JP2020002082A - Keap1−Nrf2システムによる生体防御遺伝子発現の活性化用剤 - Google Patents
Keap1−Nrf2システムによる生体防御遺伝子発現の活性化用剤 Download PDFInfo
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Abstract
Description
すなわち本発明の課題は、安全性が高く、Keap1−Nrf2システムによる生体防御遺伝子発現の活性化作用を有し、長期間にわたって安心して服用できるNrf2活性化用剤、該Nrf2活性化用剤を含む、Keap1−Nrf2システムによる生体防御遺伝子発現の低下(以下「Nrf2の活性低下」ということがある。)に起因する疾患若しくは状態(症状)の予防又は改善(治療)用飲食品を提供することにある。
(1)分けつ開始期から出穂開始前期までに成長した大麦若葉又はその処理物を有効成分として含む、Keap1−Nrf2システムによる生体防御遺伝子発現の活性化用剤であって、以下の化合物(b)及び(e)を少なくとも含み、化合物(a)、(c)及び(d)よりなる群から選ばれる少なくとも1種の化合物を含んでいてもよいことを特徴とする前記活性用剤。
(a)組成式:C33H40O19、分子量:740、化合物名:ロビニン
(b)組成式:C27H30O15、分子量:594、化合物名:サポナリン
(c)組成式:C25H37O5N2、分子量:445
(d)組成式:C21H20O10、分子量:432、化合物名:アフゼリン
(e)組成式:C29H50O、分子量:414、化合物名:β−シトステロール
(2)大麦若葉又はその処理物が、大麦若葉の搾汁液、搾汁粉末又は乾燥粉末である、(1)に記載の活性化用剤。
(3)(1)又は(2)に記載の活性化用剤を含んでなる、Keap1−Nrf2システムによる生体防御遺伝子発現の低下(以下「Nrf2の活性低下」ということがある。)に起因する疾患若しくは状態(症状)の予防又は改善(治療)用飲食品。
(a)組成式:C33H40O19、分子量:740、化合物名:ロビニン
(b)組成式:C27H30O15、分子量:594、化合物名:サポナリン
(c)組成式:C25H37O5N2、分子量:445
(d)組成式:C21H20O10、分子量:432、化合物名:アフゼリン
(e)組成式:C29H50O、分子量:414、化合物名:β−シトステロール
特開2009−148213号公報(特許文献9)に記載の方法に準じて、刈り取った大麦の若葉(茎葉)10kgを圧搾し、抽出液(搾汁液)を8kg得た。
2−1.目的
Keap1−Nrf2経路(システム)は細胞内において、一連の抗酸化遺伝子(生体防御遺伝子)を発現させることにより活性酸素等を消去する重要な経路である(図1参照)。同経路(システム)の活性化物質は新規の抗酸化物質(間接抗酸化物質)として期待することができる。
そこで、Keap1−Nrf2経路(システム)を観察できるリポータージーンアッセイ法と各種分画法を組み合させて、大麦若葉抽出物中より同経路(システム)活性化物質の探索を実施した。
まず、大麦若葉抽出液(搾汁液)(3.5L)をろ過後、その上清を凍結乾燥し、酢酸エチルによる抽出を行った。同抽出により、酢酸エチル分画(BLE)、中間層分画(BLG)、水層分画(BLW)の3つの分画を得た(図2参照)。
これらの分画をDMSO(dimethyl sulfoxide)に溶解し、肝培養細胞を用いた細胞毒性試験及びリポータージーンアッセイを行った。
試験化合物の細胞毒性はCell Counting Kit 8(CCK8、同人化学)のプロトコルに従って測定した。C3A細胞を96穴プレートに8.0×104/wellとなるよう播種し、24時間培養した。その後、大麦若葉抽出液(分画又は画分)を細胞に200μL/well、添加した。さらに24時間後、MEMで20倍希釈したCCK−8溶液を200μl/well、添加した。2時間後、プレートリーダー(Wallac 1420 ARVO Mx plate reader, PerkinElmer)で450nmの吸光度を測定した。
ヒト培養株化細胞(C3A)を白色96穴プレートに8×103個/wellとなるように播種し、Nrf2が結合するプロモーター領域に存在するARE配列(Antioxidant Response Element)とルシフェラーゼ遺伝子を有するリポーターベクターと補正用のリポーターベクター(pGL4.37[luc2P/ARE/Hygro]vector: pGL4.75[hRluc/CMV]Vector=20:1、Certificate of Analysis Part# 9PIE364, Part# 9PIE693、Promega Corporation)をFuGENE HD Transfection Reagent (FuGENE HD: Plasmid DNA= 4: 1、Promega Corporation)を用いてトランスフェクションした。24時間後、大麦若葉抽出物を添加した。さらに24時間後Dual-Glo Luciferase Assay System(Promega Corporation)を添加、ルシフェラーゼ活性を測定した(図3参照)。
CCK−8アッセイを行った結果、BLG、BLEは1.25mg/mlまで細胞毒性が観察されなかった。一方、BLEは0.12mg/mlから毒性が観察された(図4参照)。
リポータージーンアッセイを行った結果、BLE、BLGは、濃度依存的に活性の増加が観察されたが、BLWは、ほとんど活性が観察されなかった。高濃度(600μg/ml)で活性が認められたBLGは、BLEとBLWの混合した画分であることから、低濃度(15μg/ml)で活性を有するBLEをその後の分画に用いることとした(図5参照)。
次に、リポータージーンアッセイの活性の高かった分画(BLE)を、下記の条件でHPLC(CAPCELL PAK C18)による分画を行い、25の画分(HPLC画分)を得た(図6参照)。また、これら25画分以外の部分を集めたものをバックグラウンド(BG)として用いた。
HPLC条件
カラム:CAPCELL PAK C18, 250mm×10mm, 5μm
グラジエント:0〜3分、メタノール:水=35:65
30分までにメタノール100%後、15分間保持
5分間メタノール:水=35:65でコンディショニング
検出波長:210nm
流速:4ml/min
各画分のCCK−8アッセイ結果を図7〜9に示す。
各画分のリポータージーンアッセイを行った結果、他の画分と比較し、画分5,6,8,9,18及び19において、リポータージーンアッセイの活性が70以上と有望な画分が得られた(図10〜12参照)。
3−1.画分5の分析
LC−MS/MSを用いて画分5の分析を行った。得られた分子量及びフラグメントイオンからロビニン(robinin)であることが推定された(図13参照)。
LC−MS/MSを用いて画分6の分析を行った。得られた分子量及びフラグメントイオンからサポナリン(saponarin)であることが推定された(図14参照)。
LC−MS/MSを用いて画分8の分析を行った。得られた分子量及びフラグメントイオンでは成分の化学構造を推定することができなかった(図15参照)。
LC−MS/MSを用いて画分9の分析を行った。得られた分子量及びフラグメントイオンからアフゼリン(afzelin)と推定された(図16参照)。
リポータージーンアッセイの活性が低かったが、画分24について、LC−MS/MSとNMRによる分析を行った。得られた結果から、β-sitosterolと同定した(図17、図18、図19参照)。
[1] Janeesh, P. A., & Abraham, A. (2014). Robinin modulates doxorubicin-induced cardiac apoptosis by TGF-beta 1 signaling pathway in Sprague Dawley rats. Biomedicine & Pharmacotherapy, 68(8), 989-998.
[2] Kamiyama, M., & Shibamoto, T. (2012). Flavonoids with Potent Antioxidant Activity Found in Young Green Barley Leaves. Journal of Agricultural and Food Chemistry, 60(25), 6260-6267.
[3] Rosenblat, M., Volkova, N., & Aviram, M. (2013). Pomegranate phytosterol (beta-sitosterol) and polyphenolic antioxidant (punicalagin) addition to statin, significantly protected against macrophage foam cells formation. Atherosclerosis, 226(1), 110-117.
[4] Vellosa, J. C. R., Regasini, L. O., Bello, C., Schemberger, J. A., Khalil, N. M., Morandim-Giannetti, A. D., Bolzani, V. D., Brunetti, I. L., & Oliveira, O. M. M. D. (2015). Preliminary in vitro and ex vivo evaluation of afzelin, kaempferitrin and pterogynoside action over free radicals and reactive oxygen species. Archives of Pharmacal Research, 38(6), 1168-1177.
[5] Torres-Naranjo et al. (2016) Chemical constituents of Muehlenbeckia tamnifolia (Kunth) meisn (Polygonaceae) and its in vitro α-amilase and α-glucosidase inhibitory activities. Molecules21(11), 1461.
Claims (3)
- 分けつ開始期から出穂開始前期までに成長した大麦若葉又はその処理物を有効成分として含む、Keap1−Nrf2システムによる生体防御遺伝子発現の活性化用剤であって、以下の化合物(b)及び(e)を少なくとも含み、化合物(a)、(c)及び(d)よりなる群から選ばれる少なくとも1種の化合物を含んでいてもよいことを特徴とする、前記活性化用剤。
(a)組成式:C33H40O19、分子量:740、化合物名:ロビニン
(b)組成式:C27H30O15、分子量:594、化合物名:サポナリン
(c)組成式:C25H37O5N2、分子量:445
(d)組成式:C21H20O10、分子量:432、化合物名:アフゼリン
(e)組成式:C29H50O、分子量:414、化合物名:β−シトステロール - 大麦若葉又はその処理物が、大麦若葉の搾汁液、搾汁粉末又は乾燥粉末である、請求項1に記載の活性化用剤。
- 請求項1又は2に記載の活性化用剤を含んでなる、Keap1−Nrf2システムによる生体防御遺伝子発現の低下に起因する疾患若しくは状態(症状)の予防又は改善(治療)用飲食品。
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J BASIC CLIN PHYSIOL PHARMACOL., vol. 27, no. 5, JPN6022033565, 2016, pages 473 - 482, ISSN: 0004848638 * |
NUTRIENTS, vol. Vol.9, 1252, JPN6022033564, 2017, pages 1 - 14, ISSN: 0004848637 * |
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