JP5860803B2 - 生体内の蛋白質の分解抑制剤 - Google Patents
生体内の蛋白質の分解抑制剤 Download PDFInfo
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- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Description
炭素数6〜12の脂肪酸、または
生体内で炭素数6〜12の脂肪酸に変換される脂肪酸前駆体
である(1)に記載の生体内の蛋白質の分解抑制剤。
in vitroでの蛋白質の分解抑制効果の検討として、各種脂肪酸を添加した培養細胞における、mRNAの発現量を測定した。
培養細胞は、European Collection of Cell Culturesより供与された、ラット骨格筋由来の筋芽細胞株L6を用いた。
通常培地は、DEM培地(Sigma−Aldrich社製)に、10%ウシ胎児血清(MP Biomedicals社製)を添加し、さらに抗生剤であるペニシリンを100unit/mL、ストレプトマイシンを100μg/mLを添加したものを用いた。
分化誘導培地は、DEM培地(Sigma−Aldrich社製)に、2%ウシ胎児血清(MP Biomedicals社製)を添加し、ペニシリンを100unit/mL、ストレプトマイシンを100μg/mLを添加したものを用いた。
試験細胞は、9.2cm2ペトリデッシュ(Techno Plastic Products社製)に通常培地10mLをいれ、L6細胞を播種し、5%二酸化炭素、95%空気、37℃の条件下でL6細胞を培養し、細胞がコンフルエント(培養皿全体に密になった状態)となった後、分化誘導培地で、5%二酸化炭素、95%空気、37℃の条件下、2日間培養し、分化誘導した筋管細胞を用いた。
蛋白質の分解抑制剤は、炭素数8の飽和脂肪酸であるn−オクタン酸(実施例1,商品名:n−Octanoic acid,Sigma−Aldrich社製)、及び炭素数10の飽和脂肪酸であるn−デカン酸(実施例2,商品名:n−Decanoic acid,Sigma−Aldrich社製)を用い、比較品には、炭素数18の飽和脂肪酸であるステアリン酸(比較例1,和光純薬工業(株)製)を用いた。
測定サンプルは、試験細胞の培養液に、分解抑制剤及び比較品が50μmol/Lとなるように添加し、さらに、5%二酸化炭素、95%空気、37℃の条件下、1日間培養したものを用いた。また、ブランクは、DMSOのみを添加し、同条件で培養した。測定サンプルは、分解抑制剤、比較品及びブランクにつき、各5サンプル調製した。
測定サンプル中のmRNAの抽出は、RNeasy Mini Kit(QIAGEN社製)を用いた。抽出した各RNA500ng相当を、トランスクリプター ファーストストランドcDNA合成キット(Roche Diagnostics社製)を用いてcDNAへ逆転写した。
(ユビキチンmRNA)
Ubb(Genbank アクセッション番号 NM138895)
Ubb−Forward Primer:
5’−GAGTCAACCCTGCACCTGGTC−3’(配列番号1)
Ubb−Reverse Primer:
5’−AGTAATGCCATCAGTGCCCG−3’(配列番号2)
(ユビキチンリガーゼmRNA)
MAFbx(Genbank アクセッション番号 AY059628)
MAFbx−Forward Primer:
5’−TCAAAGGTCTCACGATCACCG−3’(配列番号3)
MAFbx−Reverse Primer:
5’−TCAGCCTCTGCATGATGTTCAG−3’(配列番号4)
MuRF(Genbank アクセッション番号 AY059627)
MuRF−Forward Primer:
5’−ACATCTTCCAGGCTGCCAATC−3’(配列番号5)
MuRF−Reverse Primer:
5’−GACCTCCAGACATGGACACCG−3’(配列番号6)
(カルパインmRNA)
Capn1(Genbank アクセッション番号 NM019152)
Capn1−Forward Primer:
5’−CATAAGCACTCATGCTGCCAGA−3’(配列番号7)
Capn1−Reverse Primer:
5’−CGAAATTACCTGACCATCTTCCG−3’(配列番号8)
Capn2(Genbank アクセッション番号 NM017116)
Capn2−Forward Primer:
5’−GGAGCTAACAGGGCAGACCAAC−3’(配列番号9)
Capn2−Reverse Primer:
5’−GAGGTTGATGAAGGTATCTGACCG−3’(配列番号10)
(コントロールmRNA)
RPS29(Genbank アクセッション番号 NM012876)
RPS29−Forward Primer:
5’−AAGATGGGTCACCAGCAGCTCTACT−3’(配列番号11)
RPS29−Reverse Primer:
5’−AGACGCGGCAAGAGCGAGAA−3’(配列番号12)
in vivoでの蛋白質の分解抑制効果の検討として、ラットに各種脂肪酸をトリアシルグリセロールの形態で摂取させた後、採取した筋肉について、mRNAの発現量を測定した。また、血漿中の中鎖脂肪酸の含量も測定した。
実験動物は、3週齢のWistar系雄性ラット(日本SLC社より購入)を用いた。
試験飼料は、ラットの生体内の蛋白質合成と分解のバランスを壊し、蛋白質の分解を亢進させるために、蛋白源であるミルクカゼインを、「通常食(AIN−93G)」の25%に減らした組成に設計した。すなわち、表3に示す、「低蛋白植物油食」及び「低蛋白MCT食」の組成を設計した。
試験は、「低蛋白MCT食」を摂食させる「低蛋白MCT食摂食群(実施例2)」、「低蛋白植物油食」を摂食させる「低蛋白植物油食摂食群(比較例2)」、及び「通常食」を摂食させる「対照群(対照例1)」の3群(各群9匹)にて行った。
測定試料の採取方法は、ラットを飼育最終日の最後の飼料摂取から3時間後にエーテル麻酔して解剖し、右後肢筋肉を採取した後、心臓より採血を行った。
mRNAの定量方法は、RNeasy Fibrous Tissue Mini Kit(QIAGEN社製)を用いて、ラット右後肢の筋肉中のmRNAを抽出し、その他の方法は、試験例1と同様とした。
血漿中の中鎖脂肪酸含量の測定は、採血した血液を、ヘパリンナトリウム入りの遠沈管に移し、3,000rpmで10分間遠心分離して上澄を血漿として得た。血漿中の中鎖脂肪酸含量は、「基準油脂試験法(1996)」に準じて測定した。
Claims (2)
- n−オクタン酸、n−デカン酸、およびn−オクタン酸とn−デカン酸との混合物からなる群より選択される脂肪酸を有効成分として含み、蛋白質分解因子のmRNAの発現を抑制する、経口投与用の筋蛋白質の分解抑制剤。
- n−オクタン酸、n−デカン酸、およびn−オクタン酸とn−デカン酸との混合物からなる群より選択される脂肪酸とグリセリンとのエステルを有効成分として含み、蛋白質分解因子のmRNAの発現を抑制する、経口投与用の筋蛋白質の分解抑制剤。
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PCT/JP2011/056291 WO2011115184A1 (ja) | 2010-03-18 | 2011-03-16 | 生体内の蛋白質の分解抑制剤 |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986001715A1 (en) * | 1984-09-13 | 1986-03-27 | Center For Nutritional Research Charitable Trust | Triglyceride preparations for the prevention of catabolism |
JP2006290881A (ja) * | 2005-03-15 | 2006-10-26 | Ono Pharmaceut Co Ltd | (2r)−2−プロピルオクタン酸を含有してなる運動機能障害の治療剤 |
EP2011452A1 (fr) * | 2007-07-06 | 2009-01-07 | Société de Recherche et de Développement en Esthétique sprl | Préparation injectable pour la réalisation d'un implant musculaire |
JP2009524587A (ja) * | 2005-12-15 | 2009-07-02 | ネステク ソシエテ アノニム | 脳機能を維持するための組成物及び方法 |
Family Cites Families (1)
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JPS61248308A (ja) | 1985-04-24 | 1986-11-05 | 日立電線株式会社 | 難燃性絶縁電線 |
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2011
- 2011-03-16 JP JP2012505733A patent/JP5860803B2/ja active Active
- 2011-03-16 WO PCT/JP2011/056291 patent/WO2011115184A1/ja active Application Filing
- 2011-03-16 EP EP11756368.4A patent/EP2548554A4/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986001715A1 (en) * | 1984-09-13 | 1986-03-27 | Center For Nutritional Research Charitable Trust | Triglyceride preparations for the prevention of catabolism |
JP2006290881A (ja) * | 2005-03-15 | 2006-10-26 | Ono Pharmaceut Co Ltd | (2r)−2−プロピルオクタン酸を含有してなる運動機能障害の治療剤 |
JP2009524587A (ja) * | 2005-12-15 | 2009-07-02 | ネステク ソシエテ アノニム | 脳機能を維持するための組成物及び方法 |
EP2011452A1 (fr) * | 2007-07-06 | 2009-01-07 | Société de Recherche et de Développement en Esthétique sprl | Préparation injectable pour la réalisation d'un implant musculaire |
Non-Patent Citations (4)
Title |
---|
JPN6011027523; ROE, C.R. et al.: 'Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaple' Journal of Clinical Investigation Vol.110, No.2, 2002, pp.259-269 * |
JPN6011027524; 中島一喜: 'アミノ酸による骨格筋タンパク質分解の抑制' 化学と生物 Vol.46, No.2, 2008, pp.82-84 * |
JPN6011027525; HAN, K. et al.: 'Effect of fatty acid salts on proteolysis of insulin in the nasal tissue homogenates of rabbits' Journal of Korean Pharmaceutical Sciences Vol.22, No.2, 1992, pp.97-104 * |
JPN6015037406; STEINHART, H. et al: 'In vitro digestion apparatus for the enzymic hydrolysis of proteins' Archiv fuer Tierer naehrung Vol.23, No.6, 1973, p.449-459 * |
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EP2548554A1 (en) | 2013-01-23 |
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