JP2013534517A - ラマリンを含有する炎症疾患または免疫疾患の予防または治療用医薬組成物 - Google Patents
ラマリンを含有する炎症疾患または免疫疾患の予防または治療用医薬組成物 Download PDFInfo
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Abstract
Description
完全凍結乾燥され、粉砕された地衣類ラマリナテレブラタのサンプル672gをメタノール:水(5L、80:20v/v)混合溶液を利用して3回繰り返して抽出した後、凍結乾燥を経て83gの粗抽出物を得た。前記粗抽出物を1Lの蒸溜水に溶かした後、1Lのノルマルヘキサン(n-hexane)とクロロホルム(CHCl3)で抽出してノルマルヘキサン12.7gとクロロホルム(CHCl3)9.1g、水溶性抽出物61.0gを得た。前記水溶性抽出物は、DPPH自由ラジカルに対して高い活性IC50=9μg/mLを示した。前記水溶性抽出物中5gを利用して、自動化されたMPLC(mild pressure liquid chromatography)を適用させ、0%、20%、40%、60%、80%、100%メタノール−水物混合溶液で段階的にグラジエント溶媒システムを実施した。0%メタノール−水混合溶液に溶かした抽出物は、DPPH自由ラジカルに対して高い活性IC50=8μg/mLを示し、その中100mg部分をC18ODSカラム(250cm×10cm)を用いてセミ分取逆相HPLC(semi-preparative reverse phase HPLC)で分析した。用いられた溶媒システムは、0.1%ギ酸を混合した水に対して0%メタノール−水物混合溶液の場合、10分、20%メタノール−水物混合溶液は20分、100%メタノール溶液に対しては30分以上行った。流速は2mL/分とした。
LPS誘導NO発生量に対するラマリンの前処理効果を調べるために、マウス大食細胞株RAQ264.7(ATCC、Rockville、MD、US)を利用して検証した。細胞は、RPMI1640培地(GIBCO、Grand Island、NY、US)に2mMLグルタミン、100IU/mLペニシリン、100μL/mLストレプトマイシン、及び10%熱不活性化ウシ血清アルブミン(FBS:Carlsband、US)を供給して培養した。また、37℃、5%CO2、湿った空気条件で培養され、一週間に二回培地を交換した。
LPS誘導iNOS発生量に対するラマリンの前処理効果を調べるために、mRNA発生量をRT−PCRで調べ、蛋白質発生量をウェスタンブロット(Western Blot)分析で調べた。NO産生減少は、iNOS生成抑制によるものだからである。RT−PCRは、実施例2のようにLDSとラマリンを処理した後、Trizol(Introvigen、US)を用いて培養された細胞の全てのRNAを回収した。その後、全てのRNAをPLATINUM Taq kit(Introvigen、US)を利用して、Superscript one step RT−PCRを行って増幅した。PCR結果は、1.2%アガロースゲルに掛けてEtBrで染色した。GAPDHは、対照群として調べた。PCRに用いたプライマーの配列は下記のようになる。iNOS−Fは、5'−AGA CTG GAT TTG GCT GGT CCC TCC−3'(配列番号1)、iNOS−Rは、5'−AGA ACT GAG GGT ACA TGC TGG AGC−3'(配列番号2)、GAPDH−Fは、5’−CCA TGG AGA AGG CTG GGG−3'(配列番号3)、GAPDH−Rは、5'−CAA AGT TGT CAT GGA TGA CC−3'(配列番号4)のようになった。
TLR4(Toll-like Receptor 4)信号伝達は、炎症反応の誘導の中枢的役割を果たしていると把握されており、LPSはTLR4が認識するリガンドであるため、ラマリン前処理が、TLR4の発現に及ぼす影響を分析するために、表面発現程度、mRNA量及び蛋白質量を測定した。TLR4実験方法は下記のとおりである。
その結果、図4に示したように、ラマリンを前処理した実験群においては、LPS−誘導TLR4の表面発現が顕著に減った。また、TLR4のmRNA及び蛋白質が、共に減少したことを確認した(図5、6)。
NF−κBはiNOS発現に最も重要な転写因子であるため、ラマリン前処理が、NF−κBに及ぼす効果を検討するために、ルシフェラーゼ発現量を観察した。NF−κBの発現を確認するための一つの方法が、ルシフェラーゼアッセイである。ルシフェラーゼアッセイは、プロモーター活性化の有無を確認する実験である。特定遺伝子のプロモーターの部分をルシフェラーゼを有するベクターにライゲーションさせてそのプロモーターが活性化されると、発光する原理を利用した。
p38MAPK、ERK1/2及びJNKキナーゼ経路は、炎症反応中間段階を調節する信号伝達段階として知られているため、p38MAPK、ERK1/2及びJNK発現レベルを分析して、ラマリン前処理の効果を調べてみた。実験プロトコールは、前記実施例3と同じであり、蛋白質量を分析する方法はウェスタンブロットを用いて、そのプロトコールも実施例3と同じであった。
前記実施例2−6では、in vitro状態でラマリンの処理効果を分析した。実施例7では生きているラットを利用して実際ラマリンに抗炎症効果があるか否かを実験した。従って、各々賦形剤(対照群)、ラマリン50mg/kg、ラマリン100mg/kg、インドメタシン(抗炎症剤、陽性対照群)を投与させた後、IDSの一種のカラギナンを利用して炎症反応を起こして、抗炎症効果を、足浮腫の大きさ増加比から測定した。前記一般式(1)の構造を持つラマリン(Ramalin)または薬学的に許容可能なその塩を有効性分として含有する炎症疾患または免疫疾患の予防または治療用医薬組成物:
Claims (9)
- 下記一般式(1)の構造を持つラマリン(Ramalin)、または、薬学的に許容可能なその塩を有効性分として含有する炎症疾患または免疫疾患の予防または治療用医薬組成物:
- 前記炎症疾患、または免疫疾患は、アトピー皮膚炎、関節炎、尿道炎、膀胱炎、動脈硬化症、アレルギー疾患、鼻炎、喘息、急性痛み、慢性痛み、歯周炎、歯肉炎、炎症性腸疾患、痛風、心筋梗塞、鬱血性心不全、高血圧、狭心症、胃潰瘍、脳梗塞、ダウン症候群、多発性硬化症、肥満、糖尿病、認知症、うつ病、統合失調症(精神分裂症)、結核、睡眠障害、敗血症、火傷、すい臓炎、パーキンソン病、脳卒中、発作による脳損傷、または自己免疫疾患であることを特徴とする請求項1に記載の予防または治療用医薬組成物。
- 前記組成物は、医薬組成物の製造に通常用いられる適切な担体、賦形剤または、希釈剤を追加で含むことを特徴とする請求項1に記載の予防または治療用医薬組成物。
- 前記組成物は、抗ヒスタミン剤、消炎鎮痛剤、抗癌剤及び抗生剤からなる群から選択された一つ以上の薬剤と共に製剤化したり、併用して用いることを特徴とする請求項1に記載の予防または治療用医薬組成物。
- 下記一般式(1)の構造を持つラマリンを有効性分として含有する炎症疾患または免疫疾患の予防または改善用機能性食品:
- 前記炎症疾患、または免疫疾患は、アトピー皮膚炎、関節炎、尿道炎、膀胱炎、動脈硬化症、アレルギー疾患、鼻炎、喘息、急性痛み、慢性痛み、歯周炎、歯肉炎、炎症性腸疾患、痛風、心筋梗塞、鬱血性心不全、高血圧、狭心症、胃潰瘍、脳梗塞、ダウン症候群、多発性硬化症、肥満、糖尿病、認知症、うつ病、統合失調症(精神分裂症)、結核、睡眠障害、敗血症、火傷、すい臓炎、パーキンソン病、脳卒中、発作による脳損傷、または自己免疫疾患であることを特徴とする請求項5に記載の予防または改善用機能性食品。
- 下記一般式(1)の構造を持つラマリンを有効性分として含有する機能性化粧品:
- 前記機能性化粧品は、炎症疾患改善用であることを特徴とする請求項7に記載の機能性化粧品。
- 前記炎症疾患は、アトピー皮膚炎症または火傷炎症であることを特徴とする請求項8に記載の機能性化粧品。
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JP2017533261A (ja) * | 2014-10-24 | 2017-11-09 | コリア インスティテュート オブ オーシャン サイエンス アンド テクノロジーKorea Institute Of Ocean Science And Technology | ラマリンを含有する退行性脳疾患の予防または治療用組成物 |
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KR101290745B1 (ko) | 2010-06-03 | 2013-07-29 | 한국해양과학기술원 | 라말린을 함유하는 염증질환 또는 면역질환의 예방 또는 치료용 약학 조성물 |
KR101025612B1 (ko) * | 2008-11-10 | 2011-03-30 | 한국해양연구원 | 신규 화합물인 Ramalin 및 그 용도 |
KR101182334B1 (ko) | 2010-07-14 | 2012-09-20 | 한국해양연구원 | 라말린의 합성방법 |
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KR101326256B1 (ko) | 2012-02-28 | 2013-11-11 | 한국해양과학기술원 | 라말린을 함유하는 간섬유화 및 간경화의 예방 또는 치료용 약학 조성물 |
KR101429242B1 (ko) * | 2012-03-19 | 2014-08-12 | 한국해양과학기술원 | 다공성 매트릭스를 이용한 라말린의 안정화 방법 및 안정화된 라말린 용액 |
KR101637240B1 (ko) * | 2014-10-24 | 2016-07-08 | 한국해양과학기술원 | 라말린을 함유하는 퇴행성 뇌질환의 예방 또는 치료용 조성물 |
KR101642291B1 (ko) * | 2015-01-19 | 2016-07-26 | 한국해양과학기술원 | 라말린을 유효성분으로 함유하는 암의 예방 또는 치료용 조성물 |
KR101951788B1 (ko) * | 2017-09-21 | 2019-02-25 | 한국해양과학기술원 | 라말린을 유효성분으로 함유하는 대장암 예방 또는 치료용 조성물 |
KR102393317B1 (ko) * | 2017-10-31 | 2022-05-03 | 광주과학기술원 | 글루탐산 유도체 및 이를 포함하는 조성물 |
AU2019245521A1 (en) * | 2018-03-29 | 2020-11-12 | S.I.S Shulov Innovative Science Ltd. | Pharmaceutical compositions for inhibiting inflammatory cytokines |
KR102509430B1 (ko) * | 2020-11-11 | 2023-03-13 | 한국해양과학기술원 | 남극 지의류 아만디네아 추출물의 제조방법 및 아만디네아 추출물을 포함하는 조성물 |
CN114480625A (zh) * | 2022-03-04 | 2022-05-13 | 浙江省立同德医院 | Mapk信号通路抑制在慢性骨髓炎改善、诊断和治疗中的应用 |
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JP2017533261A (ja) * | 2014-10-24 | 2017-11-09 | コリア インスティテュート オブ オーシャン サイエンス アンド テクノロジーKorea Institute Of Ocean Science And Technology | ラマリンを含有する退行性脳疾患の予防または治療用組成物 |
US9968576B2 (en) | 2014-10-24 | 2018-05-15 | Korea Institute Of Ocean Science And Technology | Composition for preventing or treating neurodegenerative diseases, containing Ramalin |
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WO2011152671A2 (ko) | 2011-12-08 |
WO2011152671A3 (ko) | 2012-03-29 |
EP2578214A4 (en) | 2013-11-20 |
KR20110132938A (ko) | 2011-12-09 |
CN103140222A (zh) | 2013-06-05 |
US20130116324A1 (en) | 2013-05-09 |
KR101290745B1 (ko) | 2013-07-29 |
US9539227B2 (en) | 2017-01-10 |
US20140235719A1 (en) | 2014-08-21 |
EP2578214A2 (en) | 2013-04-10 |
WO2011152671A9 (ko) | 2012-05-24 |
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