JP2017081922A - Sirt1発現誘導物質を含む敗血症または敗血症性ショックの予防または治療用組成物 - Google Patents
Sirt1発現誘導物質を含む敗血症または敗血症性ショックの予防または治療用組成物 Download PDFInfo
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- JP2017081922A JP2017081922A JP2016219996A JP2016219996A JP2017081922A JP 2017081922 A JP2017081922 A JP 2017081922A JP 2016219996 A JP2016219996 A JP 2016219996A JP 2016219996 A JP2016219996 A JP 2016219996A JP 2017081922 A JP2017081922 A JP 2017081922A
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- sirt1
- sepsis
- interferon beta
- septic shock
- preventing
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Abstract
Description
C57BL/6マウスの大腿骨と脛骨の骨髄細胞を、M−CSF(10ng/ml)が含まれた培養液で5〜7日間分化させた後、マウス大食細胞として使用した。大食細胞にLPS(0,100,500,1000ng/ml)とインターフェロンベータ(0,100,200,500units/ml)を濃度別に処理し、SIRT1発現量をウェスタンブロッティングにて比べた。また、LPSをインターフェロンベータ遮断抗体(IFN−β blocking antibody)とともに処理したときの、SIRT1タンパク質発現量を測定した。
図1に示したように、マウス骨髄由来大食細胞にLPSを100ng/ml処理したとき、SIRT1タンパク質の発現が最も高く増加し、500ng/ml及び1000ng/mlを処理した場合、かえってSIRT1タンパク質の発現が減少した。また、インターフェロンベータを濃度別に処理した場合、100units/ml処理したとき、SIRT1発現が最も著しく増加した(A)。
大食細胞にアデノウイルス−SIRT1を10,000MOI(multiplicity of infection)で24時間感染させた後、LPS100ng/mlを24時間処理した。また、インターフェロンベータ100units/mlと共にLPS100ng/mlを24時間処理した後、細胞培養培地の炎症性及び抗炎症性サイトカインの量をELISAにて測定した。試験は3回行い、平均±標準偏差で示した。
図2に示したように、LPS処理によって増加された炎症性サイトカインの量は、アデノウイルス−SIRT1とインターフェロンベータの前処理で、IL−6はそれぞれ40%、54%、TNF−αはそれぞれ22%、29%減少した。また、LPS処理によって増加するさらに異なる炎症性サイトカインであるMCP−1は、アデノウイルス−SIRT1とインターフェロンベータによってやや減少することを確認した。一方、抗炎症性サイトカインのIL−10の量はそれぞれ2.8倍、4.7倍増加した。従って、SIRT1の発現を促進させるサイトカインであるインターフェロンベータの処理は、LPSによる過度な炎症反応を抑制することができることが分かる。
対照遺伝子伝達体のアデノウイルス−LacZまたはSIRT1遺伝子伝達体のアデノウイルス−SIRT1をそれぞれ3X108pfu(plaque forming unit)ずつマウス尻尾静脈に注射し、48時間後にLPS15〜20mg/kgを処理した後、マウスの生存率を10日間観察した。
図3に示したように、アデノウイルス−SIRT1を前処理したマウスにLPSを投与した場合、マウスの10日後の生存率は66%であって、対照群のアデノウイルス−LacZ投与マウスの生存率20%に比べて著しく高いことがわかる。また、マウスにインターフェロンベータを投与した後、LPSを投与したマウスの10日後の生存率は70%であって、対照群の食塩水投与マウスの生存率30%に比べて著しく高いことがわかる。このような結果は、Kaplan−Meier生存統計分析によっても有意性のある差をみせた(p<0.05)。従って、SIRT1発現を誘導する物質であるインターフェロンベータは、LPSによる過度な炎症反応を抑制させることにより、LPS処理によるマウスの死亡率を著しく低めることが分かる。
内因性SIRT1の機能を妨げる遺伝子伝達体であるアデノウイルスドミナントネガティブSIRT1(Adenovirus−Dominant−negative SIRT1)(355番ヒスチジンをチロシンに変えた突然変異タンパク質を誘導するアデノウイルス)を3X108pfuずつマウスの尻尾静脈に注射し、48時間後、マウスの重さ20gあたり、インターフェロンベータ1000unitsをマウスの尻尾静脈に注射した。30分後、LPS15〜20mg/kgを処理した後、マウスの生存率を10日間観察した。
図4に示したように、マウスにアデノウイルスドミナントネガティブSIRT1を48時間前処理し、インターフェロンベータを投与した後、LPSを投与した場合、10日経過後に50%の生存率を示した。これは、対照群の食塩水投与マウスの生存率50%と類似な結果であり、これを通じて、SIRT1発現を誘導する物質であるインターフェロンベータがLPSによるマウスの死亡率を著しく低めることが分かる。
盲腸結紮及び穿孔(cecal ligation and Puncture、以下、CLP)手術を通じて誘導されたマウス敗血症モデルにおいて、SIRT1及びインターフェロンベータ投与による生存率の変化を確認するため、下記のような実験を行った。
図5に示したように、アデノウイルス−SIRT1を前処理したマウスに敗血症を誘導し、10日が過ぎた後、マウスの生存率は60%と表れた。これは、対照群のアデノウイルス−LacZを前処理した敗血症誘導マウスの生存率0%に比べて著しく高い生存率であることが分かる。
1.散剤の製造
SIRT1発現誘導物質 2g
乳糖 1g
上記の成分を混合して機密袋に充填して散剤を製造した。
SIRT1発現誘導物質 100mg
トウモロコシ澱粉 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
上記の成分を混合した後、通常の錠剤の製造方法に従って打錠して錠剤を製造した。
SIRT1発現誘導物質 100mg
トウモロコシ澱粉 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
上記の成分を混合した後、通常のカプセル剤の製造方法に従って、ゼラチンカプセルに充填してカプセル剤を製造した。
本発明のSIRT1発現誘導物質を含む食品を次のように製造した。
SIRT1発現誘導物質20〜95重量%で健康増進用調味料を製造した。
SIRT1発現誘導物質0.2〜1.0重量%をトマトケチャップまたはソースに添加して健康増進用トマトケチャップまたはソースを製造した。
SIRT1発現誘導物質0.5〜5.0重量%を小麦粉に添加し、この混合物を用いて、パン、ケーキ、クッキー、クラッカー及び麺類を製造して健康増進用食品を製造した。
SIRT1発現誘導物質0.1〜5.0重量%をスープ及び肉汁に添加して健康増信用肉加工製品、麺類のスープ及び肉汁を製造した。
SIRT1発現誘導物質10重量%をグラウンドビーフに添加して健康増進用グラウンドビーフを製造した。
SIRT1発現誘導物質5〜10重量%を牛乳に添加し、上記牛乳を用いてバター及びアイスクリームのような様々な乳製品を製造した。
1.炭酸飲料の製造
SIRT1発現誘導物質10〜15%、砂糖5〜10%、クエン酸0.05〜0.3%、キャラメル0.005〜0.02%、ビタミンC0.1〜1%の添加物を混合し、これに75〜80%の製剤水を混ぜてシロップを作った。上記シロップを85〜98℃で20〜180秒間殺菌して冷却水と1:4の割合で混合した後、炭酸ガスを0.5〜0.82%注入してSIRT1発現誘導物質を含有する炭酸飲料を製造した。
SIRT1発現誘導物質(固形分2.5%、97.16%)、なつめエキス(65brix、2.67%)、果蔕複合抽出物(固形分70%、0.12%)、ビタミンC(0.02%)、パントテン酸カルシウム(0.02%)、甘草抽出物(固形分65%、0.01%)を均質に配合して瞬間殺菌をした後、これをガラス瓶、ペットボトルなどの小さい包装容器に入れて健康飲料を製造した。
SIRT1発現誘導物質0.1gをリンゴまたはブドウジュース1,000mlに加えて健康増進用フルーツジュースを製造した。
Claims (2)
- SIRT1(silent mating type information regulation 2 homolog;Sirtuin1)発現誘導物質であるインターフェロンベータを有効成分として含み、
前記インターフェロンベータは、インターフェロンベータ1aまたはインターフェロンベータ1b中の1種以上であることを特徴とする敗血症または敗血症性ショックの予防または治療用薬学的組成物。 - SIRT1(silent mating type information regulation 2 homolog;Sirtuin1)発現誘導物質であるインターフェロンベータを有効成分として含み、
前記インターフェロンベータは、インターフェロンベータ1aまたはインターフェロンベータ1b中の1種以上であることを特徴とする敗血症または敗血症性ショックの予防または改善用食品組成物。
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