JP6117915B2 - ミゾコウジュの抽出物またはその分画物を有効成分として含む、stat3媒介性疾患の予防または治療用医薬組成物 - Google Patents
ミゾコウジュの抽出物またはその分画物を有効成分として含む、stat3媒介性疾患の予防または治療用医薬組成物 Download PDFInfo
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Description
前記ミゾコウジュ抽出物またはその分画物については前述した通りである。より具体的には、本発明の抽出物または分画物は、STAT3媒介性疾患の予防または改善を目的として、好ましくは、自己免疫疾患、炎症性疾患または代謝性疾患の予防または改善を目的として食品組成物に添加することができる。
前記ミゾコウジュ抽出物またはその分画物については、前述した通りである。より具体的には、本発明の組成物は、STAT3媒介性疾患の予防または改善を目的として、好ましくは、自己免疫疾患、炎症性疾患または代謝性疾患の予防または改善を目的として、医薬部外品組成物に添加することができる。
実施例1−1:ミゾコウジュ抽出物の製造
ミゾコウジュは水できれいに洗浄して、日陰で乾燥した後、ワーリングブレンダーで粉末化した。粉末化されたミゾコウジュ8kgをエタノール50Lに入れ、室温で7日間冷浸抽出した後、ろ紙(Whatman社、USA)で減圧濾過した後、ろ過抽出物は真空回転濃縮機を用いて室温でエタノール溶媒を除去し、その後抽出残渣としてミゾコウジュ粗抽出物1.1kgを得た。
前記粗抽出物から活性分画物を分離するために、ミゾコウジュ粗抽出物を水1Lに懸濁した後、同量の酢酸エチルを加え、混合して分画した。前記プロセスを3回繰り返して水可溶性分画物1Lおよび酢酸エチルの可溶性分画物3Lを得た後、前記酢酸エチル可溶性分画物を減圧濃縮して、酢酸エチル可溶抽出物145gを得た。残りの水可溶性分画物を減圧濃縮して35gを得て、これを水分画物として使用した。
ミゾコウジュ抽出物および分画物の、IL-6によって誘導されるSTAT3の転写活性抑制効果を測定するために、下記のような実験を行った。
Hep3B細胞(ATCC HB-8064)にSTAT3レポーター遺伝子を含むpSTAT3-LucとpcDNA3.1(+)(Clontech laboratories社、Palo Alto、CA)をリポフェクタミンプラス(lipofectamine plus、Invitrogen社、Carlsbad、CA、USA)を用いてトランスフェクションした。トランスフェクションした後、さらに2日後、ハイグロマイシンを前記トランスフェクションした細胞に100μg/mLの濃度で処理してルシフェラーゼを安定して発現するクローンを得た。このクローンからルシフェラーゼが安定して発現されるか否かについては、ルシフェラーゼアッセイによって確認した。
前記トランスフェクションした細胞をDMEM(GIBCO 119950965)培地で無血清培養(serum starvation)して試料を下記のように1時間処理した後、10ng/mL IL-6(R&D system社、USA)を添加して12時間培養した。
1:陰性対照群(非処理群)、
2:陽性対照群(IL-6 10ng/mL)、
3:抽出物および分画物(1、3、6、10μg/mL)および
4:ゲニステイン処理群(100μM)
前記反応した細胞をPBSで洗浄した後、50μLの溶解緩衝液(luciferase assay system、promega社、USA)を入れ、20分間攪拌した後、30〜100μLのルシフェラーゼ基質(luciferase assay system、promega社、USA)を入れて発色の程度をルミノメーター(EG&G BERTHOLD、USA)を用いて5分以内で測定した。実験の結果、ミゾコウジュエタノール抽出物および酢酸エチル分画物は、濃度依存的にSTAT3ルシフェラーゼ活性を阻害した。具体的には、ミゾコウジュエタノール抽出物はIL-6によって誘導されるSTAT3ルシフェラーゼ活性を10、6、3、1μg/mLでそれぞれ88%、73%、48%、23%阻害し、酢酸エチル分画物は、6、3、1μg/mLでそれぞれ100%、98%、72%阻害した(図1)。
6ウェルプレートに5X105細胞/ウェルでHep3B、U266細胞を分注し、80%の密度で培養皿いっぱいに培養した後、無血清培地に交換してさらに12時間培養し、下記のように試料を60分間処理した。
1:陰性対照群(非処理群)、
2:陽性対照群(IL-16 10ng/mL)、
3:抽出物および分画物(10、30、60μg/mL)、および
4:ゲニステイン処理群(100μM)
その後、20ng/mLの濃度のIL-6を処理して20分間反応させた後、40μLの溶解緩衝溶液([pH8、20mM Tris-HCl、137mM NaCl、10%グリセロール、1% Triton X-100、1mM Na3VO4、2mM EDTA、1mM PMSF、20mM ロイペプチン、20m/mL アプロチニン(Sigma社、USA)を用いて細胞を溶解させた後、遠心分離(13000g、15分)してタンパク質が溶解している上澄み液を得た。タンパク質の濃度はDCタンパク質検査キット(Bio-Rad社、USA)を用いて定量し、4〜12%のSDS-ポリアクリルアミドゲル(SDS−PAGE)にタンパク質をロードして175mAで2時間電気泳動した。電気泳動終了後、ゲルのタンパク質をPVDFメンブレン(Westran S、孔径0.2、Whatman社、USA)を用いて35Vで90分間転写した。転写したメンブレンをTris-緩衝溶液(T-TBS;50mM Tri-HCl、pH7.6、150mM NaCl、0.2%トウイーン-20、5%スキムミルク;Sigma社、USA)を用いて室温で1時間ブロッキングし、T-TBSで5回洗浄した。前記メンブレンに一次抗体としてphospho-STAT3、phospho-JAK2およびphospho-ERK(1:1000希釈)のポリクロナール抗体を4〜12時間処理した。 T-TBSで5回洗浄した後、二次抗体としてHRP結合抗マウス抗体(1:5000希釈)および抗ウサギ抗体(1:1000希釈)を1時間反応させた。T-TBSで洗浄した後、暗室でECLキット(Amersham社、USA)を用いてフィルムを現像した。その結果、ミゾコウジュエタノール抽出物および酢酸エチル分画物がIL-6によって誘導されたSTAT3、JAK2およびERKのリン酸化を阻害したことが確認された(図2〜4)。
6ウェルプレートに5 X104細胞/ウェルの濃度でHep3B細胞を分注し、80%の密度で培養皿いっぱいに培養した後、無血清培地に交換してさらに12時間培養して、下記の通り試料を60分間処理した。
1:陰性対照群(非処理群)、
2:陽性対照群(IL-16 10ng/ mL)、および
3:抽出物および分画物(10、30、60μg/ mL)
その後、20ng/mLの濃度のIL-6を処理して6時間反応させた後、細胞をチューブに集め、遠心分離して培地を除去し、PBSで1回洗浄した後、RNeasy Mini 溶出クリーンアップキット(RNeasy Mini Elute Cleanup kit)を用いてRNAを抽出した。 RNAの濃度と純度は、2100バイオアナライザーシステム(Agilent Technologies社)で測定し、Maxime RT PreMix(ランダムプライマー、iNtRON Biotechnology社)を使用してcDNAを合成した。
ミゾコウジュ抽出物が、2型コラーゲン(bovine typeIIcollagen)によって誘導されるリウマチ性関節炎を抑制し、リウマチ性関節炎の治療効果を有するか否かを測定するために、次のような実験を行った。
リウマチ性関節炎は、自己免疫疾患の一種で、関節の滑液膜に慢性的に肥大および炎症反応が起こることによって、軟骨と骨の破壊による関節の破壊と変形を特徴とする慢性炎症性疾患である。本発明では、このようなリウマチ性関節炎の代表的な動物モデルとして、コラーゲン誘導関節炎(collagen-induced arthritis; CIA)モデルを用いて、本発明のミゾコウジュ抽出物のコラーゲン誘導関節炎に対する治療効果を確認した。
実験終了後、マウスを犠牲死させた後、開腹して腹腔内から採血し、その後これを3,000rpmで15分間遠心分離して血清を分離した。免疫グロブリンG1とG2a測定は、BD Biosciences社のELISAキットを使用して、次のように測定した。
ミゾコウジュ抽出物のアトピー性皮膚炎抑制効果を測定するために、次のような実験を行った。
アトピー性皮膚炎を誘導するために、チリダニ抽出物(チリダニ抽出物、コナヒョウダニ抽出物、DFE)とDNCB(2,4-ジニトロクロロベンゼン)をマウスに使用し、アトピー性皮膚炎誘導過程は、図14に示した。
1:陰性対照群(非処理群)、
2:陽性対照群(DFE/ DNCB20μg/mL)および
3:抽出物(20、100mg/kg)
溶液を塗る前のマウスの耳に絆創膏を使用して、同じ力と回数でストリッピング(striping)を3、4回繰り返した後、DFEを10mg/mLで溶かした溶液を、毎週木曜日にマウスの耳の前/後面に20μgずつ塗布した。また、AOO(アセトン/ オリーブオイル、1:3)に溶かしたDNCB(1%)は、毎週月曜日にマウスの耳の前/後面に20μgずつ塗布し、火曜日と金曜日毎に耳の厚さを測定した。このように、DFEとDNCBをマウスの皮膚に塗布すると、耳の厚さが増加するようになるが、このような耳の厚さの増加をミゾコウジュ抽出物が抑制できるか否かを確認した。
4週間の実験終了後、マウスを犠牲死させてから採血し、これを3,000rpmで15分間遠心分離して血清を分離した。免疫グロブリンEと免疫グロブリンG2aの測定は、BD Biosciences社のELISAキットを用いて、次のように測定した。
エッフェンドルフチューブに血清を取り、PBSで100分の1に希釈した後、0.1M HCl 450μLと60%過塩素酸溶液50μLを混合した後、遠心分離(400g、20分)した。次いで、上澄み液800μLを取り、5M NaOH溶液500μL、蒸留水3mL、n-ブタノール10mL、NaCl 1.2gを混合した試験管に入れ、これを振とうした後、遠心分離(500g、10分)を行った。前記試験管でブタノール層8 mLを取り、0.1M HClを3mL、n-ヘプタン10mLを加えて振とうして再び遠心分離(500g、10分)を行って得られた水層2mLに1M NaOH400μL、1%の o-フタルアルデヒド溶液(Sigma社)100μLを加えて混合し、2分間放置した後、発光波長(emission)438nm、励起波長(excitation)353 nmにおいて、蛍光強度を蛍光分析装置(RF-5301 PC、Shimadzu社)を用いて測定した。
実験終了後、マウスを犠牲死させた後、耳の組織を切り取り、耳組織内の炎症誘発性サイトカインの発現を測定するために、Maxime RT PreMix(ランダムプライマー、iNtRON Biotechnology社)を用いてcDNAを合成した。各チューブ当り2μLのcDNA、1μLのセンスおよびアンチセンスプライマー溶液(0.4μM)、12.5μLのSYBR Premix Ex Taq(Takarabio社)、および9.5μLのdH2Oを共に混合して、全25μLになるようにした。 TNF-α、IFN-γ、IL-4、IL-13、IL-31、IL-17 mRNAの発現の程度は、TP850ソフトウェアを使用してリアルタイムPCRにより測定した。
Claims (5)
- ミゾコウジュ(Salvia plebeia R. Br.)の抽出物またはその分画物を有効成分として含む、STAT3媒介性疾患の予防または治療用医薬組成物であって、
前記STAT3媒介性疾患が、骨粗しょう症である、治療用医薬組成物。 - 前記組成物が、錠剤、丸剤、散剤、顆粒剤、カプセル剤、懸濁剤、内用液剤、乳剤、シロップ剤、無菌水溶液、非水性溶剤、凍結乾燥製剤および坐剤からなる群から選択されるいずれか一つの剤形で製造されることを特徴とする、請求項1に記載の医薬組成物。
- 請求項1又は2項に記載の医薬組成物を、ヒト以外のSTAT3媒介性疾患の疑いのある個体に投与する段階を含む、STAT3媒介性疾患の治療方法であって、
前記STAT3媒介性疾患が、骨粗しょう症である、STAT3媒介性疾患の治療方法。 - ミゾコウジュの抽出物またはその分画物を有効成分として含む、STAT3媒介性疾患の予防または改善用の食品医薬組成物であって、
前記STAT3媒介性疾患が、骨粗しょう症である、食品医薬組成物。 - ミゾコウジュの抽出物またはその分画物を有効成分として含む、STAT3媒介性疾患の予防または改善用の医薬部外品医薬組成物であって、
前記STAT3媒介性疾患が、骨粗しょう症である、医薬部外品医薬組成物。
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WO2017014502A1 (ko) * | 2015-07-17 | 2017-01-26 | 한국생명공학연구원 | 해당화 꽃 추출물을 유효성분으로 포함하는 il-6 매개성 질환의 예방 또는 치료용 약학적 조성물 |
KR101940042B1 (ko) | 2017-05-11 | 2019-01-21 | 주식회사 케이티앤지 | 곰보배추 및 홍삼으로 구성된 조합 추출물을 유효성분으로 함유하는 호흡기염증 질환의 예방 및 치료용 조성물 |
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