JP6293099B2 - ジンセノサイドf2の肝疾患予防又は治療用途 - Google Patents
ジンセノサイドf2の肝疾患予防又は治療用途 Download PDFInfo
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- JP6293099B2 JP6293099B2 JP2015171533A JP2015171533A JP6293099B2 JP 6293099 B2 JP6293099 B2 JP 6293099B2 JP 2015171533 A JP2015171533 A JP 2015171533A JP 2015171533 A JP2015171533 A JP 2015171533A JP 6293099 B2 JP6293099 B2 JP 6293099B2
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- Medicines Containing Plant Substances (AREA)
Description
8週齢の雄マウス(体重25〜28g)に、2週間正常食餌と共に3g/kgのエタノールに50mg/kgのジンセノサイドF2(図面にはGF2で表示)を溶解して毎日午後3〜4時頃に経口で投与し、2週間後に犠牲にして下記実験を行った。
前記マウスの腹部大動脈から採血して遠心分離機にて3,300rpmで10分間遠心分離して血清のみ分離し、血清中のALT(alanine aminotransferase)、AST(alanine aminotransferase)含有量を、アイデックスラボラトリーズ(IDEXX Laboratories, 米国)社のキットを用いて、製造会社が提供する実験方法に従ってベットテスト(VetTEST, IDEXX, 米国)で測定した。また、中性脂肪(triglyceride, TG)及び総コレステロール含有量は、肝組織50mgを摘出して粉砕し、その後クロロホルム−メタノール(2:1)溶液を添加して遠心分離し、肝組織中に含まれる脂質成分を抽出して作製した抽出液を、アイデックスラボラトリーズのキットを用いて、製造会社が提供する実験方法に従ってベットテストで測定した。
肝組織の組織学的変化を観察するためのH&E(Hematoxylin and eosin)染色、及びアポトーシスの確認のためのTUNEL(Terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling)染色を行った。前記TUNEL染色は、アポトーシス染色(TAKARA BIO INC, Shiga, Japan)を用いて、製造会社が提供する実験方法に従って行った。また、オイルレッドO(Oil-red O)染色により肝細胞の中性脂質を染色した。その結果を図3aに200倍又は400倍の倍率で示す。
過度にアルコールを摂取すると、肝臓ではエンドカンナビノイド(endocannabinoid)の一種である2−アラキドノイルグリセロール(2-arachidonoylglycerol, 2-AG)が増加し、これは肝細胞の2−アラキドノイルグリセロールの受容体であるエンドカンナビノイド受容体(CB1R)を活性化することにより、核ホルモン受容体ERRγの発現を増加させる。また、増加したERRγはCYP2E1の転写調節部位に直接結合することによりCYP2E1の発現を増加させ、これは活性酸素の増加をもたらし、結果として肝損傷を誘発する(非特許文献6)。
(1)肝細胞、肝星細砲における脂肪合成の抑制
マウスから肝細胞と肝星細砲を分離し、その後、図5aに示す模式図のように、下方の底に肝星細砲(HSC)を配置し、上方に肝細胞(hepatocyte)を配置した状態で共同培養を行った。培養時に100mMのエタノールで12時間処理し、その後30μMのジンセノサイドF2で6時間又は12時間処理した。
ジンセノサイドF2の脂肪合成抑制機序を確認するために、ヒト肝細胞株であるHepG2Aを30μMのジンセノサイドF2で処理し、30分後に脂肪生成を刺激するタンパク質であるLXRのアゴニスト(agonist)として、脂肪の合成を誘導する物質である10μMのTO901317でさらに処理し、その後9時間培養した。その後、肝細胞に対してリアルタイムPCRを行った結果、ジンセノサイドF2はTO901317により増加した脂肪合成遺伝子であるSREBP1cとFASの発現を抑制することが確認された(図5e)。
マウスに毎日正常食餌と共にエタノールを各個体に3g/kgずつ2週間与えた。ここで、1グループ(E+Veh)には担体を、2グループ(E+GF2)にはジンセノサイドF2を与えた。
マウスからナイーブT細胞(naive T cell)を分離して5ng/mlのTGF−β1、20ng/mlのIL−6で処理し、CD3/28抗体がコーティングされたDCで3.5日間培養して炎症誘発細胞であるTh17細胞(T helper 17 cell)に分化させた。ここで、様々な濃度(0〜30μM)のジンセノサイドF2で共に処理し、Th17細胞のマーカーを観察した結果を図7a〜図7cに示す。NはTGF−β1、IL−6、ジンセノサイドF2のいずれでも処理していないナイーブT細胞を示す。
8週齢のIL−10欠乏雄マウス(重量25〜28g)を対象に、2週間正常食餌と共に3g/kgのエタノールと50mg/kgのジンセノサイドF2を毎日経口で投与した(E+GF2)。対照群にはジンセノサイドF2の代わりに同量のエタノールと担体を与えた(E+Veh)。2週間後にマウスを解剖検査して血清、肝組織、肝単核球を得た。その後、実施例1の(1)に記載の方法と同様に、血清中のALT、AST、TG、コレステロールを測定し、肝組織では壊死巣(necrotic foci)を観察し、2つに分離した肝臓から壊死巣の数を計数した。肝単核球ではF4/80又はGr1抗原マーカーを用いてマクロファージ及び好中球の発現の程度を流細胞分析した。
Claims (11)
- 高麗人参抽出物から分離されたジンセノサイドF2を含むアルコール性肝疾患予防又は治療用薬学組成物。
- 前記肝疾患が、肝炎、肝硬変、脂肪肝、肝不全及び肝臓癌からなる群から選択されるものである、請求項1に記載の薬学組成物。
- 前記ジンセノサイドF2が、肝臓における脂肪の蓄積を抑制するものである、請求項1に記載の薬学組成物。
- 前記ジンセノサイドF2が、制御性T細胞(Treg)の分布を増加させて肝臓の炎症を抑制するものである、請求項1に記載の薬学組成物。
- 前記ジンセノサイドF2が、抗炎症性サイトカインIL−10の発現を増加させるものである、請求項1に記載の薬学組成物。
- 前記ジンセノサイドF2が、ナイーブT細胞(Naive T cell)のTh17細胞への分化を抑制するものである、請求項1に記載の薬学組成物。
- 前記ジンセノサイドF2が、LXRα(liver X receptor alpha)の活性を抑制するものである、請求項1に記載の薬学組成物。
- 高麗人参抽出物から分離されたジンセノサイドF2を含むアルコール性肝疾患予防又は改善用機能性食品。
- 高麗人参抽出物から分離されたジンセノサイドF2を含むアルコール性肝疾患予防又は改善用飼料組成物。
- 請求項1〜7のいずれかの組成物をヒトを除く肝疾患の疑いのある個体に投与するステップを含む、アルコール性肝疾患予防又は治療方法。
- アルコール性肝疾患を予防又は治療するための医薬の製造における、高麗人参抽出物から分離されたジンセノサイドF2の使用。
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US10912737B2 (en) | 2016-01-14 | 2021-02-09 | University-Industry Cooperation Group Of Kyung Hee University | Nano complex comprising a nano drug delivery matrix; and a ginseng extract or a ginsenoside isolated therefrom |
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CA2961005C (en) * | 2016-08-05 | 2020-01-14 | Intelligent Synthetic Biology Center | Composition for preventing or treating liver cancer containing ginsenoside f2 |
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KR101621356B1 (ko) | 2016-05-17 |
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