JP2011184411A - Lifestyle related disease amelioration agent including extract of tomato - Google Patents
Lifestyle related disease amelioration agent including extract of tomato Download PDFInfo
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- JP2011184411A JP2011184411A JP2010053886A JP2010053886A JP2011184411A JP 2011184411 A JP2011184411 A JP 2011184411A JP 2010053886 A JP2010053886 A JP 2010053886A JP 2010053886 A JP2010053886 A JP 2010053886A JP 2011184411 A JP2011184411 A JP 2011184411A
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Abstract
Description
本発明は、トマトやナス等のナス科植物の抽出物を含有する生活習慣病改善剤に関するものであり、詳細には、ナス科植物由来のPPAR活性化能を有する抽出物またはその活性フラクションを有効成分とする生活習慣病の予防または改善用の医薬または飲食品に関するものである。 The present invention relates to a lifestyle-related disease improving agent containing an extract of a solanaceous plant such as tomato or eggplant, and in particular, an extract having an ability to activate PPAR derived from a solanaceous plant or an active fraction thereof. The present invention relates to a pharmaceutical or food or drink for preventing or improving lifestyle-related diseases as an active ingredient.
近年、食生活の欧米化により、国民一人あたりの脂肪摂取量が上昇し、糖尿病、脂質異常症(高脂血症等)、高血圧、肥満などの生活習慣病と呼ばれる疾患が急激に増加している。また、メタボリックシンドロームは、代謝症候群、シンドロームX、死の四重奏、インスリン抵抗性症候群、内臓脂肪症候群とも呼ばれる複合生活習慣病であり、内臓脂肪型肥満に加えて、高血糖、高血圧、脂質異常のうちいずれか2つ以上を併せもった状態のことを言う。メタボリックシンドロームになると、糖尿病、高血圧症、高脂血症の一歩手前の段階でも、これらが内臓脂肪型肥満をベースに複数重なることによって、動脈硬化を進行させ、心臓病や脳卒中といった動脈硬化性疾患発症の相対的危険度が増すことが、国内外の疫学調査で明らかとなっている。 In recent years, with the westernization of dietary habits, per capita fat intake has increased, and so-called lifestyle-related diseases such as diabetes, dyslipidemia (hyperlipidemia, etc.), hypertension, obesity, etc. have increased rapidly. Yes. Metabolic syndrome is a complex lifestyle-related disease also called metabolic syndrome, syndrome X, death quartet, insulin resistance syndrome, visceral fat syndrome. In addition to visceral fat type obesity, hyperglycemia, hypertension, dyslipidemia It means the state that has any two or more. When it comes to metabolic syndrome, at least one step before diabetes, hypertension, and hyperlipidemia, these multiple layers based on visceral fat obesity promote arteriosclerosis and cause arteriosclerotic diseases such as heart disease and stroke Domestic and international epidemiological studies have shown that the relative risk of onset increases.
我が国では、2008年4月よりメタボリックシンドローム発症予防を目的に40歳以上の国民を対象として特定健康診断が開始され、国民のメタボリックシンドロームに対する関心が非常に高まっている。現在、メタボリックシンドロームの予防および治療には、糖尿病、高脂血症あるいは高血圧の治療薬が適応されており、疾病状態によっては、複数の薬剤服用を伴っている。 In Japan, specific health checkups have been started in April 2008 for citizens over the age of 40 with the aim of preventing the development of metabolic syndrome, and the public's interest in metabolic syndrome has increased greatly. Currently, therapeutic agents for diabetes, hyperlipidemia or hypertension are applied for prevention and treatment of metabolic syndrome, and depending on the disease state, a plurality of drugs are taken.
脂質代謝異常やインスリン抵抗性等の病態を改善する薬剤として、チアゾリジン誘導体
(ピオグリタゾン、トログリタゾンなど)やフィブレート製剤(フェノフィブレートやベザフィブレートなど)があり、これらはPPAR(Peroxisome Proliferator Activated Receptor;ペルオキシソーム増殖薬活性化受容体)のアゴニストとして作用することが明らかにされている。前者は主に脂肪組織に分布するPPARγを、後者は肝臓、腎臓、心臓、消化管に存在するPPARαをターゲットとして作用する。
Thiazolidine derivatives (pioglitazone, troglitazone, etc.) and fibrate preparations (fenofibrate, bezafibrate, etc.) are drugs that improve pathologies such as abnormal lipid metabolism and insulin resistance. These are PPAR (Peroxisome Proliferator Activated Receptor) It has been shown to act as an agonist of the activated receptor). The former acts mainly on PPARγ distributed in adipose tissue, and the latter acts on PPARα present in the liver, kidney, heart and gastrointestinal tract.
植物は多種多様な代謝産物およびそれらの中間体を含有しており、個々の植物それ自体を創薬における「化合物ライブラリー」の類似体と見なすことができる。特に遺伝子情報が詳細に判明しているトマトやナスなどのナス科植物においては、効率的生産法・先端的育種法の開発へと展開できる可能性が高い。最近、トマト摂取は循環器系糖尿病合併症のリスクを軽減することが報告され抗生活習慣病食品素材として有望であると考えられる。したがって、トマトやナスなどのナス科植物中にPPARを活性化させる成分を見出すことができれば、生活習慣病の予防や改善に高い効果を有する医薬や飲食品の開発が期待できる。 Plants contain a wide variety of metabolites and their intermediates, and individual plants themselves can be considered analogs of “compound libraries” in drug discovery. Particularly in solanaceous plants such as tomatoes and eggplants whose genetic information is known in detail, there is a high possibility that they can be developed to develop efficient production methods and advanced breeding methods. Recently, it has been reported that tomato intake reduces the risk of cardiovascular diabetic complications and is considered promising as an anti-lifestyle disease food material. Therefore, if a component that activates PPAR can be found in solanaceous plants such as tomatoes and eggplants, development of drugs and foods and drinks that are highly effective in preventing and improving lifestyle-related diseases can be expected.
トマト抽出物を抗生活習慣病食品素材として使用することに関する研究は従来行われており、例えば特許文献1には、トマト等のカロテノイドを含む野菜の抽出物を有効成分として含有する抗肥満剤が開示されている。また、例えば特許文献2には、血漿トリグリセライド濃度を下げるための薬剤を製造するために、水溶性トマト抽出物またはその活性フラクションを使用することが開示されている。しかし、トマト抽出物にPPAR活性化能を有する成分が含有されていることは報告されていない。 For example, Patent Document 1 discloses an anti-obesity agent containing a vegetable extract containing a carotenoid such as tomato as an active ingredient. It is disclosed. For example, Patent Document 2 discloses the use of a water-soluble tomato extract or an active fraction thereof for producing a drug for lowering the plasma triglyceride concentration. However, it has not been reported that the tomato extract contains a component having PPAR activation ability.
本発明は、生活習慣病やメタボリックシンドロームの予防または改善に有用なナス科植物由来の物質または成分を見出し、これを含有する医薬品および飲食品を提供することを目的とする。 An object of the present invention is to find a substance or component derived from a solanaceous plant useful for prevention or improvement of lifestyle-related diseases or metabolic syndrome, and to provide a pharmaceutical and a food or drink containing the same.
本発明は、上記課題を解決するために、以下の各発明を包含する。
[1]ナス科植物の抽出物またはその活性フラクションを有効成分とするPPAR活性化剤。
[2]ナス科植物がトマトまたはナスである前記[1]に記載のPPAR活性化剤。
[3]ナス科植物がトマトである前記[1]に記載のPPAR活性化剤。
[4]抽出物またはその活性フラクションが脂溶性である前記[1]〜[3]のいずれかに記載のPPAR活性化剤。
[5]PPARが、PPARαおよび/またはPPARγである前記[1]〜[4]のいずれかに記載のPPAR活性化剤。
[6]抽出物またはその活性フラクションが以下の化合物(I)〜(IV)の少なくとも1種を含む前記[1]〜[5]のいずれかに記載のPPAR活性化剤。
[9]メタボリックシンドロームの予防または改善用である前記[1]〜[7]のいずれかに記載のPPAR活性化剤。
[10]生活習慣病が、インスリン抵抗性、2型糖尿病、脂質異常症、高血圧、内臓脂肪型肥満または脂肪肝である前記[8]に記載のPPAR活性化剤。
[11]前記[1]〜[10]のいずれかに記載のPPAR活性化剤を含有する医薬。
[12]前記[1]〜[10]のいずれかに記載のPPAR活性化剤を含有する飲食品。
The present invention includes the following inventions in order to solve the above problems.
[1] A PPAR activator comprising a solanaceous plant extract or an active fraction thereof as an active ingredient.
[2] The PPAR activator according to [1], wherein the solanaceous plant is tomato or eggplant.
[3] The PPAR activator according to [1], wherein the solanaceous plant is tomato.
[4] The PPAR activator according to any one of [1] to [3], wherein the extract or active fraction thereof is fat-soluble.
[5] The PPAR activator according to any one of [1] to [4], wherein the PPAR is PPARα and / or PPARγ.
[6] The PPAR activator according to any one of [1] to [5], wherein the extract or an active fraction thereof contains at least one of the following compounds (I) to (IV).
[9] The PPAR activator according to any one of [1] to [7], which is used for prevention or improvement of metabolic syndrome.
[10] The PPAR activator according to [8], wherein the lifestyle-related disease is insulin resistance, type 2 diabetes, dyslipidemia, hypertension, visceral fat obesity or fatty liver.
[11] A medicament containing the PPAR activator according to any one of [1] to [10].
[12] A food or drink containing the PPAR activator according to any one of [1] to [10].
本発明によれば、ナス科植物の抽出物またはその活性フラクションを有効成分とするPPAR活性化剤を提供することができる。当該PPAR活性化剤を含有する医薬および飲食品は、生活習慣病の予防または改善に有用である。また、当該PPAR活性化剤を含有する医薬および飲食品は、メタボリックシンドロームの予防または改善に有用である。 ADVANTAGE OF THE INVENTION According to this invention, the PPAR activator which uses the extract of a solanaceous plant or its active fraction as an active ingredient can be provided. The medicine and food and drink containing the PPAR activator are useful for preventing or improving lifestyle-related diseases. Moreover, the medicine and food-drinks containing the said PPAR activator are useful for prevention or improvement of a metabolic syndrome.
本発明は、ナス科植物の抽出物またはその活性フラクションを有効成分とするPPAR活性化剤を提供する。ナス科植物は特に限定されないが、トマト、ナス等のナス属植物が好ましい。より好ましくはトマトまたはナスであり、特に好ましくはトマトである。抽出物はナス科植物の植物体の全部または一部(葉、茎、根、花、果実など)から抽出したものであればよい。トマトの場合、果実を含む植物体からの抽出物が好ましく、熟した果実を含む植物体からの抽出物がより好ましい。 The present invention provides a PPAR activator comprising a solanaceous plant extract or an active fraction thereof as an active ingredient. The solanaceous plant is not particularly limited, but solanaceous plants such as tomato and eggplant are preferred. More preferred is tomato or eggplant, and particularly preferred is tomato. The extract may be extracted from all or part of the plant body of the solanaceous plant (leaves, stems, roots, flowers, fruits, etc.). In the case of tomato, an extract from a plant containing fruits is preferred, and an extract from a plant containing ripe fruits is more preferred.
活性化フラクションは、ナス科植物の抽出物から単離されたフラクションであって、PPAR活性化能を有するフラクションを意味する。ナス科植物の抽出物または当該抽出物から単離されたフラクションがPPAR活性化能を有することは、公知のPPAR活性測定法を用いて確認することができる。公知のPPAR活性測定法としては、例えば、Gotoら(T. Goto et al., Biochemical and Biophysical Research Communications 337 (2005) 440-445)に記載のPPARレポーターアッセイなどが挙げられる。 The activated fraction means a fraction isolated from a solanaceous plant extract and having a PPAR activation ability. It can be confirmed using a known method for measuring PPAR activity that an extract of a solanaceous plant or a fraction isolated from the extract has PPAR activation ability. Examples of known methods for measuring PPAR activity include the PPAR reporter assay described in Goto et al. (T. Goto et al., Biochemical and Biophysical Research Communications 337 (2005) 440-445).
抽出物またはその活性フラクションは脂溶性であることが好ましい。脂溶性の抽出物は、例えば、ナス科植物の植物体、搾汁液、またはこれらの乾燥物や凍結乾燥物から疎水性の有機溶媒で抽出することにより取得することができる。疎水性の有機溶媒としては、例えば、エタノールなどのアルコール類、ヘキサンなどの炭化水素類、酢酸エチルなどのエステル類、アセトンなどのケトン類、ジエチルエーテル、ジオキサンなどのエーテル類、ジクロロメタン、クロロホルムなどのアルキルハライド等が挙げられる。 The extract or its active fraction is preferably fat-soluble. The fat-soluble extract can be obtained, for example, by extracting with a hydrophobic organic solvent from a plant body of a solanaceous plant, a juice, or a dried or freeze-dried product thereof. Examples of the hydrophobic organic solvent include alcohols such as ethanol, hydrocarbons such as hexane, esters such as ethyl acetate, ketones such as acetone, ethers such as diethyl ether and dioxane, dichloromethane, chloroform and the like. Examples thereof include alkyl halides.
PPARは哺乳類ではα、δおよびγの3種類のアイソフォームが知られている。本発明のPPAR活性化剤は、PPARα、δおよびγのいずれか1種を活性化できるものであればよいが、PPARαまたはPPARγを活性化できることが好ましく、PPARαおよびPPARγを活性化できることがより好ましい。PPARαは主に肝臓や骨格筋で脂肪酸の輸送や代謝に関連する遺伝子の発現を制御しており(Willson T. M. et al., J. Med. Chem. 43(4) 527-550 2000)、脂質代謝に深く関与していることから、高脂血症等の脂質異常症のための薬剤の標的タンパクとして注目されている。PPARγは、脂肪細胞の分化を司る調節因子であることが明らかにされている(Cell 79 : 1147-1156, 1994)。したがって、PPARγ活性化物質は、脂肪細胞分化を促進することにより、血液中の糖および遊離脂肪酸を低下させ、筋肉の遊離脂肪酸の低下とインスリン抵抗性を改善することができる。それゆえ、PPARαおよび/またはPPARγを活性化できる成分は、生活習慣病の予防もしくは改善に有用である。 PPAR has three known isoforms of α, δ and γ in mammals. The PPAR activator of the present invention is not particularly limited as long as it can activate any one of PPARα, δ and γ, but it is preferable that PPARα or PPARγ can be activated, more preferably PPARα and PPARγ can be activated. . PPARα regulates the expression of genes related to fatty acid transport and metabolism mainly in the liver and skeletal muscle (Willson TM et al., J. Med. Chem. 43 (4) 527-550 2000). Has been attracting attention as a protein target protein for dyslipidemia such as hyperlipidemia. PPARγ has been shown to be a regulatory factor responsible for adipocyte differentiation (Cell 79: 1147-1156, 1994). Therefore, the PPARγ activator can promote adipocyte differentiation, thereby reducing blood sugar and free fatty acid, and improving muscle free fatty acid reduction and insulin resistance. Therefore, a component capable of activating PPARα and / or PPARγ is useful for preventing or ameliorating lifestyle-related diseases.
本発明のPPAR活性化剤は、以下の化合物(I)〜(IV)の少なくとも1種を含むことが好ましい。
化合物(I)は9−oxo−10(E),12(Z)−octadecadienoic acid、化合物(II)は9−oxo−10(E),12(E)−octadecadienoic acid、化合物(III)は13−oxo−9(Z),11(E)−octadecadienoic acid、化合物(IV)は13−oxo−9(E),11(E)−octadecadienoic acidである。本発明者は、トマト果実には主として化合物(I)が存在するが、トマト抽出物の分画操作を行うことにより、主たる化合物が化合物(II)に変換されていることを確認し、トマトの加工品であるトマトジュースには化合物(I)〜(IV)の全てが存在することを確認している。したがって、詳細は不明であるが、これらの類縁化合物は、トマト抽出物の分画操作や加工操作により相互に変換されるものと考えられる。また、本発明者は、これらの化合物がそれぞれ単独でもPPARαおよびPPARγ活性化能を有していることを確認している。したがって、本発明のPPAR活性化剤には、上記化合物(I)〜(IV)の少なくとも1種を有効成分として含有するものも含まれる。 Compound (I) is 9-oxo-10 (E), 12 (Z) -octadecadienoic acid, Compound (II) is 9-oxo-10 (E), 12 (E) -octadecadienoic acid, Compound (III) is 13 -Oxo-9 (Z), 11 (E) -octadecadienic acid, compound (IV) is 13-oxo-9 (E), 11 (E) -octadecadienic acid. The present inventor confirms that the main compound is converted into the compound (II) by performing fractionation operation of the tomato extract, although the compound (I) is mainly present in the tomato fruit. It has been confirmed that all of the compounds (I) to (IV) are present in the processed tomato juice. Therefore, although details are unknown, it is considered that these related compounds are converted to each other by fractionation operation or processing operation of the tomato extract. In addition, the present inventor has confirmed that these compounds alone have PPARα and PPARγ activation ability. Therefore, the PPAR activator of the present invention includes those containing at least one of the compounds (I) to (IV) as an active ingredient.
上記化合物(I)〜(IV)を含むナス科植物の抽出物の活性フラクションは、例えば以下の方法により調製することができる。例えばトマト果実を材料とする場合、トマト果実の凍結乾燥粉末を調製し、これをエタノールなどのアルコール類、ヘキサンなどの炭化水素類、酢酸エチルなどのエステル類、アセトンなどのケトン類、ジエチルエーテル、ジオキサンなどのエーテル類またはジクロロメタン、クロロホルムなどのアルキルハライドで抽出する。抽出溶媒の量は原料の乾燥粉末に対し通常3〜20倍(w/w)である。また抽出温度は室温から使用する溶媒の沸騰点までの範囲でいずれでもよい。抽出液をろ過して残渣と分離したのち、濃縮してエキスを調製する。得られたエキスを、シリカゲルを固定相とするカラムクロマトグラフィーに付し、シリカゲルの通常10〜100倍(w/w)量の、例えばヘキサン:酢酸エチルの混合溶媒(ヘキサン100%−酢酸エチル100%のグラジエント)で溶離する溶離液中のPPAR活性を測定し、PPAR活性を有する溶離液を集め濃縮する。さらに、濃縮残留物を、逆相系シリカゲルを固定相とするカラムクロマトグラフィー(HPLC等)に付し、逆相系シリカゲルの通常10〜200倍(w/w)量の、例えばアセトニトリル/水の30−100%グラジエントで溶離して、得られたフラクションのPPAR活性を測定する。PPAR活性を有する溶離液を集めて濃縮し、逆相系シリカゲルを固定相とするカラムクロマトグラフィーを繰り返すことにより、高PPAR活性を有するフラクションを調製することができる。 The active fraction of the solanaceous plant extract containing the compounds (I) to (IV) can be prepared, for example, by the following method. For example, when tomato fruit is used as a material, a freeze-dried powder of tomato fruit is prepared, and this is made of alcohols such as ethanol, hydrocarbons such as hexane, esters such as ethyl acetate, ketones such as acetone, diethyl ether, Extract with ethers such as dioxane or alkyl halides such as dichloromethane and chloroform. The amount of the extraction solvent is usually 3 to 20 times (w / w) with respect to the dry powder of the raw material. The extraction temperature may be any range from room temperature to the boiling point of the solvent used. The extract is filtered to separate it from the residue, and then concentrated to prepare an extract. The obtained extract is subjected to column chromatography using silica gel as a stationary phase, and usually 10 to 100 times (w / w) of silica gel, for example, a mixed solvent of hexane: ethyl acetate (hexane 100% -ethyl acetate 100). The PPAR activity in the eluent eluting with a% gradient is measured, and the eluent having PPAR activity is collected and concentrated. Further, the concentrated residue is subjected to column chromatography (HPLC or the like) using reversed phase silica gel as a stationary phase, and usually 10 to 200 times (w / w) amount of reversed phase silica gel, for example, acetonitrile / water. The resulting fraction is measured for PPAR activity, eluting with a 30-100% gradient. A fraction having high PPAR activity can be prepared by collecting and concentrating the eluent having PPAR activity and repeating column chromatography using reverse phase silica gel as a stationary phase.
溶離液のPPAR活性を測定する方法は特に限定されず、公知のPPAR活性測定法を用いることができる。例えば、Gotoら(T. Goto et al., Biochemical and Biophysical Research Communications 337 (2005) 440-445)に記載のPPARレポーターアッセイを好適に用いることができる。 The method for measuring the PPAR activity of the eluent is not particularly limited, and a known PPAR activity measurement method can be used. For example, the PPAR reporter assay described in Goto et al. (T. Goto et al., Biochemical and Biophysical Research Communications 337 (2005) 440-445) can be suitably used.
また、上記化合物(I)〜(IV)は、例えば、Kuklevら(D. Kuklev et al., Chemistry and Physics of Lipids 85 (1997) 125-134)等に記載の方法およびこれに準じた方法にしたがって合成することができる。 In addition, the above compounds (I) to (IV) can be prepared, for example, by the method described in Kuklev et al. (D. Kuklev et al., Chemistry and Physics of Lipids 85 (1997) 125-134) and the like, and a method analogous thereto. Therefore, it can be synthesized.
本発明のPPAR活性化剤は、in vitroおよびin vivoの薬理試験において、脂肪酸代謝活性化作用、血糖値上昇抑制(抗糖尿病)作用、高脂血症抑制作用、脂肪肝抑制作用、耐糖能改善作用、血中インスリン上昇抑制作用を有することが確認されていることから(実施例4、5参照)、インスリン抵抗性、2型糖尿病、脂質異常症、高血圧、内臓脂肪型肥満、脂肪肝等の生活習慣病を予防または改善するために好適に用いることができる。 The PPAR activator of the present invention is used in in vitro and in vivo pharmacological tests to activate fatty acid metabolism, suppress blood glucose level elevation (antidiabetic), inhibit hyperlipidemia, inhibit fatty liver, and improve glucose tolerance. Since it has been confirmed that it has an action and an inhibitory action on blood insulin elevation (see Examples 4 and 5), insulin resistance, type 2 diabetes, dyslipidemia, hypertension, visceral fat type obesity, fatty liver, etc. It can be suitably used for preventing or improving lifestyle-related diseases.
また、本発明のPPAR活性化剤は、上記の薬理作用を有することから、メタボリックシンドロームを予防または改善するために好適に用いることができる。わが国では、以下の(1)に加えて(2)〜(4)のうち2つ以上が当てはまるとメタボリックシンドロームと診断される。
(1)腹囲(へそ周り)が、男性の場合は85cm以上、女性の場合は90cm以上
(2)中性脂肪が150mg/dL以上、HDLコレステロールが40mg/dL未満、のいずれか、または両方
(3)最高(収縮期)血圧が130mmHg以上、最低(拡張期)血圧が85mmHg以上、のいずれか、または両方
(4)空腹時血糖値が110mg/dL以上
本発明のPPAR活性化剤をメタボリックシンドロームの診断基準を満たすヒトに適用すれば、少なくとも高血糖および脂質異常が改善されるので、治療対象を外れることが期待できる。
Moreover, since the PPAR activator of the present invention has the above pharmacological action, it can be suitably used for preventing or improving metabolic syndrome. In Japan, metabolic syndrome is diagnosed when two or more of (2) to (4) are applied in addition to the following (1).
(1) Waist circumference (around navel) is 85 cm or more for men, 90 cm or more for women (2) Neutral fat is 150 mg / dL or more, HDL cholesterol is less than 40 mg / dL, or both ( 3) Either the highest (systolic) blood pressure is 130 mmHg or higher, the lowest (diastolic) blood pressure is 85 mmHg or higher, or both (4) Fasting blood glucose level is 110 mg / dL or higher Metabolic syndrome of the PPAR activator of the present invention When applied to a human who satisfies the above diagnostic criteria, at least hyperglycemia and lipid abnormalities are improved, so that it can be expected to be excluded from the treatment target.
本発明のPPAR活性化剤は、PPAR活性化作用を有する薬剤の適用対象とされる疾患、例えば、糖尿病(1型糖尿病、2型糖尿病等)、脂質異常症(高トリグリセライド血症、高LDL血症、低HDL血症等)、糖尿病性合併症(神経障害、腎症、網膜症、白内障等)、耐糖能不全(IGT)、肥満、骨粗鬆症、悪液質、脂肪肝、高血圧、多嚢胞性卵巣症候群、妊娠糖尿病、腎臓疾患、筋ジストロフィー、心筋梗塞、狭心症、脳血管障害、インスリン抵抗性症候群、シンドロームX、高インスリン血症、高インスリン血症における知覚障害、腫瘍(白血病、乳癌、前立腺癌、皮膚癌等)、過敏性腸症候群、急性または慢性下痢、内臓肥満症候群などの疾患を予防または改善するために、好適に用いることができる。 The PPAR activator of the present invention is a disease to which a drug having a PPAR activation action is applied, for example, diabetes (type 1 diabetes, type 2 diabetes, etc.), dyslipidemia (hypertriglyceridemia, high LDL blood) , HypoHDLemia, etc.), diabetic complications (neuropathy, nephropathy, retinopathy, cataract, etc.), impaired glucose tolerance (IGT), obesity, osteoporosis, cachexia, fatty liver, hypertension, polycystic Ovarian syndrome, gestational diabetes mellitus, kidney disease, muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder, insulin resistance syndrome, syndrome X, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (leukemia, breast cancer, prostate) Cancer, skin cancer, etc.), irritable bowel syndrome, acute or chronic diarrhea, visceral obesity syndrome and other diseases can be suitably used.
本発明は、上記本発明のPPAR活性化剤を含有する生活習慣病の予防または改善用医薬を提供する。また、本発明は、上記本発明のPPAR活性化剤を含有するメタボリックシンドロームの予防または改善用医薬を提供する。 The present invention provides a medicament for preventing or ameliorating lifestyle-related diseases comprising the PPAR activator of the present invention. The present invention also provides a medicament for preventing or improving metabolic syndrome, which comprises the PPAR activator of the present invention.
本発明の医薬は、経口または非経口のいずれかの経路で哺乳動物に投与することができる。経口剤としては、顆粒剤、散剤、錠剤(糖衣錠を含む)、丸剤、カプセル剤、シロップ剤、乳剤、懸濁剤などが挙げられる。非経口剤としては、注射剤(例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤)、点滴剤、外用剤(例えば、経鼻投与製剤、経皮製剤、軟膏剤)、坐剤(例えば、直腸坐剤、膣坐剤)などが挙げられる。これらの製剤は、当該分野で通常行われている手法により、薬学上許容される担体を用いて製剤化することができる。薬学上許容される担体としては、賦形剤、結合剤、希釈剤、添加剤、香料、緩衝剤、増粘剤、着色剤、安定剤、乳化剤、分散剤、懸濁化剤、防腐剤等が挙げられ、例えば、炭酸マグネシウム、ステアリン酸マグネシウム、タルク、砂糖、ラクトース、ペクチン、デキストリン、澱粉、ゼラチン、トラガント、メチルセルロース、ナトリウムカルボキシメチルセルロース、低融点ワックス、カカオバター等を担体として使用できる。 The medicament of the present invention can be administered to a mammal by either oral or parenteral routes. Examples of oral preparations include granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions, suspensions and the like. Examples of parenteral preparations include injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drops, and external preparations (for example, nasal preparations, transdermal preparations, ointments) ), Suppositories (for example, rectal suppositories, vaginal suppositories) and the like. These preparations can be formulated using a pharmaceutically acceptable carrier by a technique usually performed in the art. Pharmaceutically acceptable carriers include excipients, binders, diluents, additives, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. For example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low-melting wax, cocoa butter and the like can be used as a carrier.
経口用の固形剤(錠剤、丸剤、カプセル剤、散剤、顆粒剤等)は、有効成分を賦形剤(ラクトース、マンニトール、グルコース、微結晶セルロース、デンプン等)、結合剤(ヒドロキシプロピルセルロース、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等)、崩壊剤(繊維素グリコール酸カルシウム等)、滑沢剤(ステアリン酸マグネシウム等)、安定剤、溶解補助剤(グルタミン酸、アスパラギン酸等)等と混合し、常法に従って製剤化することができる。必要に応じて、コーティング剤(白糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等)で被覆していてもよいし、また2以上の層で被覆していてもよい。 Oral solid preparations (tablets, pills, capsules, powders, granules, etc.) have active ingredients as excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, Polyvinyl pyrrolidone, magnesium aluminate metasilicate, etc.), disintegrating agent (calcium cellulose glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, solubilizing agent (glutamic acid, aspartic acid, etc.), etc. It can be formulated according to conventional methods. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers.
経口用の液剤(水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等)は、有効成分を一般的に用いられる希釈剤(精製水、エタノールまたはそれらの混液等)に溶解、懸濁または乳化して製剤化される。さらにこの液剤は、湿潤剤、懸濁化剤、乳化剤、甘味剤、風味剤、芳香剤、保存剤、緩衝剤等を含有していてもよい。 Oral liquids (solutions, suspensions, emulsions, syrups, elixirs, etc.) are dissolved, suspended, or dissolved in diluents (purified water, ethanol or mixtures thereof, etc.) in which active ingredients are generally used. Emulsified and formulated. Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
注射剤は、溶液、懸濁液、乳濁液、および用時溶剤に溶解または懸濁して用いる固形の注射剤を包含する。注射剤は、有効成分を溶剤に溶解、懸濁または乳化して製剤化される。溶剤として、例えば注射用蒸留水、生理食塩水、植物油、プロピレングリコール、ポリエチレングリコール、エタノールのようなアルコール類等およびそれらの組み合わせが用いられる。さらにこの注射剤は、安定剤、溶解補助剤(グルタミン酸、アスパラギン酸、ポリソルベート80(登録商標)等)、懸濁化剤、乳化剤、無痛化剤、緩衝剤、保存剤等を含んでいてもよい。これらは最終工程において滅菌するか無菌操作法によって製造される。また無菌の固形剤、例えば凍結乾燥品を製造し、その使用前に無菌化または無菌の注射用蒸留水または他の溶剤に溶解して使用することもできる。 The injection includes solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is formulated by dissolving, suspending or emulsifying an active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Further, this injection may contain a stabilizer, a solubilizing agent (such as glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative and the like. . These are sterilized in the final process or manufactured by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.
本発明は、上記本発明のPPAR活性化剤を含有する生活習慣病の予防または改善用飲食品を提供する。また、本発明は、上記本発明のPPAR活性化剤を含有するメタボリックシンドロームの予防または改善用飲食品を提供する。「飲食品」には、健康食品、機能性食品、特定保健用食品、病者用食品が含まれる。 This invention provides the food-drinks for prevention or improvement of the lifestyle-related disease containing the said PPAR activator of this invention. Moreover, this invention provides the food-drinks for prevention or improvement of the metabolic syndrome containing the said PPAR activator of this invention. “Food and beverage” includes health food, functional food, food for specified health use, and food for the sick.
本発明に好適な飲食品は特に限定されない。具体例には、例えば、いわゆる栄養補助食品(サプリメント)としての錠剤、顆粒剤、散剤、ドリンク剤等を挙げることができる。これ以外には、例えば茶飲料、清涼飲料、炭酸飲料、栄養飲料、果実飲料、乳酸飲料等の飲料、そば、うどん、中華麺、即席麺等の麺類、飴、キャンディー、ガム、チョコレート、スナック菓子、ビスケット、ゼリー、ジャム、クリーム、焼き菓子、パン等の菓子およびパン類、かまぼこ、ハム、ソーセージ等の水産・畜産加工食品、加工乳、発酵乳等の乳製品、サラダ油、てんぷら油、マーガリン、マヨネーズ、ショートニング、ホイップクリーム、ドレッシング等の油脂および油脂加工食品、ソース、たれ等の調味料、カレー、シチュー、丼、お粥、雑炊等のレトルトパウチ食品、アイスクリーム、シャーベット、かき氷等の冷菓などを挙げることができる。 The food or drink suitable for the present invention is not particularly limited. Specific examples include tablets, granules, powders, and drinks as so-called dietary supplements (supplements). Other than this, for example, beverages such as tea beverages, soft drinks, carbonated beverages, nutritional beverages, fruit beverages, lactic acid beverages, noodles such as buckwheat, udon, Chinese noodles, instant noodles, strawberries, candy, gum, chocolate, snacks, Biscuits, jelly, jam, cream, baked confectionery, confectionery such as bread, bakery products, fishery products such as kamaboko, ham, sausage, dairy products such as processed milk, fermented milk, salad oil, tempura oil, margarine, mayonnaise , Shortening, whipped cream, dressing and other fats and oils and processed foods, sauces, sauces and other seasonings, curry, stew, rice cakes, rice cakes, and other retort pouch foods, ice cream, sorbets, shaved ice and other frozen desserts Can be mentioned.
本発明の医薬および飲食品は、人類が長年摂取してきたトマトやナスの抽出物を有効成分とするものであるから、毒性が低く、哺乳動物(例えば、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等)に対し安全に用いられる。また、PPARαアゴニストはげっ歯類に対して肝臓の重量を増加(ペルオキシソームを増加)させる副作用があるが、本発明のPPAR活性化剤は、マウスの肝臓を肥大させなかったことから(実施例5参照)、本発明の医薬および飲食品は高い安全性を有するものと考えられる。 The medicament and food and drink according to the present invention have tomato and eggplant extracts that have been ingested by mankind for many years as active ingredients, and therefore have low toxicity, and mammals (eg, humans, mice, rats, rabbits, dogs, Cats, cows, horses, pigs, monkeys, etc.). In addition, PPARα agonists have the side effect of increasing liver weight (increasing peroxisomes) relative to rodents, but the PPAR activator of the present invention did not enlarge mouse liver (Example 5). Reference), the medicament and food and drink of the present invention are considered to have high safety.
本発明の医薬および飲食品の投与量または摂取量は、患者または摂取者の年齢および体重、症状、投与時間、剤形、投与方法、薬剤の組み合わせ等に依存して決定できる。例えば、本発明の医薬を経口投与する場合、成人1人当たり0.5〜100mg/kg体重、好ましくは1〜50mg/kg体重の範囲で、また、非経口的に投与する場合は0.05〜50mg/kg体重、好ましくは0.5〜50mg/kg体重の範囲で一日1〜3回に分けて投与することができる。また、食品として摂取する場合には、成人1人1日当たり100〜6000mgの範囲、好ましくは200〜3000mgの範囲の摂取量となるように配合することができる。 The dose or intake of the medicament and food and drink of the present invention can be determined depending on the age and weight of the patient or the intake person, symptoms, administration time, dosage form, administration method, combination of drugs, and the like. For example, when the medicament of the present invention is orally administered, it is in the range of 0.5 to 100 mg / kg body weight, preferably 1 to 50 mg / kg body weight per adult, and 0.05 to 0.05 when administered parenterally. The dose can be divided into 1 to 3 times a day in the range of 50 mg / kg body weight, preferably 0.5 to 50 mg / kg body weight. Moreover, when ingesting as a foodstuff, it can mix | blend so that it may become the intake of the range of 100-6000 mg per day for an adult, Preferably it is the range of 200-3000 mg.
さらに、本発明は、生活習慣病の予防または改善用医薬の製造のためのナス科植物の抽出物またはその活性フラクションを有効成分とするPPAR活性化剤の使用を提供する。また、メタボリックシンドロームの予防または改善用医薬の製造のためのナス科植物の抽出物またはその活性フラクションを有効成分とするPPAR活性化剤の使用を提供する。
また、本発明は、PPAR活性化能を有するナス科植物の抽出物またはその活性フラクションを哺乳動物に投与する生活習慣病の予防または改善方法を提供する。また、PPAR活性化能を有するナス科植物の抽出物またはその活性フラクションを哺乳動物に投与するメタボリックシンドロームの予防または改善方法を提供する。
Furthermore, the present invention provides the use of a PPAR activator comprising an extract of a solanaceous plant or an active fraction thereof for the production of a medicament for preventing or ameliorating lifestyle-related diseases. The present invention also provides use of a PPAR activator comprising an extract of a solanaceous plant or an active fraction thereof for the manufacture of a medicament for preventing or improving metabolic syndrome.
The present invention also provides a method for preventing or ameliorating lifestyle-related diseases, wherein an extract of a solanaceous plant having PPAR activation ability or an active fraction thereof is administered to a mammal. The present invention also provides a method for preventing or improving metabolic syndrome, wherein an extract of a solanaceous plant having PPAR activation ability or an active fraction thereof is administered to a mammal.
以下、実施例により本発明を詳細に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these.
〔実施例1:トマト抽出物のPPARα活性フラクションの同定〕
(1−1)トマト抽出物の調製
トマト(加工用品種「ふりこま」)の果実破砕物を凍結乾燥し、トマト凍結乾燥粉末を得た。これにエタノールを添加して24時間振とうし、抽出液を濃縮乾固した。さらに、ヘキサン抽出を行い、抽出液を濃縮乾固した後、シリカゲルオープンカラムに担持させて、ヘキサン−酢酸エチルの混合溶媒で溶出、分画を行った。続いて、ODSカラムによるHPLC分画を2回行い、1分ごとにフラクションを得た。
シリカゲルオープンカラムにおける溶出には、ヘキサン100%、ヘキサン:酢酸エチル=3:1、ヘキサン:酢酸エチル=1:1、ヘキサン:酢酸エチル=1:3、酢酸エチル100%をこの順に各ステップ500mLで溶出し、回収した各溶出液のPPARα活性を測定した。
1回目のHPLCには、逆相5C18−AR−II ODSカラム(カラムA、ナカライテスク)を用いた。移動相にはアセトニトリル/水の30−100%グラジエント(0−60分)を用い、流速は1mL/分とした。1分ごとに1mLずつフラクションを回収し、各フラクションのPPARα活性を測定した。
2回目のHPLCには、逆相TSKgel ODS−100Vカラム(カラムB、東ソー)を用いた。移動相にはアセトニトリル/水の30−100%グラジエント(0−60分)を用い、流速は0.5mL/分とした。1分ごとに0.5mLずつフラクションを回収し、各フラクションのPPARα活性を測定した。
[Example 1: Identification of PPARα activity fraction of tomato extract]
(1-1) Preparation of tomato extract Fruit crushed material of tomato (variety for processing “Furikoma”) was freeze-dried to obtain a tomato freeze-dried powder. Ethanol was added thereto and shaken for 24 hours, and the extract was concentrated to dryness. Further, hexane extraction was performed, the extract was concentrated to dryness, supported on a silica gel open column, and eluted and fractionated with a mixed solvent of hexane-ethyl acetate. Subsequently, HPLC fractionation using an ODS column was performed twice, and fractions were obtained every minute.
For elution on a silica gel open column, hexane 100%, hexane: ethyl acetate = 3: 1, hexane: ethyl acetate = 1: 1, hexane: ethyl acetate = 1: 3, ethyl acetate 100% in this order in 500 mL each step. The PPARα activity of each eluate eluted and collected was measured.
A reverse phase 5C18-AR-II ODS column (column A, Nacalai Tesque) was used for the first HPLC. A 30-100% gradient of acetonitrile / water (0-60 minutes) was used as the mobile phase, and the flow rate was 1 mL / min. One mL fractions were collected every minute and the PPARα activity of each fraction was measured.
A reverse phase TSKgel ODS-100V column (column B, Tosoh) was used for the second HPLC. The mobile phase was a 30-100% gradient of acetonitrile / water (0-60 minutes) with a flow rate of 0.5 mL / min. 0.5 mL fractions were collected every minute and the PPARα activity of each fraction was measured.
(1−2)PPARα活性測定方法
PPARα活性測定には、PPARαレポーターアッセイを用いた。PPARαレポーターアッセイは、Gotoら(T. Goto et al., Biochemical and Biophysical Research Communications 337 (2005) 440-445)に記載の方法に準じて行った。すなわち、細胞には、p4xUASg−tk−luc(レポータープラスミド)、pM−hPPARα(GAL4のDNA結合ドメインとヒトPPARαのリガンド結合ドメインとのキメラタンパク質用発現ベクター)、pCMX−CBP(CBP(cAMP-response element-binding protein(CREB)-binding protein)用発現ベクター)およびpRL−CMV(トランスフェクション効率を標準化するための内部のコントロール)をトランスフェクションしたCV−1細胞(アフリカミドリザル腎細胞由来細胞株)を使用した。培地には、10%牛胎児血清、ペニシリン/ストレプトマイシン(10mg/mL)を含有するDMEM培地を使用した。
(1-2) PPARα activity measurement method PPARα reporter assay was used for PPARα activity measurement. The PPARα reporter assay was performed according to the method described in Goto et al. (T. Goto et al., Biochemical and Biophysical Research Communications 337 (2005) 440-445). That is, cells include p4xUASg-tk-luc (reporter plasmid), pM-hPPARα (expression vector for chimeric protein of DNA binding domain of GAL4 and ligand binding domain of human PPARα), pCMX-CBP (CBP (cAMP-response CV-1 cells (African green monkey kidney cell-derived cell line) transfected with expression vectors for element-binding protein (CREB) -binding protein) and pRL-CMV (internal control for standardizing transfection efficiency) used. As the medium, DMEM medium containing 10% fetal bovine serum and penicillin / streptomycin (10 mg / mL) was used.
CV−1細胞にリポフェクタミン(Invitrogen)を用いて上記ベクターをトランスフェクションし、24時間培養した。続いて、PPARα活性測定用サンプルを含む培地に交換し、さらに24時間培養した。ルシフェラーゼ活性の測定には、Dual−Luciferase(R) Reporter Assay System(Promega)およびルミノメーター(MicroLumat Plus、ベルトールジャパン)を使用し、試薬および装置の取扱説明書に従って、ルシフェラーゼ活性を測定した。なお、陽性対照として、既知のPPARαアゴニストであるGW−7647(2-[4-[2-[1-(4-シクロヘキシルブチル)-3-シクロヘキシルウレイド]エチル]フェニルチオ]イソ酪酸)を使用した。 CV-1 cells were transfected with the above vector using lipofectamine (Invitrogen) and cultured for 24 hours. Subsequently, the medium was replaced with a medium containing a sample for measuring PPARα activity, and further cultured for 24 hours. The measurement of luciferase activity using the Dual-Luciferase (R) Reporter Assay System (Promega) and a luminometer (MicroLumat Plus, Bell Torr Japan), according to the instructions of the reagent and equipment, and luciferase activity was measured. As a positive control, GW-7647 (2- [4- [2- [1- (4-cyclohexylbutyl) -3-cyclohexylureido] ethyl] phenylthio] isobutyric acid), which is a known PPARα agonist, was used.
(1−3)結果
シリカゲルオープンカラムを用いた分画により、ヘキサン:酢酸エチル=3:1で溶出したフラクションにPPARα活性が認められ、これ以外の分画にはPPARα活性が認められなかった。
PPARα活性が認められたヘキサン:酢酸エチル=3:1で溶出したフラクションを1回目のHPLCに供し、得られたフラクションのPPARα活性を測定した。40分〜45分のフラクションのPPARα活性測定結果を図1に示した。図1から明らかなように、42〜43分のフラクション(F42、F43)に強いPPARα活性が認められた。
1回目のHPLCにおいて、PPARα活性が認められたフラクションを集めて2回目のHPLCに供した。2回目のHPLCで得られたフラクションの54分〜59分のPPARα活性測定結果を図2に示した。図2から明らかなように、57分のフラクション(RF57)に強いPPARα活性が認められた。
(1-3) Results PPARα activity was observed in the fraction eluted with hexane: ethyl acetate = 3: 1 by fractionation using a silica gel open column, and no PPARα activity was observed in the other fractions.
The fraction eluted with hexane: ethyl acetate = 3: 1 in which PPARα activity was observed was subjected to the first HPLC, and the PPARα activity of the obtained fraction was measured. The results of measuring PPARα activity in the 40-45 minute fraction are shown in FIG. As is clear from FIG. 1, strong PPARα activity was observed in the fractions (F42, F43) of 42 to 43 minutes.
In the first HPLC, fractions in which PPARα activity was observed were collected and subjected to the second HPLC. The PPARα activity measurement results of the fractions obtained by the second HPLC in 54 minutes to 59 minutes are shown in FIG. As is clear from FIG. 2, strong PPARα activity was observed in the 57 minute fraction (RF57).
〔実施例2:トマト抽出物のPPARα活性フラクション(RF57)中に含有される機能性成分の同定〕
RF57のLC/MS解析を行い、RF57に含まれるPPARα活性化成分は、組成式C18H30O3の化合物であることが明らかとなった。さらに、NMRを用いてこのPPARα活性化成分の構造解析を行った結果、この成分はC18のケト不飽和脂肪酸であり、最大吸収波長(276nmで)からケトン基とジエンは共役していることが推察された。この結果から、PPARα活性化成分の候補物質として、13−oxo−9,11−octadecadienoic acid(13−oxo−ODA)および9−oxo−10,12−octadecadienoic acid(9−oxo−ODA)が考えられた。
[Example 2: Identification of functional components contained in PPARα activity fraction (RF57) of tomato extract]
LC / MS analysis of RF57 revealed that the PPARα activating component contained in RF57 was a compound having the composition formula C 18 H 30 O 3 . Furthermore, as a result of structural analysis of this PPARα activation component using NMR, this component is a C 18 keto unsaturated fatty acid, and the ketone group and the diene are conjugated from the maximum absorption wavelength (at 276 nm). Was inferred. From these results, 13-oxo-9,11-octadecadienic acid (13-oxo-ODA) and 9-oxo-10,12-octadecadienic acid (9-oxo-ODA) are considered as candidates for PPARα activation components. It was.
候補物質をさらに絞り込むために、LC/MS/MS解析を行って平面構造を推定し、PPARα活性化成分のケトン基とジエンの位置を確認した。LC/MS/MS解析による溶出時間の結果を図3(a)〜(d)に示した。(a)は13−oxo−ODAおよび9−oxo−ODAの混合物の結果であり、(b)は13−oxo−ODAの結果であり、(c)は9−oxo−ODAの結果であり、(d)はRF57の結果である。
LC/MS/MS解析によるフラグメントパターンの結果を図4(a)〜(e)に示した。(a)は13−oxo−9(Z),11(E)−ODAの結果であり、(b)は13−oxo−9(E),11(E)−ODAの結果であり、(c)は9−oxo−10(E),12(Z)−ODAの結果であり、(d)は9−oxo−10(E),12(E)−ODAの結果であり、(e)はRF57の結果である。
LC/MS/MS解析による吸収波長の結果を図5(a)〜(e)に示した。(a)は13−oxo−9(Z),11(E)−ODAの結果であり、(b)は13−oxo−9(E),11(E)−ODAの結果であり、(c)は9−oxo−10(E),12(Z)−ODAの結果であり、(d)は9−oxo−10(E),12(E)−ODAの結果であり、(e)はRF57の結果である。
図3、図4および図5に示した結果から、RF57に含まれるPPARα活性化成分は、9−oxo−10(E),12(E)−ODAであることが明らかとなった。
In order to further narrow down the candidate substances, LC / MS / MS analysis was performed to estimate the planar structure, and the positions of the ketone group and diene of the PPARα activation component were confirmed. The results of elution time by LC / MS / MS analysis are shown in FIGS. (A) is the result of a mixture of 13-oxo-ODA and 9-oxo-ODA, (b) is the result of 13-oxo-ODA, (c) is the result of 9-oxo-ODA, (D) is the result of RF57.
The fragment pattern results obtained by LC / MS / MS analysis are shown in FIGS. (A) is the result of 13-oxo-9 (Z), 11 (E) -ODA, (b) is the result of 13-oxo-9 (E), 11 (E) -ODA, (c ) Is the result of 9-oxo-10 (E), 12 (Z) -ODA, (d) is the result of 9-oxo-10 (E), 12 (E) -ODA, and (e) is It is a result of RF57.
The results of the absorption wavelength by LC / MS / MS analysis are shown in FIGS. (A) is the result of 13-oxo-9 (Z), 11 (E) -ODA, (b) is the result of 13-oxo-9 (E), 11 (E) -ODA, (c ) Is the result of 9-oxo-10 (E), 12 (Z) -ODA, (d) is the result of 9-oxo-10 (E), 12 (E) -ODA, and (e) is It is a result of RF57.
From the results shown in FIGS. 3, 4, and 5, it was revealed that the PPARα activation component contained in RF57 is 9-oxo-10 (E), 12 (E) -ODA.
〔実施例3:トマト果実、トマトジュースに含まれるPPARα活性化成分の同定〕
分画操作を施していないトマト果実や既製のトマトジュースにも、9−oxo−10(E),12(E)−ODAが含まれるか否かを確認した。すなわち、トマト(ふりこま)果実の凍結乾燥物、既製のトマトジュースの凍結乾燥物、およびトマトジュースの原料トマト(NDM736)果実の凍結乾燥物をそれぞれエタノール抽出し、その抽出物をLC/MS/MS解析に供した。
結果を図6(a)〜(c)に示した。(a)はふりこま果実の結果であり、(b)はNDM736果実の結果であり、(c)はトマトジュースの結果である。興味深いことに、トマト果実に存在するPPARα活性化成分は、RF57から同定された9−oxo−10(E),12(E)−ODAではなく、その幾何異性体である9−oxo−10(E),12(Z)−ODAが主体であることが明らかとなった。また、トマトジュース中には、9−oxo−10(E),12(E)−ODA以外に3種類の類縁体化合物(9−oxo−10(E),12(Z)−ODA、13−oxo−9(Z),11(E)−ODA、13−oxo−9(E),11(E)−ODA)が同定された。これらの結果から、分画操作や加工操作により、類縁体化合物が生成するものと推測された。
[Example 3: Identification of PPARα-activating component contained in tomato fruit and tomato juice]
It was confirmed whether 9-oxo-10 (E) and 12 (E) -ODA were also contained in tomato fruits that were not subjected to fractionation operation and ready-made tomato juice. That is, a freeze-dried product of tomato (furikoma) fruit, a freeze-dried product of ready-made tomato juice, and a freeze-dried product of tomato juice raw tomato (NDM736) fruit were extracted with ethanol, and the extract was subjected to LC / MS / It used for MS analysis.
The results are shown in FIGS. 6 (a) to (c). (A) is the result of furikoma fruit, (b) is the result of NDM736 fruit, and (c) is the result of tomato juice. Interestingly, the PPARα activating component present in tomato fruit is not 9-oxo-10 (E), 12 (E) -ODA identified from RF57, but its geometric isomer 9-oxo-10 ( E), 12 (Z) -ODA was the main component. In addition, in tomato juice, in addition to 9-oxo-10 (E), 12 (E) -ODA, three analog compounds (9-oxo-10 (E), 12 (Z) -ODA, 13- oxo-9 (Z), 11 (E) -ODA, 13-oxo-9 (E), 11 (E) -ODA) were identified. From these results, it was speculated that an analog compound was formed by fractionation operation and processing operation.
トマト果実およびトマトジュースから同定された9−oxo−10(E),12(E)−ODA以外の類縁体化合物(9−oxo−10(E),12(Z)−ODA、13−oxo−9(Z),11(E)−ODA、13−oxo−9(E),11(E)−ODA)をPPARαレポーターアッセイに供し、PPARα活性化能を有することを確認した。
結果を図7に示した。図7から明らかなように、これらの類縁体化合物も、RF57と同様に強いPPARα活性化能を有していた。
Analog compounds other than 9-oxo-10 (E), 12 (E) -ODA identified from tomato fruit and tomato juice (9-oxo-10 (E), 12 (Z) -ODA, 13-oxo- 9 (Z), 11 (E) -ODA, 13-oxo-9 (E), 11 (E) -ODA) were subjected to PPARα reporter assay, and confirmed to have PPARα activation ability.
The results are shown in FIG. As is clear from FIG. 7, these analog compounds also had a strong PPARα activation ability as with RF57.
〔実施例4:PPARγ活性化能の確認〕
9−oxo−10(E),12(E)−ODAを含むRF57、および9−oxo−10(E),12(E)−ODAの類縁体化合物(9−oxo−10(E),12(Z)−ODA、13−oxo−9(Z),11(E)−ODA、13−oxo−9(E),11(E)−ODA)について、PPARγ活性化能を有するか否かを確認するために、PPARγレポーターアッセイを行った。PPARγレポーターアッセイは、上記実施例1の(1−2)に記載のPPARαレポーターアッセイの方法において、pM−hPPARα(GAL4のDNA結合ドメインとヒトPPARαのリガンド結合ドメインとのキメラタンパク質用発現ベクター)をpM−hPPARγ(GAL4のDNA結合ドメインとヒトPPARγのリガンド結合ドメインとのキメラタンパク質用発現ベクター)に変更し、陽性対照を、既知のPPARγアゴニストであるTroglitazone((+)-5-[4-[(6-ヒドロキシ-2,5,7,8-テトラメチルクロマン-2-イル)メトキシ]ベンジル]-2,4-チアゾリジンジオン)に変更して実施した。
結果を図8に示した。図8から明らかなように、RF57および9−oxo−10(E),12(E)−ODAの類縁体化合物の類縁体化合物は、いずれもPPARγ活性化能を有していることが確認された。
[Example 4: Confirmation of PPARγ activation ability]
RF57 including 9-oxo-10 (E), 12 (E) -ODA, and analog compounds of 9-oxo-10 (E), 12 (E) -ODA (9-oxo-10 (E), 12 Whether (Z) -ODA, 13-oxo-9 (Z), 11 (E) -ODA, 13-oxo-9 (E), 11 (E) -ODA) has the ability to activate PPARγ. To confirm, a PPARγ reporter assay was performed. The PPARγ reporter assay is the same as the PPARα reporter assay described in Example 1-2 (1-2) except that pM-hPPARα (an expression vector for a chimeric protein of a DNA binding domain of GAL4 and a ligand binding domain of human PPARα) is used. pM-hPPARγ (an expression vector for a chimeric protein of a DNA binding domain of GAL4 and a ligand binding domain of human PPARγ) was changed, and the positive control was Troglizone ((+)-5- [4- [ (6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl) methoxy] benzyl] -2,4-thiazolidinedione).
The results are shown in FIG. As is clear from FIG. 8, it was confirmed that all analog compounds of analog compounds of RF57 and 9-oxo-10 (E), 12 (E) -ODA have PPARγ activation ability. It was.
〔実施例5:RF57の機能解析〕
(5−1)肝臓細胞における脂肪酸β酸化関連遺伝子発現に関する評価
遺伝子導入によりPPARαを高発現させたHepG2細胞(ヒト肝臓由来)を12wellプレートに4×105個/wellで播種し、24時間インキュベートした。サンプル(RF57またはGW−7647)を添加した培地に交換し、24時間インキュベートした。細胞を回収し、β酸化関連遺伝子CPT1A(carnitine palmitoyltransferase 1A)のmRNA発現量を定量的RT−PCR法で測定した。
結果を図9に示した。図9から明らかなように、培地にRF57を添加することにより、CPT1AのmRNA発現量がコントロールに対して有意に増加した。なお、統計処理にはunpaired Student’s t−testを用いた。図中、*はp<0.05を表す。
[Example 5: Functional analysis of RF57]
(5-1) Evaluation of fatty acid β-oxidation-related gene expression in liver cells HepG2 cells (derived from human liver) in which PPARα is highly expressed by gene transfer are seeded on a 12-well plate at 4 × 10 5 cells / well and incubated for 24 hours. did. The medium (RF57 or GW-7647) was added to the medium and incubated for 24 hours. Cells were collected, and the mRNA expression level of β-oxidation-related gene CPT1A (carnitine palmitoyltransferase 1A) was measured by a quantitative RT-PCR method.
The results are shown in FIG. As is apparent from FIG. 9, the expression level of CPT1A mRNA was significantly increased relative to the control by adding RF57 to the medium. For statistical processing, unpaired Student's t-test was used. In the figure, * represents p <0.05.
(5−2)肝臓細胞におけるトリグリセリド(TG)蓄積に関する評価
遺伝子導入によりPPARαを高発現させたHepG2細胞を12wellプレートに4×105個/wellで播種し、24時間インキュベートした。オレイン酸を添加した培地に交換し、24時間インキュベートした。RF57を添加した培地に交換し、24時間インキュベートした。細胞を回収し、細胞内のTG蓄積量をTGキット(Wako)を用いて測定した。
結果を図10に示した。図10から明らかなように、培地にRF57を添加することにより、細胞内のTG蓄積量がコントロール(OA+)に対して有意に減少した。図中、*はp<0.05を表す。
(5-2) Evaluation on accumulation of triglyceride (TG) in liver cells HepG2 cells in which PPARα was highly expressed by gene transfer were seeded on a 12-well plate at 4 × 10 5 cells / well and incubated for 24 hours. The medium was changed to a medium supplemented with oleic acid and incubated for 24 hours. The medium was replaced with a medium supplemented with RF57 and incubated for 24 hours. Cells were collected, and the amount of TG accumulated in the cells was measured using a TG kit (Wako).
The results are shown in FIG. As apparent from FIG. 10, the addition of RF57 to the medium significantly reduced the amount of intracellular TG accumulation relative to the control (OA +). In the figure, * represents p <0.05.
(5−3)肝臓細胞における酸素消費に関する評価
C57BL/6Jマウス(6週齢、♂)から肝細胞を門脈潅流法により分離し、初代培養肝細胞を調製した。得られた初代培養肝細胞をプレート(XF24専用プレート)に5×105個/wellで播種し、2時間インキュベートした。RF57を添加した培地(濃度10μMまたは20μM)に交換し、24時間インキュベートした。酸素消費量測定装置XF24(Seahorse Bioscience社製)にて、肝臓細胞の酸素消費量を測定した。
結果を図11に示した。図11から明らかなように、培地にRF57を20μMの濃度で添加することにより、肝細胞における酸素消費量(OCR)が有意に増加した。図中、*はp<0.05を表す。
(5-3) Evaluation on Oxygen Consumption in Liver Cells Hepatocytes were isolated from C57BL / 6J mice (6 weeks old, rabbit) by the portal vein perfusion method to prepare primary cultured hepatocytes. The obtained primary cultured hepatocytes were seeded on a plate (XF24 dedicated plate) at 5 × 10 5 cells / well and incubated for 2 hours. The medium was replaced with a medium supplemented with RF57 (concentration 10 μM or 20 μM) and incubated for 24 hours. The oxygen consumption of liver cells was measured with an oxygen consumption measuring device XF24 (Seahorse Bioscience).
The results are shown in FIG. As is clear from FIG. 11, the amount of oxygen consumption (OCR) in hepatocytes was significantly increased by adding RF57 to the medium at a concentration of 20 μM. In the figure, * represents p <0.05.
以上の機能解析結果から、RF57は、肝細胞に対してPPARα活性化による脂肪燃焼作用を介した脂肪蓄積抑制作用を有するものと考えられた。 From the above functional analysis results, it was considered that RF57 has a fat accumulation inhibitory action on hepatocytes via a fat burning action by PPARα activation.
〔実施例6:肥満・糖尿病モデルマウス(KKAy)による評価〕
(6−1)動物および飼育
KKAy/TaJcl(♂、日本クレア)を4週齢で購入し、4日間一般飼料を与えて予備飼育した。予備飼育終了後、下記の(1)〜(4)の4群に群分けして高脂肪飼料に切り替えて、試験を開始した。動物は個別に飼育し、高脂肪飼料を4週間給餌した。被験物質には、混餌飼料を大量調製することが容易であることから、合成13−oxo−ODAを使用した。また、陽性コントロールには、公知の高脂血症薬(PPARアゴニスト)であるベザフィブレート(Beza)を使用した。合成13−oxo−ODAおよびBezaは、下記の濃度になるように飼料に添加し、混餌投与した。
(1) コントロール群(n=7)
(2) 0.05%Beza摂食群(n=6)
(3) 0.02%合成13−oxo−ODA摂食群(n=6)
(4) 0.05%合成13−oxo−ODA摂食群(n=8)
[Example 6: Evaluation by obesity / diabetes model mouse (KKA y )]
(6-1) Animals and rearing KKA y / TaJcl (Kashiwa, Claire Japan) was purchased at 4 weeks of age, and pre-bred with general feed for 4 days. After completion of the preliminary breeding, the test was started by switching to a high-fat diet by grouping into the following four groups (1) to (4). Animals were housed individually and fed a high fat diet for 4 weeks. As the test substance, synthetic 13-oxo-ODA was used because it is easy to prepare a large amount of mixed feed. In addition, bezafibrate (Beza), which is a known hyperlipidemia drug (PPAR agonist), was used as a positive control. Synthetic 13-oxo-ODA and Beza were added to the feed so as to have the following concentrations, and were mixed and administered.
(1) Control group (n = 7)
(2) 0.05% Beza feeding group (n = 6)
(3) 0.02% synthetic 13-oxo-ODA feeding group (n = 6)
(4) 0.05% synthetic 13-oxo-ODA feeding group (n = 8)
(6−2)血糖値および血中トリグリセリド(TG)の測定
実験開始前(0日目)、7日目、14日目および21日目に採血して、血糖値(血漿中グルコース濃度)を測定した。また、21日目には血中TG濃度を測定した。
血糖値血糖値の測定結果を図12に示した。図12から明らかなように、合成13−oxo−ODA摂食群はいずれの濃度においても、0.05%Beza摂食群と同様に、高脂肪飼料の摂食による血糖値の上昇を有意に抑制した。図中、*はp<0.05を表す。
血中TG濃度の測定結果を図13に示した。図13から明らかなように、0.05%合成13−oxo−ODA摂食群は、0.05%Beza摂食群と同様に、高脂肪飼料の摂食による高脂血症の発症を有意に抑制した。図中、*はp<0.05を表す。
(6-2) Measurement of blood glucose level and blood triglyceride (TG) Blood was collected before the start of the experiment (day 0), day 7, day 14 and day 21, and blood glucose level (plasma glucose concentration) was determined. It was measured. On the 21st day, blood TG concentration was measured.
The measurement result of blood glucose level was shown in FIG. As is clear from FIG. 12, the synthetic 13-oxo-ODA feeding group significantly increased the blood glucose level due to the feeding of the high-fat diet, as in the 0.05% Beza feeding group, at any concentration. Suppressed. In the figure, * represents p <0.05.
The measurement results of blood TG concentration are shown in FIG. As is clear from FIG. 13, the 0.05% synthetic 13-oxo-ODA feeding group has a significant onset of hyperlipidemia due to the feeding of the high fat diet, similar to the 0.05% Beza feeding group. Suppressed. In the figure, * represents p <0.05.
(6−3)経口糖負荷試験(OGTT、Oral glucose tolerance test)
試験開始25日目に経口糖負荷試験を実施した。具体的には、マウスを17時間絶食後、尾静脈から採血を行い(これを0分とする)、1.5mg/g体重となるようにD−(+)−グルコースを経口投与した。以降、15、30、60、90および120分後にそれぞれ尾静脈から採血を行い血糖値を測定した。
糖負荷後の血糖値の推移を図14に示した。図14から明らかなように、0.05%合成13−oxo−ODA摂食群は、0.05%Beza摂食群と同様に、糖負荷後の血糖値の上昇を有意に抑制した。図中、*はp<0.05を、**はp<0.01を表す。
血中インスリン濃度の測定結果を図15に示した。図15から明らかなように、合成13−oxo−ODA摂食群はいずれの濃度においても、0.05%Beza摂食群と同様に、高脂肪飼料の摂食によるインスリン値の上昇(高インスリン血漿と呼ばれ、糖代謝機能が悪化した状態)を有意に抑制した。図中、*はp<0.05を、**はp<0.01を表す。
(6-3) Oral glucose tolerance test (OGTT)
On the 25th day from the start of the test, an oral glucose tolerance test was performed. Specifically, the mice were fasted for 17 hours, then blood was collected from the tail vein (this was set to 0 minute), and D-(+)-glucose was orally administered to a body weight of 1.5 mg / g. Thereafter, blood was collected from the tail vein after 15, 30, 60, 90 and 120 minutes, and the blood glucose level was measured.
The transition of blood glucose level after glucose load is shown in FIG. As is clear from FIG. 14, the 0.05% synthetic 13-oxo-ODA feeding group significantly suppressed the increase in blood glucose level after glucose loading, similar to the 0.05% Beza feeding group. In the figure, * represents p <0.05, and ** represents p <0.01.
The measurement result of blood insulin concentration is shown in FIG. As is apparent from FIG. 15, the synthetic 13-oxo-ODA feeding group increased the insulin value (high insulin content) by feeding the high fat diet at any concentration, as in the 0.05% Beza feeding group. It was called plasma and significantly reduced the glucose metabolism function. In the figure, * represents p <0.05, and ** represents p <0.01.
(6−4)肝臓重量、肝臓脂肪蓄積量および肝臓における脂肪酸β酸化関連酵素遺伝子発現量の評価
試験開始28日目にマウスを安楽死させ肝臓を摘出した。得られた肝臓の重量を測定した後、肝臓中のTGはイソプロパノールでホモジナイズすることにより抽出し、アセチルアセトンを用いた発色法により定量した。また、肝臓における脂肪酸β酸化関連遺伝子mRNAは、キアゾール(QUIAGEN)を用いて抽出し、Rneasy Mini Kit(QUIAGEN)により精製した。mRNA発現量は定量的RT−PCR法で測定した。
肝臓中のTG蓄積量を測定した結果を図16に示した。図16から明らかなように、合成13−oxo−ODA摂食群では、肝臓中のTG蓄積量が用量依存的に減少した。図中、*はp<0.05を表す。
肝臓における脂肪酸β酸化関連遺伝子発現量を測定した結果を図17に示した。図17から明らかなように、合成13−oxo−ODA摂食群では、肝臓中の脂肪酸β酸化関連遺伝子CPT1AのmRNA発現量が、用量依存的に増加した。図中、*はp<0.05を表す。
肝臓重量を測定した結果を表1に示した。
(6-4) Evaluation of Liver Weight, Liver Fat Accumulation Amount, and Fatty Acid β Oxidation Related Enzyme Gene Expression Level in the Liver On day 28 of the test, the mouse was euthanized and the liver was removed. After measuring the weight of the obtained liver, TG in the liver was extracted by homogenization with isopropanol and quantified by a color development method using acetylacetone. In addition, fatty acid β-oxidation-related gene mRNA in the liver was extracted using chiazole (QUIAGEN) and purified by Rneasy Mini Kit (QUIAGEN). The mRNA expression level was measured by quantitative RT-PCR method.
The results of measuring the amount of TG accumulated in the liver are shown in FIG. As apparent from FIG. 16, in the synthetic 13-oxo-ODA feeding group, the amount of TG accumulated in the liver decreased in a dose-dependent manner. In the figure, * represents p <0.05.
The results of measuring the expression level of fatty acid β-oxidation-related gene in the liver are shown in FIG. As is clear from FIG. 17, in the synthetic 13-oxo-ODA feeding group, the mRNA expression level of the fatty acid β oxidation-related gene CPT1A in the liver increased in a dose-dependent manner. In the figure, * represents p <0.05.
The results of measuring liver weight are shown in Table 1.
表1から明らかなように、0.05%Beza摂食群の肝臓重量は、コントロール群と比較して有意に増加していたが、合成13−oxo−ODA摂食群は、いずれの濃度でも肝臓重量を増加させなかった。一般に、PPARαアゴニストは、マウスやラット等のげっ歯類に対して肝臓の重量を増加(ペルオキシソームを増加)させる副作用があることが知られている。この結果から、本発明のPPAR活性化剤は、肝臓肥大の副作用を発症させない点で安全性が高く、非常に有用であると考えられる。 As can be seen from Table 1, the liver weight of the 0.05% Beza feeding group was significantly increased compared to the control group, but the synthetic 13-oxo-ODA feeding group was at any concentration. It did not increase liver weight. In general, it is known that PPARα agonists have a side effect of increasing liver weight (increasing peroxisomes) to rodents such as mice and rats. From these results, it is considered that the PPAR activator of the present invention is highly safe and highly useful in that it does not cause the side effects of liver hypertrophy.
なお本発明は上述した各実施形態および実施例に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。また、本明細書中に記載された学術文献および特許文献の全てが、本明細書中において参考として援用される。 The present invention is not limited to the above-described embodiments and examples, and various modifications are possible within the scope shown in the claims, and technical means disclosed in different embodiments are appropriately combined. The obtained embodiment is also included in the technical scope of the present invention. Moreover, all the academic literatures and patent literatures described in this specification are incorporated herein by reference.
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