JP2022023067A - ハマナスの花抽出物を有効成分として含むil-6媒介性疾患の予防又は治療用薬学的組成物 - Google Patents
ハマナスの花抽出物を有効成分として含むil-6媒介性疾患の予防又は治療用薬学的組成物 Download PDFInfo
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Abstract
Description
細胞で外部の微生物と抗原提示細胞によってCD4+ Tリンパ球の異常な活性化が起こり、これに伴う炎症性サイトカイン(TNF-α、IL-6、IL-12、IL-17、IL-23及びIL-27)が持続的に発現されて誘発される病気で、本発明では、DSS処理によって誘導される炎症性腸疾患の動物モデルで予防又は治療効果を確認した。
イン(TNF-related activation-induced cytokine、TRANCE)、オステオプロテゲリンリガンド(osteoprotegerinligand、OPGL)、及び破骨細胞分化因子(osteoclast differentiation factor、ODF)としても知られている。 RANKLはTNFSF11遺伝子によってコードされるヒトのタンパク質であって、タイプIIの膜タンパク質であり、腫瘍壊死因子(tumor necrosis factor、TNF)スーパーファミリーの一構成として知られている。
ラチンなどが用いられてもよい。
本発明で用語、「動物」は、家畜及びペットを含む概念であり、具体的には、犬、猫などのペットと豚、牛などであってもよいが、これに限定されたものではない。本発明の飼料組成物又は飲用水添加剤には、品質の低下を防止するために添加される結着剤、乳化剤、保存剤などをさらに含んでもよく、効用増大のために添加されるアミノ酸剤、ビタミン剤、酵素剤、プロバイオティクス、香味剤、非タンパク態窒素化合物、ケイ酸塩剤、緩衝剤、着色剤、抽出剤、オリゴ糖などをさらに含んでもよく、その他にも飼料の混合剤などをさらに含んでもよく、これに限定されるものではない。
(実施例)
以下、実施例を挙げて本発明をより詳細に説明する。これらの実施例は、本発明をより具体的に説明するためのもので、本発明の範囲がこれらの実施例に限定されるものではない。
ハマナスの花と果実を水できれいに洗浄して日陰で乾燥した後、ワーリンブランドで粉末化させた。粉末化されたハマナスの花と果実500gをエタノール5lに入れて抽出器により10時間、70℃で抽出した後、ろ紙(ワットマン社、アメリカ)で減圧ろ過した後、ろ過抽出物は、真空回転濃縮機で室温にてエタノール溶媒を除去した後、抽出された残渣としてハマナスの花と果実のエタノール抽出物を得た。また、粉末化されたハマナスの花500gを蒸留水5lに入れ、常温で24時間抽出した後、ろ紙(ワットマン社、アメリカ)で減圧ろ過した後、ろ過抽出物は真空回転濃縮機で室温にて水を除去した後、抽出された残渣としてハマナスの花の水抽出物を収得した。
ハマナスの部位別抽出物のIL-6により誘導されるSTAT3の発現抑制効果を測定するために、次のような実験を行った。
Hep3B細胞(ATCC HB-8064)にpSTAT3-LucとpcDNA3.
1(+)(Clontech laboratories、Palo Alto、CA)をリポフェクタミンプラス(Invitrogen社、Carlsbad、CA、USA)で一緒に形質転換させた。2日後からハイグロマイシン(hygromycin)を処理(100μg/ml)してルシフェラーゼ(luciferase)が安定して発現されるクローン(clone)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は、ルシフェラーゼ分析によって確認した。
前記形質転換した細胞をDMEM(GIBCO 119950965)で無血清培養(serum starvation)し、試料を下記のように1時間処理した後、10ng/mlIL-6(R&D system、USA)を添加して12時間培養した。
2:陽性対照群(IL-6 10ng/ml);
3:抽出物(10、30、60μg/ml)
前記反応した細胞をPBSで洗浄し、50μlの溶解緩衝液(luciferase assay system、promega、USA)を入れて20分間攪拌した後、30-100μlのルシフェラーゼ基質(luciferase assay system、promega、USA)を入れて発色程度をルミノメーター(luminometer; EG&G BERTHOLD、USA)で5分以内に測定した。薬物陽性対照群では、IL-6活性阻害効果を有する化合物であるOleanolic Acid Acetate(OAA)を用いた(非特許文献14)。実験の結果、ハマナスの花エタノール抽出物及び水抽出物は、濃度依存的にSTAT3ルシフェラーゼ活性を阻害し、特に、ハマナスの花抽出物が60μg/mlの時、97.9%の阻害効果が示されるほど顕著な効果があることを確認した。これに対し、ハマナスの果実エタノール抽出物は、ハマナスの花抽出物と比較するとやや弱い活性を示した(図1)。
前記形質転換した細胞を96ウェルプレート(96-well plate)にDMEM(GIBCO 119950965)で無血清培養(serum starvation)して、試料を下記のように処理した後、24時間培養した。
2:陽性対照群(IL-6 10ng/ml);
3:抽出物(10、30、60μg/ml )
24時間を反応した後、MTT溶液(5mg/ml)を20μlずつ各ウェル(well)に入れた後、4時間培養した。培養後、上澄液を除去した後、100μlのDMSOを入れて、MTT反応で生じたホルマザンクリスタル(formazan crystal)を溶かした。その後、発色程度をプレートリーダー(plate reader、Model 680、BIO-RAD)を用いて570nmで吸光度を測定した。実験の結果、ハマナスの花エタノール抽出物では、花の抽出物が60μg/mlのときも、細胞の生存率が80%以上となり、深刻な細胞毒性を示さないが、ハマナスの果実エタノール抽出物の場合は、全体的に細胞毒性が大きいだけでなく、60μg/mlのときに66.8%の生存率を示し、花抽出物より細胞毒性がはるかに大きいことが確認できた(図2)。これにより、ハマナスの花抽出物は、果実抽出物に比べて安全な物質であることが分かり、前記実施例2の結果と組み合わせてハマナス果実抽出物の結果を見ると、前記ハマナスの果実抽出物が、実施例2でのIL-6により誘導されるSTAT3ルシフェラーゼ阻害活性を有することは細胞毒性によって誘導されたものであることを予測できた。
前記実施例2で骨粗しょう症に関連されるIL-6により誘導されたSTAT3転写活性の抑制効果を確認したところ、ハマナスの花エタノール抽出物がより直接的に骨粗しょう症の治療効果を有することを確認した。
、30、10μg/mlで処理した。 4日後、培養した細胞は、TRAP溶液(Sigma Aldrich、USA)で染色して、赤色に染色された細胞を分化した骨破骨細胞と判断した。その結果、ハマナスの花エタノール抽出物は、60、30μg/ml濃度でRANKLによって誘導される破骨細胞の分化を抑制する活性が優れていた。これに対し、ハマナスの果実エタノール抽出物は、破骨細胞の分化抑制活性が微々たることを確認した(図3)。
ハマナスの花エタノール抽出物の骨粗しょう症誘導抑制の効果を確認するために、炎症性骨粗しょう症のマウスモデルを作成した。7週齢C57BL/6雌マウスの頭蓋骨の皮下部分にLPS 25mg/kgを1週間に1回ずつ、計3回にわたって皮下注射した。実験群は、PBS、LPS、LPS+ アレンドロネート(2mg/kg)、LPS+ハマナスの花エタノール抽出物(100mg/kg、300mg/kg、600mg/kg)の6グループに分けた。PBS群は、LPSを投与してない正常対照群、残りのグループはLPS誘導骨粗しょう症のグループであり、骨粗しょう症の治療剤であるアレンドロネート(alendronate)投与群は、陽性対照群及びハマナス試験群は、4週間、1日1回、それぞれの薬物を経口投与した。
ハマナスの花エタノール及び水抽出物の炎症性腸疾患の抑制効果を確認するために、炎症性腸疾患のマウスモデルを作成した。4週齢のICR雄マウス(オリエントバイオ購入)を12時間、暗光周期(dark-light cycle)に適応させ、実験開始前の7日間の適応期をもった。対照群のグループを除いて、残りのグループは蒸留水にDSSを添加して3%DSS溶液を作り、14日間任意量(ad libitum)を摂取させ、IBD動物モデルを作製した。3%DSSを添加させる2日前から対照群、3%DSSグループはPBS、スルファサラジン(sulfasalazine、SS)グループは、スルファサラジン 50mg/kg、ハマナスの花エタノール及び水抽出物のグループは、500mg/kgを毎日経口投与した。16日後、マウスは頚椎脱臼でサクリファイスして、血液、脾臓、腸の部位を切断して状態を確認した。腸は盲腸から直腸まで切断して長さを測定し、結腸部位と直腸部位を組織学に用いた。
7-1:HaCaT細胞を用いたハマナスの花エタノール及び水抽出物の抗アトピー効果ヒトケラチン細胞株(human keratinocyte cell line)であるHaCaT細胞を用いて、ハマナスの花エタノール及び水抽出物の抗アトピー効果を確認した。前記HaCaT細胞は、10%の熱非活性化された(heat-inactivated)FBSと1%ペニシリン-ストレプトマイシン(penicillin-streptomycin)が添加されたDMEM(Dulbecco's modified Eagle Medium)培地で37℃及び5%のCO2の条件下で培養した。培養が終わった細胞の生存率は、MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide]還元方法を用いて測定した。MTT溶液は、生きている細胞でミトコンドリアのデヒドロゲナーゼ(dehydrogenases)によってホルマザン(formazan)を形成し、細胞の生存有無を確認することができる。細胞毒性を確認するために、HaCaT細胞を96ウェルプレートに5×104細胞/ウェルで37℃にて培養した後、ハマナスの花エタノール抽出物を100~2000μg/ml、水抽出物を100~10000μg/mlで処理し、24時間培養した。24時間が経過した後、各ウェルに20μlのMTT溶液を添加して2時間さらに培養した後、培養液を除去して、100μlのジメチルスルホキシド(dimethylsulfoxide)を添加して570nmで吸光度を測定した。ハマナスの花エタノール抽出物及び水抽出物は、HaCaT細胞において500μg/ml以下の濃度では細胞毒性を示さなかった(図7)。
ハマナスの花水抽出物が炎症誘発性サイトカインの発現を抑制する過程に関与するシグナル伝達機序を明らかにするために、STAT1のリン酸化と炎症性サイトカインの転写を調節する因子として重要なシグナル伝達物質であるNF-κBの活性化について測定した。非活性状態のNF-κBは、内因性抑制タンパク質であるIκBαに結合して非活性化状態を維持して、活性化されるとIκBαがリン酸化されて分解され、これらから遊離して核に移動し、転写因子として活動するため、IκBαに対する分解の影響を併せて測定した。HaCaT細胞を0.5mMフェニルメタンスルホニルフルオライド(Phenylmethanesulfonyl fluoride、Sigma社、Cat No. P7626)と5μg/mlのロイペプチン(leupeptin、Sigma社、Cat No. L2884)を含有した抽出緩衝液(0.5% triton X-100、1mM Na3VO4などを含有したPBS溶液)で溶解させた後、超音波処理(sonication)してDNAを切断した。タンパク質の量は、ウシ血清アルブミン(bovineserum albumin)を標準とし、Bio-Rad社のprotein assay kit(Cat No. 500-0002)を用いて測定した。細胞の総タンパク10~50μgを0.1%SDSを含有した8~12%(w/v)ポリアクリルアミドゲル(polyacrylamide gel)で電気泳動し、ゲルに存在するタンパク質をエレクトロブロッティング(electroblotting)の方法でニトロセルロース(nitrocellulose、NC)フィルタに移した後、非特異的な結合を遮断するためにニトロセルロースフィルターを5%脱脂粉乳を含有したtris-buffered saline-tween(TBS-tween、Sigma社)溶液に入れ、室温で1時間反応させた。フィルタを標的タンパク質に対する抗体を含有したTBS-tween溶液に入れ、4℃で12時間放置した後、HRP(horseradish peroxidase、Sigma社、Cat No. P0889)で標識された2次抗体で標識し、ECL(Enhanced chemiluminescence、Thermo scientific社、Cat No.34080)を用いてバンドを測定した。その結果、ハマナスの花水抽出物は、TNF-α/INF-γによって活性化されたSTAT1のリン酸化を阻害してIκBαの分解を抑制し、核内のNF-κBが減少することを確認した(図10)。これにより、ハマナスの花水抽出物は、STAT1とNK-κBの活性化を抑制して炎症性サイトカインの発現量を減少させて抗アトピー効果があると予測することができる。
Claims (13)
- ハマナスの花抽出物を有効成分として含む、IL-6(interleukin-6)媒介性疾患の予防又は治療用薬学的組成物。
- 前記抽出物が、水、炭素数1~4の低級アルコール、又はこれらの混合溶媒で抽出して得られるものである、請求項1に記載の薬学的組成物。
- 前記低級アルコールが、メタノール、エタノール又はブタノールである、請求項2に記載の薬学的組成物。
- 前記抽出物が、STAT3(signal transducers and activators of transcription 3)の活性を阻害するものである、請求項1に記載の薬学的組成物。
- 前記IL-6媒介性疾患が、骨代謝性疾患、炎症性腸疾患、又はアトピー性皮膚炎である、請求項1に記載の組成物。
- 前記骨代謝性疾患が、骨粗しょう症である、請求項5に記載の薬学的組成物。
- 前記抽出物が、破骨細胞の分化を抑制するものである、請求項5に記載の薬学的組成物。
- ハマナスの花抽出物を有効成分として含む、IL-6(interleukin-6)媒介性疾患の予防又は治療用薬学的組成物の使用。
- 請求項1の組成物をIL-6媒介性疾患の疑いのある個体に投与する段階を含む、IL-6(interleukin-6)媒介性疾患の治療方法。
- ハマナスの花抽出物を有効成分として含む、IL-6(interleukin-6)媒介性疾患の予防又は改善用食品組成物。
- ハマナスの花抽出物を有効成分として含む、IL-6(interleukin-6)媒介性疾患の予防又は改善用医薬部外品組成物。
- ハマナスの花抽出物を有効成分として含む、IL-6(interleukin-6)媒介性疾患の予防又は改善用飼料組成物。
- ハマナスの花抽出物を有効成分として含む、IL-6(interleukin-6)媒介性疾患の予防又は改善用飲用水添加剤。
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