JP6469394B2 - アポトーシス抑制剤 - Google Patents
アポトーシス抑制剤 Download PDFInfo
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- JP6469394B2 JP6469394B2 JP2014183058A JP2014183058A JP6469394B2 JP 6469394 B2 JP6469394 B2 JP 6469394B2 JP 2014183058 A JP2014183058 A JP 2014183058A JP 2014183058 A JP2014183058 A JP 2014183058A JP 6469394 B2 JP6469394 B2 JP 6469394B2
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- exosome
- fraction
- milk
- apoptosis
- rna
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Description
本発明はまた、アポトーシス抑制剤の製造方法であって、
乳から脂質画分、細胞画分及びカゼイン画分を除去してホエイ画分を調製する工程、
前記ホエイ画分からエクソソーム画分を回収する工程、及び、
前記エクソソーム画分、または、少なくともRNAを含む該エクソソームの分画物を有
効成分として製剤化する工程、
を含む方法を提供する。
乳から脂質画分、細胞画分及びカゼイン画分を除去してホエイ(乳清)画分を調製する。得られたホエイ画分からエクソソーム画分を回収する。エクソソーム画分の回収は、超遠心法、フィルター法、密度勾配遠心法、スクロースクッション法、限外ろ過、連続フロー電気泳動法、クロマトグラフィー法等の公知の方法(国際公開第2014/030590)を用いることができる。具体的には例えば、ホエイ画分を30,000〜1,000,000×g、例えば100,000×gで、60〜120分遠心分離し、上清を除去すると、エクソソーム画分が得られる。
なお、前記のエクソソームの分画物に含まれるRNAや精製RNAとしては、マイクロRNA(miRNA)及びメッセンジャーRNA(mRNA)等を例示することができる。
ル等を、着色剤としては医薬品に添加することが許容されている赤色2号、黄色4号、及び青色1号等を、それぞれ例示することができる。
また、本発明の他の態様は、アポトーシスを原因とする、又はアポトーシスを伴う疾患の治療又は予防に用いられる乳由来のエクソソームである。また、本発明の他の態様は、乳由来のエクソソーム、又はその分画物を動物に投与する、アポトーシスを原因とする、又はアポトーシスを伴う疾患の治療又は予防法である。ここで、アポトーシスは、細胞死と置き換えることができる。
このような食品としては、液状、ペースト状、固体、粉末等の形態を問わず、錠菓、流動食、飼料(ペット用を含む)等のほか、例えば、パン、マカロニ、スパゲッティ、めん類、ケーキミックス、から揚げ粉、パン粉等の小麦粉製品;即席めん、カップめん、レトルト・調理食品、調理缶詰め、電子レンジ食品、即席スープ・シチュー、即席みそ汁・吸い物、スープ缶詰め、フリーズ・ドライ食品、その他の即席食品等の即席食品類; 農産缶詰め、果実缶詰め、ジャム・マーマレード類、漬物、煮豆類、農産乾物類、シリアル(穀物加工品)等の農産加工品; 水産缶詰め、魚肉ハム・ソーセージ、水産練り製品、水産珍味類、つくだ煮類等の水産加工品;畜産缶詰め・ペースト類、畜肉ハム・ソーセージ等の畜産加工品;加工乳、乳飲料、ヨーグルト類、乳酸菌飲料類、チーズ、アイスクリーム類、調製粉乳類、クリーム、その他の乳製品等の乳・乳製品;バター、マーガリン類、植物油等の油脂類;しょうゆ、みそ、ソース類、トマト加工調味料、みりん類、食酢類等の基礎調味料;調理ミックス、カレーの素類、たれ類、ドレッシング類、めんつゆ類、スパイス類、その他の複合調味料等の複合調味料・食品類;素材冷凍食品、半調理冷凍食品、調理済冷凍食品等の冷凍食品;キャラメル、キャンディー、チューインガム、チョコレート、クッキー、ビスケット、ケーキ、パイ、スナック、クラッカー、和菓子、米菓子、豆菓子、デザート菓子、その他の菓子などの菓子類;炭酸飲料、天然果汁、果汁飲料、果
汁入り清涼飲料、果肉飲料、果粒入り果実飲料、野菜系飲料、豆乳、豆乳飲料、コーヒー飲料、お茶飲料、粉末飲料、濃縮飲料、スポーツ飲料、栄養飲料、アルコール飲料、その他の嗜好飲料等の嗜好飲料類;ベビーフード、ふりかけ、お茶潰けのり等のその他の市販食品等;育児用調製粉乳;経腸栄養食;機能性食品(特定保健用食品、栄養機能食品)等が挙げられる。
乳製品製造に使用される原料乳を1,200×g、4℃で10分間遠心分離し、原料乳に含まれる脂肪、細胞を除去する操作を2回行い、脱脂乳を得た。得られた脱脂乳に10 %酢酸を滴下し、pHを4.6まで低下させてカゼインを沈殿させた。pH4.6の脱脂乳を4,500×g、4℃で30分間遠心分離し、カゼインを除いた。続いて20,000×g、4℃で30分間遠心分離を行ない、上清を採取する操作を2回行い、カゼインを完全に除去した。得られた試料を0.45μm及び0.22μmのフィルター(Millipore社製)で濾過し、乳清(ホエイ)を得た。得られた乳清を100,000×g, 4℃で90分間超遠心を行ない、エクソソームを含むペレット状の塊をPBSに懸濁し、上記と同様の超遠心を行なうことで、エクソソームを洗浄した。同洗浄を再度行ない、エクソソーム画分を得た。
ヒト単球性白血病細胞株であるTHP-1(ATCC TIB-202)を、10 %非働化ウシ胎仔血清(HyClone社製)(超遠心により血清中エクソソームは除去したもの)、1 %ペニシリン-ストレプトマイシン-グルタミン溶液(Gibco社製)、1 %非必須アミノ酸混合液(Gibco社製)、0.1 %β-メルカプトエタノールを含む培地(完全培地)で培養後、50 nM PMA(Phorbol 12-myristate 13-acetate)(Sigma社製)を添加し、72時間培養することでTHP-1株をマクロファージ様に分化させた。この細胞5×104個に対して80μlの完全培地を加えた細胞懸
濁液と、以下(ii)〜(vi)の被検物質を20μlのPBSに溶解した被検物質溶液((i)は20μlのPBSのみ)とを混合し、それぞれ試験溶液(100μl)とした。
(ii)10 μgのウシ血清アルブミン
(iii)タンパク質換算で10 μg(RNA換算で12 ng)のエクソソーム画分
(iv)タンパク質換算で10 μgのエクソソーム画分を超音波処理したもの *1
(v)タンパク質換算で10 μgのエクソソーム画分から精製したRNA(12 ng)
(vi)10 μgのウシ・ラクトフェリン
*1:Nissei社製超音波破砕機US-300Eを用い20秒間5回超音波処理した。
前記したように、マクロファージ様細胞はLPSによりアポトーシスが誘導されると考えられる。したがって、上記で観察された生存細胞数の増加は、アポトーシス抑制作用によるものと考えられる。
Claims (8)
- ウシの乳由来のエクソソーム、または、少なくともRNAを含む該エクソソームの分画物を有効成分として含有する、アポトーシス抑制剤。
- 前記エクソソームが、膜小胞構造が一部又は完全に破壊されている破砕物である、請求項1に記載のアポトーシス抑制剤。
- 前記破砕物が、超音波処理物である、請求項2に記載のアポトーシス抑制剤。
- アポトーシス抑制剤の製造方法であって、
ウシの乳から脂質画分、細胞画分及びカゼイン画分を除去してホエイ画分を調製する工程、
前記ホエイ画分からエクソソーム画分を回収する工程、
前記エクソソーム画分に含まれるエクソソームの膜小胞の形態を一部又は完全に破壊する工程、及び、
前記エクソソーム画分、または、少なくともRNAを含む該エクソソームの分画物を有効成分として製剤化する工程、
を含む方法。 - 前記膜小胞の形態を一部又は完全に破壊する工程が、前記エクソソーム画分を超音波処理する工程である、請求項4に記載の方法。
- ウシの乳由来のエクソソーム、または、少なくともRNAを含む該エクソソームの分画物を有効成分として含有する、アポトーシス抑制用飲食品組成物。
- 前記エクソソームが、膜小胞構造が一部又は完全に破壊されている破砕物である、請求項6に記載のアポトーシス抑制用飲食品組成物。
- 前記破砕物が、超音波処理物である、請求項7に記載のアポトーシス抑制用飲食品組成物。
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