는 DMEM 배지에서 배양하여 안정화시켰다. Fluo-3 시약(Invitrogen, 미국)을 45분간 전처리 한후, confocal microscope하에서 α-카디놀을 10 uM 농도로 처리한 후 실시간으로 칼슘 농도의 변화를 관찰하였다. C2C12 muscle cells (ATCC CRL1772) were placed in a 35-mm dish and cultured in DMEM medium containing 10% FBS for one day to stabilize. Fluo-3 reagent (Invitrogen, USA) was pretreated for 45 min. After treatment with α-cardinol at a concentration of 10 μM under confocal microscope, changes in calcium concentration were observed in real time.
그 결과, 도 2의 B에 나타난 바와 같이, 형광의 색깔(녹색)의 밝기 정도가 세포내 칼슘 농도를 대변하고 있으며, α-카디놀을 처리한 군에서 처리 후에 대조군에 비해 형광의 세기가 밝아지는 것으로 확인되었으며, 이는 α-카디놀이 근육세포내 칼슘 농도를 증가시키는 것이며, 이는 α-카디놀이 세포내 증가를 통해 활성화되는 CaMKK를 통해 당 조절 물질인 AMPK의 활성을 유도한다는 것을 의미한다.
As a result, as shown in Fig. 2B, the degree of brightness of the fluorescence color (green) represents the intracellular calcium concentration, and the fluorescence intensity of the? -Cadinol-treated group was greater than that of the control group , Which means that α-cardinol increases
3-3: AMPK 활성의 증가3-3: Increase of AMPK activity
당 조절 능력을 가지고 있다고 알려진 AMPK의 활성이 α-카디놀 처리에 의해 증가하는지를 확인하기 위하여, C2C12 세포에 α-카디놀을 0~100μM 농도로 농도별로 1시간 동안 처리한 후, AMPK의 인산화 및 그 하위 물질인 ACC의 인산화를 웨스턴 블럿을 통하여 동시에 확인하였다. To confirm whether the activity of AMPK, which is known to have the ability to regulate glucose, is increased by treatment with alpha -cadinol, C2C12 cells are treated with alpha-cardinol at a concentration of 0-100 mu M per concentration for 1 hour, Phosphorylation of ACC, a sub-substance thereof, was simultaneously confirmed through western blotting.
그 결과, 도 2의 C에 나타난 바와 같이, α-카디놀에 의해서 혈당조절 주요단백질인 AMPK 및 ACC의 인산화가 증가되는 것이 관찰되었다. AMPK의 경우 3~10 μM 농도에서 최대 효과를 나타내었다. 이는 α-카디놀에 의한 당 섭취 능력이 AMPK활성에 의해 나타날 수 있음을 의미한다.
As a result, as shown in Fig. 2C, it was observed that the phosphorylation of AMPK and ACC, major glycoprotein proteins, was increased by a-cardinol. AMPK showed maximum effect at concentrations of 3 ~ 10 μM. This means that the sugar uptake ability by? -Cadinol can be shown by the AMPK activity.
실시예 4: 사비넨(Sabinene)의 혈당조절능력 확인Example 4: Confirmation of blood glucose control ability of Sabinene
4-1: 포도당 섭취능 증가4-1: Increased glucose uptake ability
사비넨(sabinene)의 혈당조절 능력을 검증하기 위해 분화된 근육세포주를 이용해서 사비넨(sabinene)을 처리하여 당 섭취 능력이 증가되는 패턴을 비교, 분석하고, 당뇨 치료제로서의 생물학적 가능성 확인하였다.To examine the ability of sabinene to regulate blood glucose, we compared the patterns of increased glucose uptake ability by treating sabinene using differentiated muscle cell lines and confirmed the biological potential as a diabetic therapeutic agent.
L6 근육전구세포(ATCC CRL1458)를 12 웰 플레이트에 분주한 후 2% FBS가 들어 있는 DMEM 배지에서 근육세포로 분화시켰다. 근육세포에 사비넨(sabinene)을 2~20μM 농도로 60분 처리 후 포도당 유도체 2-DOG(2-deoxy-[3H]-D-glucose 100)를 100μM를 15분간 처리한 후, PBS 버퍼로 2회 세척 후 건조시켰다. Lysis buffer (0.5N NaOH + 0.5% SDS)를 well 당 500μL씩 넣어 세포를 용해시킨 후 450μL씩 LSC 바이알에 옮겨 1mL의 cocktail(Ultimagold, 미국)과 혼합 후 β-counter로 측정하였다.L6 muscle precursor cells (ATCC CRL1458) were dispensed into 12-well plates and then differentiated into muscle cells in DMEM medium containing 2% FBS. After treating muscle cells with sabinene at a concentration of 2 to 20 μM for 60 minutes, 100 μM of the glucose derivative 2-DOG (2-deoxy- [ 3 H] -D-glucose 100) was treated for 15 minutes, Washed twice and dried. Lysis buffer (0.5 N NaOH + 0.5% SDS) was added to 500 μL of each well to dissolve the cells. 450 μL of each solution was transferred to LSC vials, mixed with 1 mL of cocktail (Ultimagold, USA) and then measured by β-counter.
그 결과, 도 3의 A에 나타난 바와 같이, 근육세포의 당 섭취 능력이 20μM 사비넨(sabinene) 처리에 의해 증가하는 것을 확인하였으며, 이것은 사비넨(sabinene)이 당 조절 능력을 가지고 있음을 보여주는 것이다.
As a result, as shown in Fig. 3A, it was confirmed that the sugar uptake ability of the muscle cells was increased by treatment with 20 [mu] M sabinene, indicating that sabinene had a glucose control ability .
4-2: AMPK 활성화 4 -2: Activation of AMPK
사비넨(sabinene)에 의하여, 당 조절 능력을 가지고 있다고 알려진 AMPK,의 활성화 여부를 확인하기 위하여, 칼슘 인식 색소인 Fluo-3를 이용해서 confocal microscope를 이용하여 직접 세포내 칼슘 농도의 변화를 확인하였다.To confirm the activation of AMPK, which is known to have the ability to regulate glucose, by sabinene, changes in intracellular calcium concentration were confirmed using a confocal microscope using Fluo-3, a calcium-recognizing dye .
C2C12 근육세포를 35-mm 디쉬에 분주한 후 하루 동안 10% FBS가 들어 있는 DMEM 배지에서 배양하여 안정화시켰다. Fluo-3 시약(Invitrogen, 미국)을 45분간 전처리 한후, confocal microscope하에서 사비넨(sabinene)을 10 uM농도로 처리한 후 실시간으로 칼슘 농도의 변화를 관찰하였다. C2C12 muscle cells were divided into 35-mm dishes and stabilized in DMEM medium containing 10% FBS for one day. Fluo-3 reagent (Invitrogen, USA) was pretreated for 45 minutes and then treated with 10 μM Sabinene under confocal microscope.
그 결과, 도 3의 B에 나타난 바와 같이, 형광의 색깔(녹색)의 밝기 정도가 세포내 칼슘 농도를 대변하고 있으며, 사비넨(sabinene)을 처리한 군에서 처리 후에 대조군에 비해 형광의 세기가 밝아지는 것으로 확인되었으며, 이는 사비넨(sabinene)이 근육세포내 칼슘 농도를 증가시키는 것이며, 이는 사비넨(sabinene)이 세포내 증가를 통해 활성화되는 CaMKK를 통해 당 조절 물질인 AMPK의 활성을 유도한다는 것을 의미한다.
As a result, as shown in FIG. 3B, the degree of brightness of the fluorescence color (green) represents the intracellular calcium concentration, and the intensity of fluorescence after the treatment in the group treated with sabinene was lower than that of the control group It has been confirmed that sabinene increases intracellular calcium concentration and that sabinene induces the activity of AMPK, a sugar regulator, through CaMKK, which is activated through intracellular increase .
4-3: AMPK 활성의 증가4-3: Increase in AMPK activity
당 조절 능력을 가지고 있다고 알려진 AMPK의 활성이 사비넨(sabinene) 처리에 의해 증가하는지를 확인하기 위하여, C2C12 세포에 사비넨(sabinene)을 0~100μM 농도로 농도별로 1시간 동안 처리한 후, AMPK의 인산화 및 그 하위 물질인 ACC의 인산화를 웨스턴 블럿을 통하여 동시에 확인하였다. In order to confirm that the activity of AMPK, which is known to have the ability to regulate glucose, is increased by treatment with sabinene, C2C12 cells were treated with 0-100 μM of sabinene for 1 hour at a concentration, Phosphorylation and phosphorylation of its subcall, ACC, were simultaneously confirmed by Western blot.
그 결과, 도 3의 C에 나타난 바와 같이, 사비넨(sabinene)에 의해서 혈당조절 주요단백질인 AMPK 및 ACC의 인산화가 증가되는 것이 관찰되었다. AMPK의 경우 3~10 μM 농도에서 최대 효과를 나타내었다. 이는 사비넨(sabinene)에 의한 당 섭취 능력이 AMPK활성에 의해 나타날 수 있음을 의미한다.
As a result, as shown in Fig. 3C, it was observed that sabinene increased phosphorylation of AMPK and ACC, major blood glucose controlling proteins. AMPK showed maximum effect at concentrations of 3 ~ 10 μM. This means that the sugar uptake by sabinene can be induced by AMPK activity.
실시예 5: 미르센(myrcene)의 혈당조절능력 확인Example 5: Confirmation of blood glucose control ability of myrcene
5-1: 포도당 섭취능 증가 5 -1: Increased glucose uptake
미르센(myrcene)의 혈당조절 능력을 검증하기 위해 분화된 근육세포주를 이용해서 미르센(myrcene)을 처리하여 당 섭취 능력이 증가되는 패턴을 비교, 분석하고, 당뇨 치료제로서의 생물학적 가능성 확인하였다.To examine the ability of myrcene to regulate blood glucose, myrcene was treated with differentiated muscle cell lines to compare and analyze patterns of increased glucose uptake ability and to confirm the biological potential as a diabetic therapeutic agent.
L6 근육전구세포를 12 웰 플레이트에 분주한 후 2% FBS가 들어 있는 DMEM 배지에서 근육세포로 분화시켰다. 근육세포에 미르센(myrcene)을 각각의 군당 2μM 및 20μM 농도로 60분 처리 후 포도당 유도체 2-DOG(2-deoxy-[3H]-D-glucose 100)를 100μM를 15분간 처리한 후, PBS 버퍼로 2회 세척 후 건조시켰다. Lysis buffer (0.5N NaOH + 0.5% SDS)를 well 당 500μL씩 넣어 세포를 용해시킨 후 450μL씩 LSC 바이알에 옮겨 1mL의 cocktail(Ultimagold, 미국)과 혼합 후 β-counter로 측정하였다.L6 muscle precursor cells were plated in 12-well plates and then differentiated into muscle cells in DMEM medium containing 2% FBS. After treating the muscle cells with myrcene at a concentration of 2 μM and 20 μM for 60 minutes, 100 μM of the glucose derivative 2-DOG (2-deoxy- [ 3 H] -D-glucose 100) Washed twice with PBS buffer, and then dried. Lysis buffer (0.5 N NaOH + 0.5% SDS) was added to 500 μL of each well to dissolve the cells. 450 μL of each solution was transferred to LSC vials, mixed with 1 mL of cocktail (Ultimagold, USA) and then measured by β-counter.
그 결과, 도 4의 A에 나타난 바와 같이, 근육세포의 당 섭취 능력이 미르센(myrcene) 처리에 의해 증가하는 것을 확인하였으며, 이것은 미르센(myrcene)이 당 조절 능력을 가지고 있음을 보여주는 것이다.
As a result, as shown in Fig. 4A, it was confirmed that the glucose uptake ability of the muscle cells was increased by myrcene treatment, indicating that myrcene had a glucose control ability.
5-2: 미르센(myrcene)의 당섭취에 미치는 AMPK의 영향5-2: Effect of AMPK on glucose uptake of myrcene
미르센(myrcene)에 의하여, 당 조절 능력을 가지고 있다고 알려진 AMPK,의 활성화 여부를 확인하기 위하여, 근육세포에 AMPK 억제제인 CC(compound C)를 전처리 후, 미르센(myrcene)을 처리하였을때, AMPK 억제에 의해 미르센(myrcene)에 의한 당 섭취 증가현상이 사라지는 것을 확인하였다.In order to confirm the activation of AMPK, which is known to have sugar control ability by myrcene, when the muscle cell was pretreated with CC (compound C), which is an AMPK inhibitor, and treated with myrcene, It was confirmed that the increase of glucose uptake by myrcene disappears due to AMPK inhibition.
L6 근육전구세포를 12 웰 플레이트에 분주한 후 2% FBS가 들어 있는 DMEM 배지에서 근육세포로 분화시켰다. 근육세포에 AMPK 억제제인 CC(compound C)(Calbiochem. 미국)를 처리하고, 30분 경과후, 미르센(myrcene)을 2μM 농도로 60분 처리 후 포도당 유도체 2-DOG(2-deoxy-[3H]-D-glucose 100)를 100μM를 15분간 처리한 후, PBS 버퍼로 2회 세척 후 건조시켰다. Lysis buffer (0.5N NaOH + 0.5% SDS)를 well 당 500μL씩 넣어 세포를 용해시킨 후 450μL씩 LSC 바이알에 옮겨 1mL의 cocktail(Ultimagold, 미국)과 혼합 후 β-counter로 측정하였다.L6 muscle precursor cells were plated in 12-well plates and then differentiated into muscle cells in DMEM medium containing 2% FBS. The muscle cells were treated with the AMPK inhibitor CC (compound C) (Calbiochem, USA), treated with myrcene at a concentration of 2 μM for 60 minutes after 30 minutes, and the glucose derivative 2-DOG (2-deoxy- [ 3 H] -D-glucose 100) was treated with 100 μM for 15 minutes, washed twice with PBS buffer, and then dried. Lysis buffer (0.5 N NaOH + 0.5% SDS) was added to 500 μL of each well to dissolve the cells. 450 μL of each solution was transferred to LSC vials, mixed with 1 mL of cocktail (Ultimagold, USA) and then measured by β-counter.
여기서, 인슐린 100ng/ml 처리군을 양성대조군으로 사용하였다.
Here, 100 ng / ml insulin group was used as a positive control group.
그 결과, 도 4의 B에 나타난 바와 같이, AMPK 억제제를 전처리한 후 미르센을 처리하는 경우, 미르센에 의한 당섭취 증가효과가 나타나지 않는 것을 확인할 수 있으며, 이 결과는 미르센이 AMPK 활성화에 관여하여 당섭취를 조절한다는 것을 의미한다.
As a result, as shown in Fig. 4B, it was confirmed that when the myrcene was pretreated with the AMPK inhibitor, the effect of increasing the sugar uptake by the myrcene did not appear, And thus regulate sugar intake.
5-3: 미르센(myrcene)의 당섭취에 미치는 p38 MAPK와 CaMKK의 영향5-3: Effect of p38 MAPK and CaMKK on glucose uptake of myrcene
미르센(myrcene)에 의하여, 당 조절 능력을 가지고 있다고 알려진 p38 MAPK와 CaMKK의 활성화 여부를 확인하기 위하여, 근육세포에 p38 MAPK 억제제와 CaMKK 억제제를 전처리한 후, 미르센(myrcene)을 처리하여, p38 MAPK와 CaMKK 억제에 의해 미르센(myrcene)에 의한 당 섭취 증가현상이 사라지는 것을 확인하였다.In order to confirm the activation of p38 MAPK and CaMKK, which are known to have the ability to regulate glucose by myrcene, muscle cells were pretreated with p38 MAPK inhibitor and CaMKK inhibitor, treated with myrcene, It was confirmed that the increase of glucose uptake by myrcene disappears due to inhibition of p38 MAPK and CaMKK.
L6 근육전구세포를 12 웰 플레이트에 분주한 후 2% FBS가 들어 있는 DMEM 배지에서 근육세포로 분화시켰다. 근육세포에 p38 MAPK 억제제인 SB 화합물(SB compound)(Calbiochem. (미국)) 및 CaMKK억제제인 STO 화합물(STO compound (Calbiochem. (미국))를 처리하고, 미르센(myrcene)을 2μM 농도로 60분 처리 후 포도당 유도체 2-DOG(2-deoxy-[3H]-D-glucose 100)를 100μM를 15분간 처리한 후, PBS 버퍼로 2회 세척 후 건조시켰다. Lysis buffer (0.5N NaOH + 0.5% SDS)를 well 당 500μL씩 넣어 세포를 용해시킨 후 450μL씩 LSC 바이알에 옮겨 1mL의 cocktail(Ultimagold, 미국)과 혼합 후 β-counter로 측정하였다.
L6 muscle precursor cells were plated in 12-well plates and then differentiated into muscle cells in DMEM medium containing 2% FBS. Muscle cells were treated with SB compound (Calbiochem, USA), a p38 MAPK inhibitor, and STO compound (Calbiochem, USA), a CaMKK inhibitor, and myrcene was added at a concentration of 60 After the treatment, 100 μM of the glucose derivative 2-DOG (2-deoxy- [ 3 H] -D-glucose 100) was treated for 15 minutes, washed twice with PBS buffer and then dried. % SDS) were added to the LSC vials in a volume of 500 μL per well, and 450 μL of the cells were transferred to a LSC vial, mixed with 1 mL of cocktail (Ultimagold, USA), and then measured with a β-counter.
그 결과, 도 4의 C에 나타난 바와 같이, p38 MAPK 억제제와 CaMKK 억제제와 미르센을 함께 처리하는 경우, 미르센에 의한 당섭취 증가효과가 나타나지 않는 것을 확인할 수 있으며, 이 결과는 미르센에 의한 당섭취 반응에 p38 MAPK와 CaMKK가 중요하게 관여하고 있는 것을 의미한다.
As a result, as shown in Fig. 4C, it can be confirmed that when the p38 MAPK inhibitor, the CaMKK inhibitor and the myrcene were treated together, the effect of increasing the glucose uptake by the myrcene did not appear, This indicates that p38 MAPK and CaMKK are involved in glucose uptake.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereto will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (2)
[화학식 2]
(2)
[화학식 2]
A diabetic health functional food containing sabinene or a salt thereof represented by formula (2) as an active ingredient:
(2)
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