JP2013133312A - 非アルコール性脂肪性肝疾患および/または非アルコール性脂肪肝炎の治療薬 - Google Patents
非アルコール性脂肪性肝疾患および/または非アルコール性脂肪肝炎の治療薬 Download PDFInfo
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Abstract
【解決手段】光合成細菌と乳酸菌と酵母とからなる複合菌を有効成分とする非アルコール性脂肪性肝疾患および/または非アルコール性脂肪肝炎の治療薬である。前記光合成細菌は、ロドシュードモナス・パルストリスであることが好ましい。光合成細菌と乳酸菌と酵母とからなる複合菌はプロバイオティクスとして作用し、経口投与することでメチオニン・コリン欠乏食で誘発された肝炎症状を緩和し、レプチンレセプター欠損マウスに投与すると血清インスリン値を低下させることができる。
【選択図】なし
Description
またストレプトコッカス属の乳酸菌としては、ストレプトコッカス ファエカリス(Streptococcus faecalis)、ストレプトコッカス ファエシウム(Streptococcus faecium)などがある。
またリューコノストック属の乳酸菌としては、リューコノストック マエセンテロイデス(Leuconostoc mesenteroides)、リューコノストック ラクティス(Leuconostoc lactis)などがある。
本発明の治療薬では、光合成細菌1細胞に対し0.01〜100倍の酵母、より好ましくは0.1〜10倍の酵母が配合される。
この複合菌液や濃縮複合菌液は、そのままNAFLDやNASHの治療薬として使用することができるが、他の分散媒その他を添加し、製剤化してもよい。なお、上記した前培養液や濃縮複合菌は、冷凍や凍結乾燥などで保存することができる。
光合成細菌(Rhodopseudomonas palustris:NITE P−1166)を、ポリペプトン10g、酵母エキス2g、MgSO4・7H2O 1g、蒸留水1リットルを含む培地にて、5000ルクスの蛍光灯照射下、27℃、2週間、静置嫌気条件で前培養した。
また、乳酸菌として、乳酸菌(Lactobacillus casei: IFO(NBRC) 15883)と乳酸菌(Lactobacillus plantarum:ATCC 8014)とを、それぞれ別個にMRS培地にて37℃、3日間、静置嫌気条件にて前培養した。
また、酵母(Saccharomyces cerevisiae:ATCC番号 11909)をYM培地にて330℃、3日間、静置嫌気条件で前培養した。
上記のように前培養したそれぞれの菌を、マイクロチューブに全量を1.2ml、200μLあたり表1の菌数になるように混合した。
その後、7000rpm、15min遠心分離を行い、上清0.9mlを除去後、除去した液体培地と同量の分散媒(森永脱脂粉乳20% w/v)を加え、1.2mlとした。これを治療剤とした。
8週令C57BL6/N 雄性マウスを2群に分け、メチオニン・コリン欠乏食と分散媒(森永乳業株式会社製、森永脱脂粉乳 20%(w/v))、メチオニン・コリン欠乏食と製造例1の治療剤とをそれぞれ12週間に亘り、摂取させた。
投与後、肝臓を採取し、肝TGを測定した。肝臓組織の一部は、4%パラホルムアルデヒド固定し、パラフィン切片を作成した。ヘマトキシリン・エオジン染色を行い、肝臓組織像を評価した。血清および組織サンプルは、−80℃で保存し、血清AST、血清ALT、血清TG、肝臓組織免疫組織化学染色を行った。血清ASTおよび血清ALTの結果を図1に示す。また、肝TGおよびHE染色像の結果を図2に示す。更に、肝臓細胞からRNA、タンパク質を抽出し、リアルタイムPCR法を用いてアディポサイトカインおよびサイトカインなどの各種パラメータの変化を定量的に評価した。肝PAI−1、肝TNFαの結果をそれぞれ図3に示す。
図1(A)、図1(B)に示すように、メチオニン・コリン欠乏食が給餌されてNASH様病態が誘導されたマウス群に製造例1の治療剤を投与すると、血清ASTおよび血清ALTがやや低減し、肝機能が改善した。
7週令の雌性、レプチンレセプター欠損マウス(db/db)を2群に分け、一方に分散媒(森永乳業株式会社製、森永脱脂粉乳 20%(w/v))を、他方に製造例1の治療剤を4週間投与した。
投与後、一晩絶食の後採血および肝臓を採取した。血清および組織サンプルは、−80℃で保存し、空腹時血糖、インスリン濃度、総コレステロール値、血清TG、血清AST、血清ALTを行った。空腹時血糖およびインスリン濃度の結果を図4に示す。また、総コレステロール値、血清TGの結果を図5に示す。また、血清ASTおよび血清ALTの結果を図6に示す。更に、肝臓細胞からRNA、タンパク質を抽出し、リアルタイムPCR法、ウェスタンブロッド法、免疫沈降法を用いてアディポサイトカインおよびサイトカインなどの各種パラメータの変化を定量的に評価した。肝ピルベートカルボキシラーゼおよびグルコース6−フォスファターゼの結果を図7に示す。
図4(A)に示すように、製造例1の治療剤を投与しても、空腹時血糖値に変化はなかった。しかしながら、図4(B)に示すように血清インスリン値は低減し、インスリン抵抗性の改善が示唆された。なお、図5(A)、図5(B)に示すように総コレステロール値およびTG値は変動がないが、図6(A)、図6(B)に示すように、血清AST値およびALT値はやや低減している。更に、図7(A)、図7(B)に示すように、糖新生に関する酵素である肝ピルベートカルボキシラーゼおよびグルコース6−フォスファターゼの発現量が低減している。本発明の治療薬の作用機序は明確ではないが、糖新生に関わる酵素の発現量の低減も関与すると推察される。
Claims (2)
- 光合成細菌と乳酸菌と酵母とからなる複合菌を有効成分とする非アルコール性脂肪性肝疾患および/または非アルコール性脂肪肝炎の治療薬。
- 前記光合成細菌は、ロドシュードモナス・パルストリスであることを特徴とする、請求項1記載の治療薬。
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JP2016131512A (ja) * | 2015-01-16 | 2016-07-25 | キリン株式会社 | 流加培養した醸造酵母の発酵特性改善方法 |
JP2018507914A (ja) * | 2015-03-09 | 2018-03-22 | インテクリン・セラピューティクス・インコーポレイテッド | 非アルコール性脂肪肝疾患および/またはリポジストロフィーの処置のための方法 |
CN109749975A (zh) * | 2019-03-22 | 2019-05-14 | 北京好实沃生物技术有限公司 | 一株沼泽红假单胞菌hew-gj106及其应用 |
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