KR20120021358A - A composition comprising mollugin isolated from an extract of rubiae radix for preventing and treating obesity - Google Patents
A composition comprising mollugin isolated from an extract of rubiae radix for preventing and treating obesity Download PDFInfo
- Publication number
- KR20120021358A KR20120021358A KR1020100072777A KR20100072777A KR20120021358A KR 20120021358 A KR20120021358 A KR 20120021358A KR 1020100072777 A KR1020100072777 A KR 1020100072777A KR 20100072777 A KR20100072777 A KR 20100072777A KR 20120021358 A KR20120021358 A KR 20120021358A
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- South Korea
- Prior art keywords
- mollugin
- extract
- isolated
- cells
- composition
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
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Abstract
Description
본 발명은 천초근 추출물로부터 분리되는 몰루긴을 유효성분으로 함유하는 비만의 예방 및 치료용 조성물에 관한 것이다. The present invention relates to a composition for the prevention and treatment of obesity containing mollugin isolated from Cheoncho root extract as an active ingredient.
[문헌 1] Visscher TL, Seidell JC. 2001. The public health impact of obesity. Annu Rev Public Health . 22: pp.355-375
[문헌 2] Rayalam S, Della-Fera MA, Baile CA. 2008. Phytochemicals and regulation of the adipocyte life cycle. J. Nutr . Biochem . 19, PP. 717-726.[Reference 2] Rayalam S, Della-Fera MA, Baile CA. 2008. Phytochemicals and regulation of the adipocyte life cycle. J. Nutr . Biochem . 19, pp. 717-726.
[문헌 3] Camp HS, Ren D, Leff T. 2002. Adipogenesis and fat-cell function in obesity and diabetes. Trends Mol . Med . 8: pp.442-447.Camp HS, Ren D, Leff T. 2002. Adipogenesis and fat-cell function in obesity and diabetes. Trends Mol . Med . 8 : pp. 442-447.
[문헌 4] Gregoire FM. 2001. Adipocyte differentiation: from fibroblast to endocrine cell. Exp . Boil . Med . ( Maywood ) 226: pp.997-1002Document 4 Gregoire FM. 2001. Adipocyte differentiation: from fibroblast to endocrine cell. Exp . Boil . Med . ( Maywood ) 226 : pp.997-1002
[문헌 5] El-hady, S.; Bukuru,J.; Kesteleyn, B.; Kesteleyn, B.; Puyvelde, L. V.; Van, T. N.; Kimpe, N. D.2002, J. Nat. Prod. 65,1377.[Reference 5] El-hady, S .; Bukuru, J .; Kesteleyn, B .; Kesteleyn, B .; Puyvelde, L. V .; Van, T. N .; Kimpe, N. D. 2002, J. Nat. Prod. 65,1377.
[문헌 6] Kim SM, Park HS, Jun do Y, Woo HJ, Woo MH, Yang CH, Kim YH. 2009a. Mollugin induces apoptosis in human Jurkat T cells through endoplasmic reticulum stress-mediated activation of JNK and caspase-12 and subsequent activation of mitochondria-dependent caspase cascade regulated by Bcl-xL. Toxicol Appl . Pharmacol . 241: pp.210-220.[Reference 6] Kim SM, Park HS, Jun do Y, Woo HJ, Woo MH, Yang CH, Kim YH. 2009a. Mollugin induces apoptosis in human Jurkat T cells through endoplasmic reticulum stress-mediated activation of JNK and caspase-12 and subsequent activation of mitochondria-dependent caspase cascade regulated by Bcl-xL. Toxicol Appl . Pharmacol . 241 : pp. 210-220.
[문헌 7] Kim KJ, Lee JS, Kwak MK, Choi HG, Yong CS, Kim JA, Lee YR, Lyoo WS, Park YJ. 2009b. Anti-inflammatory action of mollugin and its synthetic derivatives in HT-29 human colonic epithelial cells is mediated through inhibition of NF-kappaB activation. Eur . J. Pharmacol . 622: pp.52-57.
[문헌 8] Son JK, Jung SJ, Jung JH, Fang Z, Lee CS, Seo CS, Moon DC, Min BS, Kim MR, Woo MH. 2008. Anticancer constituents from the roots of Rubia cordifolia L. Chem . Pharm . Bull . ( Tokyo ). 56: pp.213-216.[Reference 8] Son JK, Jung SJ, Jung JH, Fang Z, Lee CS, Seo CS, Moon DC, Min BS, Kim MR, Woo MH. 2008.Anticancer constituents from the roots of Rubia cordifolia L. Chem . Pharm . Bull . ( Tokyo ) . 56 : pp. 213-216.
[문헌 9] Lee JE, Hitotsuyanagi Y, Fukaya H, Kondo K, Takeya K. 2008, New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L. Chem. Pharm. Bull (Tokyo). 56(5), PP. 730-733.[9] Lee JE, Hitotsuyanagi Y, Fukaya H, Kondo K, Takeya K. 2008, New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L. Chem. Pharm. Bull (Tokyo). 56 (5), PP. 730-733.
[문헌 10] Zamzami N, Marchetti P, Castedo M, Zanin C, VayssiJL, Petit PX, Kroemer G. 1995. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J. Exp . Med . 181: pp.1661-167210 Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssi JL, Petit PX, Kroemer G. 1995. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J. Exp . Med . 181 : pp.1661-1672
[문헌 11] Jun DY, Kim JS, Park HS, Han CR, Fang Z, Woo MH, Rhee IK, Kim YH. 2007. Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade. Carcinogenesis . 28: pp.1303-1313.[Reference 11] Jun DY, Kim JS, Park HS, Han CR, Fang Z, Woo MH, Rhee IK, Kim YH. Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade. Carcinogenesis . 28 : pp. 1303-1313.
최근 비만 관련 연구에 의하면 체내로 섭취한 과잉의 에너지원이 지방으로 축적되어 비만이 진행되면 그 결과 인슐린 내성 획득에 따른 제2형 당뇨병, 고지혈증, 지방간, 고혈압, 동맥경화, 심혈관 질환등과 만성 혹은 대사성 질환이 수반되는 것으로 알려졌다. 따라서 비만의 기전 규명, 그리고 치료 및 예방을 위한 항비만 연구가 활발히 수행되고 있다(Visscher TL and Seidell JC., Annu . Rev . Public Health 22 pp. 355 - 375, 2001). 뿐만 아니라 인체 노화가 진행됨에 따라 비지방 세포인 근육세포나 bone marrow등에 지방이 축적되어 나타나는 근육감소증 (sarcopenia) 혹은 골다공증 등의 질환으로 발전하는 노인성 비만을 비롯하여 경제발전과 식생활의 서구화와 같은 생활 패턴의 변화에 기인하는 소아 비만도 심각한 사회적 문제로 등장하고 있어서 비만에 대한 인식이 점차 확대되고 있다. 비만에 수반되어 증가하는 지방 조직 (fat tissues)의 대표적 구성세포로서 지방세포가 알려져 있다. 지방세포의 분화 및 성숙지방세포내의 지방의 축적현상이 비만에 관련한 지방조직의 증가의 요인이 되며, 또한 성숙지방세포에 의해 분비되는 아디포카인 (adipokines)은 당대사와 에너지대사의 조절인자로 작용하여 인슐린 내성, 제2형 당뇨, 동맥경화 등의 만성 대사성 질환 유발에 핵심적인 역할을 수행하는 것으로 알려졌다. Recent studies on obesity have shown that excess energy sources in the body accumulate in fat and obesity progresses, resulting in
비만 억제 연구 분야는 크게 대사촉진제, 식욕억제제, starch blocker, diet와 직접적인 관계가 깊은 glucose/insulin 대사 관련 제제, 지방대사 및 oxidative stress 억제제, serum triglyceride level 억제제와 지방세포분화 억제제로 구분할 수 있다. 이들 연구 분야 중에서 지방세포분화 (adipogenesis)의 억제 및 fat mass 억제를 타켓으로 하는 항비만 연구 분야가 매우 효과적이므로 이와 연관된 항비만 관련 물질을 식용 및 약용식물에서 찾고자 많은 노력을 기울이고 있다(Rayalam S et al., J. Nutr . Biochem. 19, pp 717-726, 2008).Obesity inhibition research can be divided into metabolic accelerators, appetite suppressants, starch blockers, glucose / insulin metabolism-related agents, fat metabolism and oxidative stress inhibitors, serum triglyceride level inhibitors and adipocyte differentiation inhibitors. Among these research fields, anti-obesity research aimed at suppressing fat cell differentiation and fat mass inhibition is very effective. Therefore, much effort has been made to find related anti-obesity substances in edible and medicinal plants (Rayalam S et. al., J. Nutr . Biochem . 19, pp 717-726, 2008).
현재 항비만 연구에 많이 이용되고 있는 대표적인 in vitro 모델계는 마우스 유래 3T3-L1 전지방세포 (preadipocytes)에 isobutylmethylxanthine (IBMX), 인슐린 및 덱사메타손을 처리하여 성숙지방세포로의 분화를 유도하는 것이다. 이때 adipocyte-specific gene-CCAAT/enhancer binding protein (C/EBP) 유전자와 peroxisome proliferator activated receptor γ (PPARγ1, γ2) 유전자의 발현이 증가하면서 섬유아세포 형태의 세포가 구형 형태의 성숙지방세포로 분화되고, 과잉의 지방을 축적하는 특징을 보이게 된다(Camp HS et al., Trends Mol . Med ., 8, pp. 442-447, 2002; Gregoire FM., Exp . Boil . Med .(Maywood) 226, PP. 997-1002, 2001). 따라서 지방세포에서의 C/EBP 유전자와 PPARγ 유전자 발현의 억제는 지방세포에 의해 매개되는 질병의 기전과 치료, 나아가서는 예방에 있어서 중요한 타겟이 될 수 있다.Representative in which is currently used in anti-obesity research In vitro model systems induce differentiation into mature adipocytes by treating isobutylmethylxanthine (IBMX), insulin and dexamethasone in mouse-derived 3T3-L1 preadipocytes. At this time, as the expression of adipocyte-specific gene-CCAAT / enhancer binding protein (C / EBP) gene and peroxisome proliferator activated receptor γ (PPARγ1, γ2) is increased, fibroblast-like cells differentiate into spherical mature fat cells. It is characterized by the accumulation of excess fat (Camp HS et al., Trends Mol . Med ., 8, pp. 442-447, 2002; Gregoire FM., Exp . Boil . Med . (Maywood) 226, pp. 997-1002, 2001). Therefore, inhibition of C / EBP gene and PPARγ gene expression in adipocytes may be an important target in the mechanism, treatment and further prevention of disease mediated by adipocytes.
천초근은 한국과 중국에서 오랜 기간 동안 항산화, 항암, 항염증활성과 관련하여 관절염, 요결석 제거, 기관지염 치료에 사용되어 온 한약재이다. 천초근 추출물의 생리활성에 대한 연구에 따르면, 항균, antiplatelet aggregation activity, 항바이러스, 항산화, 항염증 및 항암 활성을 가지는 것으로 보고되었다. 천초근 추출물로부터 분리 동정된 몰루긴은 분자량 284의 물질(Son JK et al., Chem . Pharm. Bull(Tokyo), 56(2), PP. 213-216, 2008)이다. 몰루긴(mollugin)을 포함한 벤조크로멘(benzochromenes) 골격을 가진 나프토퀴논 물질은 자연에서 널리 발견되어 보고되었다. 중국 및 인도에서는 약용식물 갈퀴꼭두서니(Rubia cordifolia)로부터, 유럽과 아프리카에서는 꼭두서니과 허브(rubiaceous herbs) 흰갈퀴덩굴(Galium moll ugo)에서 보고되었으며, 열대 동부아프리카에서는 중요한 약용식물로 알려진 펜타스 롱기플로라(Pentas longiflora)에서 몰루긴과 몰루긴의 유도체인 시스-3,4-디히드록-3,4- 디히드로몰루긴과 트랜스-3,4-디히드록-3,4-디히드로몰루긴이 추출되었다(El-hady S et al., J. Nat. Prod. 65,PP.1377,2002). 몰루긴의 생리활성은 암세포 독성과 연관된 항암 활성(Kim SM et al., , Toxicol Appl . Pharmacol . 241, PP. 210-220, 2009)과 항염증(Kim KJ et al., Eur . J. Pharmacol . 622, PP. 52-57, 2009) 활성에 대한 연구 보고는 있으나 천초근 유래 몰루긴의 항비만 활성에 대한 연구는 국내외에 아직 보고된 바 없다. Chun Cho Geun has been used in Korea and China for a long time in the treatment of arthritis, urolithiasis and bronchitis in relation to antioxidant, anticancer and anti-inflammatory activity. Studies on the physiological activity of Cheoncho Geun extract have been reported to have antimicrobial, antiplatelet aggregation activity, antiviral, antioxidant, anti-inflammatory and anticancer activity. Molugin isolated and isolated from Cheoncho-geun extract is a substance of molecular weight 284 (Son JK et al., Chem . Pharm. Bull (Tokyo), 56 (2), PP. 213-216, 2008). Naphthoquinone substances with benzochromenes backbone, including mollugin, have been widely found and reported in nature. Pentasis longgiflora (Rubia cordifolia) has been reported in China and India, and in rubiaceous herbs (Galium moll ugo) in Europe and Africa, and Pentas longiflora, known as an important medicinal plant in tropical eastern Africa. Pentas longiflora) cis-3,4-dihydroxy-3,4-dihydromolugin and trans-3,4-dihydroxy-3,4-dihydromolugin, derivatives of molugin and molugin Extracted (El-hady S et al., J. Nat. Prod. 65, PP. 1377, 2002). Molugin's physiological activity is associated with anticancer activity associated with cancer cytotoxicity (Kim SM et al., Toxicol). Appl . Pharmacol . 241, pp. 210-220, 2009) and anti-inflammatory activity (Kim KJ et al., Eur . J. Pharmacol . 622, PP. 52-57, 2009). The study has not been reported at home or abroad.
따라서, 본 발명자는 천초근 추출물로부터 분리되는 몰루긴이 지방세포의 아포토시스를 유발할 뿐 아니라, 지방 세포 분화 유도 유전자인 C/EBP 유전자와 PPARγ 유전자 발현의 저해를 통한 지방구 형성 억제, 그리고 지방세포 및 성숙지방세포에 대한 세포사멸효과를 나타냄을 관찰하여 비만에 대한 탁월한 효과가 있음을 확인함으로써 본 발명을 완성하게 되었다. Therefore, the present inventors not only induces apoptosis of adipocytes, but also inhibits adipocyte formation by inhibiting the expression of C / EBP gene and PPARγ gene, which induces adipocyte differentiation, and adipocytes and The present invention was completed by observing the effect of apoptosis on mature fat cells and confirming that there is an excellent effect on obesity.
상기 목적을 달성하기 위하여, 천초근 추출물 또는 이로부터 분리되는 몰루긴을 유효성분으로 함유하는 비만의 예방 및 치료용 약학조성물을 제공한다.In order to achieve the above object, it provides a pharmaceutical composition for the prevention and treatment of obesity, containing cheoncho root extract or mollugin isolated from it as an active ingredient.
또한 본 발명은, 천초근 추출물로부터 분리되는 몰루긴을 유효성분으로 함유하는 비만의 예방 및 개선용 건강기능식품을 제공한다.In another aspect, the present invention provides a dietary supplement for the prevention and improvement of obesity containing mollugin isolated from the extract of Cheoncho root as an active ingredient.
본원에서 정의되는 추출물은 정제수를 포함한 물, 에탄올, 메탄올, 부탄올과 같은 저급 알콜 또는 이들의 혼합용매, 바람직하게는 물 및 메탄올 혼합용매, 보다 바람직하게는 50% 내지 100% 메탄올에 가용한 추출물을 포함한다.Extracts as defined herein include extracts available in water, including purified water, lower alcohols such as ethanol, methanol, butanol, or mixed solvents thereof, preferably water and methanol mixed solvents, more preferably 50% to 100% methanol. Include.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 몰루긴은 천초근 등의 식물 추출물로부터 당업계에 잘 알려진 추출 및 분리방법을 통하여 분리가능하거나 상용으로 구입가능하다.Molugin of the present invention is separable or commercially available from extracts and separation methods well known in the art from plant extracts, such as Cheoncho root.
예를 들어, 본 발명의 천초근 추출물로부터 상기 화합물을 수득하는 방법을 상세히 설명한다.For example, the method for obtaining the compound from the myelin extract of the present invention will be described in detail.
예를 들어, 건조한 천초근 시료 중량의 약 0.01 내지 10배(v/w), 바람직하게는 약 0.1 내지 1배(v/w)의 물, C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는 물, 메탄올 또는 이들의 혼합용매, 보다 바람직하게는 물 및 메탄올 혼합용매를 가한 후 30 내지 110℃, 바람직하게는 50 내지 100℃에서 1시간 내지 5시간, 바람직하게는 1시간 내지 3시간동안 1 내지 10회, 바람직하게는 1 내지 5회 냉침추출, 열수추출, 초음파 추출, 환류냉각추출, 가열추출 등의 추출방법, 바람직하게는 초음파 추출법을 수행하여 추출물을 수득하는 제 1단계; 상기 추출물을 디클로로메탄, 물로 추출한 후 디클로로메탄 분획물을 얻는 제 2단계; 상기 단계에서 디클로로메탄 분획물을 실리카겔 컬럼 크로마토그래피 (silicagel C.C., 전개용매: 헥산 및 디클로로메탄 혼합용매)를 반복 수행하고 당업계에 잘 알려진 재결정 방법 또는 세파덱스 컬럼크로마토그래피법 등의 정제 방법을 통하여 본 발명의 몰루긴을 수득가능하다.For example, about 0.01 to 10 times (v / w), preferably about 0.1 to 1 (v / w) water, C 1 to C 4 lower alcohols or mixed solvents , Preferably water, methanol or a mixed solvent thereof, more preferably water and methanol mixed solvent, and then 30 to 110 ℃, preferably 50 to 100
본 발명은 상기의 몰루긴을 유효성분으로 함유하는 비만의 치료 및 예방용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for the treatment and prevention of obesity containing the above mollugin as an active ingredient.
본 발명의 조성물은, 조성물 총 중량에 대하여 상기 몰루긴을 0.1 내지 50% 중량으로 포함한다.The composition of the present invention comprises 0.1 to 50% by weight of the molugin relative to the total weight of the composition.
본 발명의 몰루긴을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The composition comprising the mollugin of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.
본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 몰루긴을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The composition comprising the mollugin of the present invention may be formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to a conventional method. Can be used.
상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 몰루긴에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( sucrose), lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명에 따른 몰루긴은 실험동물의 나이, 성별, 체중에 따라 달라질 수 있으나, 일반적으로 0.01 내지 500 mg/㎏의 양, 바람직하게는 0.1 내지 100 mg/㎏의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 또한 몰루긴의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 따라서 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Molugin according to the present invention may vary depending on the age, sex and weight of the test animal, but generally in an amount of 0.01 to 500 mg / kg, preferably in an amount of 0.1 to 100 mg / kg once to several times a day. It can be administered separately. Molugin dosage may also be increased or decreased depending on the route of administration, disease severity, sex, weight, age and the like. Accordingly, the dosage is not limited in any way to the scope of the present invention.
본 발명의 약학 조성물은 랫트, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
본 발명의 몰루긴은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다.Molugin of the present invention has little toxicity and side effects, so it can be used with confidence even for prolonged administration for prophylactic purposes.
본 발명은 상기 몰루긴을 유효성분으로 함유하는 비만의 예방 및 개선용 건강기능식품을 제공한다. The present invention provides a dietary supplement for the prevention and improvement of obesity containing the mollugin as an active ingredient.
본 발명의 몰루긴을 포함하는 조성물은 비만의 예방을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다.The composition containing the mollugin of the present invention can be used in a variety of drugs, foods and drinks for the prevention of obesity.
본 발명의 몰루긴을 첨가할 수 있는 식품으로는, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Foods to which the mollugin of the present invention can be added include various foods, for example, beverages, gums, teas, vitamin complexes, health supplements, and the like, pills, powders, granules, acupuncture tablets, capsules or beverages. Can be used in the form of phosphorus.
이때, 식품 또는 음료 중의 상기 몰루긴의 양은, 일반적으로 본 발명의 건강식품 조성물의 경우 전체 식품 중량의 0.01 내지 15중량%로 가할 수 있으며, 건강 음료 조성물의 경우 100㎖를 기준으로 0.02 내지 10g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.At this time, the amount of the mollugin in the food or beverage, in the case of the health food composition of the present invention can generally be added to 0.01 to 15% by weight of the total food weight, 0.02 to 10g, based on 100ml for the health beverage composition, Preferably it can be added in the ratio of 0.3-1 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 몰루긴을 함유하는 것 외에는 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 쳔연 탄수화물의 예로는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 폴리사카라이드, 예를 들어 텍스트린, 시클로덱스트린; 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 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. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100㎖ 당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다. 상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 증진제(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. The health beverage composition of the present invention has no particular limitation on the liquid component except for containing the above-mentioned molugin as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. Examples of the above described natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as textrin, cyclodextrin; Conventional sugars such as and the like and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have. The proportion of such natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention. In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and enhancers (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. The compositions of the present invention may also contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can 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.
본 발명의 몰루긴은 전지방세포의 지방으로의 분화 억제 및 지방세포 및 성숙지방세포의 세포사멸효과를 나타내는바, 비만의 예방 및 치료용 약학조성물 및 연구용 약학조성물로 유용하게 사용될 수 있다.Molugin of the present invention exhibits the effect of inhibiting the differentiation of fat cells into fat and apoptosis of adipocytes and mature fat cells, and can be usefully used as a pharmaceutical composition for the prevention and treatment of obesity and a pharmaceutical composition for research.
도 1은 본 발명에서 분리 동정한 몰루긴의 HPLC 결과이며
도 2는 몰루긴의 전지방세포와 성숙지방세포의 생존 능력에 대한 영향을 나타낸 도이며 (몰루긴을 다양한 농도(0, 20, 40 및 60 μM)로 세포 (농도는 1x104/well)에 24시간 및 48시간 처리하여 MTS 방법으로 측정하였다. 각각의 발현정도의 수치는 ±SD (N=6)으로 표시하며. P<0.05 );
도 3은 몰루긴에 의한 미토콘드리아 막 붕괴에 따른 세포자살 유도와 이에 관여하는 단백질 인자에 대한 도이며;
도 4는 전지방세포주의 지방세포로의 분화에 대한 몰루긴의 저해효과를 나타낸 도이며(A: 지방세포분화를 유도하면서 분화유도 단계별로 몰루긴을 처리하여 MTS colorimetric 어세이법으로 측정함, B: 세포내 triglyceride 함량을 기준으로 세포내 지방의 축적 강도를 AdipoRedTM Assay 시약으로 측정함, C: 지방세포분화에 관여하여 C/EBP 와 PPAR 발현에 대한 몰루긴의 영향을 웨스턴 블롯 분석법으로 측정함.);
도 5는 Oil Red O staining을 통한 몰루긴의 항비만 활성을 나타낸 도이다(A: 전지방세포주, B: 지방세포주, C: 몰루긴 0-6일 처리, D: 몰루긴 0-2일 처리(초기 단계), E: 몰루긴 2-4일 처리(중기 단계), F: 몰루긴 4-6일 처리(후기 단계)).1 is an HPLC result of mollugin isolated and identified in the present invention.
2 is a diagram showing the effect on the viability of mollugin cell and mature adipocytes (Molugin in various concentrations (0, 20, 40 and 60 μM) cells (concentration is 1x10 4 / well) Treatment was performed by MTS method for 24 hours and 48 hours, and the expression level of each expression was expressed as ± SD (N = 6) P <0.05);
3 is a diagram illustrating apoptosis induction and protein factors involved in mitochondrial membrane disruption by mollugin;
4 is a diagram showing the inhibitory effect of mollugin on the differentiation of fat cells into fat cells (A: induction of differentiation and treatment of mollugin by differentiation induction step, measured by MTS colorimetric assay method, B : Intracellular fat accumulation intensity based on intracellular triglyceride content measured by AdipoRed TM Assay reagent, C: Influence of adipocyte differentiation, Molugin's influence on C / EBP and PPAR expression by Western blot analysis .);
5 is a diagram showing the anti-obesity activity of mollugin through Oil Red O staining (A: cell line cell, B: fat cell line, C: mollugin 0-6 days treatment, D: mollugin 0-2 days treatment (Early stage), E: mollugin 2-4 days treatment (middle stage), F: mollugin 4-6 days treatment (late stage)).
이하, 본 발명을 하기 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to the following examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예, 참고예 및 실험예에 의해 한정되는 것은 아니다.
However, the following Examples and Experimental Examples are only illustrative of the present invention, the contents of the present invention is not limited by the following Examples, Reference Examples and Experimental Examples.
실시예 1. 몰루긴 화합물의 제조Example 1 Preparation of Molugin Compound
1-1. 천초근 추출물의 제조1-1. Preparation of Cheoncho Geun Extract
대구 약령시장에서 구입한 국내산 천초근 10kg을 1cm 크기로 분쇄한 후 94% 메탄올 (MeOH) 1000 ml로 1시간 동안 4회 초음파 추출 (ultrasonication)하고 얻어진 추출액을 여과, 농축 및 건조하여 약 1 kg의 천초근 추출물을 얻었다.After crushing 10kg of Korean cheoncho root purchased from Daegu Yangnyeong Market into 1cm size, ultrasonic extraction was performed four times for 1 hour with 1000ml of 94% methanol (MeOH) for 1 hour, and the extract was filtered, concentrated and dried. Cheoncho root extract was obtained.
상기 천초근 추출물을 물(H2O)과 디클로로메탄(CH2Cl2)에 분획하였고, 확보한 디클로로메탄(CH2Cl2)층 360g을 실리카겔 컬럼크로마토그래피법을 반복 수행하여 (전개용매: 헥산(hexane) 및 CH2Cl2 혼합용매로 극성을 높여가며 용출)도 RA-MC-1에서 RA-MC-34로 총 34 분획물로 나누어 회수하였다.
The Cheoncho-geun extract was partitioned into water (H 2 O) and dichloromethane (CH 2 Cl 2 ), and 360 g of the obtained dichloromethane (CH 2 Cl 2 ) layer was repeatedly subjected to silica gel column chromatography (developing solvent: Hexane and CH 2 Cl 2 Elution with increasing polarity with mixed solvent) was also divided into 34 fractions from RA-MC-1 to RA-MC-34.
1-2. 몰루긴의 분리 및 동정1-2. Isolation and Identification of Molugin
상기 실시예 1에서 얻은 분획물 중 RA-MC-2의 분획물 5g을 실리카겔 컬럼 크로마토그래피를 (3.2 x 60 cm, 70 mesh) 이용하여 (전개용매: 헥산 (hexane) 및 CH2Cl2 혼합용매로 극성을 높여가며 용출) 본 발명의 몰루긴 250mg을 수득하였고 이를 확인하기 위하여 시판되는 몰루긴과 함께 HPLC로 확인하였다 (도 1 참조, Kim SM et al., Toxicol Appl. Pharmacol. 241, PP. 210-220, 2009).
5 g of the fraction of RA-MC-2 in the fraction obtained in Example 1 was subjected to silica gel column chromatography (3.2 x 60 cm, 70 mesh) (developing solvents: polar with a mixed solvent of hexane and CH 2 Cl 2 ). Elution with increasing elution) 250 mg of the mollugin of the present invention was obtained and confirmed by HPLC with a commercially available mollugin (see FIG. 1, Kim SM et al., Toxicol Appl. Pharmacol. 241, PP. 210-). 220, 2009).
참고예1Reference Example 1 . 실험재료의 준비. Preparation of Experimental Materials
Dulbecco's Modified Eagle Medium (DMEM), 우태아혈청 (fetal bovine serum, FBS), 스트렙토마이신-페니실린 (streptomycin-penicillin) 등의 세포 배양용 시약들은 Gibco BRL사 (Grand Island, USA)에서 구입하였으며, Sodium Dodesyl Sulfate (SDS), 아크릴아마이드 (Acrylamide), Bis, Protein assay reagent는 Bio-Rad사 (Hercules, USA)에서 구입하였고, NP-40, CAPS, tween 20, protease inhibitors 등은 Sigma사 (St. Louis, MO, USA)에서 구입하였다. 실험에 사용된 1차 항체인 anti-PPAR gamma, anti-adiponectin 또는 anti-β-actin 및 2차 항체인 horseradish peroxidase (HRP)-conjugated anti-mouse IgG antibody 및 HRP-conjugated anti-rabbit IgG antibody는 Santa Cruz Biotechnology사 (Santa Cruz, CA, USA)에서 구입하였다. 세포 생육저해능 측정을 위한 CellTiter 96？ Aqueous One Solution Cell proliferation assay kit는 Promega (Madison, UI, USA)사에서 구입하였고, 비만세포 분화 유도에 사용한 이소부틸메틸잔틴 (isobutylmethylxanthine, IBMX), 인슐린 (insulin), 덱사메타손 (dexamethason)은 Sigma 사 (St. Louis, MO, USA)에서, 지방 함량 및 지방구 염색에 사용한 AdipoRed™ assay kit 은 Cambrex 회사 (Walkersville, MD, USA)로부터 구입하였다. 그 외 실험에 사용된 모든 시약은 분석용 등급 이상으로 사용하였다.
Cell culture reagents such as Dulbecco's Modified Eagle Medium (DMEM), fetal bovine serum (FBS), and streptomycin-penicillin were purchased from Gibco BRL (Grand Island, USA), Sodium Dodesyl Sulfate (SDS), acrylamide, Bis, and protein assay reagents were purchased from Bio-Rad (Hercules, USA). NP-40, CAPS,
참고예 2. 세포배양Reference Example 2. Cell Culture
American Type Culture Collection(Manassas, VA, USA)에서 구입한 마우스 preadipocyte 세포주인 3T3-L1 세포는 10% 우아혈청(bovine calf serum)과 1% 페니실린-스트렙토마이신(penicillin-streptomycin)을 포함하는 DMEM(Dulbecco's Modified Eagle Medium) 배지를 사용하여 37℃Mouse preadipocyte cell line 3T3-L1 cells purchased from the American Type Culture Collection (Manassas, VA, USA) were DMEM (Dulbecco's) containing 10% bovine calf serum and 1% penicillin-streptomycin. 37 ° C using Modified Eagle Medium)
, 5% CO2의 조건에서 배양하면서 본 실험에 사용하였다.
, 5% CO 2 was used in this experiment while incubated in the conditions.
실험예Experimental Example 1. One. 몰루긴의Mollugin 전지방세포Cell ( ( preadipocytespreadipocytes ) 와 성숙지방세포 () And mature fat cells ( maturemature adipocytesadipocytes )의 )of viabilityviability 에 대한 영향Impact on
1-1. 세포독성 측정1-1. Cytotoxicity Measurement
몰루긴 화합물의 세포독성을 측정하기 위하여 기존문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Lee JE et al., Chem . Pharm . Bull . 56, PP. 730-733, 2004).In order to determine the cytotoxicity of the mollugin compound, the experiment was performed by applying the method described in the literature (Lee JE et al., Chem . Pharm . Bull . 56, PP. 730-733, 2004).
세포독성 분석을 위해 96-웰 마이크로타이터 플레이트 (96-well microtiter plate)에 세포농도 1 x 104 cells/well로 조절하여 3T3-L1세포를 분주한 후 16 시간 배양하고, 이어서 몰루긴을 농도별(0, 20, 40, 60 μM)로 첨가하고 24시간 또는 48 시간 배양한 후 50㎕의 MTS (Promega, Mdadison, WI, USA)를 첨가하고 2시간 반응시켜 ELISA reader (Variokan, Thermo Electron, USA)로 540nm 파장에서 측정하였다.For cytotoxicity analysis, 3T3-L1 cells were dispensed in a 96-well microtiter plate at a cell concentration of 1 x 10 4 cells / well, and cultured for 16 hours, followed by concentration of mollugin. Add to stars (0, 20, 40, 60 μM), incubate for 24 hours or 48 hours, and then add 50 μl of MTS (Promega, Mdadison, WI, USA) and react for 2 hours. ELISA reader (Variokan, Thermo Electron, USA) at 540 nm wavelength.
실험 결과, 도 2a에 나타난 바와 같이, 3T3-L1 전지방세포 (preadipocytes)에 대한 몰루긴의 영향을 몰루긴 농도별로 처리하였을 때, 24시간 처리 시 세포 증식에는 별 영향을 미치지 않았으나 처리시간을 48시간 하였을 때 40 μM 에서 12%, 60 μM 농도에서 31%의 저해율을 보였다 (도 2a 참조).
As a result, as shown in Figure 2a, when the effect of mollugin on the 3T3-L1 preadipocytes by the mollugine concentration, the treatment did not affect the cell proliferation after treatment for 24 hours, but the treatment time was 48 In time, the inhibition rate was 12% at 40 μM and 31% at 60 μM concentration (see FIG. 2A).
1-2. 성숙지방세포 생존율 측정1-2. Mature fat cell survival rate measurement
성숙지방세포에 대한 몰루긴의 영향을 조사하기 위하여 재료 및 방법에 따라 분화시킨 후 (days 6) 몰루긴을 농도별로 24시간과 48시간 처리하면서 성숙지방세포 생존율을 조사하였다.In order to investigate the effect of mollugin on mature fat cells, the differentiation according to materials and methods (days 6) was performed for 24 hours and 48 hours by molargin concentrations.
실험결과, 도 2b에서 나타난 바와 같이, 몰루긴 40 μM 농도로 24시간 처리하여도 세포 생존에 큰 영향을 미치지 않았으나 60 μM 농도에서 47.5% 생존율을, 48시간 처리 시에는 40 μM 과 60 μM 농도에서 세포 생존율을 각각 40% 와 66% 정도 저해하는 것으로 확인되었다. 이는 몰루긴이 전지방세포(preadipocytes)에 비해 성숙지방세포에 대하여 훨씬 강하게 세포 생존율을 저해함을 보여 주었다(도 2b 참조).
As shown in FIG. 2B, treatment with 40 μM concentration of mollugin did not significantly affect cell survival, but 47.5% survival at 60 μM concentration and 40 μM and 60 μM concentration at 48 hours treatment. Inhibition of cell viability by 40% and 66%, respectively. This showed that molugin inhibited cell viability much more strongly against mature adipocytes than preadipocytes (see FIG. 2B).
실험예Experimental Example 2. 2. 미토콘트리아Mitochondria 막 전위( Membrane potential ( MitochondrialMitochondrial membranemembrane potentialpotential ; Δψm); Δψm)
상실(loss( lossloss )의 측정)
몰루긴 처리에 의한 세포 손상이 미토콘드리아-의존성 세포사멸(mitochondria-dependent apoptosis)과 연관 있는지를 조사하기 위하여 미토콘드리아 막 전위 변화를 3,3'-dihexyloxacarbocyanime iodide (DiOC6)염색과 flow cytometry (Ben) 분석으로 측정하였다 (Zamzami N et al., J. Exp . Med . 181, PP. 1661-1672, 1995). 이를 위하여 몰루긴을 처리한 1 x 106 세포를 PBS 완충용액으로 씻은 다음 50 nM DiOC6를 함유한 PBS 완충용액에서 15분간 반응시킨 후 flow cytometry로 분석하였다.3,3'-dihexyloxacarbocyanime iodide (DiOC 6 ) staining and flow cytometry (Ben) analysis of mitochondrial membrane potential changes to investigate whether cell damage by mollugin treatment is associated with mitochondria-dependent apoptosis (Zamzami N et al., J. Exp . Med . 181, PP. 1661-1672, 1995). To this end, 1 x 10 6 cells treated with mollugin were washed with PBS buffer and then reacted in PBS buffer containing 50 nM DiOC 6 for 15 minutes and analyzed by flow cytometry.
그 결과, 도 3에서 나타난 바와 같이 3T3-L1 전지방세포를 40 μM 혹은 60 μM 농도의 몰루긴으로 48시간 처리하였을 경우, 40 μM 처리에 의해서는 약 7.4%, 또한 60 μM 처리에 의해서는 약 23.6%의 3T3-L1 세포가 미토콘드리아에 손상을 받아서 Δψm을 상실하는 것으로 확인되었다. 이는 도 2의 MTS assay에서 나타난 몰루긴의 세포독성 결과와 잘 일치하는 결과였다(도 3 참조).As a result, as shown in FIG. 3, when 3T3-L1 cells were treated with 40 μM or 60 μM of mollugin for 48 hours, the treatment was performed at about 7.4% by 40 μM and about 60 μM by treatment. 23.6% of 3T3-L1 cells were damaged by mitochondria and lost Δψm. This was in good agreement with the results of the cytotoxicity of mollugin in the MTS assay of FIG. 2 (see FIG. 3).
이와 같은 몰루긴 처리에 의한 3T3-L1 세포의 Δψm loss의 정도는, 몰루긴 처리에 의한 3T3-L1 세포의 세포생존율 감소와 잘 일치하므로, 몰루긴이 3T3-L1 세포에 대해 나타내는 세포독성은 몰루긴에 의한 에폽토시스의 유도 때문임을 확인할 수 있었다.
Since the degree of Δψm loss of 3T3-L1 cells by such mollugin treatment is in good agreement with the decrease in cell viability of 3T3-L1 cells by mollugin treatment, the cytotoxicity of mollugin against 3T3-L1 cells is molar. It was confirmed that it was due to the induction of epoptosis by lugin.
실험예Experimental Example 3. 3. 전지방세포의Cell-like 지방세포로의 분화에 대한 For differentiation into adipocytes 몰루긴의Mollugin 저해효과 Inhibitory effect
3-1. 33-1. 3 T3T3 -- L1L1 세포의 비만세포로의 분화 유도 Induction of differentiation of cells into mast cells
마우스 유래 전지방세포주 3T3 L1 세포를 10% bovine calf serum (BCS)을 함유한 DMEM 완전배지에서 2일간 배양한 후, 10% fetal bovine serum (FBS) 함유한 DMEM 완전배지에 0.5 mM IBMX, 200 nM 인슐린 및 1 μM 덱사메타손 (dexamethason)을 첨가한 분화유도배지를 이용하여 2일간 배양하였다 (day2, D0-D2). 이어서 분화유도배지를 200 nM 인슐린을 함유한 10% FBS/DMEM 완전배지로 대체하여 2일간 배양하였고 (day 4, D2-D4), 최종적으로 10% FBS/DMEM 완전배지에서 2일간 더 배양하여 지방세포로의 분화를 완성하였다 (day 6, D4-D6). 이때 분화유도에 사용한 3T3-L1 세포의 경우, 세포 계대회수를 3~9 범위에 해당하는 세포를 사용하였다.
Mouse-derived cell line 3T3 L1 cells were cultured in DMEM medium containing 10% bovine calf serum (BCS) for 2 days, and then 0.5 mM IBMX, 200 nM in DMEM medium containing 10% fetal bovine serum (FBS). Cultures were incubated for 2 days using differentiation-inducing medium with insulin and 1 μM dexamethasone (dexamethason) (day2, D0-D2). Subsequently, differentiation-inducing medium was replaced with 10% FBS / DMEM complete medium containing 200 nM insulin and cultured for 2 days (day 4, D2-D4), and finally cultured in 10% FBS / DMEM complete medium for another 2 days Complete differentiation of prisoners (day 6, D4-D6). At this time, in the case of 3T3-L1 cells used for differentiation induction, cells corresponding to the passage number of 3 to 9 were used.
3-2. 마우스 유래 전지방세포주 33-2. Mouse-derived
지방세포분화를 유도하면서 분화유도 단계별로 즉, 초기 (D0-D2), 중기 (D2-D4) 와 후기 (D4-D6) 로 구분하여 각각의 시기에 20 μM 농도로 몰루긴을 처리하고 분화 유도 최종일인 6일째 되었을 때, 각각 세포의 세포생존율과 세포내에 축척된 지방의 양을 재료 및 방법에서 서술한 바와 같이 측정하였다.Induces adipocyte differentiation and induces differentiation in different stages of induction, namely early (D0-D2), mid (D2-D4) and late (D4-D6). At the end of the sixth day, the cell viability of the cells and the amount of fat accumulated in the cells, respectively, were measured as described in Materials and Methods.
그 결과, 몰루긴을 20 uM 농도로 처리하였을 경우, 세포의 생존율은 처리시기에 상관없이 큰 영향을 받지 않는 것으로 나타났다 (도 4a 참조). 그러나 세포내 triglyceride 함량을 기준으로 세포내 지방의 축적 정도를 조사한 결과 분화 유도 초기 (D0-D2) 단계에 몰루긴을 처리한 경우는 세포내 triglyceride 함량이 대조구에 비해 약 70% 감소하였으며, 또한 중기 (D2-D4) 와 후기 (D4-D6) 단계에 몰루긴을 처리하여도 세포내 triglyceride 함량이 각각 44% 와 32% 감소하는 것으로 나타났다 (도 4b 참조).
As a result, when the molugin is treated at a concentration of 20 uM, the survival rate of the cells was not significantly affected regardless of the treatment time (see Fig. 4a). However, as a result of investigating the accumulation of intracellular fat on the basis of intracellular triglyceride content, in the early stage of induction of differentiation (D0-D2), mollugin treatment reduced the intracellular triglyceride content by about 70% compared to the control group. Molugin treatment in the (D2-D4) and later (D4-D6) stages resulted in a 44% and 32% decrease in intracellular triglyceride content, respectively (see Figure 4b).
3-3. 3-3. 웨스턴Weston 블롯Blot 분석법 ( Method ( WesternWestern blotblot analysisanalysis ))
지방세포로 분화됨에 따라 발현되는 분화 유도 단백질 발현 측정을 하기 위해 전 등의 방법을 이용하여 웨스턴 블롯 분석법을 하기와 같이 수행하였다 (Jun DY et al., Carcinogenesis, 28(6), PP. 1303-1313, 2007). Western blot analysis was performed using the method described above to measure the differentiation-induced protein expression expressed as the differentiation into adipocytes (Jun DY et al., Carcinogenesis, 28 (6), PP.1303- 1313, 2007).
배양된 4 x 106 세포를 ice-cold PBS로 3회 세척한 후, 용해 완충액 (lysis buffer: 137 mM NaCl, 15 mM EGTA, 1 mM sodium orthovanadate, 15 mM MgCl2, 0.1% Triton X-100, 25 mM MOPS, 1 mM PMSF, 2.5 ㎍/ml proteinase inhibitor E-64, pH 7.2)로 현탁하고 초음파 분쇄기 (Vibra cell, Sonics & Materials INC, USA)로 파쇄한 다음, 4℃에서 30분간 반응시키고 14000 rpm에서 20분간 원심 분리하여 상층액을 모았다. 동일한 양의 단백질을 7.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)로 분리시킨 후, 단백질을 Immobilon-P 멤브레인에 전기전달 (electrotransfer)하였다. 이 멤브레인을 항체의 비특이적 결합을 차단하기 위하여 블로킹 용액 (3% Nonfat milk와 0.1% Tween 20을 함유한 TBS 용액)에서 1시간 동안 반응시킨 후, 각 단백질에 대한 항체를 가하여 반응시켰다. 이어서 0.1% Tween 20을 함유한 TBST 용액으로 세척한 다음, 2차 항체로 90분에서 2시간 반응시켰다. 이를 ECL system으로 X-ray film (Kodak, USA) 상에서 단백질을 확인하였다. The cultured 4 × 10 6 cells were washed three times with ice-cold PBS, followed by lysis buffer (137 mM NaCl, 15 mM EGTA, 1 mM sodium orthovanadate, 15 mM MgCl 2 , 0.1% Triton X-100, Suspended in 25 mM MOPS, 1 mM PMSF, 2.5 μg / ml proteinase inhibitor E-64, pH 7.2), crushed in an ultrasonic grinder (Vibra cell, Sonics & Materials INC, USA), reacted for 30 minutes at 4 ° C., and then 14000 The supernatant was collected by centrifugation at rpm for 20 minutes. The same amount of protein was separated by 7.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the protein was then electrotransfered to the Immobilon-P membrane. The membrane was reacted for 1 hour in a blocking solution (TBS solution containing 3% Nonfat milk and 0.1% Tween 20) to block nonspecific binding of the antibody, and then reacted by adding an antibody to each protein. Subsequently, the resultant was washed with a TBST solution containing 0.1
그 결과, 도 4c에서 보는 바와 같이, 분화 유도 초기 (D0-D2) 단계와 후기 (D4-D6) 단계에 몰루긴을 처리하였을 때, 대조구보다 C/EBP α, PPARγ1 와 PPARγ2의 발현이 상당히 억제되었다. 이상의 연구를 통해 몰루긴이 전지방세포(preadipocytes)의 지방세포(adipocytes)로의 분화를 강하게 저해하는 물질이며, 그 저해능은 분화 초기 단계에 필수적으로 관여하는 유전자들 (C/EBP α 와PPARγ)의 발현을 강하게 억제하여 지방세포로의 분화를 차단하기 때문인 것으로 확인되었다 (도 4c 참조). As a result, as shown in Fig. 4c, when mollugin was treated in the early (D0-D2) and late (D4-D6) stages of differentiation induction, the expression of C / EBP α, PPARγ1 and PPARγ2 was significantly suppressed compared to the control. It became. Molugin is a substance that strongly inhibits the differentiation of preadipocytes into adipocytes through the above studies. It was confirmed that this is because it strongly inhibits the expression to block differentiation into adipocytes (see FIG. 4C).
실험예Experimental Example 4. 4. OilOil RedRed O O stainingstaining 을 통한 through 몰루긴의Mollugin 항비만Anti-obesity 활성 검정 Active black
4-1. 4-1. 지방구District ball 염색법 process of dyeing
대조구와 몰루긴 처리구에서의 지방 축척을 가시화하기 위하여 생성된 지방구를 키트 (Adipogenesis Assay kit; Cayman Chemical Company, Ann Arbor, MI, USA)를 이용하여 염색하였다.The resulting fat globules were stained using a kit (Adipogenesis Assay kit; Cayman Chemical Company, Ann Arbor, MI, USA) to visualize fat accumulation in the control and mollugin treatments.
4-2. 지방축적의 측정4-2. Measurement of fat accumulation
3T3-L1 지방세포로의 분화에 미치는 몰루긴의 저해활성에 의한 지방 세포 형성 억제 및 지방축적 억제능을 조사하기 위해, 세포내에 축척된 지방의 함량을 Oil Red O 염색법으로 염색하였다. 그 결과, 몰루긴 (20 μM)을 분화 초기 (D0-D2) 단계 혹은 분화 유도 기간 전반 (D0-D6)에 걸쳐 처리한 세포의 대부분은 섬유아세포형태 (fibroblastic morphology)를 유지하며 Oil Red O staining에 의해서도 거의 염색되지 않는 것으로 나타났다 (도 5 참조). 이에 반해, 중기 (D2-D4) 단계와 후기 (D4-D6) 단계에 몰루긴을 처리한 세포의 경우에는 세포 형태도 구형으로 일부 변하였으며, Oil Red O 염색법에 대해 양성인 세포들이 다소 확인되는 것으로 나타났다.
In order to investigate the inhibition of adipocyte formation and the accumulation of fat by the inhibitory activity of mollugin on the differentiation into 3T3-L1 adipocytes, the amount of fat accumulated in the cells was stained by Oil Red O staining. As a result, most of the cells treated with Molugin (20 μM) during the differentiation stage (D0-D2) or throughout the differentiation induction period (D0-D6) maintain fibroblastic morphology and maintain Oil Red O staining. Almost no staining was observed (see FIG. 5). In contrast, in the middle (D2-D4) and late (D4-D6) treated cells, the morphology was partially changed to spherical, and the cells positive for Oil Red O staining were somewhat confirmed. appear.
따라서, 상기의 연구결과를 요약하면, 몰루긴은 마우스 유래 전지방세포주 3T3-L1 세포의 지방세포로의 분화 (adipogenesis)를 효과적으로 저해하는 활성을 가지고 있을 뿐만 아니라 전지방세포 (preadipocytes)와 성숙지방세포 (mature adipocytes)의 세포 사멸을 유도할 수 있는 것으로 확인하였다. 이때 몰루긴에 의한 지방세포분화 (adipogenesis) 억제는 몰루긴을 분화 초기 (D0-D2) 단계에 처리하였을 때 가장 크게 나타났으며, 또한 분화 유도 중기 (D2-D4) 단계와 분화유도 후기 (D4-D6) 단계에 처리하여도 성숙지방세포 생성과 세포내 지방 축척을 상당히 저해함을 확인하였다.
Therefore, summarizing the above findings, Molugin not only has the activity of effectively inhibiting the differentiation of adipocytes into mouse adipocyte cell line 3T3-L1 cells, but also adipocytes (preadipocytes) and mature adipocytes. It was confirmed that cell death of (mature adipocytes) can be induced. The inhibition of adipocyte differentiation by molugin was most significant when Molugin was treated at the early stage of differentiation (D0-D2), and also during the differentiation-inducing stage (D2-D4) and late differentiation induction (D4). -D6) also significantly inhibited the production of mature adipocytes and intracellular fat accumulation.
하기에 본 발명의 몰루긴을 함유하는 약학조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Hereinafter, an example of the preparation of the pharmaceutical composition containing the mollugin of the present invention will be described, but the present invention is not intended to be limited thereto, but is intended to be described in detail.
제제예Formulation example 1. One. 산제의Powder 제조 Produce
몰루긴 300 mg
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예Formulation example 2. 정제의 제조 2. Preparation of Tablets
몰루긴 300 mg
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Manufacture of capsule
몰루긴 300 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
제제예Formulation example 4. 주사제의 제조 4. Preparation of injections
몰루긴 300 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO412H2O 26 mgNa 2 HPO 4 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2 ㎖) 상기의 성분 함량으로 제조한다.
According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예Formulation example 5. 5. 액제의Liquid 제조 Produce
몰루긴 300 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액제를 제조한다.According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle. The solution is prepared by sterilization.
Claims (5)
The dietary supplement of claim 4 which is a tablet, capsule, pill or liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100072777A KR20120021358A (en) | 2010-07-28 | 2010-07-28 | A composition comprising mollugin isolated from an extract of rubiae radix for preventing and treating obesity |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020100072777A KR20120021358A (en) | 2010-07-28 | 2010-07-28 | A composition comprising mollugin isolated from an extract of rubiae radix for preventing and treating obesity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101322664B1 (en) * | 2013-04-04 | 2013-10-30 | 충남대학교산학협력단 | A composition comprising mollugin for treating cancer |
| KR101322661B1 (en) * | 2013-03-12 | 2013-10-30 | 충남대학교산학협력단 | A composition comprising mollugin for treating or preventing breast and ovary cancer |
-
2010
- 2010-07-28 KR KR1020100072777A patent/KR20120021358A/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101322661B1 (en) * | 2013-03-12 | 2013-10-30 | 충남대학교산학협력단 | A composition comprising mollugin for treating or preventing breast and ovary cancer |
| KR101322664B1 (en) * | 2013-04-04 | 2013-10-30 | 충남대학교산학협력단 | A composition comprising mollugin for treating cancer |
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