JP2023534496A - ペディオコッカスイノピナタス又はそれに由来する細胞外小胞体を有効成分として含む脳疾患の治療用組成物 - Google Patents
ペディオコッカスイノピナタス又はそれに由来する細胞外小胞体を有効成分として含む脳疾患の治療用組成物 Download PDFInfo
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Classifications
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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Abstract
Description
(a)ペディオコッカスイノピナタス菌株を準備する段階;及び
(b)前記菌株を培養液で培養する段階。
(i)本発明は、ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を有効成分として含む脳疾患の予防、改善又は治療用組成物を提供する。
1.菌株の準備
ペディオコッカスイノピナタスLB-400菌株(受託番号KCCM12653P、韓国微生物保存センター)を実験に使用したものであり、MRSブロス(broth)培地に1%接種して24時間培養した後、3500rpmで10分間4℃遠心分離を行って菌体をPBS(Phosphate-buffered saline)に洗浄し、残っているMRSブロス培地を除去した。その後、PBSに均質化されている菌体をそれぞれ、適合な実験に使用された細胞の10倍(以下、MOI 10)、1倍(MOI 1)、0.1(MOI 0.1)倍の割合で細胞に処理できるように準備した。
ペディオコッカスイノピナタスLB-400菌株の培養液を使用したものであり、MRSブロス培地に1%接種して24時間培養した後、3500rpmで10分間4℃遠心分離を行って菌体をPBS(Phosphate-buffered saline)に洗浄し、残っているMRSブロス培地を除去した。その後、1×109CFU/mL菌数でDMEM(Dulbecco’s Modified Eagle’s Medium,Welgene、韓国)培地に接種して30℃、24時間培養した後に8,000rpmで5分間4℃遠心分離して培養液を得、pHを7.2に補正した後、シリンジフィルター(Syringe filter)(0.2μm細孔径)を用いて濾過した後に使用した。
ペディオコッカスイノピナタスLB-400菌株の培養液から100kDa、300kDa遠心濾過機(Centrifugal Filter)で分画した後、最終に0.22μm濾過(filteration)処理して各測定サンプルを確保した。Nanosight LM 10(Malvern Panalytical,韓国)を用いて各分画別に細胞外小胞体の含有量を比較した結果、カットオフ(cuff off)値が、0~100、100~300、300以上が各分画当たり35%、35%、30%の含有量比であり、4×107粒子/mlを含有していることを確認した。
測定のために準備されたペディオコッカスイノピナタスLB-400菌株を用いて0.1M PB(Phosphate-buffer)に30分間2回洗浄を行った後、OsO4に追加固定を2時間行い、50~100%エタノールに順次に脱水作用を行った。その後、臨界点乾燥装置(Critical point Dryer)(LEICA EM CPD 300)を用いて十分に乾かした後、イオンスパッタ(ion sputter)(LEICA EM ACE 600)でプラチナコーティング(Platinum coating)作業をし、SEM(Field emission scanning electron microscopy,FE-SEM MERLIN,ZEISS)撮影した(図1)。
抗神経炎症反応実験のためにイファ女子大学校から分譲された小膠細胞(microglia)BV-2細胞を培養するためにDMEMを使用し、5% FBS(Fetal bovine serum)(Gibco,BRL)及び1%ペニシリン/ストレプトマイシン(Welgene,韓国)を用いて5% CO2を含む培養器で37℃条件で培養した(図2)。
神経細胞保護効能実験のために神経芽細胞腫(neuroblastoma)SH-SY5Y細胞(cat.22266,韓国細胞株銀行)を培養するためにDMEM/F-12を使用し、10% FBS(Fetal bovine serum)(Gibco,BRL)及び1%ペニシリン/ストレプトマイシン(Welgene,韓国)を用いて5% CO2を含む培養器で37℃条件で培養した(図3)。
ペディオコッカスイノピナタスLB-400菌株培養液(図4A)及び前記LB-400菌株に由来する細胞外小胞体(EV、図4B)の神経炎症抑制効果を確認するために、BV-2神経小膠細胞の数を2×105cell/mLにし、LB-400の培養液を培地に希釈して培地の総容量の5%と20%に希釈して使用したし、LPS(Lipopolysaccharide)は培地に希釈して5ng/mlを使用した(図4)。前記EVは1×107粒子/ml容量で処理し、対照群(con)はEV処理量と同量のPBSを処理した。
ペディオコッカスイノピナタスLB-400菌株の神経細胞保護効能を確認するために、SH-SY5Y神経芽腫細胞株の数を1×106cell/mLにし、LB-400の菌体を細胞対比で10倍(MOI 10)、1倍(MOI 1)、0.1倍(MOI 0.1)を処理し、EVは4×106粒子/mlを処理した。H2O2(Hydrogen peroxide)(図6)、6-OHDA(6-hydroxydopamine)(図7)は培地に希釈して200μMで使用した。対照群(con)は、菌体及びEV処理量と同量のPBSを処理した。
ペディオコッカスイノピナタスLB-400菌株培養液の神経細胞保護効能を確認するために、SH-SY5Y神経芽腫細胞の数を1×106cell/mLにし、LB-400の培養液を培地に希釈して培地の総容量の5%に希釈して使用し、H2O2(Hydrogen peroxide)(図8)は培地に希釈して200μMで使用したし、Aβ(Amyloid-beta)(図9)は、37℃で7日間培養後に培地に希釈して25μMで使用した。
NO(Nitric Oxide)の生産量を定量的に測定する方法によって上澄液100μlとグリース試薬(Griess reagent)(1%スルファニルアミド、0.1%N-(1-ナフチル)-エチレンジアミンジクロリド、2.5% H3PO4)100μlで1:1反応後に、波長が540nmであるMultiskan sky(Thermoscientific,米国)96ウェルマイクロプレート分光光度計(microplate spectrophotometer)を用いて値を測定した(図4)。
生きている細胞を比色法(colorimetric method)で確認できる定量的測定方法である。細胞にQuanti-Max WST-8を各ウェルに10μlずつ処理後に1時間CO2培養器で培養して反応させた後、波長が450nmであるMultiskan sky(Thermoscientific,米国)96ウェルマイクロプレート分光光度計を用いて値を測定した(図5)。
トリパンブルー染色を用いて生きている細胞を測定した。ペディオコッカスイノピナタスLB-400菌株に由来する細胞外小胞体(EV)と6-OHDAを細胞に処理した後、細胞懸濁液をトリパンブルー染色薬と1:1で混ぜて2分間反応後に、位相差顕微鏡下で細胞数を確認した。総細胞数において染色されていない細胞数のパーセントを計算して細胞生存率を測定した(図7B)。
ペディオコッカスイノピナタスLB-400培養液及び菌株に由来する細胞外小胞体(EV)の記憶力又は認知改善効果を試験するために、アセチルコリンエステラーゼ(AChE)の活性阻害効果を試験した(図10)。アセチルコリンエステラーゼ(AChE)に対する阻害効果は、AChE活性測定キット(AChE activity assay kit)(sigma)を用いて確認した。96ウェルプレートにAChE(5unit/ml)、それぞれの試料(LB-400培養液又はEV)及び緩衝溶液を入れた後、さらに反応混合物(reaction mixture)を入れて常温で10分間反応させた。AChE酵素活性は、試料を添加しない対照群(con)の吸光度を100%にしてマイクロプレートリーダー(Microplate Reader)を用いて410nmで吸光度を測定した。対照群(con)は、LB-400培養液及びEVを用いた試験においてそれぞれ同量の培地及びPBSを処理したものを表す。LB-400の培養液は、総容量の1%と2%に希釈して使用し、EVは4×105粒子/ml(1X)、2×106粒子/ml(5X)を処理した。
ペディオコッカスイノピナタスLB-400菌株に由来する細胞外小胞体(EV)の炎症性サイトカインIL-1βの生成減少効果を確認した(図11)。前記試験は、細胞にLPSとEV処理後に得た細胞上澄液を使用してIL-1β ELISAキット(invitrogen)のプロトコル通りに実験を行った後、IL-1β生成量は、Multiskan sky(Thermoscientific,米国)マイクロプレート分光光度計を用いて450nmで吸光度を測定した。LPS(Lipopolysaccharide)は、培地に希釈して200ng/mlを使用した。EVは、1×107粒子/mlを処理し、対照群(con)は、EV処理量と同量のPBSを処理した。
ペディオコッカスイノピナタスLB-400菌株に由来する細胞外小胞体(EV)の抗炎症性サイトカインIL-10生成増加効果を確認した(図12)。前記試験は、細胞にLPSとEV処理後に得た細胞上澄液を使用してIL-10ELISAキット(MyBioSource)のプロトコル通りに実験を行った後、IL-10生成量はMultiskan sky(Thermoscientific,米国)マイクロプレート分光光度計を用いて450nmで吸光度を測定した。LPS(Lipopolysaccharide)は培地に希釈して200ng/mlを使用した。EVは、1x107粒子/mlを処理し、対照群(con)は、EV処理量と同量のPBSを処理した。
受託番号:KCCM12653P
受託日:20200114
Claims (25)
- ペディオコッカスイノピナタス(Pediococcus inopinatus)、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する(derived)細胞外小胞体(Extracellular vesicle);を有効成分として含む脳疾患の予防又は改善用食品組成物。
- 前記ペディオコッカスイノピナタスは、ペディオコッカスイノピナタスWIKIM27(Pediococcus inopinatus WIKIM27;受託番号KCCM12653P)であることを特徴とする、請求項1に記載の食品組成物。
- 前記脳疾患は、パーキンソン病(Parkinson’s disease)、アルツハイマー病(Alzheimer’s disease)、ハンチントン病(Huntington’s disease)、ルゲリック病(amyotrophic lateral sclerosis)、クロイツフェルトヤコブ病(Creutzgeldt-Jacob disease)、脳卒中(stroke)、多発性硬化症(multiple sclerosis)、学習障害(learning disorder)、認知障害(cognitive impairment)、神経炎症、神経細胞損傷及び記憶力損傷からなる群から選ばれる1以上の疾患であることを特徴とする、請求項1に記載の食品組成物。
- 前記脳疾患は、神経炎症であることを特徴とする、請求項3に記載の食品組成物。
- 前記脳疾患は、神経細胞損傷であることを特徴とする、請求項3に記載の食品組成物。
- 前記脳疾患は、記憶力損傷であることを特徴とする、請求項3に記載の食品組成物。
- 前記脳疾患は、学習障害、認知障害又はアルツハイマー病であることを特徴とする、請求項3に記載の食品組成物。
- 前記組成物は、アセチルコリンエステラーゼ(AChE)の活性を阻害することを特徴とする、請求項1に記載の食品組成物。
- ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を有効成分として含む脳疾患の予防又は治療用薬剤学的組成物。
- 前記ペディオコッカスイノピナタスは、ペディオコッカスイノピナタスWIKIM27(Pediococcus inopinatus WIKIM27;受託番号KCCM12653P)であることを特徴とする、請求項9に記載の薬剤学的組成物。
- 前記脳疾患は、パーキンソン病、アルツハイマー病、ハンチントン病、ルゲリック病、クロイツフェルトヤコブ病、脳卒中、多発性硬化症、学習障害、認知障害、神経炎症、神経細胞損傷及び記憶力損傷からなる群から選ばれる1以上の疾患であることを特徴とする、請求項9に記載の薬剤学的組成物。
- 前記脳疾患は、神経炎症であることを特徴とする、請求項11に記載の薬剤学的組成物。
- 前記脳疾患は、神経細胞損傷であることを特徴とする、請求項11に記載の薬剤学的組成物。
- 前記脳疾患は、記憶力損傷であることを特徴とする、請求項11に記載の薬剤学的組成物。
- 前記脳疾患は、学習障害、認知障害又はアルツハイマー病であることを特徴とする、請求項11に記載の薬剤学的組成物。
- 前記組成物は、アセチルコリンエステラーゼ(AChE)の活性を阻害することを特徴とする、請求項11に記載の薬剤学的組成物。
- 治療学的有効量のペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を対象体(subject)に投与する段階を含む脳疾患の予防又は治療方法。
- 前記脳疾患は、パーキンソン病、アルツハイマー病、ハンチントン病、ルゲリック病、クロイツフェルトヤコブ病、脳卒中、多発性硬化症、学習障害、認知障害、神経炎症、神経細胞損傷及び記憶力損傷からなる群から選ばれる1以上の疾患であることを特徴とする、請求項17に記載の方法。
- ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を含む組成物の治療用途(for use in therapy)。
- 前記治療用途は、脳疾患の治療用途であることを特徴とする、請求項19に記載の用途。
- 下記の段階を含む脳疾患の予防、改善又は治療用組成物の製造方法:
(a)ペディオコッカスイノピナタス菌株を準備する段階;及び
(b)前記菌株を培養液で培養する段階。 - ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体を準備する段階を含む脳疾患の予防、改善又は治療用組成物の製造方法。
- ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を有効成分として含む飼料添加剤。
- ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を有効成分として含む飼料。
- ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物;又は、前記ペディオコッカスイノピナタス、その培養物、破砕物、抽出物又は発酵物に由来する細胞外小胞体;を含む食品発酵用乳酸菌スターター。
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PCT/KR2021/009001 WO2022015033A1 (ko) | 2020-07-14 | 2021-07-13 | 페디오코쿠스 이노피나투스 또는 이로부터 유래된 세포밖 소포체를 유효성분으로 포함하는 뇌질환의 치료용 조성물 |
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