JP6473759B2 - 概日性タンパク質関連状態の治療または予防のための組成物および方法 - Google Patents
概日性タンパク質関連状態の治療または予防のための組成物および方法 Download PDFInfo
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Description
免疫蛍光法およびウェスタンブロッティング分析を使用して、正常ラットC6神経膠腫細胞およびIPEC−1(ブタ腸上皮細胞株)において、ローズマリーの抽出物(RME:extract of rosemary)およびhemerocallis fulvaの抽出物(HFE:extract of hemerocallis fulva)が、鍵となる概日タンパク質発現を調節するか否かを調べた。血圧および睡眠/覚醒サイクルから、健康と疾患とにおいて重要な役割を果たす細胞性シグナル伝達経路に至るまで、恒常性を維持するための無数の生理的プロセスにおいて、酸素および概日リズム性が必須である。酸化ストレスは概日リズムの調節不全を引き起こし得る。本発明者らは、RMEおよびHFEが、酸素・グルコース欠乏(OGD)によるこれらのタンパク質発現のダメージを減弱するか否かも試験する。
iPEC−1細胞を、10%ウシ胎仔血清(FBS)および必要な補助剤を伴うDMEM中で37℃にて、5%CO2を用いた加湿インキュベーター内で、単層として増殖させた。iPEC−1細胞を35mm皿上に播いた。プレートに播いた48時間後に実験を開始した。培地中、食塩水または3つの異なる量(1μM、5μM、および20μM)のウルソール酸で、37℃において24時間細胞を処理した。その後、細胞を氷冷PBSで洗浄し、4%パラホルムアルデヒドで室温において10分間固定し、それから0.3%のTriton X−100で10分間透過処理した。PBSで3回洗浄した後、10%正常ヤギ血清ブロッキング溶液を含むPBS中で細胞を1時間インキュベートした。標的特異的抗体(SIRT1、CLOCK、およびBmal1)を用いて4℃で一晩、細胞を免疫蛍光染色に付した。それから細胞を冷PBSで3分間ずつ3回洗浄し、Alexa標識二次抗体(インビトロジェン)と共に室温で1時間インキュベートした。蛍光顕微鏡(ニコンTE2000−S顕微鏡、ニコン社、日本国東京)によって細胞を調べた。
[参考文献]
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3. Bray MS, Young ME: Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Obes.Rev. 8:169-181, 2007
4. Gale JE, Cox HI, Qian J, et al: Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction. J.Biol.Rhythms 26:423-433, 2011
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6. Wyatt JK: Circadian rhythm sleep disorders. Pediatr.Clin.North Am. 58:621-635, 2011
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11. Chang HC, Guarente L: SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448-1460, 2013
12. Hirano A, Yumimoto K, Tsunematsu R, et al: FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152:1106-1118, 2013
13. Sanjust E, Mocci G, Zucca P, et al: Mediterranean shrubs as potential antioxidant sources. Nat.Prod.Res. 22:689-708, 2008
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21. 米国出願公開第2011/0076349号
22. 国際公開第2001/080818 A1号
<付記>
<1>
概日リズム関連タンパク質の発現に関連する疾患または状態の治療または予防のための組成物であって、
ローズマリーの抽出物、hemerocallis fulvaの抽出物、その活性部分もしくは活性成分、またはそれらの組合せの有効量を含み、前記抽出物は、概日リズムに関連する疾患または状態の処置を必要とする対象に投与して前記対象における前記疾患または状態の症状を寛解、予防、または調節するために製剤され、前記有効量は、前記対象において、CLOCK、BMAL1、FBXL3、FBXL21、SIRT1、またはこれらの組合せからなる群から選択されるタンパク質の1つまたは複数の発現特性を改変させるために十分な量である、
組成物。
<2>
抽出物は水抽出物である、<1>に記載の組成物。
<3>
抽出物がサプリメントにおける成分である、<1>に記載の組成物。
<4>
前記投与は1日あたり1回である、<1>に記載の組成物。
<5>
前記抽出物はローズマリーの抽出物であり、前記タンパク質はBMAL1タンパク質である、<1>に記載の組成物。
<6>
前記抽出物はローズマリーの抽出物であり、前記タンパク質はFBXL3、FBXL21、またはそれらの組合せである、<1>に記載の組成物。
<7>
前記抽出物はローズマリーの抽出物であり、前記タンパク質はSIRT1である、<1>に記載の組成物。
<8>
前記抽出物はhemerocallis fulvaの抽出物であり、前記タンパク質はCLOCKである、<1>に記載の組成物。
<9>
前記抽出物はhemerocallis fulvaの抽出物であり、前記タンパク質はBMAL1である、<1>に記載の組成物。
<10>
前記抽出物はhemerocallis fulvaの抽出物であり、前記タンパク質はFBXL3、FBXL21、またはそれらの組合せである、<1>に記載の組成物。
<11>
前記抽出物はhemerocallis fulvaの抽出物であり、前記タンパク質はSIRT1である、<1>に記載の組成物。
<12>
前記疾患または状態は時差ぼけである、<1>〜<11>のいずれか1項に記載の組成物。
<13>
前記投与は、時差が関わる旅行の前または後における投与である、<12>に記載の組成物。
<14>
前記疾患または状態は二日酔いである、<1>〜<11>のいずれか1項に記載の組成物。
<15>
前記抽出物は、アルコールを消費する前、間、もしくは後、またはそれらの組合せにおいて投与される、<14>に記載の組成物。
<16>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する代謝性状態である、<1>〜<11>のいずれか1項に記載の組成物。
<17>
前記代謝性状態は、コレステロールのレベルの異常、肥満、メタボリック症候群もしくはその要素、高血糖、低血糖、インスリン産生の異常、または糖尿病である、<16>に記載の組成物。
<18>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する炎症性障害である、<1>〜<11>のいずれか1項に記載の組成物。
<19>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する神経性障害である、<1>〜<11>のいずれか1項に記載の組成物。
<20>
前記神経性障害はアルツハイマー病である、<19>に記載の組成物。
<21>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する筋障害である、<1>〜<11>のいずれか1項に記載の組成物。
<22>
前記筋障害は筋ジストロフィーまたはミオパチーである、<21>に記載の組成物。
<23>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する睡眠障害である、<1>〜<11>のいずれか1項に記載の組成物。
<24>
前記睡眠障害は、不眠症、時差ぼけ、交代勤務睡眠障害、睡眠相後退症候群(DSPS)、睡眠相前進症候群(ASPS)、非24時間睡眠覚醒障害、または不規則型睡眠・覚醒パターンである、<23>に記載の組成物。
<25>
前記投与は、光に晒される−4時間〜12時間後において、または0時間〜12時間後においてなされる、<24>に記載の組成物。
<26>
前記投与は、光に晒される1時間〜3時間後において、または光に晒される10〜14時間後においてなされる、<24>に記載の組成物。
<27>
前記投与は、光に晒される4時間〜0時間前においてなされる、<24>に記載の組成物。
<28>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する精神障害である、<1>〜<11>のいずれか1項に記載の組成物。
<29>
前記精神障害は、うつ、季節性感情障害、認知症、または急速交代型双極性障害である、<28>に記載の組成物。
<30>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する心血管障害である、<1>〜<11>のいずれか1項に記載の組成物。
<31>
前記心血管障害は、血圧異常または心拍異常である、<30>に記載の組成物。
<32>
前記心血管障害は、アテローム性動脈硬化症または心筋症である、<30>に記載の組成物。
<33>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する肝毒性である、<1>〜<11>のいずれか1項に記載の組成物。
<34>
前記疾患または状態は、CLOCK、BMAL1、FBXL3、FBXL21、またはSIRT1のうちの1つまたは複数の発現特性に関連する脳障害である、<1>〜<11>のいずれか1項に記載の組成物。
<35>
前記脳障害は、脳卒中、またはフリーラジカルによる脳変性である、<34>に記載の組成物。
<36>
前記組成物は必要に応じて投与される、<1>〜<11>のいずれか1項に記載の組成物。
<37>
前記タンパク質はSIRT1ではない、<1>〜<11>のいずれか1項に記載の組成物。
<38>
前記抽出物は10重量%以上のウルソール酸を含む、<1>〜<11>のいずれか1項に記載の組成物。
<39>
前記抽出物は25重量%以上のウルソール酸を含む、<1>〜<11>のいずれか1項に記載の組成物。
<40>
前記抽出物はウルソール酸からなる、<1>〜<11>のいずれか1項に記載の組成物。
<41>
前記投与は2週間以上の期間に渡ってなされる、<1>〜<11>のいずれか1項に記載の組成物。
<42>
前記投与は4週間以上に渡ってなされる、<1>〜<11>のいずれか1項に記載の組成物。
<43>
前記投与は3ヶ月間以上に渡ってなされる、<1>〜<11>のいずれか1項に記載の組成物。
<44>
前記投与は1日あたり1回、2回、3回、または4回なされる、<1>〜<11>のいずれか1項に記載の組成物。
<45>
前記サプリメントは、粉末、ゲル、液体、食品、固形物、またはその他の形態である、<3>に記載の組成物。
<46>
必要とする対象において肥満を治療または予防するための組成物であって、
ローズマリーの抽出物、hemerocallis fulvaの抽出物、その活性部分もしくは活性成分、またはそれらの組合せを含み、前記抽出物は、CLOCK、BMAL1、FBXL3、FBXL21、SIRT1、またはこれらの組合せの発現特性に関連する肥満の治療または予防を必要とする対象に投与し、前記対象において肥満を寛解、予防、または調節するためのものであり、前記有効量は、前記対象において、CLOCK、BMAL1、FBXL3、FBXL21、SIRT1、またはこれらの組合せからなる群から選択されるタンパク質の1つまたは複数の発現特性を改変させるために十分な量である、
組成物。
<47>
必要とする対象において癌を治療または予防するための組成物であって、
ローズマリーの抽出物、hemerocallis fulvaの抽出物、その活性部分もしくは活性成分、またはそれらの組合せを含み、前記抽出物は、CLOCK、BMAL1、FBXL3、FBXL21、SIRT1、またはこれらの組合せの発現特性に関連する癌の治療または予防を必要とする対象に投与し、前記対象において癌を寛解、予防、または調節するためのものであり、前記有効量は、前記対象において、CLOCK、BMAL1、FBXL3、FBXL21、SIRT1、またはこれらの組合せからなる群から選択されるタンパク質の1つまたは複数の発現特性を改変させるために十分な量である、 組成物。
<48>
実質的に本明細書に記載されている通りの方法。
<49>
実質的に本明細書に記載されている通りの組成物。
Claims (4)
- 対象においてCLOCK、BMAL1、FBXL3、FBXL21、SIRT1、およびこれらの組合せからなる群から選択されるタンパク質の発現を増加させるための組成物であって、
hemerocallis fulvaの抽出物およびローズマリーの抽出物の有効量を含み、前記抽出物は、必要とする対象に投与するために製剤され、前記有効量は、前記対象において、CLOCK、BMAL1、FBXL3、FBXL21、SIRT1、およびこれらの組合せからなる群から選択されるタンパク質の発現を増加させるために十分な量である、
組成物。 - 前記タンパク質は、CLOCK、BMAL1、SIRT1、およびこれらの組合せからなる群から選択される、請求項1に記載の組成物。
- 前記タンパク質はSIRT1ではない、請求項1または2項に記載の組成物。
- 前記抽出物は10重量%以上のウルソール酸を含む、請求項1〜3のいずれか1項に記載の組成物。
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