JP4886087B2 - 免疫刺激及び転移阻害用の発酵植物性材料 - Google Patents
免疫刺激及び転移阻害用の発酵植物性材料 Download PDFInfo
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- JP4886087B2 JP4886087B2 JP2011168726A JP2011168726A JP4886087B2 JP 4886087 B2 JP4886087 B2 JP 4886087B2 JP 2011168726 A JP2011168726 A JP 2011168726A JP 2011168726 A JP2011168726 A JP 2011168726A JP 4886087 B2 JP4886087 B2 JP 4886087B2
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Description
小麦胚芽の実験室スケール発酵
33.3gの酵母(サッカロマイセス・セレビジア)及び1000mlの飲料水の懸濁物をフラワー品質に至るまで粉砕した100gの新鮮な小麦胚芽に加えた(ハンガリー国基準MSZ−081361−80に従い)。この混合物を30℃で18時間シェーカーの中で振盪させた。その間、この発酵液は発泡状となり、そしてそのもとの容積の約3倍にまで達した。発酵の後、この混合物を3000/min で15分遠心分離した。煮沸及び冷却の後、その上清液を凍結乾燥により乾かし、そして得られる凍結乾燥材料を次に使用するまで冷凍庫(−10℃)に保存した。得られる凍結乾燥品の2.6DMBQ含有量は0.4mg/g乾燥材料(0.04重量%)であった。
小麦胚芽の大量スケール発酵
フラワー品質(ハンガリー国基準に従う)にまで粉砕した300kgの小麦胚芽及び100kgの酵母を5m3 の発酵槽に入れ、そして飲料水を容量が4000lとなるまで加えた。発酵時間は18時間とし、その間連続的な通気(0.5lのエアー/発酵液l/分)及びゆっくりとした撹拌(30回転/分)を利用した。発泡を防ぐため、1l/m3 のひまわり油をこの混合物に加えた。発酵の後、通気及び撹拌を止め、そして発酵液をスクリューデカンターで、次いでセパレーターで、そして最後に繊維フィルターの付いたフィルタープレスで分離した。補助物質として、10kgの濾過用パーライト/m3 を加えた。この発酵液を厳格に濾過し、そしてその厳格さを顕微鏡によりチェックした。濾過した発酵液は細胞を事実上含まず、このことは10回の検査視野当り最大で1個の酵母細胞しか見つからないことを意味する。約1.5重量%の乾燥材料を含む得られる発酵液を真空コンデンサーの中で40〜50℃の温度でエバポレーションし、そして真空を破った後、大気圧で約15分煮沸した。その後、この溶液の乾燥材料含有量を決定し、そしてまず熱湯に溶かし、次いで冷却したマルトデキストリンをその溶液の乾燥材料含有量が約30重量%となるように加えた。しかる後この溶液を剪断ノズル回転スプレードライヤーの中でスプレー乾燥し、その出口温度は90℃とした。得られる最終製品(粉末)は本発明に係る発酵植物性材料60重量%及びマルトデキストリン40重量%を含んだ。2.6DMBQ含有量は下記の実施例に記載の方法に従うHPLCによる決定に従い、0.4mg/g乾燥材料であった。
本発明に係る材料の特性決定
本発明に係る材料を、その2.6DMBQ含有量を決定することにより、及びいわゆるフィンガープリントクロマトグラフィーにより2通りの方法で特性決定した。共にHPLCクロマトグラフィーを使用する。
サンプルの調製
分析の前に、凍結乾燥品中のベンゾキノン濃度を高めることが必要となった。そのため、この凍結乾燥品を蒸留水でそのもとの濃度にまで希釈した(1重量%の乾燥材料含有量)〔0.5gの凍結乾燥品、50mlの蒸留水〕。その溶液を3×25mlのクロロホルムで3回抽出した。クロロホルム相に残った最終的な水分を無水硫酸Naで除去した。濾過後、クロロホルム相をエバポレーションし、残りのクロロホルムを5mlの最終容量となるように加えた。このサンプルをHPLC分析の際にインジェクションした。
利用したHPLC装置はBeckman モデル114Mポンプ、Labor Mim UV, Merck-Hitachi-DAD mod. 4500 ダイオードアレー検出器、及びWaters 740型インテグレーターユニットから成る。測定のためにChromsil C18(250×4mm)10μlカラムを使用した。UV検出は290nmの周波数で実施し、流速は2ml/minとした。利用する溶出液の組成は下記の通りとした:Na2 HPO4 25mmol、NaH2 PO4 25mmol、Na2 EDTA 25mmol、NH2 OH・HCl 20mmol、10容量%のメタノール、pH=6.05。
サンプルの調製
96容量%のエタノール50mlを5gのスプレー乾燥材料(実施例2に記載の通りに調製)に加えた。この混合物を50℃の温度で30分、200/min で振盪した。しかる後、この混合物を濾過し、エバポレーション乾燥し、そして残留材料を10mlのメタノールに溶かした。濾過溶液をカラムにインジェクションした。
HPLC法
上記のHPLC装置、カラム及び条件をここでも利用したが、ただし溶出液の組成は下記の通りとした:Na2 HPO4 1.25mmol、NaH2 PO4 1.25mmol、Na2 EDTA 1.25mmol、NH2 OH・HCl 2.50mmol、5容量%のメタノール。
本発明に係る材料の分解を2,6−ジメトキシ−p−ベンゾキノンの濃度の変化を介してチェックした。我々は3通りの温度(室温20℃、40℃及び60℃)での貯蔵実験を実施した。凍結乾燥品(約1g)を密閉した試験管に保存した。実験期間は8週間とし、別々の温度で保存した3系列全てから採取したサンプルに対して毎週3回の平行測定を行った。ベンゾキノン誘導体の定量分析をHPLCにより実施した。
効果についての試験
実施例1に記載の通りにして調製した凍結乾燥品及び実施例2に記載の通りにして調製したスプレー乾燥材料の双方を結果について試験した。0.4mg/g乾燥材料の2.6DMBQ含有量及び図2に示す通りのHPLC曲線を有する標準化乾燥材料を使用した。双方の材料は同じ結果を示した。従って、本発明に係る材料は以降、単純に凍結乾燥品と呼ぶ。この凍結乾燥品についての生物学的及び毒素学的試験の結果を以下に、免疫再構築並びに腫瘍増殖及び転移阻害効果を特に強調しながら説明する。
この試験のため、マウス又はラットの中で増殖中の以下の注入可能な腫瘍タイプを利用した:ルイス肺癌腫(マウス肺癌)の高度転移形成変異体(3LL−HH)、B16マウス黒色腫及びHCR−25ヒト結腸癌腫異種移植片。
上記の試験が本発明に係る凍結乾燥品が悪性腫瘍の転移を著しく減少できることを明確に示したため、転移形成の様々な段階に対するこの製品の効果も調べた。転移の形成は複数の段階から成り、それにおいては一次腫瘍の細胞の増殖及びアポプト−シス活性の他に、腫瘍細胞の接着能力及び生体の腫瘍細胞に対する防御メカニズムが役割を果たしている。in vitro試験において、細胞増殖並びにアポプト−シス及び接着に対する当該凍結乾燥品の効果を研究した。
腫瘍細胞の接着力を96穴マイクロプレートで試験した。凍結乾燥品の用量は300,3000及び30000μg/mlとした。RPMI培地を血清の非存在下及び10%のFCSの存在下の双方で使用した。評価はSRBアッセイに基づく比色方法により実施した(Mossmann. T.: J.Immunol.Neth. 65, 55-63/1983)。この試験は培養物の総タンパク質含有物のスルホローダミンB発色を基礎とし、吸収は光度計で570nmで測定した。図4は2回の瞬間しか示さないが、凍結乾燥品の効果が適切に表わされている。もし凍結乾燥品の用量が3000μg/ml又はその10倍高いなら、それは血清の存在下及び非存在下の双方で腫瘍細胞の接着力を劇的に低下させた。もし用量が300μg/mlなら、かかる効果は観察できなかった。
この試験において腫瘍細胞を処理の24時間前に96穴マイクロプレートに入れた。適当な用量の凍結乾燥品による処理の後、細胞に対する増殖活性を処理の24,48及び72時間後にSRBアッセイによっても試験した。反復試験の結果は900〜15,000μg/mlの範囲における処理の効果として、腫瘍細胞が単層の表層に移動し(トリパンブルー色素排除法により示される)、そして死ぬことを示した(Kaltenbach, J.P.ら、: Exp.Cell Res. 15, 112-117 (1985))(図5)。
本発明に係る凍結乾燥品の効果を2通りのモデルで試験した。一連の試験において、凍結乾燥品で処理した動物の脾臓から獲得した単核細胞の出芽形質転換(blast transformation)の可能性を試験し、一方で、同種移植皮膚モデルでは、マウスの背領域に移植した皮膚の総結合を調べた。
本発明に係る凍結乾燥品による処理は免疫反応において重要な役割を果たすT−リンパ球の出芽形質転換を著しく高める。これは下記の実験により示される。
ベンゾキノンがフリーラジカルの形成に対する周知の効果を有するため、本発明に係る凍結乾燥品のラジカル結合活性も試験した。スーパーオキサイド(SSA)及びヒドロキシル基結合(OH−SA)の双方を電子スピン共鳴法により測定した。この凍結乾燥品は有意義なSSA活性を有し、1mgのクリーンラジカル結合活性は5.64μgのスーパーオキサイドジスムターゼ(SOD)活性に相当する。この凍結乾燥品はOH−SA活性は有さないが、過酸化水素/Feヒドロキシル基形成系は崩壊し、従ってそれはいわゆる非錯形成活性を有すると考えられうる。
77日間の毒性試験をRegistry of Industrial Toxicology Animal-data (RITA)(Exp.Toxic.Pathol. 47, 247-266 (1995))の推奨に従いF344ラット及びC57B10マウスに対して実施した。これらの動物を毎日3g/kg(0.6g/mlの水性懸濁物)の用量で処理した。処理の間、動物の体重変化、究極的な病理生理学的変化、動物の自発的死を観察した。試験を終了したら、心臓、肺、胸腺、脾臓、肝臓、腎臓及び精巣の重量を測定し、そしてRITAに規定の24の器官を病理検査した。自発的死は観察されず、動物の体重はコントロールグループのそれと似たように変化した。試験が終了時に、様々な器官の重量はコントロールと比べて変化していなかった。処理動物の病理進行の間にこの凍結乾燥品を原因とする変化は観察されなかった。
Claims (8)
- 小麦胚芽をサッカロマイセス・セレビジア〔Saccharomyces cerevisiae〕と水性媒体の中で発酵させることにより得られる発酵液に由来する免疫刺激及び転移阻害用の発酵乾燥植物性材料。
- HPLCによる決定に従い、2,6−ジメトキシ−p−ベンゾキノン含有量が0.12〜0.52mg/g乾燥材料であり、そして2−メトキシ−p−ベンゾキノン含有量が0.05〜0.28mg/g乾燥材料である請求項1記載の材料。
- 2,6−ジメトキシ−p−ベンゾキノン含有量が0.4mg/g乾燥材料である、請求項2記載の材料。
- 免疫刺激及び転移阻害用の発酵乾燥植物性材料を製造するための方法であって、粉砕小麦胚芽を水性媒体の中でサッカロマイセス・セレビジアの存在下で発酵させ、そしてその発酵液を分離し、厳格に濾過し、エバポレーションし、煮沸し、そしてそのまま又は補助乾燥物質の存在下で乾燥することを特徴とする方法。
- 前記発酵を約30℃の温度で約18時間、連続的に通気及び撹拌しながら実施する、請求項4記載の方法。
- 前記乾燥をマルトデキストリンの存在下で実施する、請求項5記載の方法。
- 小麦胚芽の水性媒体の中でのサッカロマイセス・セレビジアの存在下での発酵により得られる発酵液に由来する乾燥材料を活性成分として含む免疫刺激及び転移阻害用医薬製品。
- 請求項1〜3のいずれか1項記載の乾燥植物性材料の、免疫刺激及び転移阻害用医薬組成物の製造における使用。
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HU9701392A HUP9701392D0 (en) | 1997-08-13 | 1997-08-13 | Immunostimulating and methastasis-inhibiting plant extract, pharmaceutical compositions containing thereof, process for production of plant extract and use for production of immunostimulating and metastasis-inhibiting pharmaceutical composition thereof |
HUP9701392 | 1997-08-13 | ||
HU9801797A HU223344B1 (hu) | 1997-08-13 | 1998-08-05 | Immunstimuláns és metasztázist gátló fermentált, szárított anyag, ezt tartalmazó gyógyszerkészítmények, eljárás az előállítására és alkalmazásai |
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JP2009170505A Expired - Fee Related JP4861458B2 (ja) | 1997-08-13 | 2009-07-21 | 免疫刺激及び転移阻害用の発酵植物性材料 |
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EP (1) | EP1003536B1 (ja) |
JP (3) | JP4387586B2 (ja) |
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CN (1) | CN1192099C (ja) |
AT (1) | ATE227580T1 (ja) |
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BR (1) | BR9811936B1 (ja) |
CA (1) | CA2300208C (ja) |
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DK (1) | DK1003536T3 (ja) |
EA (1) | EA003090B1 (ja) |
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ES (1) | ES2186208T3 (ja) |
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HK (1) | HK1033097A1 (ja) |
HU (1) | HU223344B1 (ja) |
ID (1) | ID25515A (ja) |
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Families Citing this family (22)
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CN1235931C (zh) | 1998-04-24 | 2006-01-11 | Ck威特科有限公司 | 使用硅烷或硅烷处理的填料的粉末涂料或粘合剂 |
FR2815822B1 (fr) * | 2000-10-30 | 2004-08-27 | Roquette Freres | Additif carbone pour fermentations alimentaires et compositions alimentaires le contenant |
FR2834718B1 (fr) * | 2002-01-15 | 2004-12-24 | Cognis France Sa | Substances actives cosmetiques et/ou pharmaceutiques |
US20040043084A1 (en) * | 2002-05-02 | 2004-03-04 | George Cioca | Method of enhancing biological activity of plant extracts |
HUP0202638A3 (en) * | 2002-08-09 | 2007-08-28 | Hidvegi Mate Dr | Use of fermented wheat-germ extract for preparation of antiphlogistic compositions |
BR0215836A (pt) * | 2002-08-13 | 2005-06-07 | Mate Hidvegi | Uso de germe de trigo fermentado na alimentação e na prática veterinária |
EA009170B1 (ru) * | 2002-08-13 | 2007-10-26 | Мате Хидвеги | Применение ферментированных зародышей пшеницы в ветеринарной практике |
WO2007140277A1 (en) | 2006-05-24 | 2007-12-06 | Vitality Concepts Corporation | Method for embedding and targeted release of micronutrients in activated dietary fibers |
US7365102B1 (en) | 2007-02-26 | 2008-04-29 | Delphi Technologies, Inc. | Process for pre-reforming hydrocarbon fuels |
HUP0900614A2 (en) | 2009-09-29 | 2011-05-30 | Mate Dr Hidvegi | Preparation comprising dehydrated, fermented material with amorphous crystaline structure and process for its production |
WO2010100515A2 (en) * | 2009-03-06 | 2010-09-10 | Hidvegi Mate | Fractions of wheat germ ferment |
JPWO2011083768A1 (ja) * | 2010-01-08 | 2013-05-13 | 住友ベークライト株式会社 | 細胞凝集塊形成用培養容器 |
US20120164132A1 (en) * | 2010-08-02 | 2012-06-28 | Mate Hidvegi | Anticancer and immunomodulating molecules and fractions containing said molecules, and process for preparing said fractions and said molecules from fermented vegetal material, and their uses |
GB201108560D0 (en) | 2011-05-20 | 2011-07-06 | 3 Ch Ltd | Use of fermented wheat germ in the treatment of inflammatory bowel disease |
GB201110746D0 (en) | 2011-06-23 | 2011-08-10 | Biropharma Uk Ltd | Wheat germ derived material |
US11090353B2 (en) | 2013-04-22 | 2021-08-17 | David Wales | Gluten-free grain-concentrate substitute for fermented wheat germ drug product and method preparation |
US11129389B2 (en) | 2013-04-22 | 2021-09-28 | David Wales | Gluten-free grain-concentrate substitute for fermented wheat germ food product and method of preparation |
JP2017033691A (ja) * | 2015-07-30 | 2017-02-09 | 三菱自動車工業株式会社 | 車載電池パック、リチウムイオン補充装置、及びリチウムイオン補充方法 |
CN107455551A (zh) * | 2016-06-06 | 2017-12-12 | 铜陵安尔生物科技有限公司 | 麦胚发酵黄酮提取物及其制备方法与在动物饲养中的应用 |
JP6739774B2 (ja) * | 2018-06-25 | 2020-08-12 | 学校法人立命館 | がんの治療、予防、改善、抑制又は転移抑制用組成物 |
HUE065477T2 (hu) | 2018-11-27 | 2024-05-28 | Gyula Bencze | Fermentált búzacsíra élelmiszer termék helyettestésére alkalmas gluténmentes gabonakoncentrátum és eljárás annak elõállítására |
WO2022091075A1 (en) * | 2020-11-01 | 2022-05-05 | Aili Life Sciences Ltd. | Combination compositions of probiotics with fermented wheat germ extract and uses thereof |
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JPS63230774A (ja) * | 1987-03-19 | 1988-09-27 | Seinosuke Ueda | 紫青系色素の製法 |
JP2618286B2 (ja) * | 1990-10-25 | 1997-06-11 | 免疫代謝薬製造株式会社 | 降圧酵母製剤及びその製造法 |
KR940001544B1 (ko) * | 1990-11-21 | 1994-02-24 | 강권중 | 은행잎을 위시한 천연약재로부터 미생물의 공서배양에 의한 건강식품의 제조방법 |
JP3296433B2 (ja) * | 1990-11-30 | 2002-07-02 | 日本食品化工株式会社 | 酒類の製造法 |
US5231017A (en) | 1991-05-17 | 1993-07-27 | Solvay Enzymes, Inc. | Process for producing ethanol |
EP0625187B1 (en) * | 1992-02-06 | 1997-04-23 | Bio-Technical Resources, Inc. | Concentrated beer flavor product |
KR100340091B1 (ko) * | 1993-08-09 | 2002-09-27 | 베르찌 이스트반 | 킬러세포개재세포용해를위한암세포감작용약학적제제 |
JPH07155136A (ja) * | 1993-12-03 | 1995-06-20 | Nippon Mektron Ltd | 植物発酵エキス粉末の製造方法 |
EP1090553A3 (en) * | 1993-12-24 | 2001-04-18 | Dsm N.V. | Dry yeast compositions |
ES2163430T3 (es) * | 1994-01-06 | 2002-02-01 | Hyd Kutato Fejleszto Ktf | Productos alimenticios para la prevencion del desarrollo de enfermedades y procedimiento para su preparacion. |
JP3471879B2 (ja) * | 1994-01-20 | 2003-12-02 | ルードヴィッヒ インスティテュート フォー キャンサー リサーチ | セリンキナーゼ活性の抑制方法、pi3−キナーゼのサブユニット間の結合活性の調整方法、pi3−キナーゼのサブユニット結合抗体、この抗体を生成するハイブリドーマ細胞系、核酸分子、プラスミド、アゴニスト、アンタゴニスト、pi3−キナーゼ活性を抑制するサブユニット結合分子、サブユニットの存在検出方法、pi3−キナーゼ活性の抑制剤製造方法、およびpi3−キナーゼ活性の抑制剤 |
JP2875739B2 (ja) * | 1994-04-27 | 1999-03-31 | エーザイ株式会社 | NFκB活性阻害剤 |
DK0684306T4 (da) * | 1994-05-27 | 2004-05-10 | Agrano Ag | Fremgangsmåde til fremstilling af en biomasse ud fra et kornsubstrat, anvendelse af de ved fremgangsmåden opnåede produkter, samt brödbagningsgærstof |
JP4167733B2 (ja) * | 1996-12-16 | 2008-10-22 | 花王株式会社 | NF−κB活性化抑制剤 |
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