JP6283346B2 - 4−オキソ−2−ペンテン酸及び脳の健康 - Google Patents
4−オキソ−2−ペンテン酸及び脳の健康 Download PDFInfo
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- JP6283346B2 JP6283346B2 JP2015502269A JP2015502269A JP6283346B2 JP 6283346 B2 JP6283346 B2 JP 6283346B2 JP 2015502269 A JP2015502269 A JP 2015502269A JP 2015502269 A JP2015502269 A JP 2015502269A JP 6283346 B2 JP6283346 B2 JP 6283346B2
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Description
本発明は一般に、健康上の利益を有する組成物に関する。詳細には、本発明は、脳の健康、例えば脳の保護、認知機能の維持、認知低下の予防及び認知障害の予防の分野に関する。本発明の主題は、認知低下の処置又は予防に使用するための4−オキソ−2−ペンテン酸を含む組成物である。
Nrf2レポーターアッセイ
Nrf2の活性化を、Nrf2レポーターアッセイを用いて測定した。このアッセイは、AREの制御下のルシフェラーゼ遺伝子構築体を含む安定にトランスフェクションしたMCF7(乳腺癌)細胞株である、CRX biosciences(Dundee、Scotland)製のAREc32細胞株に基づいている。ルシフェラーゼは、ルシフェリンを基質として作用して蛍光を生成する酵素である。Tert−ブチルヒドロキノン(TBHQ)等の抗酸化性分子は、AREに結合しているNrf2の活性化によりルシフェラーゼ転写を誘導する。ルシフェラーゼ活性は、Promega(Madison、WI)製のルシフェラーゼキットを用いて測定する。ルシフェラーゼ活性は、Nrf2の活性化に比例する。
3つの細菌菌株を使用して、微生物:ビフィドバクテリウム・ブレヴェCNCM I−3865(NCC2950)、ビフィドバクテリウム・ブレヴェCNCM I−3914(NCC466)及びビフィドバクテリウム・ブレヴェATCC15700(商標)(NCC2791)によるNrf2の活性化を調査した。ビフィドバクテリウム・ブレヴェCNCM I−3914を、COLLECTION NATIONALE DE CULTURES DE MICROORGANISMES(CNCM)、INSTITUT PASTEUR、25 rue du Docteur Roux、F−75724 PARIS Cedex 15、France、2008年2月5日によって沈着した。
4−オキソ−2−ペンテン酸(Alfa Aesar−照合番号L02185)を、Nrf2レポーターアッセイにより試験した。異なる用量の4−オキソ−2−ペンテン酸を、24時間かけてAREc32細胞に施用し、次いでルシフェラーゼ活性を上述したようにして定量化した。細胞生存率も、細胞Titer−Gloキット(ATP定量化)を用いて測定した。
細胞生存に対する化合物の有益な効果は、古典的には、細胞培養物を神経毒性侵襲に曝露し、限定された期間の時間にわたって得られた酸化ストレス及び興奮毒性を測定することにより調査される(Aksenovaら、Current Neurovascular Research、2、73〜89(2005年))。したがって、本発明者らは、ニューロン−アストロサイト共培養モデルを使用して、酸化ストレスにより誘導された神経変性に対する4−オキソ−2−ペンテン酸の潜在的な有益な効果を試験した。酸化ストレスを過酸化水素により誘導し、細胞生存を、4−オキソ−2−ペンテン酸で処置した培養物と未処理のままの培養物との間で比較した。
4−オキソ−2−ペンテン酸を定量化するために、高速液体クロマトグラフィーをエレクトロスプレーイオン化タンデム質量分析法(HPLC−ESI−MS/MS)と結びつけるものである、高い処理能力の分析法を開発した。
4−オキソ−2−ペンテン酸標準物質は、Alfa Aesar(Ward Hill、USA)から購入した。4−オキソ−2−ペンテン酸は、少なくとも20mg/mlまで水に可溶であることが見出された。4−オキソ−2−ペンテン酸標準物質化合物を水に可溶化して10mg/mlの最終的なストック溶液にし、水にさらに希釈して校正曲線を作成した。
4−オキソ−2−ペンテン酸を1× PBS又は水に可溶化し、HPLC−MS/MSによる検出を、上記の部分で説明したようにして実施した。m/z 113→69の遷移反応に伴うSRMは、1.25分の保持時間における遷移m/z 113→41に伴うSRMに比較して、より強烈な信号を明らかにした。両方の遷移に関して類似した保持時間が、分析の妥当性を確認したときに観察された(図6)。分子4−オキソ−2−ペンテン酸を、1× PBS(データは図示せず)と水の両方で検出することに成功した(図6)。
細菌画分中の4−オキソ−2−ペンテン酸の量を正確に定量化するために、標準曲線を、1× PBS又はHPLCグレード水等の簡便な媒体中の4−オキソ−2−ペンテン酸に関して確立した。商業的な4−オキソ−2−ペンテン酸を、異なる用量で1× PBS及び水に懸濁した。次いでHPLC−ESI−MS/MS法を使用して、見積もった用量の4−オキソ−2−ペンテン酸を定量化した。良好な線形性が、4−オキソ−2−ペンテン酸(0.1〜25μg/ml)の量と、1× PBSとHPLCグレード水の両方で得られた強度(cpsで表している)との間に観察された。
4−オキソ−2−ペンテン酸を、実施例1の熱処理した細菌調製物中で定量化した。すべての試料を、HPLC−ESI−MS/MS分析前にHPLCグレード水に希釈した(3希釈物/試料)。結果は表Eに要約している。
熱処理の際のビフィドバクテリウム・ブレヴェCNCM I−3865からの4−オキソ−2−ペンテン酸の生成を特性決定するために、様々な温度を用いて速度実験を実施した。この実験に使用したバイオマスの「マスターストック」は、嫌気性のpH調整した条件下で、37℃の生物反応器中でMRS培地によって生成した。増殖培養(16時間)の後、培地を除去し、細胞を1× PBSで2回洗浄し、10%グリセロールを有する1× PBS中でOD134(1.5E+10cfu/ml)まで濃縮し、次いで50mlの一定分量にして−80℃で貯蔵した。
Claims (12)
- 認知低下の処置又は予防に使用するための4−オキソ−2−ペンテン酸を含む組成物であって、医薬として使用されない、組成物。
- 記憶喪失の処置又は予防に使用するための、請求項1に記載の組成物。
- 学習能力の喪失の処置又は予防に使用するための、請求項1又は2に記載の組成物。
- 4−オキソ−2−ペンテン酸が天然源から得られた、請求項1〜3のいずれか一項に記載の組成物。
- 4−オキソ−2−ペンテン酸が、ビフィドバクテリウム・ブレヴェCNCM I−3865又はビフィドバクテリウム・ブレヴェATCC15700から得ることができる、請求項1〜4のいずれか一項に記載の組成物。
- ビフィドバクテリウム・ブレヴェCNCM I−3865又はビフィドバクテリウム・ブレヴェATCC15700が、60〜180℃で熱処理されたものである、請求項5に記載の組成物。
- 組成物1kg当たり少なくとも1mgの量で4−オキソ−2−ペンテン酸を含む、請求項1〜6のいずれか一項に記載の組成物。
- 体重1kg当たり2μg〜20mgの4−オキソ−2−ペンテン酸に相当する一日量で投与される、請求項1〜7のいずれか一項に記載の組成物。
- 経口投与又は経腸投与される、請求項1〜8のいずれか一項に記載の組成物。
- ヒト又はペットに投与される、請求項1〜9のいずれか一項に記載の組成物。
- 成人に投与される、請求項1〜10のいずれか一項に記載の組成物。
- 食品組成物、食品添加剤、機能性食品、飲料、栄養製剤、経管製剤、牛乳又は水中で再構成される粉末状組成物、及びペット食品組成物から成る群より選択される、請求項1〜11のいずれか一項に記載の組成物。
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