KR101793654B1 - Pharmaceutical composition or functional food containing malaxinic acid for improvement of lipid related metabolic diseases - Google Patents
Pharmaceutical composition or functional food containing malaxinic acid for improvement of lipid related metabolic diseases Download PDFInfo
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- KR101793654B1 KR101793654B1 KR1020170033785A KR20170033785A KR101793654B1 KR 101793654 B1 KR101793654 B1 KR 101793654B1 KR 1020170033785 A KR1020170033785 A KR 1020170033785A KR 20170033785 A KR20170033785 A KR 20170033785A KR 101793654 B1 KR101793654 B1 KR 101793654B1
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- functional food
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- 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
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- 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
- A23V2200/332—Promoters of weight control and weight loss
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Abstract
Description
본 발명은 약학조성물 및 건강기능성식품에 대한 것으로, 보다 구체적으로는 지방세포 분화인자들의 활성을 억제함으로써 지방전구세포에서 지방세포로의 분화가 억제되는 특성을 갖는 말락시닉산을 이용한 지방대사성 질환 개선용조성물 및 건강기능성식품에 관한 것이다.The present invention relates to a pharmaceutical composition and a health functional food. More specifically, the present invention relates to a pharmaceutical composition and a health functional food for improving fat metabolism diseases using malacicnic acid having the property of inhibiting differentiation from adipocytes into adipocytes by inhibiting the activity of adipocyte differentiation factors Compositions and health functional foods.
비만은 지질대사의 항상성(lipid homeostasis)이 원활하게 유지되지 않음에 따라 지방세포의 분화(differentiation)가 촉진되어 지방세포의 수와 크기가 증가되고, 그로 인해 지방조직에 과도하게 지질이 축적됨에 따라 발병한다(Ferranti et al. Clin. Chem. 54, 945-955, 2008). 또한, 비만은 인슐린 저항성(insulin resistance)과 같은 대사이상을 유발하여 당뇨 및 심혈관계질환 등과 같은 다른 대사성질환의 발병가능성을 높일 수 있기 때문에 최근 전 세계적으로 비만에 대한 치료 및 예방법에 대한 관심이 증가하고 있다(Ye. Front Med. 7, 14-24, 2013). 이처럼 비만은 최근 식습관의 불균형 및 운동부족 등으로 인해 전 세계적으로 발병률이 증가되고 있는 대사성질환 중 하나로 인식되고 있다. Obesity is caused by the fact that the lipid homeostasis is not maintained smoothly and thus the differentiation of adipocytes is promoted, thereby increasing the number and size of adipocytes and thereby causing excessive lipid accumulation in adipose tissue (Ferranti et al. Clin. Chem. 54, 945-955, 2008). In addition, since obesity induces metabolic abnormalities such as insulin resistance, it is possible to increase the possibility of other metabolic diseases such as diabetes and cardiovascular diseases. Therefore, there is a growing interest in the treatment and prevention of obesity worldwide (Ye, Front Med 7, 14-24, 2013). Thus, obesity is now recognized as one of the metabolic diseases whose incidence is increasing worldwide due to imbalance of eating habits and lack of exercise.
지방조직의 증식 및 분열기전에 관해서는 아직 완벽한 해석이 이루어지지 못하고 있지만, 종래의 연구결과들로부터 지방전구세포에서 지방분화세포로 변하는 과정 중에 퍼옥시좀 증식체 활성화 수용체(peroxisome proliferator-activated receptors-γ, PPARγ) 및 C/EBPα (CCAAT/enhancer-binding protein-α)와 같은 전사인자의 발현이 증가하고, 그에 따라 지질합성에 관여하는 유전자들이 증가함이 보고된 바 있다(Kim et al. Diabetes, 53, 2748-2756, 2004). Although there is no complete interpretation of the proliferation and division of adipose tissue, previous studies have shown that peroxisome proliferator-activated receptors-γ , PPARγ) and C / EBPα (CCAAT / enhancer-binding protein-α), thereby increasing the genes involved in lipid synthesis (Kim et al. Diabetes, 53, 2748-2756, 2004).
배는 우리나라의 4대 과실류 중의 하나이며, 우리나라를 포함한 아시아 지역에서는 예로부터 기침, 가래 및 변비 등을 개선하는 효능이 있다고 알려져 한방에서는 치료의 목적으로 사용되어져 왔다(Cui et al. J. Agric. Food Chem., 53, 3882-3887, 2005). 종래의 연구결과로부터 배추출물은 위궤양 (Huang et al. J. Agric. Food Chem., 58, 8983-8987, 2010), 항산화 (Li et al. J. Agric. Food Chem., 60, 8737-8744, 2012) 및 항염증(Li et al. Food Chem. Toxicol., 50, 3673-3679, 2012) 등에 활성을 발현함이 보고된 바 있다. 하지만 종래의 연구들은 정확한 배의 생리활성 원인물질을 제시하는 수준에는 이르지 못하였다. 본 발명그룹은 정확한 배의 생리활성 원인물질을 구명하고자 다년간의 연구를 통해 배로부터 50여종의 유용생리활성화합물을 분리 및 구조 해석하여 보고한 바 있다[(Lee et al. J. Agric. Food Chem. 59, 10124-10128, 2011); (Lee et al. Food Sci. Biotechnol. 20, 1539-1545, 2011); (Lee et al. Food Sci.Biotechnol. 22, 803-810, 2013); (Lee et al. Korean J. Food Sci. Technol. 45, 557~564 (2013); (Lee et al. Korean J. Food Sci. Technol. 45, 174~179 (2013); (Cho et al. J. Agric. Food Chem. 61, 4563-4569, 2013); (Lee et al. Food Sci. Biotechnol. 23, 253-259, 2014); (Lee et al. Korean J. Food Sci. Technol. 47, 170~175 (2015)]. 특히, 배로부터 말락시닉산[malaxinic acid; 4-(오-베타-디-글루코피나노실-3-(3'-메틸-2'-뷰테닐)벤조익산; 4-(O -β-D-glucopyranosyl)-3-(3′-methyl-2′-butenyl)benzoic acid]의 존재가 본 발명그룹의 결과로부터 처음 밝혀진 바 있다. 또한 말락시닉산은 배재배과정 중 고품질의 배를 생산하기 위하여 적과를 행하는 과정에 생성되는 미활용 미성숙과 자원에 다량 함유(1-6 mg/100 g 배 미성숙과 신선중량)되어 있음이 확인되었으며(Cho et al. Biosci. Biotechnol. Biochem. 79, 260-270, 2015), 배 미성숙과로부터 말락시닉산의 고순도 정제법 또한 보고된 바 있다[(Lee et al. Food Sci.Biotechnol. 22, 1539-1545, 2013); (국내공개특허 제 10-2014-0094109)]. 종래의 연구결과에 따르면, 말락시닉산의 aglycone (4-Hydroxy-3-(3'-methyl-2'-butenyl)-benzoic acid)은 항균활성[(Abraham et al. Phytochemistry. 29, 2641-2644, 1990); Venkatasubbaiah et al. J. Nat. Prod. 54, 1293-1297, 1991)] 및 자궁경부암세포 사멸효과(Kim et al, J. Antibiot. 57, 605-608, 2004)를 발현함이 in vitro 수준에서 보고되었지만, 보다 자세한 생리활성 연구결과는 보고된 바 없다. It has been used for treatment purposes in Korea (Cui et al., J. Agric., 2002). It is known that there is an effect of improving cough, sputum and constipation in ancient Asia including Korea. Food Chem., 53, 3882-3887, 2005). From the results of previous studies, it has been found that the extract of the embryo can be used for the treatment of gastric ulcer (Liang et al., J. Agric. Food Chem., 58, 8983-8987, 2010) , 2012) and antiinflammation (Li et al., Food Chem. Toxicol., 50, 3673-3679, 2012). However, conventional studies have not reached the level of presenting accurate physiologically active substances in the abdomen. In the present invention group, about 50 kinds of useful physiologically active compounds have been isolated and analyzed by structural analysis through a multi-year study in order to identify the physiologically active substance of an accurate embryo [Lee et al. J. Agric. Food Chem 59, 10124-10128, 2011); (Lee et al., Food Sci. Biotechnol., 20, 1539-1545, 2011); (Lee et al., Food Sci. Biotechnol., 22, 803-810, 2013); (Cho et al., J Korean J. Food Sci. Technol. 45, 174-179 (2013)); (J. et al., J. Food Sci. Technol. 47, 170 (1982)); (Agric. Food Chem. 61, 4563-4569, 2013) (Lee et al., Food Sci. Biotechnol. In particular, malaxinic acid 4- (o-beta-di-glucopyranosyl-3- (3'-methyl-2'-butenyl) benzoic acid 4- ( O - ? - D-glucopyranosyl) -3- (3'-methyl-2'-butenyl) benzoic acid was found for the first time from the results of the group of the present invention. (1-6 mg / 100 g times of immature and fresh weight) in the enrichment and non-immune immaturity and resources of the embryo to produce the embryo (Cho et al., Biosci. Biotechnol. Biochem. 79, 260-270, 2015), and a high purity purification of malic acid from malignant glands has also been reported (Lee et al. According to the results of the conventional studies, it was found that aglycone (4-Hydroxy-3- (3'-hydroxy-3- methyl-2'-butenyl) -benzoic acid has been reported to have antimicrobial activity (Abraham et al. Phytochemistry. 29, 2641-2644, 1990; Venkatasubbaiah et al., J. Nat. Prod. 54, 1293-1297, 1991) And cervical cancer cell death (Kim et al, J. Antibiot. 57, 605-608, 2004) were reported at the in vitro level, but no more detailed results of the physiological activity studies have been reported.
본 발명자들은 배 함유성분의 비만으로 인한 대사장애 개선효과를 나타는 활성물질 탐색과정 중 말락시닉산이 지방세포의 증식 및 분화를 억제하는 활성을 나타내는 것을 확인하고 본 발명을 완성하였다. The inventors of the present invention have confirmed that malaconic acid inhibits the proliferation and differentiation of adipocytes during the search for an active substance exhibiting an effect of improving the metabolic disorder caused by obesity of the pear-containing component, and completed the present invention.
따라서, 본 발명의 목적은 지방세포의 증식 및 분화억제에 효과를 나타내는 말락시닉산의 활성을 확인하였을 뿐만 아니라, 이러한 말락시닉산의 새로운 용도를 통해 이전에 전혀 알려지지 않았던 지방세포의 분화 및 증식을 억제할 수 있는 지방대상성 질환 개선용 약학조성물 및 건강 기능성식품을 제공하는 것이다. Accordingly, it is an object of the present invention to provide a method for inhibiting the proliferation and differentiation of adipocytes, and to provide a method for inhibiting the proliferation and differentiation of adipocytes by using the malacicnic acid. And to provide a health functional food composition.
본 발명의 다른 목적은 배 및 배미성숙과를 포함하는 배미활용자원 중 하나 이상으로부터 분리된 말라시닉산을 유효성분으로 포함함으로써 식용가능한 천연물에서 추출된 것이므로 자원재활용은 물론 독성에 대한 염려도 없는 지방대사성 질환 개선용 약학조성물 및 건강 기능성식품을 제공하는 것이다. Another object of the present invention is to provide a method for producing malicinic acid, which is extracted from natural edible material by containing maliconic acid isolated from at least one of abundant utilization resources including abalone and abalone, A pharmaceutical composition for improving metabolic diseases, and a health functional food.
본 발명의 목적은 이상에서 언급한 목적으로 제한되지 않으며, 언급되지 않은 또 다른 목적들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.The objects of the present invention are not limited to the above-mentioned objects, and other objects not mentioned can be clearly understood by those skilled in the art from the following description.
상술된 목적을 달성하기 위하여, 본 발명은 말락시닉산 및 이의 약학적으로 허용되는 염 중 하나 이상을 유효성분으로 포함하는 지방대사성 질환 개선용 약학조성물을 제공한다.In order to achieve the above-mentioned object, the present invention provides a pharmaceutical composition for improving lip metabolic diseases, comprising at least one of malacicnic acid and a pharmaceutically acceptable salt thereof as an active ingredient.
바람직한 실시예에 있어서, 상기 말락시닉산은 지방세포의 증식 및 분화억제활성을 갖는다.In a preferred embodiment, the malicic acid has an activity of inhibiting proliferation and differentiation of adipocytes.
바람직한 실시예에 있어서, 상기 말락시닉산은 지방세포의 분화에 관여하는 퍼옥시좀 증식체 활성화 수용체(peroxisome proliferator-activated receptors-γ, PPARγ), C/EBPα (CCAAT/enhancer-binding protein-α), FABP4 (fatty acid-binding protein) 및 FASN (fatty acid synthase)으로 구성되는 그룹에서 선택되는 하나 이상의 발현을 감소시키는 활성을 갖는다.In a preferred embodiment, the malaconic acid is a peroxisome proliferator-activated receptors-γ (PPARγ), C / EBPα (CCAAT / enhancer-binding protein-α) , FABP4 (fatty acid-binding protein) and FASN (fatty acid synthase).
바람직한 실시예에 있어서, 상기 말락시닉산은 배 및 배미성숙과를 포함하는 배미활용자원 중 하나 이상으로부터 분리된 것이다. In a preferred embodiment, the maliconic acid is separated from one or more of the abiotic utilization resources, including abundance and abundance.
또한, 본 발명은 말락시닉산 및 이의 약학적으로 허용되는 염 중 하나 이상을 유효성분으로 포함하는 지방대사성 질환 개선용 건강기능성식품을 제공한다.In addition, the present invention provides a health functional food for improving fat metabolic diseases, comprising at least one of malacicnic acid and a pharmaceutically acceptable salt thereof as an active ingredient.
바람직한 실시예에 있어서, 분말, 과립, 정제, 캡슐 및 음료 중 어느 하나의 제형을 갖는다.In a preferred embodiment, it has a formulation of either powder, granules, tablets, capsules or beverages.
바람직한 실시예에 있어서, 상기 말락시닉산은 배 및 배미성숙과를 포함하는 배미활용자원 중 하나 이상으로부터 분리된 것이다. In a preferred embodiment, the maliconic acid is separated from one or more of the abiotic utilization resources, including abundance and abundance.
본 발명은 다음과 같은 우수한 효과를 갖는다.The present invention has the following excellent effects.
먼저, 본 발명의 지방대사성 질환 개선용 약학조성물 및 건강기능성식품은 은 말락시닉산이 지방세포의 증식 및 분화 억제활성을 가지므로 비만을 포함한 지방대사성 질환의 예방 또는 개선에 효과를 나타내는 활성원인물질이 될 수 있다는 이전에 전혀 알려지지 않았던 말라시닉산의 새로운 용도를 활용한 것으로, 지방세포에서의 과도한 분화를 원인으로 하는 대사성질환을 개선시킬 수 있다. First, since the pharmaceutical composition and the health functional food for improving the fat metabolism disease of the present invention have the activity of inhibiting the proliferation and differentiation of adipocytes, silver malaconic acid has an activity to prevent or improve fat metabolic diseases including obesity Which can not be known before, can be used to improve metabolic diseases caused by excessive differentiation in adipocytes.
또한, 본 발명의 지방대사성 질환 개선용 약학조성물 및 건강 기능성식품은 배 및 배미성숙과를 포함하는 배미활용자원 중 하나 이상으로부터 분리된 말라시닉 산을 유효성분으로 포함함으로써 식용가능한 천연물에서 추출된 것이므로 자원재활용은 물론 독성에 대한 염려 없이 활용이 가능하다. The pharmaceutical composition and the health functional food for improving lip metabolic diseases of the present invention can also be prepared by incorporating malacicnic acid isolated from at least one of the abataceous utilization resources including pear and abalone into an active ingredient, Therefore, it is possible to use it without worrying about toxicity as well as resource recycling.
본 발명의 이러한 기술적 효과는 이상에서 언급한 범위만으로 제한되지 않으며, 명시적으로 언급되지 않았더라도 후술되는 발명의 실시를 위한 구체적 내용의 기재로부터 통상의 지식을 가진 자가 인식할 수 있는 발명의 효과 역시 당연히 포함된다.Although the present invention has been fully described by way of example with reference to the accompanying drawings, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Of course.
도 1은 선행 발명에 의해 분리 및 구조결정된 말락시닉산의 구조도이다.
도 2는 말락시닉산의 처리농도에 따른 지방세포에 대한 독성평가결과이다 (MTT 실험). MA, malaxinic acid.
도 3은 말락시닉산의 지방세포 내 지방축적 억제효과를 관찰한 현미경 사진이다. MDI, methylisobutylxanthine, dexamethasone, insulin.
도 4는 말락시닉산의 지방세포 지방축적 억제정도를 나타낸 그래프(Oil Red O staining, ORO)이다[Turkey's test에 의한 유의차 검정(*P<0.05)]. MDI, methylisobutylxanthine, dexamethasone, insulin; MA, malaxinic acid.
도 5는 말락시닉산의 mRNA 수준에서 지방세포 내 분화촉진인자를 억제하는 정도를 나타낸 그래프이다[Turkey's test에 의한 유의차 검정(*P<0.05)]. PPARγ, Peroxisome proliferator-activated receptor γ; C/EBP, CCAAT-enhancer-binding proteins α; FABP4, fatty acid-binding protein 4; FASN, fatty acid synthase.
도 6은 말락시닉산의 단백질 수준에서 지방세포 내 분화촉진인자를 억제하는 정도를 나타낸 결과이다. FASN, fatty acid synthase; C/EBP, CCAAT-enhancer-binding proteins α; PPARγ, Peroxisome proliferator-activated receptor γ. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a structural diagram of malacicinic acid separated and structured by the prior art. Fig.
Fig. 2 shows the results of evaluation of toxicity to adipocytes according to the treatment concentration of malacicinic acid (MTT test). MA, malaxinic acid.
FIG. 3 is a microscopic photograph showing the inhibitory effect of malic acidic acid on fat accumulation in adipocytes. MDI, methylisobutylxanthine, dexamethasone, insulin.
FIG. 4 is a graph showing the inhibitory effect of malacicnic acid on fat cell fat accumulation (Oil Red O staining, ORO) (significant difference test by Turkey's test (* P <0.05)). MDI, methylisobutylxanthine, dexamethasone, insulin; MA, malaxinic acid.
FIG. 5 is a graph showing the degree of suppression of adipocyte differentiation-promoting factors at the mRNA level of malacicinic acid (significant difference test by Turkey's test (* P <0.05)). PPARγ, Peroxisome proliferator-activated receptor γ; C / EBP, CCAAT-enhancer-binding proteins α; FABP4, fatty acid-
FIG. 6 shows the inhibition of the adipocyte differentiation promoting factor at the protein level of malacicinic acid. FASN, fatty acid synthase; C / EBP, CCAAT-enhancer-binding proteins α; PPARγ, Peroxisome proliferator-activated receptor γ.
본 발명에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. While the present invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not limited to the disclosed embodiments. Also, in certain cases, there may be a term selected arbitrarily by the applicant, in which case the meaning thereof will be described in detail in the description of the corresponding invention.
본 명세서 상에서 언급한 '포함한다', '갖는다', '이루어진다' 등이 사용되는 경우 '~만'이 사용되지 않는 이상 다른 부분이 추가될 수 있다. 구성 요소를 단수로 표현한 경우에 특별히 명시적인 기재 사항이 없는 한 복수를 포함하는 경우를 포함한다.In the case where the word 'includes', 'having', 'done', etc. are used in this specification, other parts can be added unless '~ only' is used. Unless the context clearly dictates otherwise, including the plural unless the context clearly dictates otherwise.
구성 요소를 해석함에 있어서, 별도의 명시적 기재가 없더라도 오차 범위를 포함하는 것으로 해석한다.In interpreting the constituent elements, it is construed to include the error range even if there is no separate description.
본 발명의 여러 구현예들 각각의 특징적인 부분들은 부분적으로 또는 전체적으로 서로 결합 또는 조합가능하고, 기술적으로 다양한 연동 및 구동이 가능하며, 각 구현예들은 서로에 대하여 독립적으로 실시 가능할 수도 있고 연관 관계로 함께 실시할 수도 있다.It is to be understood that each characteristic portion of the various embodiments of the present invention may be partially or wholly combined or combinable with each other and technically various interlocking and driving are possible and that each implementation may be feasible independently of each other, It can be done together.
이하, 첨부한 도면 및 바람직한 실시예들을 참조하여 본 발명의 기술적 구성을 상세하게 설명한다.Hereinafter, the technical structure of the present invention will be described in detail with reference to the accompanying drawings and preferred embodiments.
그러나, 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화 될 수도 있다. 명세서 전체에 걸쳐 본 발명을 설명하기 위해 사용되는 동일한 참조번호는 동일한 구성요소를 나타낸다.However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Like reference numerals used to describe the present invention throughout the specification denote like elements.
본 발명의 기술적 특징은 배에 함유된 것으로 알려진 말락시닉산이 지방세포의 증식 및 분화를 억제하는 활성을 갖는다는 말락시닉산의 이제까지 전혀 알려지지 않은 새로운 용도를 확인한 것에 있다. 즉, 기존에 알려진 말락시닉산의 용도는 자궁경부암세포 사멸효과와 항균효과에 불과하였으나, 본 발명을 통해 말락시닉산이 지방세포 증식 및 분화 억제활성을 갖는 것이 확인됨으로써 종래 배추출물이 비만방지효과를 갖게 된 원인물질이 말락시닉산 임을 밝혔기 때문이다.The technical feature of the present invention is to confirm a new and totally unknown novel use of malacicinic acid, in which malic cyclic acid, which is known to be contained in the stomach, has an activity of inhibiting proliferation and differentiation of adipocytes. That is, the use of malacicnic acid, which is known in the art, was only a cervical cancer cell killing effect and an antibacterial effect. However, it was confirmed that malaconic acid has an adipocyte proliferation and differentiation inhibiting activity through the present invention, Because it was maliconic acid.
따라서, 본 발명의 지방대사성 질환 개선용 약학조성물은 말락시닉산 및 이의 약학적으로 허용되는 염 중 하나 이상을 유효성분으로 포함한다.Accordingly, the pharmaceutical composition for improving lip metabolic diseases of the present invention contains at least one of malic acid and its pharmaceutically acceptable salt as an active ingredient.
말락시닉산은 상술된 바와 같이 배 및 배미성숙과를 포함한 배미활용자원에 다량 포함되어 있는 천연물질로서 화학식 1과 같은 구조[malaxinic acid; 4-(오-베타-디-글루코피나노실-3-(3'-메틸-2'-뷰테닐)벤조익산]를 갖는다.As mentioned above, malic acidic acid is a natural substance which is abundantly contained in abiotic utilization resources including abalone and abalone, and has a structure of [malaxinic acid; 4- (O-beta-di-glucopyranosyl-3- (3'-methyl-2'-butenyl) benzoic acid].
[화학식 1][Chemical Formula 1]
여기서, 말락시닉산은 지방세포의 증식 및 분화억제활성을 갖는데, 말락시닉산은 퍼옥시좀 증식체 활성화 수용체(peroxisome proliferator-activated receptors-γ, PPARγ), C/EBPα (CCAAT/enhancer-binding protein-α), FABP4 (fatty acid-binding protein) 및 FASN (fatty acid synthase)으로 구성되는 그룹에서 선택되는 하나 이상의 발현을 감소시키는 활성을 갖는다. 특히, 후술하는 실험예를 통해 알 수 있듯이 지방세포의 분화과정 중 퍼옥시좀 증식체 활성화 수용체(peroxisome proliferator-activated receptors-γ, PPARγ) 및 C/EBPα (CCAAT/enhancer-binding protein-α)의 발현을 억제함으로써 FABP4 (fatty acid-binding protein 4) 및 FASN (fatty acid synthase)과 같은 지방합성 유전자 발현을 억제시킴에 따라 지방세포 내 지방축적억제활성을 갖게 된다.Malaconic acid has the activity of inhibiting the proliferation and differentiation of adipocytes. The malic acid is a peroxisome proliferator-activated receptors-γ (PPARγ), C / EBPα (CCAAT / enhancer-binding protein -α), FABP4 (fatty acid-binding protein) and FASN (fatty acid synthase). In particular, as shown in the experimental examples to be described later, peroxisome proliferator-activated receptors-γ (PPARγ) and C / EBPα (CCAAT / enhancer-binding protein-α) (FABP4) and FASN (fatty acid synthase), thereby inhibiting fat accumulation in adipocytes.
본 발명의 지방대사성 질환 개선용 약학조성물은 말락시닉산 및 이의 약학적으로 허용되는 염 중 하나 이상을 단독으로 포함할 수 있으며, 이외 제형, 사용방법 및 사용목적에 따라 약리학적으로 허용가능한 담체 또는 부형제를 더 포함할 수 있다. 혼합물로 제공되는 경우, 유효성분인 말락시닉산 및/또는 이의 약학적으로 허용되는 염은 약학조성물에 0.1 내지 99 중량%로 포함될 수 있다. The pharmaceutical composition for improving lipid metabolic diseases of the present invention may contain at least one of malic acid and its pharmaceutically acceptable salts alone or may be used as a pharmacologically acceptable carrier or excipient depending on the formulation, And may further comprise excipients. When provided as a mixture, the active ingredient malaconic acid and / or its pharmaceutically acceptable salt may be included in the pharmaceutical composition in an amount of 0.1 to 99% by weight.
담체 또는 부형제로는 물, 덱스트린, 칼슘카보네이드, 락토스, 프로필렌글리콜, 리퀴드 파라핀, 생리식염수, 덱스트로스, 수크로즈, 솔비톨, 만니톨, 자이리톨, 에리스리톨, 말티톨, 전분, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유가 있으며, 이들은 1종이상 사용될 수 있으나, 이에 한정되는 것은 아니며 통상의 담체 및 부형제는 모두 사용가능하다. Examples of the carrier or excipient include water, dextrin, calcium carbonate, lactose, propylene glycol, liquid paraffin, physiological saline, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. These may be used alone or in combination, but not limited thereto, All excipients are available.
또한 본 발명의 지방대사성 질환 개선용 약학조성물을 약제화하는 경우, 통상의 충진제, 증량제, 결합제, 붕해제, 계면활성제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등을 더 포함할 수 있다.In addition, when the pharmaceutical composition for the alleviation of fat metabolism diseases of the present invention is formulated, it may further contain conventional fillers, extenders, binders, disintegrants, surfactants, anticoagulants, lubricants, wetting agents, flavors, emulsifiers or preservatives .
개별 투약 형태에서 이의 유효성분인 말락시닉산 및/또는 이의 약학적으로 허용되는 염의 함량은 1회에 투여되는 양으로, 예컨대 통상 1일 투여량의 전부, 1/2, 1/3 또는 1/4배일 수 있다.The content of malic acidic acid and / or a pharmaceutically acceptable salt thereof, which is an active ingredient thereof in the form of an individual dosage form, can be adjusted in a single administration amount, for example, 4 times.
본 발명의 지방대사성 질환 개선용 약학조성물의 투여량은 환자의 연령, 성별, 상태, 체내에서 활성 성분의 흡수도, 불활성율 및 병용되는 약물을 고려하여 결정하는 것이 좋으며, 예컨대 1회 유효성분을 기준으로 하였을 때 0.1 μM 내지 1 M로, 1일 1 내지 5회 투여할 수 있다. The dosage of the pharmaceutical composition for improving lip metabolic diseases of the present invention is preferably determined in consideration of the age, sex, condition of the patient, the degree of absorption of the active ingredient, the inactivation rate of the active ingredient and the drug to be used in combination. As a standard, it may be administered at a dose of 0.1 μM to 1 M, 1 to 5 times a day.
다음으로, 본 발명의 지방대사성 질환 개선용 건강기능성식품은 상술된 약학조성물에 포함되는 말락시닉산 및/또는 이의 약학적으로 허용되는 염을 유효성분으로 포함함으로써 지방세포 내 지방축적억제활성을 갖게 되므로 비만을 예방하는 목적으로 사용될 수 있다.Next, the health functional food for improving the fat metabolism disorder of the present invention contains malic acidic acid and / or its pharmaceutically acceptable salt contained in the above-mentioned pharmaceutical composition as an active ingredient, And thus can be used for the purpose of preventing obesity.
본 발명에서 '건강기능성식품'이란 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하며, 바람직하게는 식품에 물리적, 생화학적, 생물공학적 수법 등을 이용하여 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병방지와 회복 등에 관한 체조절기능을 생체에 대하여 충분히 발현하도록 설계하여 가공한 식품을 의미한다. 건강기능성식품에는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 건강기능성 식품의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.In the present invention, the term 'health functional food' means a natural product or a processed product containing one or more nutrients. Preferably, the function of the food is determined by physical, biochemical, biotechnological, Means a food group that has been imparted with added value to function and express, and a food which is designed and manufactured so that the body control function related to regulation of bio-defense rhythm of food composition, prevention and recovery of disease, etc. is sufficiently expressed in living body. The health functional food may include a pharmaceutically acceptable food supplementary additive and may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of health functional foods.
본 발명의 말락시닉산 및/또는 이의 약학적으로 허용되는 염을 첨가할 수 있는 건강 기능성 식품으로는 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제 등이 있다. 추가로, 특수영양식품(예, 조제유류, 영,유아식 등), 건강보조식품, 과자류(예, 스넥류), 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 음료(예, 과실,채소류 음료, 두유류, 발효음료류 등) 등을 포함하나 이에 한정되지 않는다. 상술된 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다.Examples of the health functional food to which the malacicnic acid and / or the pharmaceutically acceptable salt thereof of the present invention can be added include various foods, beverages, gums, tea and vitamin complexes. In addition, it is also possible to use nutritional products such as special nutritious foods (eg crude oil, milk, baby food), health supplements, confectionery (eg snacks), dairy products (eg fermented milk, Beverages, two-oil, fermented beverages, etc.), but are not limited thereto. The food, beverage or food additives described above can be produced by a conventional production method.
본 발명의 건강 기능성 식품은 여러 가지 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, 보호성콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 물, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분을 독립적으로 또는 조합하여 사용할 수 있다. The health functional food of the present invention can be used as a nutritional supplement, a vitamin, a mineral (electrolyte), a flavoring agent such as a synthetic flavor agent and a natural flavor agent, a colorant and an aging agent (cheese, chocolate etc.), a pectic acid and its salt, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, water, carbonating agents used in carbonated beverages and the like. These components can be used independently or in combination.
이와 같이 본 발명의 건강기능성식품은 상술된 바와 같이 다양한 제형을 갖는데, 특히 분말, 과립, 정제, 캡슐 및 음료 중 어느 하나의 제형을 가질 수 있다.Thus, the health functional food of the present invention has various formulations as described above, and may have any one of powder, granule, tablet, capsule and beverage.
일 구현예로서, 본 발명의 건강기능성식품을 음료로 구현하는 경우 필수 성분으로서 본 발명의 말락시닉산 및/또는 이의 약학적으로 허용되는 염을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 천연 탄수화물의 예는 모노사카라이드, 예를 들어 포도당, 과당 등 디사카라이드, 예를 들어 말토스, 수크로스 등 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상기한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. In one embodiment, when the health functional food of the present invention is implemented as a beverage, there are no particular restrictions on other components other than the malic acidic acid and / or the pharmaceutically acceptable salt thereof of the present invention as an essential ingredient, , As well as various flavoring agents or natural carbohydrates. Examples of natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrins, cyclodextrins and the like, and xylitol, Sorbitol, and erythritol. Natural flavors (tau martin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above .
또한, 비만억제를 목적으로 하는 건강기능성식품에서도 유효성분인 말락시닉산 및/또는 이의 약학적으로 허용되는 염의 함량은 0.1 μM 내지 1 M의 비율로 포함될 수 있을 것이다.In addition, in the health functional food for the obesity-suppressing purpose, the content of the active ingredient malacicinic acid and / or its pharmaceutically acceptable salt may be included in a ratio of 0.1 μM to 1 M.
한편, 본 발명의 지방대사성 질환 개선용 약학조성물 및 건강기능성식품에 포함되는 말락시닉산은 상기 화학식1을 갖기만 하면 공지된 모든 말락시닉산이 사용가능하지만, 화학적으로 합성된 것이 아니라, 천연물유래인 것일 수 있는데, 특히 자원재활용 및 안전을 위해 배 및/또는 배 미성숙과를 포함하는 배미활용자원으로부터 분리된 것일 수 있다.On the other hand, the malic cyclic acid contained in the pharmaceutical composition for the alleviation of fat metabolism and the health functional food of the present invention can be any malicyclic acid known in the art if it has the above-mentioned formula (1), but it is not chemically synthesized, , Especially for resource recycling and safety, may be segregated from the abattoir resources, including ship and / or shipyards.
실시예 Example
배 미성숙과는 전라남도 나주시에서 재배된 것으로 개화 후 35일이 경과된 것이며, 실험 직전까지 -70℃에서 보관하여 사용하였다. 시료로 배 미성숙과(18 kg, 신선중량)에 60% 에탄올 64 L를 가하고 실온 및 암실에서 24시간 방치한 후 여과(No. 2, Whatman)하고, 그 잔사를 60% 에탄올 60 L로 재여과(No. 2, Whatman)하였다. 얻어진 1차 및 2차 여과액을 합하여 38℃에서 감압농축하여 농축물(Solvent extraction)을 얻었다. 농축물(1081.9 g)을 물(10 L)로 용해하여 현탁액을 얻었다. 얻어진 현탁액을 1 N 염산을 이용하여 pH 3.0으로 조절하였다. 산성으로 조절된 현탁액에 대해 에틸아세테이트 10 L로 3회 반복하여 용매분획하여 물층과 에틸아세테이트층(Solvent fractionation)으로 분획하였다. 말락시닉산이 함유된 유기용매층, 즉 에틸아세테이트층(134.75 g)을 감압농축하여 정제용 농축물을 얻었다. 그 후 정제용 농축물을 대상으로 H2O/EtOH 용매계(H2O/EtOH = 100:0, 80:20, 40:60, 0:100, v/v) 각 6 L씩을 이용하여 step-wise 용출법에 의해 Amberlite XAD-2 (40-60 mesh, Bellefonte PA, USA) 컬럼(9.0 × 900 mm)에 흡착시킨 후 용출시켰다. 도 4 및 도 5에 도시된 바와 같이 대부분의 말락시닉산이 60% 에탄올 층에서 용출되므로 60% 에탄올 용출획분을 회전 감압농축기를 이용하여 1차 용출농축물(Amberlite XAD-2 C.C)을 얻었다. 얻어진 1차 용출농축물(23.8 g)로부터 유리당 등 극성화합물을 추가적으로 제거하기 위해, 소량의 물로 용해시켜 Diaion HP-20 (Mitsubishi chemical Industrial, Tokyo, Japan) 컬럼 (6.0 × 950 mm)에 흡착시킨 후, H2O/MeOH (H2O/MeOH = 100:0, 70:30, 40:60, 0:100, v/v) 각 3 L씩을 이용하여 step-wise법에 의해 용출시켰다. 얻어진 각 획분들 중 60% 에탈올 층에 대부분의 말락시닉산이 용출되므로, 60% 에탄올 용출획분을 회전 감압농축을 행하여 2차 용출농축물(Diaion HP-20)을 얻었다. 얻어진 2차 용출농축물(8.56 g)을 대상으로 H2O/MeOH = 20:80 (v/v)을 용출용매로 한 Sephadex LH-20 (70-230 mesh, Pharmacia, Sweden) 컬럼(50 × 900 mm)크로마토그래피에 의해 정제하였다. 얻어진 각 획분 중 Ve/Vt (elution volume/total volume) 0.84-1.03의 용출용액(Sephadex LH-20 C.C : 1.33 g, 말락시닉산의 순도 70%)이 말락시닉산의 주요 용출위치였다. 말락시닉산의 주요 용출획분인 Ve/Vt 0.84-1.03의 용출용액으로부터 고순도의 말락시닉산을 단리하기 위해 아마이드 컬럼(10 × 250 mm, 5 μm, Supelco, Bellefonte, PA, USA)이 연결된 시스템에서, H2O/MeCN 85:15 (v/v, TFA로 pH 2.65, A)와 70:30 (v/v, B)을 이용하여 A용액을 출발 용출용매로 하여 50분 후 B가 100%가 되도록 하여 10분간 유지시키는 용출계를 이용하였다. 그리고 254 nm (SPD-M20A, Shimadzu, Japan)의 파장과 유속 4.5 mL/min (LC-6AD, Shimadzu, Japan)의 조건으로 degaser (DGU-20A3, Shimadzu, Japan)가 장착되고, Shimadzu LC Solution의 프로그램이 설치된 분취용 고속액체크로마토그래피를 행하였다. 이 용출계에 있어 21분에 용출된 피크를 분취하여 노란색 분말형태의 화합물(793 mg)인 말락시닉산을 정제하였다. It was cultivated in Naju City, Jeollanam-do, 35 days after flowering. It was stored at -70 ℃ until the experiment. The filtrate (No. 2, Whatman) was placed in a dark room and in a dark room for 24 hours, and the residue was re-filtered with 60 L of 60% ethanol. (No. 2, Whatman). The obtained primary and secondary filtrates were combined and concentrated under reduced pressure at 38 DEG C to obtain a concentrate (Solvent extraction). The concentrate (1081.9 g) was dissolved in water (10 L) to give a suspension. The resulting suspension was adjusted to pH 3.0 with 1 N hydrochloric acid. The acid-regulated suspension was subjected to solvent fractionation by repeating 3 times with 10 L of ethyl acetate, and then fractionated into a water layer and an ethyl acetate layer (Solvent fractionation). An organic solvent layer containing malachic acid, i.e., ethyl acetate layer (134.75 g) was concentrated under reduced pressure to obtain a concentrate for purification. Thereafter, the concentrate for purification was purified by using 6 L of H 2 O / EtOH solvent system (H 2 O / EtOH = 100: 0, 80:20, 40:60, 0: 100, v / v) (40-60 mesh, Bellefonte PA, USA) column (9.0x900 mm) by the -Wise elution method. As shown in FIG. 4 and FIG. 5, most of the malicyclic acid was eluted from the 60% ethanol layer. Thus, the 60% ethanol eluting fraction was subjected to the first elution concentrate (Amberlite XAD-2 CC) using a rotary evaporator. In order to further remove the polar compound from the first eluting concentrate (23.8 g) obtained, it was dissolved in a small amount of water and adsorbed on a Diaion HP-20 (Mitsubishi Chemical Industrial, Tokyo, Japan) column (6.0 × 950 mm) And 3 L each of H 2 O / MeOH (H 2 O / MeOH = 100: 0, 70:30, 40:60, 0: 100, v / v) were eluted by a step-wise method. Since 60% of the obtained fractions eluted most of the malicyclic acid into the deionized layer, the 60% ethanol eluting fraction was concentrated by rotary evaporation to obtain a second elution concentrate (Diaion HP-20). The second elution concentrate (8.56 g) thus obtained was subjected to column chromatography (Sephadex LH-20 (70-230 mesh, Pharmacia, Sweden) column (50 占 ×) using H 2 O / MeOH = 20:80 900 mm) chromatography. Among the obtained fractions, elution solution (Sephadex LH-20 CC: 1.33 g, maliconic acid purity: 70%) of Ve / Vt (elution volume / total volume) of 0.84-1.03 was the main release site of malacicinic acid. A system (10 × 250 mm, 5 μm, Supelco, Bellefonte, PA, USA) was connected in order to isolate high purity malic acid from the elution solution of Ve / Vt 0.84-1.03 which is the main eluting fraction of malacic acid , B was 100% after 50 minutes with A solution as starting elution solvent using H 2 O / MeCN 85:15 (v / v, pH 2.65, A with TFA) and 70:30 (v / v, And maintained for 10 minutes. (DGU-20A3, Shimadzu, Japan) was mounted at 254 nm (SPD-M20A, Shimadzu, Japan) with the wavelength and flow rate of 4.5 mL / min (LC-6AD, Shimadzu, Japan) And then subjected to preparative high performance liquid chromatography equipped with a program. In this elution system, eluted peaks at 21 minutes were aliquoted to purify malaconic acid as a yellow powdery compound (793 mg).
실험예 1Experimental Example 1
지방세포분화 및 말락시닉산의 지방세포에 대한 독성 측정. Adipocyte Differentiation and Toxicity Measurement of Malic Acidic Acid to Adipocytes.
말락시닉산의 지방세포 내 세포독성을 평가하기 위하여 엠티티[(3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨브로마이드, 3-(4,5-dimethyl thiazol -2-yl)-2,5-diphenyltetrazolium bromide, MTT] 분석법을 이용하였다. 본 발명에서는 쥐 지방세포인 3T3-L1 세포를 사용하였으며, 배양은 Dulbecco's modified Eagle's medium (DMEM)배지에 10% fetal bovine serum (FBS) 및 1% 페니실린-스트렙토마이신 항생제 용액을 첨가하여 37℃ 및 5% 이산화탄소 조건에서 배양되었다. (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, 3- (4,5-dimethylthiazol-2-yl) 3T3-L1 cells were used in the present invention. The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin antibiotic solution were added and cultured at 37 ° C and 5% carbon dioxide conditions.
지방세포에 실시예에서 얻어진 말락시닉산을 농도별(0, 3, 10, 30 및 100μM)로 처리하면서 분화를 유도하였다. 분화유도는 분화유도배지[0.5 μM IBMX (3-isobutyl-1-methylxanthine), 1 μM dexamenthason 및 10 μg/mL insulin을 함유]를 이용하여 실시하였다. 분화를 유도하지 않은 지방세포[지방전구세포(pre-adipocyte)]를 음성대조군으로 하였으며, 분화를 유도한 지방세포[지방분화세포(adipocyte)]에 말락시닉산을 처리하지 않은 지방세포를 양성대조군으로 하였다. Differentiation was induced by treating malicocinic acid obtained in the examples in fat cells with concentrations (0, 3, 10, 30 and 100 μM). Differentiation induction was carried out using differentiation induction medium [0.5 μM IBMX (3-isobutyl-1-methylxanthine), 1 μM dexamethasone and 10 μg / mL insulin]. Adipocytes that did not induce differentiation (pre-adipocyte) were used as a negative control. Adipocytes that did not undergo malacicnic acid treatment in the adipocytes that induced differentiation (adipocyte) Respectively.
지방세포에 대한 말락시닉산의 독성을 평가하기 위하여, 3T3-L1 세포주를 96-웰 플레이트에 접종한 다음, 48시간 동안 말락시닉산을 3-100 μM 농도로 각각 처리하였다. 시료 처리 후 MTT를 0.5 mg/mL 농도가 되도록 첨가하였으며, 2시간 동안 37℃ 및 5% 이산화탄소 조건에서 배양하였다. 배양 종료 후, 상층액을 제거하고 인산완충용액(phosphate buffered saline, PBS)으로 세척을 행한 다음, 각 웰에 디메틸설폭사이드(dimethylsulfoxide, DMSO)를 100 μL 가한 후, 흡광도 분석기(Biotek, Wknooski, VT, USA)를 이용하여 540 nm의 파장에서 흡광도를 측정하였다. 세포 생존도는 화합물을 처리하지 않은 대조군의 세포주를 이용하여 백분율로 계산하였고 그 결과를 도 2에 나타내었다.To evaluate the toxicity of malacicnic acid to adipocytes, 3T3-L1 cell lines were inoculated into 96-well plates and then treated with malic acid at a concentration of 3-100 μM for 48 hours. MTT was added at a concentration of 0.5 mg / mL after the sample treatment and incubated for 2 hours at 37 ° C and 5% carbon dioxide. After the completion of the incubation, the supernatant was removed and washed with phosphate buffered saline (PBS). Then, 100 μL of dimethylsulfoxide (DMSO) was added to each well, and the resultant was analyzed with an absorbance analyzer (Biotek, Wknooski, VT , USA) was used to measure the absorbance at a wavelength of 540 nm. The cell viability was calculated as a percentage using a cell line of the control group not treated with the compound. The results are shown in Fig.
도 2에 나타난 바와 같이, 말락시닉산은 0-100 μM 처리농도에서 지방세포에 대해 어떠한 독성도 관찰되지 않았다As shown in Fig. 2, malicyclic acid showed no toxicity to adipocytes at a treatment concentration of 0-100 [mu] M
실험예 2Experimental Example 2
말락시닉산의 지방세포 내 지방축적 억제활성 측정.Measurement of fatty acid accumulation inhibitory activity of malacicnic acid in adipocytes.
분화를 마친 지방세포에 배양액을 제거하고 PBS로 세포주를 세척한 후, 4% 포말린(formalin)을 가하여 1시간 동안 세포를 고정시켰다. 그 후 오일 레드 오(Oil Red O, Sigma-Aldrich; 0.05 g in 60% 이소프로판올) 용액을 넣고 상온에서 1시간 동안 세포를 염색하였다. 염색된 cell은 현미경(inverted microscope)을 이용하여 세포내 지방 축적정도를 사진으로 기록하여 도 3에 제시하였으며, 사진 촬영 후 염색된 cell은 100% 이소프로판올로 추출하여 지방세포 전체에 축적된 지방의 양을 500 nm 파장에서의 흡광도로 비교ㆍ평가하여 그 결과를 그래프로 도 4에 도시하였다.The cells were washed with PBS and the cells were fixed with 4% formalin for 1 hour. Then, a solution of Oil Red O (Sigma-Aldrich; 0.05 g in 60% isopropanol) was added and the cells were stained at room temperature for 1 hour. The stained cells were photographed with a microscope (inverted microscope) to record the degree of accumulation of intracellular fat. The stained cells were extracted with 100% isopropanol to measure the amount of accumulated fat With an absorbance at a wavelength of 500 nm, and the results are shown in FIG. 4 as a graph.
도 3으로부터, 음성대조구(지방전구세포)에 비하여 양성대조구(지방분화세포)에 과도한 지방이 축적되었음이 확인되었다. 반면, 말락시닉산을 처리한 지방분화세포로부터 농도의존적으로 지방축적이 억제됨이 현상학적으로 관찰되었다. 이어 염색된 지방세포를 이소프로판올로 추출한 다음, 지방세포 전체의 지방축적을 확인한 결과, 도 4에 도시된 바와 같이, 지방분화세포에 말락시닉산을 무처리한 군(양성대조구)을 100%으로 하였을 때, 말락시닉산을 30 및 100 μM 처리한 지방분화세포에서 약 25-30% 정도 지방축적이 억제됨이 확인되었다. 3, it was confirmed that excessive fat was accumulated in the positive control (fat-differentiated cells) as compared with the negative control (fat precursor cells). On the other hand, fat accumulation was inhibited by malacic acid - treated lipid - differentiated cells in a concentration - dependent manner. The dyed adipocytes were then extracted with isopropanol and the fat accumulation of the whole adipocytes was examined. As shown in Fig. 4, 100% of the malignant acid-treated group (positive control) was added to the fat-differentiated cells , It was confirmed that fat accumulation was inhibited by about 25-30% in malignant acidic cells treated with 30 and 100 μM of adipose differentiated cells.
실험예 3Experimental Example 3
mRNA수준에서 말락시닉산의 지방세포 내 지방분화 조절인자의 발현 및 활성에 미치는 효과 확인. Identification of the effect of malacicnic acid on the expression and activity of adipogenic differentiation regulators in adipocytes at the mRNA level.
실험예 3과 4에서 행해진 mRNA 및 단백질 수준에서의 말락시닉산의 지방세포 내 지방분화 조절인자의 발현 및 활성에 미치는 효과 확인은 단일화합물의 합리적인 처리농도를 고려하여 100 μM 처리군을 제외한 3, 10, 및 30 μM 처리군을 이용하여 행하였다. 이에, 말락시닉산의 지방세포 내 지방분화 조절인자의 발현 및 활성에 미치는 효과를 mRNA수준에서 다음과 같이 확인하여 그 결과를 도 5에 나타내었다.The effect of malacicinic acid on the expression and activity of lipoprotein regulatory factors in mRNA and protein levels in Experimental Examples 3 and 4 was evaluated in terms of the effect of 3, 10, and 30 μM treatment groups. Thus, the effects of malacicnic acid on the expression and activity of lipoprotein regulatory factors in adipocytes were confirmed as follows at the level of mRNA, and the results are shown in FIG.
Total RNA는 지방세포로부터 트라이졸(Trizol, Invitrogen Corp. Carlsbad, CA, USA)을 이용하여 분리하였으며, iscript cDNA synthesis kit (Bio-Rad)를 이용해 cDNA를 합성한 후 SYBR Green Master Mix와 유전자 특이적 primer를 이용해 real-time PCR을 행하였다. mRNA 발현량은 comparative threshold cycle 방법으로 계산하고, 이때 control 유전자인 ribosomal 단백질 Large, P0 (RPLP0) 값으로 normalization하여 보정하였다. 본 발명에서 사용된 primer squence들은 아래 표 1에 제시한 바와 같다. 하기 표 1에서 사용된 약어에 대한 설명은 다음과 같다. C/EBP, CCAAT-enhancer-binding proteins α; FABP4, fatty acid-binding protein 4; FASN, fatty acid synthase; PPARγ, Peroxisome proliferator-activated receptor γ; RPLP0, ribosomal protein, Large, P0. Total RNA was isolated from adipocytes using a triazole (Trizol, Invitrogen Corp., Carlsbad, CA, USA) and cDNA was synthesized using iscript cDNA synthesis kit (Bio-Rad) Real-time PCR was performed using primers. The amount of mRNA expression was calculated by a comparative threshold cycle method and normalized by the control gene Large, P0 (RPLP0). The primer squans used in the present invention are as shown in Table 1 below. The abbreviations used in the following Table 1 are as follows. C / EBP, CCAAT-enhancer-binding proteins α; FABP4, fatty acid-binding
mRNA수준에서 말락시닉산의 지방세포 내 지방분화 조절인자의 발현 및 활성에 미치는 효과 확인 실험 결과, mRNA 수준에서 음성대조군에 비하여 양성대조군에서 지방세포 분화촉진인자인 PPARγ와 C/EBPα의 발현이 현저히 증가함이 관찰되었다. 반면, 말락시닉산을 처리한 결과, 농도의존적으로 PPARγ와 C/EBPα의 발현량이 유의하게 감소됨이 관찰되었다. 그리고 지방합성에 관여하는 유전자인 FABP4 및 FASN 또한 말락시닉산을 처리하였을 때, 양성대조군에 비하여 발현량이 농도의존적으로 감소함이 관찰되었다.mRNA levels of malacicnic acid in the adipocyte showed that the expression of PPARγ and C / EBPα, which are promoters of adipocyte differentiation in the positive control group, was significantly higher than that of the negative control group at the mRNA level . On the other hand, as a result of treatment with malic acidic acid, the expression levels of PPARγ and C / EBPα were significantly decreased in a concentration-dependent manner. FABP4 and FASN, which are involved in lipogenesis, also showed a dose - dependent decrease in the expression level of malacicinic acid compared with the positive control.
실험예 4Experimental Example 4
단백질 수준에서 말락시닉산의 지방세포 내 지방분화 조절 인자의 발현 및 활성에 미치는 효과 확인.Effect of Malacicinic Acid on the Expression and Activity of Fatty Differentiation Regulators in Adipocytes at Protein Levels.
말락시닉산이 지방세포 내 지방분화 조절 인자의 발현 및 활성에 미치는 효과를 단백질수준에서 다음과 같이 확인하여 그 결과를 도 6에 나타내었다.The effect of malaconic acid on the expression and activity of lipoprotein regulatory factors in adipocytes was confirmed at the protein level as follows, and the results are shown in Fig.
지방세포로부터 단백질을 추출하기 위하여 차가운 PBS로 두 차례 세척한 다음, 원심분리(1,000 × g, 4℃, 8 분)를 행하여 pellet을 분리하였다. Pellet은 extraction buffer (radioimmunoprecipitation assay buffer with protease and ptoteasome inhibitors)로 resuspend하고 4℃에서 15분간 반응한 다음, 울트라 소니케이터(UH-50, SMT Company, Tokyo, Japan)를 이용하여 균질화하였다. 반응액은 원심분리(20,000 × g, 4℃, 10분)를 행한 후 얻어진 상층액(단백질)을 immunoblotting에 이용하였다. 단백질은 8% 또는 10% (v/v) sodiumdodecylsulfate polyacrylamide gell electrophoresis (SDS-PAGE)를 수행하여 분리하였으며, gel을 PVDF membrane에 transfer하였다. Transfer된 membrane은 1시간 동안 실온에서 blocking buffer (5% skim milk in TBS-T)에 의해 blocking되고, 그 후 membrane을 anti-C/EBPα (Cell Signaling Technology, Beverly, MA, USA), anti-PPARγ (Santa Cruz Biotechnology, Dallas, TX), anti FASN (Cell Signalling Technology), 그리고 β-actin (Santa Cruz Biotechnology)의 primary antibody solution으로 4℃에서 12시간 이상 반응하였다. 이어 secondary antibody solution (Santa Cruz Biotechnology)으로 1시간 동안 실온에서 incubation 한 후, ECL detection reagent로 반응시키고 단백질 발현을 확인하였다. To extract proteins from adipocytes, the cells were washed twice with cold PBS and centrifuged (1,000 × g , 4 ° C, 8 min) to separate the pellet. Pellet was resuspended in extraction buffer (radioimmunoprecipitation assay buffer with protease and ptoteasome inhibitors), reacted at 4 ° C for 15 minutes, and homogenized using an ultrasonic cooker (UH-50, SMT Company, Tokyo, Japan). The reaction solution was subjected to centrifugation (20,000 × g , 4 ° C., 10 minutes), and the obtained supernatant (protein) was used for immunoblotting. Proteins were separated by 8% or 10% (v / v) sodium dodecylsulfate polyacrylamide gell electrophoresis (SDS-PAGE) and gels were transferred to a PVDF membrane. The membranes were blocked with blocking buffer (5% skim milk in TBS-T) at room temperature for 1 hour and then the membranes were incubated with anti-C / EBPα (Cell Signaling Technology, Beverly, (Santa Cruz Biotechnology, Dallas, TX), anti-FASN (Cell Signaling Technology) and β-actin (Santa Cruz Biotechnology) primary antibody solutions at 4 ° C for 12 hours or more. After incubation with secondary antibody solution (Santa Cruz Biotechnology) for 1 hour at room temperature, the protein was reacted with ECL detection reagent.
그 결과, 도 6에 나타낸 바와 같이 단백질 수준에서도 말락시닉산은 지방세포의 분화촉진에 관여하는 PPARγ와 C/EBPα의 발현을 억제함이 관찰되었다. 즉, 음성처리군에 비하여 증가되었던 양성처리군의 PPARγ와 C/EBPα의 발현량이 말락시닉산을 처리하였을 때, 농도의존적으로 발현량이 억제됨이 확인되었다. 또한 지방합성에 관여하는 유전자인 FASN의 발현 또한 말락시닉산을 처리하였을 때 농도의존적으로 감소됨이 확인되었다. 이상의 결과들로부터 말락시닉산은 지방분화에 관여하는 유전자를 조절함으로써 지방세포 내 분화촉진을 억제함이 확인되었다. As a result, as shown in FIG. 6, malic acid also inhibited the expression of PPARγ and C / EBPα, which are involved in the promotion of differentiation of adipocytes, at the protein level. In other words, it was confirmed that the expression level of PPARγ and C / EBPα in the positive treatment group, which was increased compared with the negative treatment group, was suppressed in a dose dependent manner when malacicnic acid was treated. In addition, the expression of FASN, a gene involved in lipogenesis, was also found to decrease in a dose dependent manner when malacicinic acid was treated. From these results, it was confirmed that malacic acid suppresses the promotion of differentiation into adipocytes by regulating genes involved in lipid differentiation.
상술된 실험결과들은 화학식 1을 갖는 말락시닉산이 지방세포 내에서 분화를 촉진하는 PPARγ와 C/EBPα의 발현을 조절함으로써 지방합성 유전자 발현을 억제시켜 지방세포 내 지방축적억제활성을 갖는 것을 보여준다. The above-mentioned experimental results show that malacicnic acid having the formula (1) inhibits lipid synthesis gene expression by controlling the expression of PPARγ and C / EBPα promoting differentiation in adipocytes, and thus has an activity of inhibiting fat accumulation in adipocytes.
따라서, 말락시닉산 및/또는 이의 약리학적으로 허용되는 염을 유효성분으로 포함하는 약학조성물 및 건강기능성식품은 지방세포의 증식 및 분화 억제활성을 갖게 되므로, 본 발명과 같이 말락시닉산 및/또는 이의 약리학적으로 허용되는 염을 유효성분으로 포함하도록 하여 지방세포 증식 및 분화를 통해 발생되는 비만과 같은 지방대사성 질환 개선용 약학조성물 및 건강기능성 식품을 제조할 수 있음을 알 수 있다.Therefore, the pharmaceutical composition and the health functional food comprising malic acidic acid and / or pharmacologically acceptable salt thereof as an active ingredient have an activity of inhibiting the proliferation and differentiation of adipocytes. Therefore, malic acid and / A pharmacologically acceptable salt thereof as an active ingredient and a pharmaceutical composition for improving fat metabolic diseases such as obesity which are generated through adipocyte proliferation and differentiation and a health functional food can be produced.
본 발명은 이상에서 살펴본 바와 같이 바람직한 실시 예를 들어 도시하고 설명하였으나, 상기한 실시 예에 한정되지 아니하며 본 발명의 정신을 벗어나지 않는 범위 내에서 당해 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 다양한 변경과 수정이 가능할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, Various changes and modifications will be possible.
Claims (7)
A pharmaceutical composition for anti-obesity comprising at least one of malic acid and its pharmaceutically acceptable salt as an active ingredient.
상기 말락시닉산은 지방세포의 증식 및 분화억제활성을 갖는 것을 특징으로 하는 항비만용 약학조성물.
The method according to claim 1,
Wherein said malacic acid has an activity of inhibiting proliferation and differentiation of adipocytes.
상기 말락시닉산은 지방세포의 분화에 관여하는 퍼옥시좀 증식체 활성화 수용체(peroxisome proliferator-activated receptors-γ, PPARγ), C/EBPα (CCAAT/enhancer-binding protein-α), FABP4 (fatty acid-binding protein) 및 FASN (fatty acid synthase)으로 구성되는 그룹에서 선택되는 하나 이상의 발현을 감소시키는 활성을 갖는 것을 특징으로 하는 항비만용 약학조성물.
The method according to claim 1,
The malic cyclic acid may be a peroxisome proliferator-activated receptor-γ (PPARγ), C / EBPα (CCAAT / enhancer-binding protein-α), FABP4 (fatty acid- binding protein, and FASN (fatty acid synthase). < Desc / Clms Page number 14 >
상기 말락시닉산은 배 및 배미성숙과를 포함하는 배미활용자원 중 하나 이상으로부터 분리된 것을 특징으로 하는 항비만용 약학조성물.
The method according to claim 1,
Wherein said malacicnic acid is isolated from one or more of abiotic utilization resources comprising abdomen and abdomen.
An anti-obesity health functional food comprising at least one of malic acid and its pharmaceutically acceptable salt as an active ingredient.
분말, 과립, 정제, 캡슐 및 음료 중 어느 하나의 제형을 갖는 것을 특징으로 하는 항비만용 건강기능성식품.
6. The method of claim 5,
Characterized in that it has a formulation of any one of powder, granule, tablet, capsule and beverage.
상기 말락시닉산은 배 및 배미성숙과를 포함하는 배미활용자원 중 하나 이상으로부터 분리된 것을 특징으로 하는 항비만용 건강기능성식품.6. The method of claim 5,
Wherein said malacicnic acid is isolated from at least one of abiotic utilization resources, including abalone and abalone.
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