JP2019534273A - モノアセチルジアシルグリセロール化合物を含有する肝炎の予防または治療用組成物 - Google Patents
モノアセチルジアシルグリセロール化合物を含有する肝炎の予防または治療用組成物 Download PDFInfo
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Landscapes
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Abstract
Description
(化学式1)
式中、R1及びR2は、それぞれ独立して、炭素原子数14〜22の脂肪酸基である。
式中、R1およびR2は、それぞれ独立して、炭素原子数14〜22、好ましくは炭素原子数15〜20の脂肪酸基である。
(化学式2)
。
(化学式1)
式中、R1及びR2はそれぞれ独立して、炭素原子数14〜22の脂肪酸基である。
マウスを、対照群、ConA処理群、およびPLAG前処理群の3つのグループに無作為に分けた。前記ConAおよびPLAGは、何れもPBS(phosphate buffer saline)に溶解させて使用した。マウスにPBSまたはPLAGを口腔投与し、2時間後に、20mg/kg BWのConAをConA処理群およびPLAG前処理群にそれぞれ静脈注射した。その後、PLAGは、100mg/kg BWの量をマウスに口腔投与した。ここで、BWはbody weightを意味する。
血液サンプルは、実施例1のマウスから、ConA投与18時間後に心臓穿刺(cardiac puncture)により得て、3,000rpmで10分間遠心分離した。肝組織のホモジネートにあるサイトカインを測定するために、動物を犠牲にした後、PBSを用いて肝を洗浄した。肝を均質化させ、PBS中で、70μmメッシュセルストレーナー(mesh cell strainer、BD Falcon cell strainer、BD Biosciences、Bedford、MA)を用いて濾過した。また、上清液は、2,000rpmの速度で5分間遠心分離して収集した。下層のセルペレットはPBS中で再浮遊させ、一般の血液検査(complete blood cell count、CBC)分析した。血漿サンプルおよび肝ホモジネートの上清液は、サイトカインが測定されるまで零下20度を維持させた。IL‐6、IL‐10、IL‐4、MIP‐2、およびIFNγの濃度はエリサ(ELISA)セットを用いて検出した。
全血および肝サンプルは、実施例1のマウスから、ConA投与18時間後に採取した。マウスから採取した切断された肝は、実験例1で上述したように均質化させた。血液検査(Complete blood count、CBC)分析は、全白血球細胞の定量、全白血球細胞の好中球およびリンパ球の一部を含み、血液学分析では、マインドレイBC5300を用いて測定した(Shenzhen Mindray Bio―medical Electronics、China)。
肝部位は、実施例1のマウスから、ConA投与8時間後に採取した。上記の肝部位を10%の中性緩衝ホルマリン(neutral buffered formarlin)に固定し、パラフィンに包埋して5umの厚さに切断した。パラフィンを除去し、再水和(rehydration)した後、薄片をヘマトキシリン(hematoxylin)およびエオシン(eosin)で染色した。また、好中球を識別するために、肝部位を抗‐マウス好中球抗体で染色した。全てのサンプルをレイカ(Leica、Wetzlar、Germany)光学顕微鏡下で組織学的に評価し、デジタル画像をX200倍率で撮影した。
Hep3B細胞を、12穴のウェルプレート(well plate、各ウェル当たり2.5x10^5)に入れ、様々な濃度(0.1、1、10、100ug/mL)のPLAGで処理して2時間後に、IL‐4で1時間活性化させた。全タンパク質抽出物は、phospho‐STAT6、STAT6、phospho‐JAK1、およびphosphor‐PKCξ/λ Abs(細胞信号、Cell signaling)で免疫ブロット法を用いて確認した。
全RNAは、TRIzol試薬(Incitrogen, Carlsbad, CA)で肝ホモジネートから分離した。HL‐60細胞を12穴のウェルプレート(各ウェル当たり1x10^6)に入れ、実験例4と同様に処理した。cDNAは、M‐MLV逆転写酵素とオリゴ‐dT(Promega, Madison, WI)を用いて、全細胞RNAから合成した。PCRプライマー(Bioneer、Daejeon)は、プライマー3プログラムを利用してデザインし、マウスおよびヒトのプライマー配列は、下記表1のとおりである。
HepG2およびHep3B細胞を、STAT6の結合部位(p4xSTAT6-Luc2P; Addgene, Cambridge, MA)の4つの対を含んでいるレポータールシフェラーゼプラスミド(plasmid)に形質移入し、レポーターベクターをAttractene試薬と細胞系中に形質移入した。STAT6レポーターベクターの活性のために、10ng/mlのIL‐4を6時間細胞に処理して使用し、ルシフェラーゼの活性は、ルミノメータにより、ルシフェラーゼ分析システムを用いて測定した。各サンプルのルシフェラーゼの活性は、PLAGに形質移入されたサンプルに該当するものとして正規化された。
フィブロネクチン(fibronectin)の好中球吸着に対するPLAGの効果有無を調べるために、24穴の組織培養プレートを、以前研究(Wang YH, Wang WY, Liao JF, Chen CF, Hou YC, Liou KT, Chou YC, et al. Prevention of macrophage adhesion molecule-1 (Mac-1)-dependent neutrophil firm adhesion by taxifolin through impairment of protein kinase-dependent NADPH oxidase activation and antagonism of G protein-mediated calcium influx. Biochem Pharmacol 2004;67:2251-2262.)と同様にフィブロネクチンでコーティングした。前記プレートを、25ug/mlのフィブロネクチンと37℃で2時間培養させた。結合していないタンパク質(unbund protein)を洗浄して除去し、好中球を、実験2時間前にPLAGで前処理した。好中球の活性は、4時間IL‐4とともに行った。吸着されていない好中球は、吸引(誤嚥、aspiration)により溶離し、PBSで2回洗浄した。付着された好中球は、血球計算板(hemocytometer)を用い、各ウェルの底にある細胞の数を計算して測定した。残っている吸着細胞を培養器で18時間保管し、この際、細胞への分光計評価のために、WST‐1試薬(Roche Applied Science)に曝した。
Claims (10)
- 下記化学式1で表示されるモノアセチルジアシルグリセロール化合物を有効成分として含有する、肝炎の予防または治療用薬学的組成物:
(化学式1)
式中、R1及びR2はそれぞれ独立して、炭素原子数14〜22の脂肪酸基である。 - 前記R1およびR2はそれぞれ独立して、パルミトイル、オレオイル、リノレオイル、リノレノイル、ステアロイル、ミリストイル、およびアラキドノイルで構成される群から選択されることを特徴とする請求項1に記載の肝炎の予防または治療用薬学的組成物。
- 前記モノアセチルジアシルグリセロール化合物は下記の化学式2で表示される化合物であることを特徴とする請求項1に記載の肝炎の予防または治療用薬学的組成物:
(化学式2)
。 - 前記モノアセチルジアシルグリセロール化合物は、IL‐4、IL‐6および/またはMIP‐2の発現および/または活性を抑制することを特徴とする請求項1に記載の肝炎の予防または治療用薬学的組成物。
- 前記MIP‐2は、CXCL2および/またはIL‐8であることを特徴とする請求項4に記載の肝炎の予防または治療用薬学的組成物。
- 前記IL‐4は、肝サイトカインのリン酸化、吸着分子の発現、および/または好中球の移動を抑制することを特徴とする請求項4に記載の肝炎の予防または治療用薬学的組成物。
- 前記サイトカインは、PKC‐ζ、PKCδ、PKCθ、STAT6、およびこれらの混合物からなる群から選択されることを特徴とする請求項6に記載の肝炎の予防または治療用薬学的組成物。
- 下記化学式1で表示されるモノアセチルジアシルグリセロール化合物を有効成分として含有し、肝炎を予防または改善することができる健康機能食品組成物:
(化学式1)
式中、R1及びR2はそれぞれ独立して、炭素原子数14〜22の脂肪酸基である。 - 請求項1または請求項8に記載の組成物を肝炎疾患の疑心個体に投与するステップを含む、肝炎の予防または治療方法。
- 前記組成物に含まれるモノアセチルジアシルグリセロール化合物の投与量は、1日0.001〜2000mg/kgであることを特徴とする請求項9に記載の肝炎の予防または治療方法。
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WO2020178803A1 (en) * | 2019-03-07 | 2020-09-10 | Enzychem Lifesciences Corporation | Composition comprising monoacetyldiacylglycerol compound for treating fatty liver disease |
KR102218545B1 (ko) * | 2019-03-07 | 2021-02-22 | 주식회사 엔지켐생명과학 | 모노아세틸디아실글리세롤 화합물을 유효성분으로 함유하는 지방간 질환 치료용 조성물 |
CN113194940A (zh) * | 2019-03-07 | 2021-07-30 | Enzychem生命科学株式会社 | 治疗脂肪肝的包含单乙酰基二酰基甘油化合物的组合物 |
KR20210094997A (ko) * | 2020-01-22 | 2021-07-30 | (주) 에프엔지리서치 | 녹용에서 분리한 신규 화합물을 유효성분으로 하는 비알코올성 지방간 질환의 예방 또는 치료용 약학적 조성물 또는 건강기능식품 |
WO2023133230A1 (en) * | 2022-01-08 | 2023-07-13 | Sohn Joanna | Monoacetyldiglycerides (plag) as a mitigating agent for traumatic brain injury and ischemia-reperfusion injury |
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CA3040444A1 (en) | 2018-04-19 |
EP3527206A4 (en) | 2020-05-27 |
KR101817552B1 (ko) | 2018-01-11 |
US20190350890A1 (en) | 2019-11-21 |
AU2017341663B2 (en) | 2020-08-27 |
JP2021130670A (ja) | 2021-09-09 |
EP3527206A2 (en) | 2019-08-21 |
CN110121339A (zh) | 2019-08-13 |
AU2017341663A1 (en) | 2019-05-23 |
WO2018070854A2 (ko) | 2018-04-19 |
WO2018070854A3 (ko) | 2018-06-07 |
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