JP5473191B2 - ペルオキシソーム増殖剤応答性受容体(ppar)活性化剤、ならびにそれを用いた医薬、サプリメント、機能性食品および食品添加物 - Google Patents
ペルオキシソーム増殖剤応答性受容体(ppar)活性化剤、ならびにそれを用いた医薬、サプリメント、機能性食品および食品添加物 Download PDFInfo
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- JP5473191B2 JP5473191B2 JP2006542437A JP2006542437A JP5473191B2 JP 5473191 B2 JP5473191 B2 JP 5473191B2 JP 2006542437 A JP2006542437 A JP 2006542437A JP 2006542437 A JP2006542437 A JP 2006542437A JP 5473191 B2 JP5473191 B2 JP 5473191B2
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- nobiletin
- ppar
- activator
- pparγ
- adiponectin
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/752—Citrus, e.g. lime, orange or lemon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Description
a)ノビレチン、
b)インスリン抵抗性、高インスリン血症、2型糖尿病、高血圧、高脂血症、動脈硬化および肥満からなる群から選択される少なくとも一つの疾病の予防または治療に有用な第二の化合物を含む第二医薬組成物、および
c)前記ノビレチンおよび前記第二医薬組成物を入れるための容器を含むキットである。
まず、以下の2種類の培地を準備した。
1.分化誘導培地(0.25μM:DEX、0.5mM:MIX、10μg/mL:インスリン/10%FBS/DMEM)
DMEM(SIGMA製)500mLに、FBS(ウシ胎仔血清(GIBCO製))を55mL加え、10%FBS/DMEMを調製した。これに、1mM DEX(dexamethasone)/DMSO(ナカライ製)を138.75μL、10mg/mLインスリン/PBS(SIGMA製)を555μL加えた。なお、インスリン/PBSは、予めPBSに1N HClを加え、インスリンが溶ける程度に酸性にした後、インスリンを溶解させた。MIX(3−Isobutyl−1−methylxanthine)(ナカライ製)を、0.5mMとなるように、使用する直前に必要な量の前記培地に加えることにより、分化誘導培地を調製した。MIXは非常に溶けにくいため、まず少量の99.5%エタノールに溶解させた後、10%FBS/DMEMに加えた。このとき99.5%エタノールは最終濃度が、1%を越えないようにした。
2.分化促進培地(5μg/mL:インスリン/10%FBS/DMEM)
10%FBS/DMEM 555mLに、10mg/mLインスリン/PBSを277.5μL加え、分化促進培地を調製した。
total RNAの抽出と定量
前記6ウェルプレートから培地を除去し、各ウェルに1mLずつセパゾールRNA Isuper(ナカライ製)を加え、ピペッティングを数回繰り返すことにより細胞を分散させた。この液を1.5mLのチューブに移し、室温で5分間放置した後、クロロホルムを200μL加え、Vortexでよく撹絆し、室温で3分間放置した。4℃に冷却し、12000×gで15分間遠心した。フェノール層(下層、黄色)と水層(上層、無色)との界面を乱さないように注意しながら、水層のみを別のチューブ(容量1.5mL)へ移した。この際、中間に浮いているタンパク質を取らないようにした。前記チューブにイソプロパノールを500μL加えて混和し、室温で10分間放置した。4℃に冷却し、12000×gで10分間遠心し、上清約1mLを除去した。この沈殿に75%エタノールを1mL加えて撹拌して沈殿を十分に懸濁した後、4℃に冷却し、12000×gで10分間遠心し、上清を除去した。得られた沈殿(total RNA)を乾燥させた後、20μLのnuclease free waterに溶かし、NanoDrop(スクラム製)によりmRNAの濃度を測定した。
抽出し、測定したmRNA溶液を、mRNA濃度が1μg/μLになるように調製した。8連チューブ(容量0.2mL)に、Oligo dTプライマー1μLと前記RNA溶液10μLとを添加した。Thermal Cyclerにおいて、前記混合液を70℃で10分間インキュベートし、RNAの高次構造を破壊して氷上に移し、一分以上放置した後、以下のような試薬を順に加えた。
以下の操作は全てクリーンベンチ内で行った。発現量を測定する遺伝子の断片が入ったプラスミド溶液5mLを、0.65mLのチューブに加え、Light Cycler(TM)DNA Master SYBR Greenに付属の水45mLで10倍に希釈した。この作業を繰り返し、102、103、104、105、106、107および108倍の希釈溶液を作製した。Light Cycler(TM)Centrifuge Adapterに専用キャピラリーを、ピンセットを用いてセットし、前記試薬を18μLずつ分注した。さらに、ネガティブコントロールとして水、スタンダードとして7段階の希釈溶液、ならびに測定用サンプルのcDNAの10倍希釈液をそれぞれ2μLずつ添加した後、ピンセットを用いて蓋をした。5000rpm、4℃で10秒間遠心した後、キャピラリーをカルーセルに装填してチャンバーにセットし、測定を行った。
酵素免疫測定法(ELISA法)によるアディポネクチン分泌量の測定は、マウス/ラット アディポネクチンELISAキット(商品名)(大塚製薬株式会社製)を用いて行った。なお、前記キットの構成は、以下の通りである。
洗浄用原液
検体希釈用原液
抗体プレート(抗マウスアディポネクチンポリクローナル抗体(ウサギ)固相プレート)
標準品8.0ng/mL(リコンビナントマウスアディポネクチン)
ビオチン標識抗体液(ビオチン標識抗マウスアディポネクチン ポリクロナール抗体(ウサギ))
酵素標識ストレプトアビジン原液(HRP標識ストレプトアビジン)
酵素標識ストレプトアビジン希釈液
基質液A(3,3’,5,5’−テトラメチルベンジジン)
基質液B(過酸化水素)
反応停止液
洗浄液
前記洗浄用原液40mLに対して、精製水を960mLの割合で混合し、2.8℃で保存した。
検体希釈液
前記検体希釈用原液50mLに対して、精製水を200mLの割合で混合し、2.8℃で保存した。
標準液
前記標準品8.0ng/mLを、前記検体希釈液で2段階希釈し、4.0ng/mL、2.0ng/mL、1.0ng/mL、0.5ng/mLおよび0.25ng/mLの濃度の標準液を調製した。
酵素標織ストレプトアビジン液
前記酵素標識ストレプトアビジン希釈液12mLに対して、前記酵素標識ストレプトアビジン原液を60μLの割合で混和した。
基質液
前記基質液B6mLに対して、前記基質液Aを6mLの割合で混和した。
検体液
前記コントロール群および前記NOB群の血清を、4万倍に希釈した。
Claims (7)
- ペルオキシソーム増殖剤応答性受容体(PPAR)γの活性化剤であって、シイクワシャー(Citrus depressa HAYATA)由来のノビレチンを含み、アディポネクチンの分泌促進を介した肥満の予防又は改善のために使用する、PPARγ活性化剤。
- ペルオキシソーム増殖剤応答性受容体(PPAR)γの活性化剤であって、アディポネクチンの分泌促進を介した肥満の予防又は改善のために使用する、シイクワシャー(Citrus depressa HAYATA)由来のノビレチンからなるPPARγ活性化剤。
- アディポネクチンの分泌促進を介した肥満の予防若しくは治療のための医薬であって、請求項1記載のPPARγ活性化剤を含む医薬。
- PPARγ活性化方法(但し、対象からヒトを除く)であって、シイクワシャー(Citrus depressa HAYATA)由来のノビレチンによりPPARγを活性化するPPARγ活性化方法。
- 哺乳動物(ヒトを除く)においてアディポネクチンの分泌促進を介した肥満の予防、治療または改善方法であって、請求項1又は2に記載のPPARγ活性化剤を投与することを含む予防、治療または改善方法。
- PPARγ活性化剤の製造のためのシイクワシャー(Citrus depressa HAYATA)由来のノビレチンの使用。
- 哺乳動物(ヒトを除く)においてアディポネクチンの分泌促進を介した肥満の予防、治療または改善のために、シイクワシャー(Citrus depressa HAYATA)由来のノビレチンを投与することを含む使用。
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PCT/JP2005/020268 WO2006049234A1 (ja) | 2004-11-08 | 2005-11-04 | ペルオキシソーム増殖剤応答性受容体(ppar)活性化剤、ならびにそれを用いた医薬、サプリメント、機能性食品および食品添加物 |
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EP (1) | EP1829542B1 (ja) |
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JP2013163684A (ja) * | 2004-11-08 | 2013-08-22 | Arkray Inc | ペルオキシソーム増殖剤応答性受容体(ppar)活性化剤、ならびにそれを用いた医薬、サプリメント、機能性食品および食品添加物 |
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JP2013163684A (ja) * | 2004-11-08 | 2013-08-22 | Arkray Inc | ペルオキシソーム増殖剤応答性受容体(ppar)活性化剤、ならびにそれを用いた医薬、サプリメント、機能性食品および食品添加物 |
JP2013163685A (ja) * | 2004-11-08 | 2013-08-22 | Arkray Inc | ペルオキシソーム増殖剤応答性受容体(ppar)活性化剤、ならびにそれを用いた医薬、サプリメント、機能性食品および食品添加物 |
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US20070213282A1 (en) | 2007-09-13 |
US9573919B2 (en) | 2017-02-21 |
JPWO2006049234A1 (ja) | 2008-05-29 |
EP1829542B1 (en) | 2012-07-18 |
CN104306367A (zh) | 2015-01-28 |
EP1829542A4 (en) | 2009-05-27 |
EP1829542A1 (en) | 2007-09-05 |
JP2013163684A (ja) | 2013-08-22 |
JP2013163685A (ja) | 2013-08-22 |
CN101052391A (zh) | 2007-10-10 |
WO2006049234A1 (ja) | 2006-05-11 |
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