JP6305422B2 - 老化関連疾患を克服するためにshc−1/p66を抑制する方法 - Google Patents
老化関連疾患を克服するためにshc−1/p66を抑制する方法 Download PDFInfo
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 229910052698 phosphorus Inorganic materials 0.000 description 1
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- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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Description
SHC(Src Homology and Collagen)タンパク質ファミリーの66kDアイソフォーム欠損マウスは、p66機能正常(proficient)同腹仔に比べ、30%長く生存したことが報告されている。p66KOマウスは長命であり、かつ表現型的に正常で、繁殖力があり、健常と考えられる(Migliaccio et al., “The p66shc adaptor protein controls oxidative stress response and the life span in mammals. Nature. 1999; 402:309-313; さらにAlam et al., Endocr. Relat Cancer. 2009 March ; 16(1): 1.も参照)。SHCタンパク質は、アダプター分子、つまり活性化した成長因子受容体(RTKs)の下流で巨視的な研究視点の分子複合体(macro- Research Perspective molecular complexes)の会合に関与するシグナル伝達成分として知られている。インスリンのシグナル伝達にSHCsが果たす役割も報告されている(Giorgetti et al. “Involvement of Src homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor.” Eur. J. Biochem. 1994; 223:195-202)。よって、p66KOマウスは、インスリン/IGFシグナル伝達の遺伝的な減衰(genetic attenuation)により寿命が延長された初めての哺乳動物の例のうちの1つである。
活性酸素種(ROS)スーパーオキシドおよび過酸化水素は、多くの生理学および病態生理学的過程において重要なシグナル伝達機能を果たす。細胞の老化および生物の寿命は免れられない(Afanas’ev, Igor, Oxidative Medicine and Cellular Longevity, V.3 (2010), Issue 2, pages 77-85)。ROSはアポトーシスの強力な誘発因子であり、かつそれ自身でアポトーシスのプログラムを実行する(Giorgio et al. “Electron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial Apoptosis,” Cell Vol. 122, 221-233, July 29, 2005)。
老化した肝臓は、若い肝臓に比べて増加した細胞変性を示し得る。詳細には、老化した肝細胞は、低下した細胞代謝、ならびにミトコンドリア機能および形態の特定の変化を示し得る(Sastre et al. “Aging of the Liver: Age-Associated Mitrochondrial Damage in Intact Hepatocytes,” Hepatology November. (1996) pp. 1199-1205、およびKoch et al., “Role of the life span determinant P66shcA in ethanol-induced liver damage,” Laboratory investigation (2008) 88, 750-760)。例えば、糖新生およびケトン生成が低くなり得る一方で、ミトコンドリアのサイズは増大し得る。肝細胞の変性は、風船(ballooning)もしくは“泡沫(foamy)”細胞、または脂肪変性(Steatosis)(脂肪変化、脂肪変性(fatty degeneration)もしくは脂肪変性(adipose degeneration)とも称される)の兆候によって病理学的に検出され得る。
年齢が上がるにつれ感覚運動の制御および機能は低下する。これら細かい運動(fine motor)の制御、歩行およびバランスの低下は、高齢者が日常生活の活動を行い、かつ彼らの自立を維持する能力に影響を及ぼす(Yankner BA, Lu T, Loerch P. The aging brain. Annu Rev Pathol 2008;3:41-66.; Twohing, J. P. et al., “Age-dependent maintenance of motor control and corticostriatal innervation by death receptor 3.” J. Neurosci. 2010. 30:3782-3792.)。これら運動障害の原因は多因子的であり、中枢神経系の減退、ならびに感覚受容器、筋肉、および末梢神経の変化が所定の役割を果たしている。
balance, posture and gait. London: Arnold;1996.)が含まれる。
本発明の方法を実施するため、上述した1つもしくはそれ以上のポリマー化合物を含む組成物、またはそれらの構成成分のモノマーは、非経口、経口(例えばp.o.)、経鼻(nasally)、経直腸(rectally)、局所的(topically)、または口腔内(buccally)投与され得る。本明細書において用いられる用語“非経口(parenteral)”とは、皮下、皮内、静脈内、筋肉内、関節内、動脈内、滑液嚢内、胸骨内(intrasternal)、髄腔内(intrathecal)、病巣内(intralesional)、または頭蓋内(intracranial)注射、および任意の適した注入法のことをいう。
苧麻の根および茎を洗浄し、自然環境中で乾燥した。乾燥した苧麻を5mm厚の薄片にカットし、4℃で保管した。次いで、保管した苧麻を粉砕機で粉砕してから、20メッシュのスクリーンを用いてふるい分けた。そのふるい分けた粉末を取り、95%エタノール中に加え(1:10、w/v)、2時間加熱還流してから (2回行った)、室温まで冷却した。その加熱してから室温まで冷却した抽出液を遠心バッグに入れ遠心分離によりろ過した。そのろ過した溶液を40℃よりも低い温度にて真空エバポレーターで濃縮し、次いで凍結乾燥機で凍結乾燥した。その凍結乾燥した抽出物を、プロアントシアニジンの成分を含有する医薬組成物とした。
手法1において4℃で保管した苧麻を粉砕機で粉砕してから、20メッシュのスクリーンを用いてふるい分けた。そのふるい分けた粉末(20メッシュ未満)を取り、RO水に加え(1:10、w/v)、2時間加熱還流してから(2回行った)、室温まで冷却した。その加熱してから室温まで冷却した抽出液をエタノール水溶液(95〜50%)中に加えて混合した。その抽出液を冷却して沈殿させた後、その上層液を遠心バッグに入れ、遠心分離によりろ過した。ろ過した溶液を40℃よりも低い温度にて真空エバポレーターで濃縮してから、凍結乾燥機で凍結乾燥した。その凍結乾燥した抽出物を、プロアントシアニジンの成分を含有する医薬組成物とした。
溶媒抽出−1
プロアントシアニジンを含有する苧麻抽出物をヘキサン(1:10、w/v)に加え、6時間加熱還流して抽出物中の脂質を除去した。この固体抽出物を70%メタノール水溶液および/または0.3%ビタミンC溶液に溶解し、40℃よりも低い温度にて真空エバポレーターで濃縮して溶媒を除去した。次いで、その抽出物をクロロホルム(抽出物:クロロホルム=1:1、v/v)に加え、30分間ボルテックスした(複数回の抽出を行った)。その水層を酢酸エチル(抽出物:酢酸エチル=1:1、v/v)に加え、30分間ボルテックスした(複数回の抽出を行った)。その水層を酢酸エチルに加え(抽出物:酢酸エチル=1:1、v/v)、30分間ボルテックスした(複数回の抽出を行った)。その水層を40℃よりも低い温度にて真空エバポレーターで濃縮した後、凍結乾燥機で凍結乾燥した。
溶媒抽出−2
プロアントシアニジンを含有する苧麻抽出物を水/エタノール溶液に溶解し、40℃よりも低い温度にて真空エバポレーターでエタノールを除去し、ヘキサン(1:10、v/v)に加えた後、30分間ボルテックスして(複数回の抽出を行った)抽出物中の脂質を除去した。その水層を酢酸エチル(水層:酢酸エチル=1:1、v/v)に加え、30分間ボルテックスした(複数回の抽出を行った)。その水層を1−ブタノール(1:1、v/v)に加え、30分間ボルテックスした(複数回の抽出を行った)。その水層を40℃よりも低い温度にて真空エバポレーターで濃縮した後、凍結乾燥機で凍結乾燥した。
ゲル浸透クロマトグラフィー
プロアントシアニジンを含有する部分精製された手法1の苧麻抽出物を、ゲル浸透クロマトグラフィー(直径4cm×長さ45cmのSephadex LH−20)により、極性比率の異なる溶液を用いて溶出することにより分離し、その中の不純物を除去した。その部分精製された物質2.5gを95%エタノール0.5mLに溶解し、ゲル浸透クロマトグラフィーカラムに投入した後、一連の溶媒で連続して溶出した。異なる溶媒で溶出したそれら溶出液を回収した。溶媒はそれぞれ、95%エタノール300ml、95%エタノール/メタノール(1/1、v/v)300ml、メタノール300ml、50%メタノール水溶液300ml50%アセトン水溶液300ml、およびアセトン300mlとした。95%エタノール300mLで溶出した溶出液を除き、その他すべての溶出液を40℃よりも低い温度にて真空エバポレーターで濃縮してから、凍結乾燥機で凍結乾燥した。凍結乾燥した物質を−20℃で保管し、使用に備えた。部分精製および/または精製プロアントシアニジンを含有する凍結乾燥した苧麻抽出物の物理的および化学的な特性を分析した。この凍結乾燥した溶出物質は、部分精製および/または精製プロアントシアニジン成分を含んでいた。
精製されたプロアントシアニジン試料を13C核磁気共鳴分光測定および1H核磁気共鳴分光分析測定により検出した。13C核磁気共鳴分光分析の結果が図6a〜図6cに示されており、145.2〜145.7ppmに、二重項−二重項のピークがあるのみで、他のピークは無い。したがって、このモノマーは、シアニジンを有するが、デルフィニジンは有さない、つまりB環が3つのOH基を有しており、これはEGA/MS分析の結果と一致していた。図6において、R1=HまたはOHであり、かつR2=H、OHまたはOCHである。
マウスの犠牲死時に、マウスの体重および肝重量を測定する。その肝臓を回収し、ホルマリンで固定し、パラフィンに包埋する。肝切片をヘマトキシリンおよびエオシン染色する。固定および染色した肝切片の顕微鏡観察および組織病理学的評価によって肝細胞腫脹を評価する。
リアルタイムRT−PCR:Trizol RNA単離プロトコールとして説明されているように、冷凍したマウスの肝臓から全RNA抽出を行う。cDNA合成は、ランダムプライマーおよびSuperScript IIキットを用いる。目的遺伝子SHC1アイソフォームp66のフォワードプライマー、5’−CGGAATGAGTCTCTGTCATCGCTGGA(配列番号1);リバースプライマー5’−CGCCGCCTCCACTCAGCTTGTT(配列番号2)、および内在性コントロール(internal control)ハウスキーピング遺伝子GAPDHのフォワードプライマー、5’−GAAGGTGAAGGTCGGAGT(配列番号3)、リバースプライマー、5’−GAAGATGGTGATGGGATTTC(配列番号4)の脱塩(salt-free)プライマーを生成する。各種肝組織における目的遺伝子の発現量を検出するため、全cDNA1マイクロリットルをガラス毛管中のリアルタイムPCRマスターミックス(Roche Molecular Biochemicals)9mlに加える。4ステップの実験プロトコール:(i)変性プログラム(95℃で20秒);(ii)増幅および定量化プログラムを、SHC−1/p66について60回またはGAPDHについて40回繰り返す(単一の蛍光測定で、95℃で20秒;SHC−1/p66ついて62℃で20秒またはGAPDHについて60℃で20秒;72℃で20秒;SHC1/p66およびGAPDHについて82℃で20秒、);(iii)融解曲線プログラム(1秒あたり0.1℃の加熱率とし60〜95℃、連続蛍光測定);(iv)40℃まで下げる冷却プログラム、を用いる。
ウエスタンブロッティング:肝細胞に10倍量のRIPAバッファーを加え、ホモジナイズし、次いで遠心分離により組織残屑を除去し、その溶液を用いSDS−PAGEによりタンパク質を分離した。SDS−PAGE中のタンパク質をPVDF膜(Millipore)上に転写し、それぞれ特異的抗SHC1/p66およびGAPDH抗体と共に培養した。その特異的タンパク質の発現をUVP Biospectrumを用いて検出すると共に分析した。
Claims (5)
- SHC−1/p66の発現低下剤の製造におけるポリマー組成物の使用であって、
前記ポリマー組成物が、式Iを有するモノマー単位および/またはその薬学的に許容される塩、溶媒化合物、もしくはプロドラッグを含み、
(式I中、R1およびR2の各々は独立してH、アルキル、またはアシルであり;R3、R4、R5、R6、およびR7の各々は独立してH、OH、アルコキシル、またはアシルであり;かつR8はHまたは糖質部分(saccharide moiety)である。)
かつ、重合される前記モノマーの数が2〜30であり、前記ポリマーの平均分子量が600〜10000である、使用。 - 前記方法が、前記組成物を非経口、経口、経鼻(nasally)、経直腸(rectally)、局所的(topically)、または口腔内(buccally)投与することを含む、請求項1に記載の使用。
- 前記組成物が50から1500mg/kg/dayの用量で投与される、請求項1または2に記載の使用。
- 前記組成物が、栄養剤(nutrient)、栄養補給食品(nutriceutical)、健康食品(health food)またはサプリメント(supplement)の形式である、請求項3に記載の使用。
- 栄養剤(nutrient)、栄養補給食品(nutriceutical)、健康食品(health food)またはサプリメント(supplement)の形式で、式Iを有するモノマー単位を含むポリマー組成物を含み、
SHC−1/p66の発現を低下させるための組成物であって、
(式I中、R1およびR2の各々は独立してH、アルキル、またはアシルであり;R3、R4、R5、R6、およびR7の各々は独立してH、OH、アルコキシル、またはアシルであり;かつR8はHまたは糖質部分(saccharide moiety)である。)
かつ、栄養剤、栄養補給食品、健康食品またはサプリメントの形式で、重合される前記モノマーの数が2〜30である、組成物。
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US13/727,387 US20140179774A1 (en) | 2012-12-26 | 2012-12-26 | Methods for inhibition of shc-1/p66 to combat aging-related diseases |
US13/727,387 | 2012-12-26 | ||
PCT/CN2013/075599 WO2014101366A1 (en) | 2012-12-26 | 2013-05-14 | Methods for inhibition of shc-1/p66 to combat aging-related diseases |
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