JP2017514897A - ループス腎炎を処置するためのジンセノサイドm1の使用 - Google Patents
ループス腎炎を処置するためのジンセノサイドm1の使用 Download PDFInfo
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- JP2017514897A JP2017514897A JP2017508732A JP2017508732A JP2017514897A JP 2017514897 A JP2017514897 A JP 2017514897A JP 2017508732 A JP2017508732 A JP 2017508732A JP 2017508732 A JP2017508732 A JP 2017508732A JP 2017514897 A JP2017514897 A JP 2017514897A
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Abstract
Description
1.1 動物モデルおよび実験プロトコル
雌NZB/W F1マウスをジャクソンラボラトリー(Jackson Laboratory)から購入した。動物実験はすべて、国防医学院の動物実験委員会、台湾(the Institutional Animal Care and Use Committee of The National Defense Medical Center,Taiwan)の倫理的承認を受けて実施し、実験動物の管理使用に関するNIH指針(NIH Guide for the Care and Use of Laboratory Animals)の倫理規定に準拠して行った。
ジンセノサイドM1、20−O−β−D−グルコピラノシル−20(S)−プロトパナキサジオールは、台湾特許出願第094116005(I280982)号および米国特許第7,932,057号に記載された方法など当該技術分野において公知の方法により調製した。
以前記載されたように(Ka,S.M.ら著、Decoy receptor 3 ameliorates an autoimmune crescentic glomerulonephritis model in mice.Journal of the American Society of Nephrology、第18巻:p.2473〜2485;2007年)、尿サンプルを代謝ケージ内で毎週採取し、尿タンパク質レベルを測定し、血清サンプルを採取して血中尿素窒素(BUN)およびクレアチニン(Cr)の血清レベルを測定した。
以前記載されたように、腎組織をホルマリン固定してパラフィンに包埋し、切片(3μm)を調製し、腎臓病理組織に対してヘマトキシリンおよびエオシン(H&E)で染色した。定量解析は、光学顕微鏡(Olympus BX51、反射蛍光システム(Reflected Fluorescence System)、日本)により行った。腎臓の病態の検査およびスコアリングは、病理学者が盲検方式で行い、腎臓の病変の重症度をスコア化した。増殖、好中球浸潤、半月体形成、フィブリノイド壊死および糸球体周囲の炎症を示す糸球体の割合は、無作為にサンプル採取した少なくとも100の糸球体から算出した。
抗dsDNA抗体の血清レベルを、抗マウスdsDNA酵素免疫測定法(ELISA)キット(アルファダイアグノスティック(Alpha Diagnostic)、テキサス州、米国)を用いて製造者の指示に従い測定した。ELISAプレートリーダー(バイオテック(Bio−Tek)、ヴァーモント州、米国)を用いて450nmの吸光度を測定した。
マウス由来の脾細胞を以前記載されたように調製し、次いで予め4℃にて一晩0.25μg/mlの抗マウスCD3(145−2C11)抗体(BDバイオサイエンス(BD Biosciences))でコートした96ウェル平底マイクロタイタープレートのウェル(2.5×105細胞/ウェル)に3ウェルずつ培養した。48時間後、以前記載されたように培養物を1μlの3H−メチルチミジン(アマシャムファルマシアバイオテク(Amersham Pharmacia Biotech)、ピスカタウェイ(Piscataway)、ニュージャージー州)でパルスし、16〜18時間後に回収し、Top Count(パッカード、パーキンエルマー(Packard,PerkinElmer)、ボストン、マサチューセッツ州)を用いて取り込まれた3H−メチルチミジンを測定した。
腎のin situスーパーオキシドアニオン産生を、ジヒドロエチジウム(DHE:dihydroethidium)標識により判定した。蛍光画像は、腎断面ごとに核全体における陽性核の割合をカウントすることにより定量化した。血清および腎臓組織中のスーパーオキシドアニオンレベルを、以前記載されたように測定し、結果を1ミリグラム乾燥重量当たり15分毎の相対発光単位(RLU:reactive luminescence units)(すなわち、RLU/15分/mg乾燥重量)として表した。
標準的なプロトコルに従いBD Cytometric Bead Array Mouse Inflammationキット(BDバイオサイエンス)、続いてフローサイトメトリー(BDバイオサイエンス)を使用することにより、血清中のINF−γ、MCP−1、IL−12 p70、IL−6、TNF−αおよびIL−10のレベルを検出する。
腎皮質RNAを、製造者の指示に従いTRIzol試薬(インビトロジェン(Invitrogen))を用いて抽出し、リアルタイム逆転写ポリメラーゼ連鎖反応(RT−PCR)を使用してToll様受容体(TLR)7遺伝子発現を測定した。リアルタイム定量は、製造者の指示に従いBio−Rad iCycler iQシステムを用いて行った。増幅は、2−ΔCt法を用いてGAPDHの値に対して正規化した。
結果を平均値±SEMとして示す。2群間の比較は、スチューデントt検定を用いて行った。p値が<0.05の場合に統計学的に有意と見なした。
2.1 ジンセノサイドM1はループス腎炎を寛解させた
タンパク尿を検出すると、正常対照群のマウスと比較してASLN群のマウスは、タンパク尿(図1A)および血尿(図1B)の有意な増加を示した(p<0.005)。タンパク尿および血尿の量は、ASLN群のマウスと比較してASLN+LCHK168群のマウスで有意に減少した。LCHK168で処置したマウスの腎機能の保護を検出すると、正常対照群のマウスと比較してASLN群のマウスは、BUN(図1C)および血清クレアチニン(図1D)の有意な増加を示した(p<0.05)。ASLN群のマウスと比較して、BUNおよびクレアチニンの血清レベルは、ASLN+LCHK168群のマウス(p<0.05)で有意に減少した。
腎臓における自己抗体誘導性の免疫複合体沈着がループス腎炎の主な原因と考えられるため、我々は血清中の抗dsDNA自己抗体レベルを測定した。図3に示すように、血清抗dsDNA抗体レベルは、ASLN群のマウスで正常対照マウスより有意に高かった。次いで、ASLN+LCHK168群のマウスではASLN群のマウスと比較して、dsDNAの血清レベルは、有意に減少した(p<0.01)。
正常対照マウスと比較してASLN群のマウスは、早くも3週目に腎臓のROS産生の発現の有意な増加を示し、ASLN群のマウスでは5週目で劇的に増加した。ASLN+LCHK168群のマウスではASLN群のマウスと比較して、腎臓のROS産生の発現は有意に減少した(p<0.01)(図4A)。
マウスにおけるインターフェロンγ(INF−γ)、単球走化性タンパク質1(MCP−1)、IL−12 p70、IL−6、TNFαおよびIL−10の血清レベルを測定する。図5Aに示すように、INF−γの血清レベルは、ASLN群のマウスでは早くも3週目に有意に増加し、5週目で劇的に増加した。ASLN群のマウスと比較して、ASLN+LCHK168群のマウスではINF−γの発現は有意に減少した(p<0.01)。次いで、図5B〜Fに示すように、MCP−1、IL−12 p70、IL−6、TNFαおよびIL−10の血清レベルは、ASLN群のマウスでは早くも3週目に有意に増加し、5週目で劇的に増加した。ASLN群のマウスと比較して、ASLN+LCHK168群のマウスではMCP−1、IL−12 p70、IL−6、TNFαおよびIL−10の発現は、有意に減少した(p<0.005)。
正常対照マウスと比較して、ASLN群のマウスは、脾細胞において早くも3週目にT細胞の増殖の有意な増加を示し、ASLN群のマウスでは5週目で劇的に増加した。ASLN群のマウスと比較して、ASLN+LCHK168群のマウスでは脾細胞におけるT細胞の増殖は有意に減少した(p<0.01)(図6)。
リアルタイムRT−PCRの結果から、図7に示すように腎臓のTLR7mRNAレベルの増加が立証され、TLR7のmRNAレベルは、ASLN群のマウスでは有意に増加した(p<0.005)。ASLN群のマウスと比較して、ASLN+LCHK168群のマウスではTLR7のmRNAレベルは有意に減少した(p<0.01)。
Claims (10)
- 必要とする被検体に治療有効量のジンセノサイドM1を投与することを含む、ループス腎炎を処置する方法。
- 前記方法は、前記被検体の(1)糸球体における:固有細胞の増殖、半月体、好中球浸潤およびフィブリノイド壊死;ならびに(2)尿細管間質コンパートメントにおける:間質単核白血球炎症およびタンパク円柱を伴う尿細管萎縮からなる群から選択されるループス腎炎の1つまたは複数の症状を減少させるまたは軽減するのに効果的である、請求項1に記載の方法。
- 前記方法は前記被検体の糸球体周囲の単核白血球炎症を減少させるのに効果的である、請求項1に記載の方法。
- 前記方法は、前記被検体においてタンパク尿もしくは血尿を減少させるまたは血清尿素窒素レベルもしくは血清クレアチニンレベルを低下させるのに効果的である、請求項1に記載の方法。
- 前記ジンセノサイドM1は、コルチコステロイド、非ステロイド性抗炎症薬(NSAID)、細胞傷害性薬、免疫抑制剤および血管拡張薬からなる群から選択されるループス腎炎を処置するための1つまたは複数の治療薬と組み合わせて投与される、請求項1に記載の方法。
- 必要とする被検体のループス腎炎を処置するための薬物を製造するための、ジンセノサイドM1の使用。
- 前記薬物は、前記被検体の(1)糸球体における:固有細胞の増殖、半月体、好中球浸潤およびフィブリノイド壊死;ならびに(2)尿細管間質コンパートメントにおける:間質単核白血球炎症およびタンパク円柱を伴う尿細管萎縮からなる群から選択されるループス腎炎の1つまたは複数の症状を減少させるまたは軽減するのに効果的である、請求項6に記載の使用。
- 前記薬物は前記被検体の糸球体周囲の単核白血球炎症を減少させるのに効果的である、請求項6に記載の使用。
- 前記薬物は、前記被検体のタンパク尿もしくは血尿を減少させるまたは血清尿素窒素レベルもしくは血清クレアチニンレベルを低下させるのに効果的である、請求項6に記載の使用。
- 前記薬物は、コルチコステロイド、非ステロイド性抗炎症薬(NSAID)、細胞傷害性薬、免疫抑制剤および血管拡張薬からなる群から選択されるループス腎炎を処置するための1つまたは複数の治療薬と組み合わせて投与される、請求項6に記載の使用。
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JP2021519746A (ja) * | 2018-04-23 | 2021-08-12 | リー・シュー−ロンSheau−Long LEE | ハンチントン病の治療のためのジンセノサイドm1の使用 |
JP7406496B2 (ja) | 2018-04-23 | 2023-12-27 | リー・シュー-ロン | ハンチントン病の治療のためのジンセノサイドm1の使用 |
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DK3137089T3 (en) | 2019-01-28 |
US9844560B2 (en) | 2017-12-19 |
ES2704027T3 (es) | 2019-03-13 |
KR102402139B1 (ko) | 2022-05-25 |
CN106573009B (zh) | 2019-03-29 |
EP3137089B1 (en) | 2018-10-10 |
TW201613610A (en) | 2016-04-16 |
WO2015165422A1 (en) | 2015-11-05 |
KR20170005045A (ko) | 2017-01-11 |
CN106573009A (zh) | 2017-04-19 |
EP3137089A4 (en) | 2017-09-06 |
TWI672143B (zh) | 2019-09-21 |
US20170049792A1 (en) | 2017-02-23 |
JP6696972B2 (ja) | 2020-05-20 |
EP3137089A1 (en) | 2017-03-08 |
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