JP7396737B2 - ラクトバチルス・パラカゼイ由来細胞外小胞を含む眼疾患の予防または治療用組成物 - Google Patents
ラクトバチルス・パラカゼイ由来細胞外小胞を含む眼疾患の予防または治療用組成物 Download PDFInfo
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Description
本発明は、ラクトバチルス・パラカゼイ由来小胞およびその用途に関する。
本明細書において、「糖尿病性網膜症(diabetic retinopathy)」とは、糖尿病に現れる微細血管合併症の一つであり、高血糖とこれに伴う様々な生化学的な変化によって網膜の血管透過性増加虚血と新生血管生成のような毛細血管の機能的形態学的変化によって発生する。本発明において、前記糖尿病性網膜症は、非増殖性または増殖性網膜症を含んでもよいが、これに制限されるものではない。「非増殖性網膜症」は、網膜の小さい血管が弱くなって血清が漏れたり、血管が詰まって栄養供給が中断される状態をいう。「増殖性網膜症」は、血液循環が悪いところに新生血管が生じることによって、適切な治療を受けなければ、新生血管で発生する出血により5年以内に失明することになることが知られている。
ラクトバチルス・パラカゼイ由来小胞(extracellular vesicle;EV)を分離するために、様々なラクトバチルス・パラカゼイを自体製作した培地に接種し、37℃で200rpmで吸光度OD600nmが1.0~1.5になるまで培養した後に、培地に再接種して培養した。そして、菌体が含まれている培養液を回収して、10,000gで4℃で20分間遠心分離して、菌体が除去された上澄み液を獲得した。獲得した上澄み液は、さらに、0.22μmのフィルターを用いてろ過した。ろ過した上澄み液は、100kDa Pellicon 2 Cassetteフィルターメンブレン(Merck Millipore)とMasterFlex pump system(Cole-Parmer)を用いて50mL以下の体積に濃縮した。濃縮させた上澄み液は、さらに、0.22μmのフィルターを用いてろ過させて、ラクトバチルス・パラカゼイ由来小胞を分離した。上澄み液に含まれているタンパク質の量は、Pierce BCA Protein Assay kit(Thermo Fisher Scientific)を用いて測定した。分離した小胞に対して下記の実験を実施した。
ラクトバチルス由来小胞の経口投与時に薬物動態学的特性を調べるために、蛍光染色試薬であるCy7-NHSで染色した小胞をマウスに経口投与して、投与直前から投与後72時間まで身体の各臓器で発現した蛍光を測定した。
ラクトバチルス・パラカゼイ由来小胞の抗炎症効果を確認するために、マウスマクロファージ(RAW264.7細胞)にラクトバチルス・パラカゼイ由来小胞を各10μg/mlおよび100μg/mlずつ前処理した後、炎症誘導物質であるLPS(Lipopolysaccharide)を100ng/ml処理した後、炎症関連マーカーであるIL-6の分泌量を測定した。また、ラクトバチルス・パラカゼイ由来小胞を経口投与が可能であるかを評価するために、前記小胞に熱処理、酸処理および胆汁処理を行った後、IL-6の分泌量を測定した。
AMPK(AMP-activated protein kinase)シグナルは、自食作用(autophagy)などの機序を通じてエネルギーの枯渇時に発生する代謝障害を抑制する。本発明では、ラクトバチルス・パラカゼイ由来細胞外小胞(MDH-001-CM)を細胞で処理してAMPK活性化に及ぼす影響を評価した。60mmの細胞培養ペトリ皿に細胞を2×106個ずつ分注したDMEM無血清培地を入れて2時間培養した。以後、ラクトバチルス・パラカゼイ由来小胞を0、0.1、1、10μg/mLの濃度で1時間処理し、比較群であるインスリン(1μM)とメトホルミン(50mM)も、1時間処理した。細胞溶解アッセイを進めるために、サンプルを処理したペトリ皿を氷の上に載置し、上澄み液を吸入(suction)した後、冷たいPBSバッファーを5mLずつ入れて、2回洗浄した。溶解バッファー(Lysis buffer)1mLにprotease/phosphatase抑制剤10μLを入れてよく混ぜた後、各ディッシュに細胞溶解バッファー100μLずつを滴下して、5分間氷でインキュベーションした。スクラッパーで細胞を取り外した後、1.5mLマイクロチューブに移して、ボルテックスおよび氷でのインキュベーション過程を各1分ずつ20分間繰り返した。以後、14,000rpm、10分、4℃の条件で遠心分離し、溶解したサンプル上澄み液を新しい1.5mLマイクロチューブ2個にそれぞれ5μL、70μLずつ移した。5μLを移したマイクロチューブは、-20℃に保管し、70μLを移したマイクロチューブには、5Xサンプルバッファーを16.5μL入れた後、100℃で5分間ボイルした。ボイルしたサンプルは、-20℃に保管した。BCA定量分析を進めるために、溶解したサンプル上澄み液5μLずつを入れた1.5mLマイクロチューブは、常温に取り出しておいて、滅菌蒸留水20μLを入れてボルテックスした後、スピンダウンした。ウシ血清アルブミン(BSA)を滅菌蒸留水に2mg/mLの濃度で溶かした後、1/2ずつ希釈して2、1、0.5、0.25、0.125、0.0625、0.03125、0mg/mLのストックを製造した。96ウェルポリスチレンプレートにBSA濃度別に25μLずつ3個のウェルに入れ、溶解したサンプルも25μLずつ1個のウェルに入れた。8mLのBCA Protein Assay Reagent Aと160μLのBCA Protein Assay Reagent Bを混合した後、200μLずつウェルに入れた。37℃インキュベーターで30分間反応させた後に、SpectraMax M3 microplate reader(Molecular Devices,USA)を用いて562nmで吸光度を測定した。ウェスタンブロットのためにTris-glycine SDS-ポリアクリルアミドゲル電気泳動を進める過程で10%ゲルを製造し、各サンプル当たりタンパク質50μgを定量してローディングした。ニトロセルロース膜にトランスファーした後に、5%スキムミルクでブロッキングする過程を経て、AMPKα抗体は1:400、phospho-AMPKα抗体は1:400,β-actin抗体は1:1,000の割合で5%スキムミルクに希釈してメンブレンとともに一晩中混和した。1X PBST(0.05%tween20が入っているPBS)溶液で5分ずつ3回洗った後、抗ウサギIgG、HRP-linked抗体を1:1,000の割合で希釈して1時間メンブレンと混和した。1X PBST溶液で5分ずつ3回洗った後、West-Q Chemiluminescent Substrate Kitのsolution Aとsolution Bを1:1で混ぜた溶液をメンブレンに十分に散布し、Chemidoc機器でバンドを確認した。
酸化ストレスは、加齢黄斑変性(AMD)、早産児網膜症、網膜光損傷、緑内障および白内障のような無数に多くの眼疾患において病理学的観点から重要な役割をするという点は知られている(文献Beatty S., Koh H., Phil M.,Henson D., and Boulton M., “The role of oxidative stress in the pathogenesis of age-related macular degeneration”, Surv. Ophthalmol., 45(2):115-134 (2000) 参照)。
Claims (12)
- ラクトバチルス・パラカゼイ由来小胞を有効成分として含む、眼疾患の予防または治療用薬学的組成物。
- 前記眼疾患は、加齢に伴う眼疾患であることを特徴とする、請求項1に記載の薬学的組成物。
- 前記眼疾患は、炎症性眼疾患であることを特徴とする、請求項1に記載の薬学的組成物。
- 前記眼疾患は、レーバー先天性黒内障(LCA)、スタルガルト病、アッシャー症候群、脈絡膜欠如、錐体桿体または桿体錐体ジストロフィー、繊毛病、ミトコンドリア障害、進行性網膜萎縮症、退行性網膜疾患、加齢黄斑変性(age-related macular degeneration,AMD)、湿性AMD、乾性AMD、地図状萎縮症、家族性または後天性黄斑症、網膜光受容体疾患、網膜色素上皮疾患、糖尿病性網膜症(diabetic retinopathy)、嚢胞様黄斑浮腫、網膜剥離、外傷性網膜損傷、医原性網膜損傷、黄斑円孔、黄斑部毛細血管拡張症、神経節細胞疾患、視神経細胞疾患、緑内障(glaucoma)、白内障(cataract)、視神経症、虚血性網膜疾患、未熟児網膜症、網膜血管閉塞症、家族性細動脈瘤(familial macroaneurysm)、網膜血管疾患、眼血管疾患、緑内障による網膜神経細胞退化および虚血性視神経症からなる群から選ばれた一つ以上であることを特徴とする、請求項1に記載の薬学的組成物。
- 前記炎症性眼疾患は、色素性網膜炎(RP)、結膜炎(conjunctivitis)、強膜炎(scleritis)、角膜炎(keratitis)、虹彩炎(iritis)、ブドウ膜炎(uveitis)、脈絡網膜炎(chorioretinitis)、脈絡炎(choroiditis)、および網膜炎(retinitis)からなる群から選ばれた一つ以上であることを特徴とする、請求項3に記載の薬学的組成物。
- 前記小胞は、平均直径が10~300nmであることを特徴とする、請求項1~5のいずれか一項に記載の薬学的組成物。
- ラクトバチルス・パラカゼイ由来小胞を有効成分として含む、眼疾患の予防または改善用食品組成物。
- ラクトバチルス・パラカゼイ由来小胞を有効成分として含む、眼疾患の予防または改善用医薬部外品組成物。
- ラクトバチルス・パラカゼイ由来小胞を有効成分として含む、眼疾患の予防または改善用吸入用組成物。
- ラクトバチルス・パラカゼイ由来小胞を有効成分として含む、眼疾患治療薬物伝達用組成物。
- ラクトバチルス・パラカゼイ由来小胞の眼疾患の予防または治療薬剤の製造のための使用。
- ラクトバチルス・パラカゼイ由来小胞の眼疾患の予防または治療薬物伝達剤の製造のための使用。
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