JP2019156786A - Exosome production promotor - Google Patents
Exosome production promotor Download PDFInfo
- Publication number
- JP2019156786A JP2019156786A JP2018047738A JP2018047738A JP2019156786A JP 2019156786 A JP2019156786 A JP 2019156786A JP 2018047738 A JP2018047738 A JP 2018047738A JP 2018047738 A JP2018047738 A JP 2018047738A JP 2019156786 A JP2019156786 A JP 2019156786A
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- JP
- Japan
- Prior art keywords
- exosome production
- exosome
- trans
- production promoter
- sphingadienin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
本発明は、神経細胞におけるエクソソームの産生を促進できるエクソソーム産生促進剤に関する。 The present invention relates to an exosome production promoter that can promote exosome production in nerve cells.
アルツハイマー病は（ＡＤ）、認知症の過半数を占める神経変性疾患であり、加齢とともにその発症率は上昇する。ＡＤの病理学的特徴として、老人班の出現が挙げられるが、これはアミロイドβ（Ａβ）と呼ばれるタンパク質が細胞外に沈着したものである。Ａβは、アミロイド前駆体タンパク質（ＡＰＰ）の連続的なプロセッシングによって生成される。正常な状態では、Ａβの生成と分解／排出のバランスが保たれているため、過剰な量のＡβが脳内に蓄積することはない。しかしながら、一度そのバランスが崩れると、脳内で過剰な量のＡβが蓄積し、ＡＤを発症するリスクを高める。 Alzheimer's disease (AD) is a neurodegenerative disease that accounts for the majority of dementia, and its incidence increases with age. A pathological feature of AD is the appearance of a senile plaque, which is a protein called amyloid β (Aβ) deposited extracellularly. Aβ is produced by the continuous processing of amyloid precursor protein (APP). Under normal conditions, the balance between Aβ production and degradation / excretion is maintained, so that an excessive amount of Aβ does not accumulate in the brain. However, once the balance is lost, an excessive amount of Aβ accumulates in the brain, increasing the risk of developing AD.
Ａβの蓄積を抑制する薬剤についてはこれまでにも広く研究がされている。例えば、特許文献１には、水溶性ペプチド金属錯体アレイを含むアミロイド繊維の形成を抑制する抑制剤が開示されている。また、特許文献２には、シソの抽出物を有効成分とする、Ａβの凝集阻害組成物が開示されている。さらに、特許文献３では、Ｎ−アセチルノイラミン酸、Ｎ−アセチルマンノサミン、およびシアリルラクトースの少なくとも何か一つを含有する、GNE遺伝子変異に起因するＡβ凝集抑制剤が開示されている。 There have been extensive studies on drugs that suppress the accumulation of Aβ. For example, Patent Document 1 discloses an inhibitor that suppresses the formation of amyloid fibers including a water-soluble peptide metal complex array. Patent Document 2 discloses an Aβ aggregation-inhibiting composition containing a perilla extract as an active ingredient. Furthermore, Patent Document 3 discloses an Aβ aggregation inhibitor caused by a GNE gene mutation, which contains at least one of N-acetylneuraminic acid, N-acetylmannosamine, and sialyl lactose.
また、最近、神経細胞から分泌されたエクソソームがＡβの分解に関与していることが報告されており（非特許文献１）、Ａβの蓄積抑制には神経細胞におけるエクソソームの産生促進が有効であると考えられる。エクソソームとは、細胞から放出される小型膜小胞（直径約４０〜１００ｎｍ）であり、ｍＲＮＡ等を内包し、細胞間のコミュニケーションに重要であると考えられている（非特許文献２）。 Recently, it has been reported that exosomes secreted from nerve cells are involved in the degradation of Aβ (Non-patent Document 1), and promotion of exosome production in nerve cells is effective in suppressing Aβ accumulation. it is conceivable that. Exosomes are small membrane vesicles (diameter of about 40 to 100 nm) released from cells, and are considered to be important for communication between cells, including mRNA and the like (Non-patent Document 2).
本発明者等のこれまでの研究により、細胞外へ分泌されたＡβは神経細胞から分泌されるエクソソームと結合し、ミクログリアに移動、その後分解されることが解明されている。例えば、非特許文献３では、神経細胞由来エクソソームがＡβ結合糖脂質を高発現し、Ａβを結合する能力を有すること、更にはＡβを結合した状態のエクソソームがミクログリアに取り込まれ、分解されることを報告している。更に、非特許文献４及び非特許文献５では、神経細胞由来のエクソソームを脳内投与することによって、脳内のＡβレベルが低下することも報告されている。 It has been elucidated by previous studies by the present inventors that Aβ secreted extracellularly binds to exosomes secreted from nerve cells, moves to microglia, and is then degraded. For example, in Non-Patent Document 3, neuronal cell-derived exosomes highly express Aβ-linked glycolipids and have the ability to bind Aβ, and further, exosomes in a state of binding Aβ are taken up by microglia and degraded. Has been reported. Furthermore, Non-Patent Document 4 and Non-Patent Document 5 report that administration of neuronal cell-derived exosomes in the brain reduces the Aβ level in the brain.
しかしながら、エクソソームの産生を促進し得る薬剤については、未だに十分な検討が行われていない。 However, drugs that can promote exosome production have not yet been fully studied.
本発明の目的は、神経細胞におけるエクソソームの産生を促進できるエクソソーム産生促進剤を提供することである。 An object of the present invention is to provide an exosome production promoter that can promote exosome production in nerve cells.
本発明者等が前記課題を解決すべく鋭意検討を行ったところ、スフィンゴイド塩基には神経細胞におけるエクソソームの産生を促進させる作用があり、エクソソーム産生促進剤として使用し得ることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 As a result of intensive studies by the present inventors to solve the above-mentioned problems, it was found that sphingoid bases have an action of promoting exosome production in nerve cells and can be used as an exosome production promoter. The present invention has been completed by further studies based on this finding.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． スフィンゴイド塩基を有効成分とするエクソソーム産生促進剤。
項２． スフィンゴイド塩基が、４−トランス，８−トランス−スフィンガジエニン、４−トランス，８−シス−スフィンガジエニン、及びスフィンゴシンよりなる群から選択される少なくとも１種である、項１に記載のエクソソーム産生促進剤。
項３． アミロイドβタンパク質の蓄積に起因する疾患を予防又は改善するために使用される、項１又は２に記載のエクソソーム産生促進剤。
項４． アミロイドβタンパク質の蓄積に起因する認知機能の低下を予防又は改善するために使用される、項１又は２に記載のエクソソーム産生促進剤。
項５． アミロイドβタンパク質の蓄積に起因する記憶障害を予防又は改善するために使用される、項１又は２に記載のエクソソーム産生促進剤。
項６． エクソソーム産生促進用飲食品である、項１〜５のいずれかに記載のエクソソーム産生促進剤。
項７． エクソソーム産生促進用医薬品である、項１〜５のいずれかに記載のエクソソーム産生促進剤。
That is, this invention provides the invention of the aspect hung up below.
Item 1. An exosome production promoter containing sphingoid base as an active ingredient.
Item 2. Item 2. The sphingoid base is at least one selected from the group consisting of 4-trans, 8-trans-sphingadienin, 4-trans, 8-cis-sphingadienin, and sphingosine. Exosome production promoter.
Item 3. Item 3. The exosome production promoter according to Item 1 or 2, which is used for preventing or ameliorating a disease caused by accumulation of amyloid β protein.
Item 4. Item 3. The exosome production promoter according to Item 1 or 2, which is used for preventing or improving a decrease in cognitive function caused by accumulation of amyloid β protein.
Item 5. Item 3. The exosome production promoter according to Item 1 or 2, which is used for preventing or ameliorating a memory impairment caused by accumulation of amyloid β protein.
Item 6. Item 6. The exosome production promoter according to any one of Items 1 to 5, which is a food and drink for promoting exosome production.
Item 7. Item 6. The exosome production promoter according to any one of Items 1 to 5, which is a pharmaceutical product for promoting exosome production.
本発明によれば、神経細胞におけるエクソソームの産生を促進できる、エクソソーム産生促進剤を提供することができる。また、本発明のエクソソーム産生促進剤は、経口投与、飲食品の形態で投与又は摂取できるので、非侵襲的で患者への負担が少なく、容易に神経細胞におけるエクソソーム産生を促進することができる。 ADVANTAGE OF THE INVENTION According to this invention, the exosome production promoter which can accelerate | stimulate the production of exosome in a nerve cell can be provided. In addition, since the exosome production promoter of the present invention can be administered or ingested in the form of oral administration and food and drink, it is non-invasive and less burdensome on the patient, and can easily promote exosome production in nerve cells.
本発明は、スフィンゴイド塩基を有効成分とするエクソソーム産生促進剤である。以下、本発明のエクソソーム産生促進剤について詳述する。 The present invention is an exosome production promoter containing a sphingoid base as an active ingredient. Hereinafter, the exosome production promoter of the present invention will be described in detail.
［スフィンゴイド塩基］
本発明のエクソソーム産生促進剤は、スフィンゴイド塩基を有効成分として使用する。スフィンゴイド塩基は、スフィンゴ脂質を構成する塩基部分（長鎖アミノアルコール）として公知の化合物である。
[Sphingoid base]
The exosome production promoter of the present invention uses a sphingoid base as an active ingredient. A sphingoid base is a compound known as a base moiety (long-chain amino alcohol) that constitutes a sphingolipid.
本発明で使用されるスフィンゴイド塩基の種類については、特に制限されないが、例えば、スフィンゴシン（４−スフィンゲニン）、４−トランス，８−トランス−スフィンガジエニン、４−トランス，８−シス−スフィンガジエニン、４−シス，８−トランス−スフィンガジエニン、４−ヒドロキシスフィンガニン（フィトスフィンゴシン）、４−ヒドロキシ−８−トランス−スフィンゲニン、４−ヒドロキシ−８−シス−スフィンゲニン、スフィンガニン、８−トランス−スフィンゲニン、８−シス−スフィンゲニン、４−トランス−スフィンゲニン、４−シス，８−シス−スフィンガジエニン、４−トランス，１４−シス−スフィンガジエニン、４−トランス，１４−トランス−スフィンガジエニン等が挙げられる。 The type of sphingoid base used in the present invention is not particularly limited. For example, sphingosine (4-sphingenin), 4-trans, 8-trans-sphingadienin, 4-trans, 8-cis-sus Fingeradienin, 4-cis, 8-trans-sphingadienin, 4-hydroxysphinganin (phytosphingosine), 4-hydroxy-8-trans-sphingenin, 4-hydroxy-8-cis-sphingenin, sphinganine, 8-trans-sphingenin, 8-cis-sphingenin, 4-trans-sphingenin, 4-cis, 8-cis-sphingadienin, 4-trans, 14-cis-sphingadienin, 4-trans, 14- Examples include trans-sphingadienin.
これらのスフィンゴイド塩基は、１種単独で使用してもよく、２種以上を組み合わせて使用してもよい。 These sphingoid bases may be used individually by 1 type, and may be used in combination of 2 or more type.
これらのスフィンゴイド塩基の中でも、神経細胞におけるエクソソームの産生をより一層効果的に促進させるという観点から、好ましくはスフィンゴシン（４−スフィンゲニン）、４−トランス，８−トランス−スフィンガジエニン、４−トランス，８−シス−スフィンガジエニン、更に好ましくは４−トランス，８−トランス−スフィンガジエニン、４−トランス，８−シス−スフィンガジエニンが挙げられる。 Among these sphingoid bases, sphingosine (4-sphingenin), 4-trans, 8-trans-sphingadienin, 4- is preferable from the viewpoint of more effectively promoting exosome production in nerve cells. Examples include trans, 8-cis-sphingadienin, more preferably 4-trans, 8-trans-sphingadienin, and 4-trans, 8-cis-sphingadienin.
スフィンゴイド塩基は、植物由来、動物由来のいずれであってもよいが、安全性がより一層高い点で、植物由来が好ましい。 The sphingoid base may be derived from a plant or an animal, but is preferably derived from a plant in terms of higher safety.
本発明で使用されるスフィンゴイド塩基の由来動物としては、具体的には、ウニやヒトデ、タコ、イカ等の棘皮動物、軟体動物の組織全て又は一部、ウマ、ウシ等の哺乳動物の脳組織及び皮膚組織、ヒト、ウシ、ヤギ等哺乳動物の乳及びその発酵物等が挙げられる。 Specific examples of the animal derived from the sphingoid base used in the present invention include echinoderms such as sea urchins, starfish, octopus and squid, all or part of mollusc tissues, and brains of mammals such as horses and cows. Examples include tissues and skin tissues, milk of mammals such as humans, cows and goats, and fermented products thereof.
本発明で使用されるスフィンゴイド塩基の由来植物としては、アーモンド、アオサ、アオノリ、アカザ、アカシア、アカブドウ、アカマツ、アガリクス、アキノノゲシ、アケビ、アサガオ、アザレア、アジサイ、アシタバ、アズキ、アスパラガス、アセロラ、アセンヤク、アニス、アボガド、アマクサ、アマチャ、アマチャズル、アマナツ、アマリリス、アルテア、アルニカ、アロエ、アンジェリカ、アンズ、アンコール、アンソッコウ。イグサ、イザヨイ、バラ、イチイ、イチジク、イチョウ、イヨカン、イランイラン、ウイキョウ、ウーロン茶、ウコン、ウスベニアオイ、ウツボグサ、ウド、ウメ、ウラジロガシ、温州ミカン、エイジル、エシャロット、エゾウコギ、エニシダ、エノキタケ、エルダーフラワーエンソウ、オーキッド、オウゴンカン、オオバコ、オオヒレアザミ、オオムギ、オケラ、オスマンサス、オトギリソウ、オドリコソウ、オレンジ、カーネーション、カカオ、カキ、カキドオシ、カクテルフルーツ、カッコン、カシワ、カタクリ、カボチャ、カミツレ、カムカム、カモミール、カラウスウリペイ、キイチゴ、キウイ、キキョウ、キャベツ、キャラウェイ、キュウリ、キヨミ、キンカン、ギンナン、ガァバ、クコ、クズ、クチナシ、クミン、クランベリー、クルミ、グレープフルーツ、クレメンタイン、クローブ、クロマル、クロマメ、クロレラ、ケツメイシ、ゲンノチョウコ、コケモモ、コチョウ、コスモス、ゴノウ、コムギ、ゴマ、コマツネ、コメ、コリアンガダー、コンニャク、コンブ、サーモンベリー、サイオウレス、ザクロ、サツマイモ、サトイモ、サトウキビ、サトウダイコン、サフラン、ザボン、サンザシ、サンショウ、シイタケ、シクラメン、ショウガ、シソ、シメジ、ジャガイモ、シャクヤク、ジャスミン、ジュズダマ、シュンギク、チョウブ、シラカシ、ジンチョウゲ、シンナモン、スイカ、スイトピー、スイートスプリング、スギナ、スターアニス、スターアップル、ロリ、センキュウ、センブリ、ソバ、ソラマメ、ダイコン、ダイズ、ダイダイ、タイムタケノコ、タマネギ、タモギタケ、タラゴン、タロイモ、タンカン、タンゴール、タンジン、タンゼロ、タンポポ、チコリ、ツキミソウ、ツクシ、ツバキ、ツボクサ、ツメクサ、ツルクサ、ツルナ、ツワブキ、ディル、デコポン、テンジクアオイ、トウガ、トウガラシ、トウキ、トウキュウカソウ、トウモロコシ、ドクダミ、トコン、トチュウ、トネリコ、ナガイモ、ナズナ、ナツミ、ナツミカン、ナツメグ、ナンテン、ニガウリ、ニガヨモギ、ニラ、ニンジン、ニンニク、ネギ、ノコギリソウ、ノコギリヤシ、ノビル、バーベナ、パーム、パイナップル、ハイビスカス、ハコベ、パプリカ、ハマメリス、ハルカ、ハルミ、ハレヒメ、バンペイユ、ビート、ピーマン、ヒガンバナ、ヒバ、ヒシ、ヒジキ、ピスタチオ、ヒソップ、ヒナギク、ヒナゲシ、ヒノキ、ヒマシ、ヒマワリ、ヒメノツキ、ヒュウガナツ、ビワ、ファレノプシス、フェネグリーク、フキノトウ、ブラックベリー、プラム、ブルーベリー、ビルベリー、プルーン、ブンタン、ヘチマ、ベニバナ、ベニマドンナ、ベラドンナ、ベルガモット、ホウセンカ、ホウレンソウ、ホオズキ、ボダイジュ、ボタン、ホップ、ホホバ、ポンカン、マイタケ、マオウ、マカ、マカデミアンナッツ、マーコット、マタタビ、マリーゴールド、メリヒメ、マンゴー、ミツバ、ミネオラ、ミモザ、ミョウガ、ミルラ、ムラサキ、メース、メリッサ、メリロート、メロン、メン、モヤシ、ヤグルマソウ、ヤマイモ、ヤマユリ、ヤマヨモギ、ユーカリ、ユキノシタ、ユズ、ユリ、ヨクイニン、ヨメナ、ヨモギ、ライム、ライムギ、ライラック、ラズベリー、ラカッセイ、ラッキョウ、リンゴ、リンドウ、レイコウ、レイシ、レタス、レモン、レンゲソウ、レンコン、ローズヒップ、ローズマリー、ローリエ、ワケギ、ワサビ等が挙げられる。これらの中でも、好ましくは、コムギ、コメ、トウモロコシ、ダイズ、コンニャク、マイタケ、タモギタケ；更に好ましくはコンニャクが挙げられる。 Examples of the plant derived from sphingoid base used in the present invention include almond, aosa, aonori, red aza, acacia, red grape, red pine, agaricus, akinonageshi, akebi, morning glory, azalea, hydrangea, ashitaba, azuki, asparagus, acerola, Asenayak, Anise, Avocado, Amakusa, Achacha, Amatazur, Amanatsu, Amaryllis, Altea, Arnica, Aloe, Angelica, Apricot, Angkor, Angsukkou. Rush, isayoi, rose, yew, fig, ginkgo, yeokan, ylang ylang, fennel, oolong tea, turmeric, euglena, crabs, udo, ume, vulgaris , Orchid, Ogoncan, Plantain, Great White Thistle, Barley, Ochera, Osmanthus, Hypericum, Olysam, Orange, Carnation, Cacao, Oyster, Prickly Pear, Cocktail Fruit, Cuckoo, Kashiwa, Katakuri, Pumpkin, Chamomile, Strawberry , Kiwi, kikyo, cabbage, caraway, cucumber, kiyomi, kumquat, ginnan, gaba, wolfberry, crap, gardenia, cumin, cranberry , Walnut, Grapefruit, Clementine, Clove, Chroma, Black beans, Chlorella, Ketsumeishi, Gentle butterfly, Cowberry, Kocho, Cosmos, Gonow, Wheat, Sesame, Komatsu, Rice Taro, sugar cane, sugar beet, saffron, pomelo, hawthorn, salamander, shiitake mushroom, cyclamen, ginger, perilla, shimeji, potato, peonies, jasmine, juzudama, sangiku, butterfly, birch, ginkgo biloba, cinnamon, watermelon, sweet pea, sweet spring , Horsetail, Star anise, Star apple, Lori, Senkyu, Assembly, Buckwheat, Broad bean, Japanese radish, Soybean, Daidai, Time bamboo shoot, Ta Leek, Tamogitake, Taragon, Taro, Tankan, Tangor, Tanjin, Tan Zero, Dandelion, Chicory, Primrose, Tsukushi, Camellia, Clover, Clover, Crane, Tulna, Azalea, Dill, Decopon, Tenjikuaoi, Toga, Cage, Pepper Cassow, corn, dodami, tocon, eucommia, ash, potato, natsuna, natsumi, jujube, nutmeg, nanten, bitter gourd, sagebrush, leek, carrot, garlic, leek, yarrow, saw palmetto, nobil, verbena, palm, pineapple, pineapple, pineapple, pineapple Jacobe, Paprika, Hamamerisu, Haruka, Harumi, Harehime, Bumpei, Beat, Pepper, Higanbana, Hiba, Hishi, Hijiki, Pistachio, Hyssop, Daisies, Daisies, Hinoki , Castor, sunflower, cyprinus, hyuganatsu, loquat, phalaenopsis, phenegrek, fukinotou, blackberry, plum, blueberry, bilberry, prune, buntan, loofah, safflower, safflower, belladonna, bergamot, spinach, jujube , Hop, jojoba, ponkan, maitake, maou, maca, macadamian nut, marcot, matatabi, marigold, merihime, mango, honeybee, minneola, mimosa, ginger, myrrh, murasaki, mace, melissa, merirot, melon, men, Sprout, cornflower, yam, wild lily, porcupine, eucalyptus, saxifrage, yuzu, lily, yokuinin, yomena, mugwort, lime, rye, lilac, raspberry, la Assay, shallot, apple, gentian, enforced, litchi, lettuce, lemon, Rengesou, lotus root, rose hips, rosemary, bay leaves, scallions, wasabi, and the like. Among these, Preferably, wheat, rice, corn, soybeans, konjac, maitake, tamagotake, and more preferably konjac.
本発明で使用されるスフィンゴイド塩基は、前述する動物又は植物から公知の生成方法によって得ることができる。また、スフィンゴイド塩基は、市販のものを購入してもよい。 The sphingoid base used in the present invention can be obtained from the aforementioned animals or plants by a known production method. Moreover, you may purchase a commercially available sphingoid base.
スフィンゴイド塩基の生成方法としては、例えば、前述する動物又は植物からスフィンゴ糖脂質を抽出し、酵素反応等により糖を除去、その後、化学反応等により脂肪酸を除去することで得ることができる。この際、原料として使用するスフィンゴ糖脂質は、目的のスフィンゴイド塩基が得られるのであれば特に限定されず、セラミドにグルコースやガラクトース等の、いずれの糖が結合したものであってもよい。また、糖を除去するための酵素としては、スフィンゴ糖脂質―セラミド間の結合を加水分解できる酵素であれば特に限定されず、例えば、エンドグリコシダーゼ（ＥＧＣａｓｅ）が挙げられる。ＥＧＣａｓｅは、等電点および、分子量のことなる３つの種（ＥＧＣａｓｅＩ、ＥＧＣａｓｅＩＩ、及びＥＧＣａｓｅＩＩＩ）が知られており、分子種に応じて基質特異性がことなることが知られている。使用するＥＧＣａｓｅの分子種は、基質として使用するスフィンゴ糖脂質の構造に応じて適宜選択すればよい。 As a method for producing a sphingoid base, for example, it can be obtained by extracting a sphingoglycolipid from the aforementioned animal or plant, removing the sugar by an enzymatic reaction or the like, and then removing the fatty acid by a chemical reaction or the like. In this case, the glycosphingolipid used as a raw material is not particularly limited as long as the target sphingoid base can be obtained, and may be one obtained by binding any sugar such as glucose or galactose to ceramide. The enzyme for removing the sugar is not particularly limited as long as it is an enzyme that can hydrolyze the bond between glycosphingolipid and ceramide, and examples thereof include endoglycosidase (EGCase). As for EGCase, three species (EGCase I, EGCase II, and EGCase III) having different isoelectric points and molecular weights are known, and it is known that the substrate specificity varies depending on the molecular species. The molecular species of EGCase to be used may be appropriately selected according to the structure of glycosphingolipid used as a substrate.
生成したスフィンゴイド塩基は、必要に応じて、濃縮・精製処理に供してもよい。濃縮処理としては、例えば、エバポレーター等の減圧濃縮装置を用いた公知の濃縮処理が挙げられる。また、精製処理としては、例えば、イオン交換樹脂、アルカリ処理、溶媒分画、シリカゲルクロマトグラフィー等の公知の精製処理が挙げられる。 The generated sphingoid base may be subjected to a concentration / purification treatment as necessary. As a concentration process, the well-known concentration process using vacuum concentration apparatuses, such as an evaporator, is mentioned, for example. Examples of the purification treatment include known purification treatments such as ion exchange resin, alkali treatment, solvent fractionation, and silica gel chromatography.
本発明のエクソソーム産生促進剤におけるスフィンゴイド塩基の含有量としては、生体内でエクソソームの産生を促進できる有効量であることを限定されず、用途、剤型、投与形態等に応じて適宜調整することができる。 The sphingoid base content in the exosome production promoter of the present invention is not limited to an effective amount that can promote the production of exosomes in vivo, and is appropriately adjusted according to the use, dosage form, administration mode, and the like. be able to.
［その他の添加成分］
本発明のエクソソーム産生促進剤は、前述したスフィンゴイド塩基以外に、本発明の効果を損なわない範囲で、剤型に応じて、他の添加成分を含有してもよい。本発明のエクソソーム産生促進剤に含有され得る添加成分としては、例えば、水、油脂類、ロウ類、炭化水素類、脂肪酸類、高級アルコール類、エステル類、植物抽出エキス類、彗星高分子、界面活性剤、金属石鹸、アルコール類、多価アルコール、pH調製剤、酸化防止剤、紫外線吸収剤、防腐剤、香料、粉黛、増粘剤、色素、キレート剤等が挙げられる。これらの添加成分は、１種類単独で混合しても、２種類以上を組み合わせて使用してもよい。また、これらの添加成分の含量については、使用する添加成分の種類や本発明のエクソソーム産生促進剤の剤型等に応じて適宜設定される。
[Other additive components]
The exosome production promoter of the present invention may contain other additive components in addition to the sphingoid base described above, depending on the dosage form, as long as the effects of the present invention are not impaired. Examples of additive components that can be contained in the exosome production promoter of the present invention include water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, plant extracts, comet polymers, interfaces Examples include activators, metal soaps, alcohols, polyhydric alcohols, pH adjusters, antioxidants, ultraviolet absorbers, preservatives, fragrances, powder cakes, thickeners, dyes, chelating agents, and the like. These additive components may be used alone or in combination of two or more. The content of these additive components is appropriately set according to the type of additive component used, the dosage form of the exosome production promoter of the present invention, and the like.
［剤型・製剤形態・用途］
本発明のエクソソーム産生促進剤の剤型については、特に限定されず、固体状、半固体状、又は液体状のいずれであってもよく、エクソソーム産生促進剤の種類、用途、投与方法などに応じて適宜設定すればよい。
[Dosage form / formulation / use]
The dosage form of the exosome production promoter of the present invention is not particularly limited, and may be solid, semi-solid, or liquid, depending on the type, use, administration method, etc. of the exosome production promoter. May be set as appropriate.
本発明のエクソソーム産生促進剤の投与方法としては、特に限定されず、適用する疾患の種類に応じて適宜選択すればよく、全身投与であっても、局所投与であってもよい。具体的には、経口、経血管内（動脈内又は静脈内）、経皮、経腸、経肺、鼻腔内投与等が挙げられる。経血管内投与には、血管内注射、持続点滴も含まれる。中でも、投与が容易であり、且つエクソソーム産生促進効果を効果的に奏させるという観点から、経口投与が好ましい。 The administration method of the exosome production promoter of the present invention is not particularly limited, and may be appropriately selected according to the type of disease to be applied, and may be systemic administration or local administration. Specific examples include oral, intravascular (intraarterial or intravenous), transdermal, enteral, transpulmonary, intranasal administration, and the like. Intravascular administration includes intravascular injection and continuous infusion. Of these, oral administration is preferable from the viewpoint of easy administration and effective production of exosome production.
本発明のエクソソーム産生促進剤の製剤形態については、特に限定されず、投与方法に適した製剤形態に適宜設定することができ、例えば、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、注射剤、点滴剤、坐剤等の任意の製剤形態を挙げることができる。例えば、本発明のエクソソーム産生促進剤の投与形態が経口投与である場合は、経口投与が可能であることを限度として特に限定されないが、具体的には、飲食品及び内服用医薬品が挙げられる。 The formulation form of the exosome production promoter of the present invention is not particularly limited, and can be appropriately set to a formulation form suitable for the administration method, for example, tablet, capsule, granule, powder, syrup, injection And any preparation form such as drops, suppositories and the like. For example, when the dosage form of the exosome production promoter of the present invention is oral administration, it is not particularly limited as long as oral administration is possible, and specific examples thereof include foods and drinks and drugs for internal use.
本発明のエクソソーム産生促進剤を飲食品の製剤形態にする場合、本発明のエクソソーム産生促進剤をそのまま、または他の食品素材や添加成分と組み合わせて所望の形態に調製すればよい。このような飲食品としては、一般の飲食品のほかに、特定健康保険用食品、栄養補助食品、機能性食品、病者用食品等が挙げられる。これらの飲食品の形態として、特に限定されないが、具体的には、カプセル剤（ソフトカプセル剤、ハードカプセル剤）、錠剤、下流剤、粉剤、ゼリー剤、リポソーム製剤等のサプリメント、栄養ドリンク、果汁飲料、炭酸飲料、乳酸飲料等の飲料；団子、アイス、チョコレート、グミ、キャンディー等の嗜好品；等が例示される。これらの飲食品のなかでも、好ましくは飲料、サプリメント、より好ましくは飲料、カプセル剤が挙げられる。 When the exosome production promoter of the present invention is used in the form of a food or drink product, the exosome production promoter of the present invention may be prepared in a desired form as it is or in combination with other food materials or additive ingredients. Examples of such foods and drinks include foods for specific health insurance, dietary supplements, functional foods, foods for sick people, etc. in addition to general foods and drinks. The form of these foods and drinks is not particularly limited, and specifically, supplements such as capsules (soft capsules, hard capsules), tablets, downstream agents, powders, jellies, liposome preparations, nutritional drinks, fruit juice beverages, Examples include drinks such as carbonated drinks and lactic acid drinks; luxury goods such as dumplings, ice, chocolate, gummi, and candy. Among these foods and beverages, beverages and supplements are preferable, and beverages and capsules are more preferable.
本発明のエクソソーム産生促進剤を内服用医薬品の製剤形態にする場合、本発明のエクソソーム産生促進剤を、そのまま又は他の添加成分と組み合わせて所望の形態に調製すればよい。このような内服用医薬品としては、具体的には、ドリンク剤、カプセル剤（ソフトカプセル剤、ハードカプセル剤）、錠剤、顆粒剤、粉剤、ゼリー剤、シロップ剤、リポソーム製剤等が挙げられる。これらの内服用の医薬品の中でも、好ましくはカプセル剤、ドリンク剤が挙げられる。 When making the exosome production promoter of the present invention into a pharmaceutical preparation for internal use, the exosome production promoter of the present invention may be prepared in a desired form as it is or in combination with other additive components. Specific examples of such pharmaceuticals for internal use include drinks, capsules (soft capsules, hard capsules), tablets, granules, powders, jellies, syrups, liposome preparations and the like. Among these medicines for internal use, capsules and drinks are preferable.
本発明のエクソソーム産生促進剤が飲食品又は内服用医薬品の製剤形態である場合、有効成分であるスフィンゴイド塩基の含有量としては、エクソソームの産生が促進される有効量である限り特に限定されず、製剤形態に応じて適宜設定すればよいが、例えば、０．１〜２０質量％等が挙げられ、好ましくは０．５〜１０質量％、より好ましくは１〜５質量％が挙げられる。 When the exosome production promoter of the present invention is in the form of a food or drink or a pharmaceutical product for internal use, the content of the sphingoid base that is an active ingredient is not particularly limited as long as it is an effective amount that promotes exosome production. However, 0.1-20 mass% etc. are mentioned, for example, Preferably it is 0.5-10 mass%, More preferably, 1-5 mass% is mentioned.
本発明のエクソソーム産生促進剤は、神経細胞におけるエクソソームの産生促進に基づいて、症状が軽減又は改善させる疾患に対して適用することができる。また、本発明のエクソソーム産生促進剤は、アミロイドβタンパク質の蓄積に起因する疾患の予防や改善目的で使用することができる。 The exosome production promoter of the present invention can be applied to diseases whose symptoms are reduced or ameliorated based on the promotion of exosome production in nerve cells. Further, the exosome production promoter of the present invention can be used for the purpose of preventing or ameliorating diseases caused by accumulation of amyloid β protein.
例えば、神経細胞から分泌されたエクソソームは、アルツハイマー病の発症原因の一つであるアミロイドβタンパク質の蓄積を抑制することができるので、神経細胞におけるエクソソームの産生を促進すると、アルツハイマー病の発症を抑制したり、症状を軽減したりすることができると考えられる。つまり、本発明のエクソソーム産生促進剤は、アルツハイマー病の発症を抑制したり、症状を軽減したりすることができ、アルツハイマー病予防剤としても好適に使用することができる。更に、本発明のエクソソーム産生促進剤は、アミロイドβタンパク質の蓄積が原因で引き起こされる、記憶障害、認知機能低下等の抑制の目的で使用することができる。 For example, exosomes secreted from nerve cells can suppress the accumulation of amyloid β protein, which is one of the causes of Alzheimer's disease. Therefore, promoting the production of exosomes in neurons suppresses the development of Alzheimer's disease. It is thought that symptom can be reduced. That is, the exosome production promoter of the present invention can suppress the onset of Alzheimer's disease or reduce symptoms, and can also be suitably used as an agent for preventing Alzheimer's disease. Furthermore, the exosome production promoter of the present invention can be used for the purpose of suppressing memory impairment, cognitive decline, etc. caused by accumulation of amyloid β protein.
また、神経細胞におけるエクソソームの産生を促進することによって症状が改善され得る他の疾患としては、例えば、パーキンソン病、前頭側頭型変性症、ポリグルタミン病等の神経変性疾患等が挙げられる。 Examples of other diseases whose symptoms can be improved by promoting exosome production in nerve cells include neurodegenerative diseases such as Parkinson's disease, frontotemporal degeneration, and polyglutamine disease.
本発明のエクソソーム産生促進剤の適用量としては、特に限定されず、製剤形態、用途、投与対象、期待される効果等に応じて適宜設定するとよい。例えば、本発明のエクソソーム産生促進剤を経口摂取する場合、摂取量としては、スフィンゴイド塩基量で成人一日当たり０．１〜５ｍｇ、好ましくは０．１〜１ｍｇが挙げられる。本発明のエクソソーム産生促進剤は、一日あたりの量が前述の範囲となるように、１回又は数回に分けて投与してもよい。 The application amount of the exosome production promoter of the present invention is not particularly limited, and may be appropriately set according to the preparation form, use, administration target, expected effect, and the like. For example, when the exosome production promoter of the present invention is orally ingested, the ingestion amount is 0.1 to 5 mg, preferably 0.1 to 1 mg per day for an adult in the amount of sphingoid base. The exosome production promoter of the present invention may be administered once or divided into several times so that the amount per day falls within the above-mentioned range.
次に、本発明を実施例によりさらに詳細に説明するが、本発明は、これらの例によって何ら限定されるものではない。 EXAMPLES Next, although an Example demonstrates this invention still in detail, this invention is not limited at all by these examples.
［実験例１］
１．スフィンゴイド塩基の調製
こんにゃく抽出物（株式会社ダイセル提供）を１０倍量のアセトンで処理し、単純脂質を除去した後、適量のクロロホルム／メタノール／０．４Ｍ ＫＯＨ水溶液（クロロホルム：メタノール：０．４Ｍ ＫＯＨ水溶液の容積比１：１：１）の混合溶媒中でグリセロ脂質をケン化分解し、シリカゲルカラムクロマトグラフィーによりグルコシルセラミドを精製した。精製したグルコシルセラミドを適量のジオキサン／１０%水酸化バリウム水溶液（ジオキサン：１０%水酸化バリウム水溶液の容積比１：１）中で１１０℃で加熱分解し、スフィンゴイド塩基を遊離させた。スフィンゴイド塩基は最終的にＯＤＳカラムを装備したHPLCで精製し、スフィンゴシン、４−トランス，８−シス−スフィンガジエニン、及び４−トランス，８−トランス−スフィンガジエニンをそれぞれ得た。
[Experimental Example 1]
1. Preparation of sphingoid base A konjac extract (provided by Daicel Corporation) was treated with 10 times the amount of acetone to remove simple lipids, and then an appropriate amount of chloroform / methanol / 0.4M KOH aqueous solution (chloroform: methanol: 0.4M). Glycerolipid was saponified and decomposed in a mixed solvent having a KOH aqueous solution volume ratio of 1: 1: 1), and glucosylceramide was purified by silica gel column chromatography. The purified glucosylceramide was thermally decomposed at 110 ° C. in an appropriate amount of dioxane / 10% barium hydroxide aqueous solution (dioxane: 10% barium hydroxide aqueous solution volume ratio 1: 1) to liberate sphingoid base. The sphingoid base was finally purified by HPLC equipped with an ODS column to obtain sphingosine, 4-trans, 8-cis-sphingadienin, and 4-trans, 8-trans-sphingadienin, respectively.
２．ヒト神経由来細胞へのスフィンゴイド塩基処理と培養上清からのエクソソーム回収
ヒト神経芽細胞腫SH-SY5Y細胞（ATCCから購入）を使用し、実験を行った。細胞を、培地（５０％Ｈａｍ’ｓ Ｆ１２／５０％Ｅ−ＭＥＭ、１０％仔牛血清含有）と共に６ウェルプレートに２．２×１０7ｃｅｌｌｓ／ｗｅｌｌとなるよう播種し、３７℃で２４時間培養した後、スフィンゴシン(Avanti Polar Lipids社製)、４−トランス，８−シス−スフィンガジエニン、及び４−トランス，８−トランス−スフィンガジエニンを、３％ウシ血清アルブミン（ＢＳＡ）を含む血清不含培地（５０％Ｈａｍ’ｓ Ｆ１２／５０％Ｅ−ＭＥＭ）に懸濁して、ウェル中での終濃度が５μＭとなるように各ウェルに添加した。また、スフィンゴイド塩基の代わりにジメチルスルホキシド（ＤＭＳＯ）をウェル中での終濃度が５μＭとなるように各ウェルに添加した場合とコントロールとした。
2. Experiments were conducted using sphingoid base treatment to human nerve-derived cells and exosome recovery from culture supernatant using human neuroblastoma SH-SY5Y cells (purchased from ATCC). Cells were seeded in a 6-well plate with medium (50% Ham's F12 / 50% E-MEM, 10% calf serum) to 2.2 × 10 7 cells / well and cultured at 37 ° C. for 24 hours. After that, sphingosine (Avanti Polar Lipids), 4-trans, 8-cis-sphingadienin, and 4-trans, 8-trans-sphingadienin contain 3% bovine serum albumin (BSA). It was suspended in serum-free medium (50% Ham's F12 / 50% E-MEM) and added to each well so that the final concentration in the well was 5 μM. Further, dimethyl sulfoxide (DMSO) instead of sphingoid base was used as a control when added to each well so that the final concentration in the well was 5 μM.
スフィンゴイド塩基を添加して２４時間経過後に培養上清（１．５ｍＬ／ｗｅｌｌ）を回収し、その中のエクソソームを回収した。エクソソームの回収には遠心法を用いた。具体的には、回収した培養上清について、２，０００ｇ １０分、１０，０００ｇ ３０分、１００，０００ｇ ７０分の段階的な遠心を行い、沈渣としてエクソソームを回収した。 After adding sphingoid base, 24 hours later, the culture supernatant (1.5 mL / well) was recovered, and the exosomes were recovered. Centrifugation was used to collect exosomes. Specifically, the collected culture supernatant was subjected to stepwise centrifugation at 2,000 g for 10 minutes, 10,000 g for 30 minutes, and 100,000 g for 70 minutes to collect exosomes as sediment.
３．エクソソーム粒子数測定
遠心法で回収したエクソソームを、ＨＥＰＥＳ／ＫＣｌバッファーに懸濁した後、ナノパーティクルアナライザーｑＮａｎｏ（Ｉｚｏｎ社）で粒子数を測定した。測定値は、ＢＣＡ法で算出した由来細胞のタンパク質量（ｍｇ）当たりのエクソソーム粒子数粒子数として表示した。エクソソーム粒子数は、測定を２回行って得られた各値の平均値である。また、エクソソーム粒子数は、コントロールを１００％とした場合の比率（％ ｏｆ ｃｏｎｔｏｒｏｌ）として算出した。また、得られた値について、Ｏｎｅ−ｗａｙ ＡＮＯＶＡ法による有意差検定（***Ｐ＜０．００１、**Ｐ＜０．０１、*Ｐ＜０．０５）を行った。
3. Exosome collected by exosome particle number measurement centrifugation was suspended in HEPES / KCl buffer, and then the number of particles was measured with Nanoparticle Analyzer qNano (Izon). The measured value was expressed as the number of exosome particles per protein amount (mg) of the derived cells calculated by the BCA method. The number of exosome particles is an average value of values obtained by performing measurement twice. The number of exosome particles was calculated as a ratio (% of control) when the control was 100%. Moreover, about the obtained value, the significant difference test ( *** P <0.001, ** P <0.01, * P <0.05) by the One-way ANOVA method was performed.
４．結果
結果を図１及び２に示す。図１には、スフィンゴシンを添加した場合のエクソソーム粒子数を示し、図２には、４−トランス，８−シス−スフィンガジエニン、及び４−トランス，８−トランス−スフィンガジエニンンを添加した場合のエクソソーム粒子数を示す。
4). The results are shown in FIGS. FIG. 1 shows the number of exosome particles when sphingosine is added, and FIG. 2 shows the addition of 4-trans, 8-cis-sphingadienin and 4-trans, 8-trans-sphingadienin. The number of exosome particles is shown.
図１から明らかなように、スフィンゴシンを添加した場合、神経細胞におけるエクソソーム粒子数がコントロールに対して増加する傾向が認められ、スフィンゴシンがエクソソームの産生を促進し得ることが確認された。 As is apparent from FIG. 1, when sphingosine was added, the number of exosome particles in the nerve cells tended to increase relative to the control, and it was confirmed that sphingosine could promote exosome production.
また、図２から明らかなように、４−トランス，８−シス−スフィンガジエニン、及び４−トランス，８−トランス−スフィンガジエニンンの添加により、神経細胞におけるエクソソーム粒子数がコントロールに対し、統計的にも有意に増加することが確認された。 In addition, as is apparent from FIG. 2, the addition of 4-trans, 8-cis-sphingadienin and 4-trans, 8-trans-sphingadienin reduces the number of exosome particles in neurons relative to the control. It was confirmed that the increase was statistically significant.
以上の結果から、スフィンゴイド塩基には神経細胞におけるエクソソームの産生を促進する作用があり、特に、４−トランス，８−シス−スフィンガジエニン、及び４−トランス，８−トランス−スフィンガジエニンンは当該作用が卓越していることが明らかとなった。 From the above results, sphingoid bases have the effect of promoting exosome production in nerve cells, and in particular, 4-trans, 8-cis-sphingadienin, and 4-trans, 8-trans-sphingadie. Ninning was found to have an excellent effect.
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| WO2022259526A1 (en) | 2021-06-11 | 2022-12-15 | 株式会社フルステム | Exosome production promoting agent and exosome production promoting method |
| WO2022259525A1 (en) | 2021-06-11 | 2022-12-15 | 株式会社フルステム | Exosome recovery method |
| KR20220167354A (en) | 2021-06-11 | 2022-12-20 | 풀스템 코., 엘티디. | Exosome recovery method |
| KR20220167383A (en) | 2021-06-11 | 2022-12-20 | 풀스템 코., 엘티디. | Method of collecting for exosome |
| US11613734B2 (en) | 2021-06-11 | 2023-03-28 | Fullstem Co., Ltd. | Method of collecting for exosome |
| KR20240000582A (en) | 2021-06-11 | 2024-01-02 | 풀스템 코., 엘티디. | Exosome production promoter and method for promoting exosome production |
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