JP2016514146A - 抗糖尿病及び他の有用な活性を有する植物抽出物 - Google Patents
抗糖尿病及び他の有用な活性を有する植物抽出物 Download PDFInfo
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Abstract
Description
本出願は、2013年3月12日出願の米国特許出願第61/777,657号及び2013年3月12日出願の米国特許出願第61/777,927号の優先権を主張し、これらは、その全体が参照により本明細書に組み込まれる。
本発明は、栄養的に有益な、または医薬的に活性な化合物を含有する植物抽出物に関する。これらの抽出物またはそれらに含有される精製された化合物の幾つかは、インスリンシグナル伝達を制御することによって、1型及び2型糖尿病を含むヒト及び動物における様々な代謝及び他の疾患及び障害の栄養支援、予防、治療または可能性のある治癒のために使用することができる。この制御効果には、身体中の細胞及び組織におけるインスリン受容体(IR)、インスリン様増殖因子(IGF)受容体及び/またはインスリン受容体基質(IRS)タンパク質のレベル及び/または活性の調節が含まれうる。主な焦点は、IRSタンパク質に向けられる。IRSファミリーのタンパク質の2つのメンバーであるIRS1及びIRS2は、インスリンまたはインスリン様増殖因子シグナル伝達経路の一部であるが、IFN−γ、IL−2、IL−4、IL−7、IL−9、IL−13もしくはIL−15、成長ホルモン、プロラクチンまたはレプチンを含む他の増殖因子及びサイトカインを介するシグナルも調整する。IRS1またはIRS2の機能活性は、TFN−α,IL−6、IL−1β及び関連する因子を含む、炎症促進性サイトカインから発せされるシグナルを統合もする。一般に、炎症促進性サイトカインは、IRS1/IRS2シグナル伝達を阻害し、それはインスリン抵抗性症候群に寄与する。
哺乳動物は、3つのインスリン様ペプチド、すなわちインスリン、インスリン様増殖因子−1(IGF−1)及びインスリン様増殖因子−2(IGF−2)を生成し、これらはインスリン受容体(IR)遺伝子及びインスリン様増殖因子−1受容体(IGF1R)遺伝子によりコードされる5つの相同性インスリン様受容体チロシンキナーゼを活性化する(図1A/B)。インスリンは、循環グルコース濃度に応答して膵臓のβ細胞により生成され、一方、内分泌IGF−1は、栄養素及び成長ホルモンにより刺激された肝細胞からほとんどが分泌され、IGF−1及びIGF−2は、また、中枢神経系を含む多くの組織及び細胞から局所的にも生成される(9)。IGF1は、インスリンと協調的に作動して、栄養素恒常性、インスリン感受性及び膵臓β細胞機能を調節する(9)。インスリン受容体及びIGF受容体の遺伝子は、タンパク質分解により開裂されて2つの細胞外α−サブユニット及び2つの膜透過β−サブユニットを有する四量体を生じる、共有結合した二量体を形成する相同性前駆体をコードする。細胞外α−サブユニットは、膜貫通β−サブユニットの細胞内部分へのチロシンキナーゼの活性を調節するリガンド結合ドメインを作り出す(10)。
細胞に基づいた及びマウスに基づいた実験は、全部ではないとしても大部分のインスリンシグナルが、IRS1、IRS2もしくはその相同体、またはSHC、CBL、APS及びSH2B、GAB1、GAB2、DOCK1及びDOCK2を含む他の足場タンパク質のチロシンリン酸化を介して生成または調節されることを示す(15)。これらの基質のそれぞれの役割が注目に値するが、遺伝子導入マウスによる研究は、多くのインスリン応答、とりわけ体細胞増殖及び栄養素恒常性に関するものが、IRS1またはIRS2を介して調整されることを示唆している(1)。
最も良く研究されているインスリン様シグナル伝達カスケードは、ホスファチジルイノシトール3−キナーゼ(PI3−キナーゼ)によるPI−3,4,5−P3の生成が関与する。1型PI−3キナーゼは、2つのsrc−相同性−2(SH2)ドメインを含有する調節サブユニット及び、そのSH2ドメインがIRSタンパク質のリン酸化チロシン残基より占められるまで調節サブユニットにより阻害されている、触媒サブユニットから構成される(23)。PI−3,4,5−P3は、Ser/ThrキナーゼPDK1及びAKT(PKBとしても知られている)を、形質膜に動員し、そこでAKTは、PKD1媒介リン酸化により活性化される(図1A/B)。AKTは、細胞の生存、増殖、繁殖、血管新生、代謝及び遊走において中心的な役割を果たす多くのタンパク質をリン酸化する(24)。幾つかの真正AKT基質のリン酸化が、インスリン様シグナル伝達にとりわけ関連性がある。GSK3α/β(グリコーゲンシンターゼの阻害を遮断する)、AS160(GLUT4の転位を促進する)、BAD・BCL2ヘテロ二量体(アポトーシスを阻害する)、FOXO転写因子(遺伝子発現を調節する)、p21CIP1及びp27KIP1(細胞周期の阻害を遮断する)、eNOS(NO合成及び血管拡張を刺激する)及びPDE3b(cAMPを加水分解する)(図1A/B)。またAKTはツベリン(TSC2)をリン酸化して、低分子量Gタンパク質RHEBへのそのGAP活性を阻害し、mTROを活性化するRHEB・GTP複合体の蓄積を促進する(24)。この経路は、インスリンシグナル伝達と、細胞増殖に必要なタンパク質合成との直接的な関連を提供する(図1A/B)。
IRSタンパク質シグナル伝達の調節は、様々な組織におけるインスリン応答の強度及び持続時間を協調させる重要な方法であるが、これらの機構の不全は、インスリン抵抗性を引き起こしうる。IRS1遺伝子の転写は、一般に安定している。対照的に、IRS2の生成は、cAMP応答要素結合タンパク質(CREB)及びその結合パートナーCRTC2、フォークヘッドボックスO1(FOXO1)、転写因子E3(TFE3)、並びにステロール調節要素結合/因子−1c(SREBF−1c)を含む複数の栄養素感受性転写因子により制御される(26、27)。興味深いことに、CREB/CRTC2転写複合体は、cAMP応答要素(CRE)に結合するが、β細胞及び肝臓におけるIRS2発現に対して逆の効果を有する。食事の後、グルコース酸化によるATP生成は、β細胞を脱分極し、このことは、CREB/CRTC2の活性化を含む多くの重要な効果を有する、Ca2+流入とcAMP生成の両方を促進する(26)。このように、グルコースは、β細胞においてIRS2発現と直接関連し、このことは、β細胞増殖及び代償的なインスリン分泌を刺激する。対照的に、CREB/CRTC2は、空腹時の肝臓においてIRS2発現を促進し、このことは、基礎インスリン応答を増強することにより、糖新生プログラムを阻害しうる。
インスリン抵抗性は、多くの健康障害、すなわち糖尿病、高血圧症、慢性感染症、女性生殖調節不全、並びに腎臓及び心血管の疾患に関連する一般的な病理状態である(1)。過去15年間にわたって、マウスに基づいた実験は、インスリンシグナルを媒介する、インスリンシグナルを調節する、またはインスリンシグナルに応答する遺伝子における変異が、どのようにインスリン抵抗性及び糖尿病に寄与するかを明らかにしている。遺伝子の突然変異が生涯にわたるインスリン抵抗性の明確な源であるが、これらは、通常、希な代謝障害と関連している。環境的、生理学的及び免疫学的なストレスが、複雑な遺伝子背景により連携される異種シグナル伝達カスケードを介してインスリン抵抗性を引き起こす(1)。
Irs1またはIrs2の遺伝子を欠いているマウスは、損なわれた末梢グルコース利用を伴ってインスリン抵抗性である。両方の種類のノックアウトマウスは、代謝調節不全を示すが、Irs2−/−マウスのみが、膵臓β細胞のほぼ完全な欠失のために、8〜12週齢で糖尿病を発生する(32)。この結果は、IRS2を介したインスリン様シグナル伝達カスケードを、β細胞機能の中心に置く。
インスリン感作単位−(IS単位)
インスリン感作活性−(ISA単位)
インスリン最適化活性−(IOA単位)
インスリン最適化単位−(IO単位)
インスリン追加免疫活性−(IBA単位)
インスリン追加免疫単位−(IB単位)
インスリン増幅単位−(IA単位)
インスリン増幅活性−(IAA単位)
インスリン増感単位−(IIn単位)
インスリン増感活性−(IInA単位)
インスリン増強活性−(IAA単位)
インスリン改善活性−(IImA単位)
インスリン改善単位−(IIm単位)
インスリン強化単位−(ISt単位)
インスリン濃縮単位−(IEn単位)
インスリン等価単位−(IEq単位)
インスリン等価活性−(IEA単位)
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Claims (17)
- 1ミリリットルに少なくとも1×104インスリン等価単位を提供する、植物抽出物。
- 前記抽出物が、1ミリリットルに少なくとも3.6×104インスリン等価単位を提供する、請求項1に記載の抽出物。
- 前記抽出物が、1ミリリットルに1×104〜1×105インスリン等価単位を提供する、請求項1に記載の抽出物。
- キクジャ(Cichorium endivia,var.latifolium)から調製される、請求項1〜3のいずれか一項に記載の抽出物。
- リーフレタス(Lactuca sativa,var.crispa)から調製される、請求項1〜3のいずれか一項に記載の抽出物。
- コスレタス(Lactuca sativa,var.longifolia)から調製される、請求項1〜3のいずれか一項に記載の抽出物。
- 前記抽出物が水性抽出物である、請求項1〜6のいずれか一項に記載の抽出物。
- 請求項1〜6のいずれか一項に記載の抽出物を含む、薬学的組成物。
- 請求項1〜6のいずれか一項に記載の抽出物を含む、栄養補助食品。
- IRS媒介疾患または状態を治療する方法であって、有効量の請求項8に記載の薬学的組成物を投与することを含む、前記方法。
- IRS媒介疾患または状態を治療する方法であって、有効量の請求項9に記載の栄養補助食品を投与することを含む、前記方法。
- 前記IRS媒介疾患または状態が、糖尿病、前糖尿病、代謝症候群、インスリン抵抗性または認知症である、請求項10または11に記載の方法。
- 抗糖尿病剤のインスリン、メトホルミン、エキセナチド、ビルダグリプチン、シタグリプチン、DPP4阻害剤、メグリチニド、エキセンディン−4またはGLP1作動薬を投与することを更に含む、請求項10または11に記載の方法。
- 対象においてIRS2依存性シグナル伝達を刺激する方法であって、有効量の請求項1〜6のいずれか一項に記載の抽出物を前記対象に投与することを含む、前記方法。
- IRS2依存性シグナル伝達を刺激する方法であって、細胞を請求項1〜6のいずれか一項に記載の抽出物と接触させることを含む、前記方法。
- 植物においてIRS2刺激活性を検出する方法であって、前記植物の抽出物を、IRS2を発現する試験細胞と接触させ、細胞繁殖の増加を検出することを含む、前記方法。
- 前記試験細胞が、IRS2を過剰発現する32D細胞である、請求項16に記載の方法。
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- 2014-03-12 CN CN201480026762.7A patent/CN105392491A/zh active Pending
- 2014-03-12 US US14/775,220 patent/US20160022752A1/en active Pending
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JP2020519688A (ja) * | 2017-05-12 | 2020-07-02 | ハウジー ファーマシューティカル リサーチ ラボラトリーズ、エル.エル.シー. | 抗糖尿病活性および他の有用な活性を有する植物抽出物 |
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SG10201707324WA (en) | 2017-10-30 |
US20160022752A1 (en) | 2016-01-28 |
SG11201507522XA (en) | 2015-10-29 |
AU2014248449A1 (en) | 2015-10-15 |
AU2018278958B2 (en) | 2020-11-12 |
BR112015022710A2 (pt) | 2017-07-18 |
US20230338449A1 (en) | 2023-10-26 |
KR20150138225A (ko) | 2015-12-09 |
IL241578B (en) | 2020-06-30 |
CN105392491A (zh) | 2016-03-09 |
US20180256660A1 (en) | 2018-09-13 |
EP2968426A4 (en) | 2016-10-12 |
KR20230017357A (ko) | 2023-02-03 |
EP2968426A1 (en) | 2016-01-20 |
MX2015012606A (es) | 2016-08-04 |
KR20220079691A (ko) | 2022-06-13 |
JP2020059726A (ja) | 2020-04-16 |
MX2022008220A (es) | 2022-08-08 |
CA2905857A1 (en) | 2014-10-09 |
AU2018278958A1 (en) | 2019-01-17 |
CN114796292A (zh) | 2022-07-29 |
JP2022070891A (ja) | 2022-05-13 |
WO2014165297A1 (en) | 2014-10-09 |
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