JP2022528087A - 線維症の予防、改善または治療のためのchp(シクロ-ヒスプロ)の用途 - Google Patents
線維症の予防、改善または治療のためのchp(シクロ-ヒスプロ)の用途 Download PDFInfo
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Abstract
Description
本発明は、線維症の予防、改善または治療のためのCHP(シクロ-ヒスプロ)の用途に関し、より詳細には、CHPを含む線維症の予防または治療用薬学組成物、線維症の予防または改善用健康機能食品組成物、抗線維性組成物、CHPを用いた線維症の予防または治療方法および/または線維症を予防または治療するための薬学組成物の製造時におけるCHPの用途に関する。
[背景技術]
[発明の概要]
[発明が解決しようとする課題]
[課題を解決するための手段]
[発明の効果]
以下、本発明をより詳細に説明する。
前記の他に、本発明の健康機能食品は、色々な栄養剤、ビタミン、電解質、風味剤、着色剤、ペクチン酸、ペクチン酸塩、アルギン酸、アルギン酸塩、有機酸、保護性コロイド増粘剤、pH調節剤、安定化剤、防腐剤、グリセリン、アルコールまたは炭酸化剤などを含有できる。その他、本発明の健康食品は、天然フルーツジュース、フルーツジュース飲料、または野菜飲料の製造のための果肉を含有できる。このような成分は、独立して、または混合して使用できる。このような添加剤の割合は、大きく重要なことではないが、本発明の組成物100重量部当たり0.01~0.1重量部の範囲で選択されることが一般的である。
下記実施例で使用したCHP(シクロ-ヒスプロ)は、バッケム社から購入して使用した。
CHP処理による人体由来近位尿細管上皮細胞における抗線維効果の確認
1-1.人体由来近位尿細管上皮細胞の分離および培養
図1に示されたように、正常な成人の腎臓組織から糸球体および尿細管間質組織を分離し、これを初代培養することによって、細胞実験に活用可能な人体由来糸球体内皮細胞および人体由来近位尿細管上皮細胞を純粋分離および培養した。
前記実施例1-1で分離および初代培養された人体由来近位尿細管上皮細胞に組換えTGFβ(2ng/ml)を処理して細胞線維化を誘導することによって、細胞骨格リモデリング(cytoskeletal remodeling)と形態学的変化(細くて長くなり、構造が消える)が発生して、線維化が適切に誘導されたことを確認した(図2)。
前記実施例1-2と同様の条件で、CHP投与後に接合マーカー(junction marker)であるE-カドヘリン、線維化マーカーであるフィブロネクチンおよび線維化転写因子であるpSTAT3タンパク質の発現レベルをウェスタンブロットで確認した。
CHPによる人体由来糸球体内皮細胞における抗線維効果の確認
人体由来糸球体内皮細胞の線維化モデルでCHP処理後に細胞学的形態の観察
前記実施例1-1の人体由来近位尿細管上皮細胞の線維化モデルと同様に、rTGFβ(2ng/ml)を処理して糸球体内皮細胞で細胞線維化を誘導することによって、細胞骨格リモデリング(cytoskeletal remodeling)と形態学的変化が発生して、線維化が適切に誘導されたことを確認した(図4)。
CHP処理によるヒト由来肝細胞における抗線維効果の確認
3-1.ヒト由来肝細胞の培養および線維化誘導後にCHP処理
Huh7肝細胞株の培養のために、Hyclone社からDMEM培地とFBSを購入し、線維化誘導のためのTGFβは、R&D systems社から購入した。10%FBSを添加したDMEM培地で37℃で5%CO2インキュベーターで培養し、TGFβを2ng/mlの濃度になるように処理すると同時に、CHPを0、62.5、125、250ng/mlになるように処理し、処理48時間目に細胞を回収した。
線維化タンパク質であるフィブロネクチン(Fibronectin)タンパク質発現分析のために、Thermo社のRIPA溶解バッファー(lysis buffer)とHaltTMプロテアーゼ(Protease)およびホスファターゼ(Phosphatase)阻害剤カクテルを購入し、タンパク質定量のためには、Thermo社のBCAタンパク質定量キットを購入した。ウェスタンブロットは、Thermo社のBoltTMタンパク質ゲル電気泳動システムとBio-rad社のWetトランスファーシステムを準備した。肝線維症マーカーであるフィブロネクチンタンパク質の抗体とローディングコントロールとして使用されるGAPDH抗体は、Abcam社から購入した。回収したHuh7細胞にプロテアーゼおよびホスファターゼ阻害剤が添加されたRIPAバッファー100μlを入れ、ピペッティングで細胞を溶解させた。10分間氷に放置させた後、4℃で15,000rpmで10分間遠心分離した。上澄み液を集めて、BCA定量法でタンパク質の濃度を測定し、同量のサンプルをBoltTMタンパク質ゲル電気泳動システムを用いてタンパク質を分離させ、ニトロセルロースメンブレン(Nitrocellulose membrane)に移した。メンブレンは、5%スキムミルク(skim milk)で常温で1時間遮断(blocking)を進めた後、1次抗体であるフィブロネクチンおよびGAPDH抗体と4℃で一晩中(overnight)反応させた。TBSTで10分ずつ3回洗った後、2次抗体と常温で1時間反応させた。TBSTで10分ずつ3回洗った後、ECLで反応させて、発現程度を測定した。現れるバンドのサイズは、ImageJプログラムを用いて定量し、フィブロネクチンバンドのサイズ値をGAPDHバンドのサイズ値で割って補正した。統計的有意性は、対照群とのスチューデントt-検定(Student’s t-test)統計法を使用して分析した。#p<0.05(陰性対照群:TGFβ処理対照群)。
CHP投与による肝線維化動物モデルにおける抗線維効果の確認
長期間の高脂肪食の摂取は、肝線維化を誘発するリスク要素と知られている。脂肪食を長期間摂取時に現れるインスリン抵抗性と増加した血中脂肪酸、アディポカイン、サイトカインによって肝組織に炎症環境が誘発され、肝組織に蓄積された免疫細胞の相互作用は線維化を進行させるが、特に、Th2 CD4+ T細胞が分泌するIL-13サイトカインが、マクロファージから線維化の核心誘発因子であるTGFβを多量生成させる。TGFβによるシグナル伝達は、肝組織内細胞の変形を引き起こし、線維化の進行を促進する(Rosselli,M et al.,Current Pharmaceutical Design,20(31),5010-5024,2014;Wu.D et al.,Science,332:243-7,2011;J Investig Med,60(8):1147-1150,2012;Fichtner-Feigl S et al.,Nat Med,12:99-106,2006;Lee CG et al.,J Exp Med,194:809-21,2001)。
動物における肝線維症の実験のために、米国のJackson社から6週間60%脂肪含有高脂肪食を摂取した12週齢のC57BL/6マウスを購入し、60%脂肪含有高脂肪食の飼料は、Research diets D12492をセロンバイオ社から購入して17週間摂取させた。マウスは、24±3℃の環境で飼料と水に自由に接近が可能に飼育した。6週間高脂肪食を摂取したC57BL/6マウスを1週間飼育環境に適応させ、体重を測定して、表1のように均等に3グループに分けた。CHPは、5mg/kgまたは35mg/kgの濃度で各グループに1日に1回、16週間経口投与し、対照群には、同量の蒸留水を同一の方法で経口投与した。
マウスの麻酔と解剖に必要なイソフルレン(Isoflurane)をハナ製薬から購入し、Vetequip社のRC2 Rodent Circuit Controller Anesthesia Systemを準備した。リン酸緩衝生理食塩水(PBS)は、Hyclone社から購入した。マウスの肝組織の分離のために、3~3.5%イソフルレンでマウスを呼吸麻酔させた。麻酔したマウスの心臓から血液を採取した後、肝組織を直ちに摘出してPBSで洗浄した後、肝組織を50mg切り出して、プロテアーゼおよびホスファターゼ阻害剤が添加されたRIPAバッファー500μlに入れ、IKA社のT10ホモジナイザー(homogenizer)を用いて粉砕した。15分間氷に放置させた後、4℃で15,000rpmで遠心分離した。線維化タンパク質であるフィブロネクチンタンパク質発現の分析のために、実施例3-2と同一の方法でウェスタンブロットを実施した。統計的有意性は、HFD対照群とのスチューデントt-検定(Student’s t-test)統計法を使用して分析した(*p<0.05、**p<0.01)。
CHP処理によるヒト由来肺細胞における抗線維効果の確認
5-1.ヒト由来肺細胞の培養および線維化誘導後にCHP処理
L-132肺細胞株の培養のために、Hyclone社からMEM培地とFBSを購入し、線維化誘導のためのTGFβは、R&D systems社から購入した。10%FBSを添加したMEM培地で37℃、5%CO2インキュベーターで培養し、TGFβを2ng/mlの濃度になるように処理すると同時に、CHPを0、62.5または125ng/mlになるように処理し、処理48時間目に細胞を回収した。
線維化タンパク質であるフィブロネクチンタンパク質発現の分析のために、実施例3-2と同一の方法でウェスタンブロットを実施した。統計的有意性は、対照群とのスチューデントt-検定(Student’s t-test)統計法を使用して分析した(#p<0.05(陰性対照群:TGFβ処理対照群)、**p<0.01(TGFβ処理対照群:CHP 125ng/ml処理群))。
CHP投与による肺線維化動物モデルにおける抗線維効果の確認
長期間の高脂肪食の摂取によって肺線維化が発生する。これは、高脂肪の摂取による炎症数値の増加によるものと見られるが、正常マウスに60%脂肪含有高脂肪食を15週間摂取させたとき、肺線維化が現れた報告がある(Ge,X.N et al.,Experimental Lung Research、39(9),365-378,2016)。具体的に、高脂肪食の長期間摂取は、肥満を誘導し、肥大化した脂肪組織とこちらに集まった免疫細胞が分泌するアディポカインとサイトカインは、骨髄から肺への免疫細胞の移動をかく乱させ、慢性炎症反応を起こす(de Vries A et al.,Clin Exp Allergy,39:731-739,2009)。また、Th2 CD4+ T細胞が分泌するIL-13サイトカインは、線維化の核心誘発因子であるTGFβが多量生成されるようにし、TGFβによるシグナル伝達は、肺組織の変形と線維化現象を促進する(Fichtner-Feigl S et al.,Nat Med,12:99-106,2006;Lee CG et al.,J Exp Med,194:809-21,2001)。肺の線維化は、正常に比べて増加したTGFβ遺伝子などの発現量を通じて確認が可能である(Ge,X.N et al.,Experimental Lung Research,39(9),365-378,2016)。
動物における肺線維症の実験のために、実施例4-1と同一の方法で肺線維化動物モデルを確立した。
マウスの麻酔と解剖に必要なイソフルレン(Isoflurane)をハナ製薬から購入し、Vetequip社のRC2 Rodent Circuit Controller Anesthesia Systemを準備した。リン酸緩衝生理食塩水(PBS)は、Hyclone社から購入した。マウスの肺組織分離のために、3~3.5%イソフルレンでマウスを呼吸麻酔させた。麻酔したマウスの心臓から血液を採取した後、肺組織を直ちに摘出して肺50mgを切り出して、NucleoZOL 500μLを入れ、IKA社のT10ホモジナイザーを用いて粉砕した。次に、NucleoZOLのTotal RNA分離プロトコルによってRNAを抽出し、1μgのRNAをiScript cDNA合成キットを用いて逆転写ポリメラーゼ連鎖反応(Reverse Transcription Polymerase Chain Reaction)でcDNAを合成した。合成したcDNAは、各遺伝子に該当する正方向/逆方向プライマーセットを用いてiQ SYBR Green SupermixでリアルタイムPCRを進めて分析した。各遺伝子の発現値は、ハウスキーピング遺伝子であるGAPDHの発現値で割って補正した。リアルタイムPCRのためのプライマーは、表2のような塩基配列でBioneer社で合成して使用した。
CHP処理によるヒト由来皮膚細胞における抗線維効果の確認
7-1.ヒト由来皮膚細胞の培養および線維化誘導後にCHP処理
HS68皮膚線維芽細胞由来細胞株の培養のために、Hyclone社からDMEM培地とFBSを購入し、線維化誘導のためのTGFβは、R&D systems社から購入した。10%FBSを添加したDMEM培地で37℃、5%CO2インキュベーターで培養し、TGFβを2ng/mlの濃度になるように処理すると同時に、CHPを0、62.5、125、250または500ng/mlになるように処理し、処理48時間目に細胞を回収した。
線維化タンパク質であるフィブロネクチンタンパク質発現の分析のために、実施例3-2と同一の方法でウェスタンブロットを実施した。統計的有意性は、対照群とのスチューデントt-検定(Student’s t-test)統計法を使用して分析した(#p<0.05(陰性対照群:TGFβ処理対照群)、*p<0.05(TGFβ処理対照群:CHP 500ng/ml処理群))
CHP投与による心臓線維化動物モデルにおける抗線維効果の確認
心臓線維症のリスク要因としては、誤った食習慣と肥満、高いコレステロール数値などがよく知られている。高脂肪食を長期間摂取時、肥満による血量過多症が発生して、心臓に過負荷が誘発されて、心臓の収縮と弛緩機能に変形が引き起こされる。これと共に現れる高血糖、インスリン抵抗性、高脂血症、慢性炎症などの症状は、心臓線維化に決定的に作用することが知られている(Kaltman AJ,Goldring RM.,Am J Med,60:645-653,1976;Xia Y et al.,Histochem Cell Biol,131:471-481,2009;Ulasova E et al.,J Mol Cell Cardiol.,50:147-156,2011;Lo CS et al.,J Cell Biochem.,103:1999-2009,2008;Cavalera,M et al.,Translational Research,164(4),323-335,2014)。特に、肥満による心臓肥満細胞(Cardiac mast cell)の増加とこれらの脱顆粒現象は、心臓組織にTGFβのような線維化誘発因子を提供し、心臓線維化をさらに促進することが知られている(Kong P,Christia P,Frangogiannis NG,Cell Mol Life Sci.,71:549-574,2014)。
動物における心臓線維症の実験のために、実施例4-1と同一の方法で心臓線維化動物モデルを確立した。
マウスの麻酔と解剖に必要なイソフルレン(Isoflurane)をハナ製薬から購入し、Vetequip社のRC2 Rodent Circuit Controller Anesthesia Systemを準備した。リン酸緩衝生理食塩水(PBS)は、Hyclone社から購入した。マウスの心臓組織分離のために、3~3.5%イソフルレンでマウスを呼吸麻酔させた。麻酔したマウスの心臓から血液を採取した後、心臓組織を直ちに摘出して心臓50mgを切り出し、RNA抽出および遺伝子発現分析は、実施例6-2と同一に行った。リアルタイムPCRのためのプライマーは、表3のような塩基配列でBioneer社で合成して使用した。各遺伝子の発現値は、ハウスキーピング遺伝子であるβ-アクチンの発現値で割って補正した。
CHP投与による脂肪線維化動物モデルにおける抗線維効果の確認
線維症を防ぐためには、炎症反応を遮断することが最善であると知られている。特に、脂肪組織は、炎症物質を分泌して炎症による脂肪線維化の悪循環を惹起する。正常マウスに60%脂肪含有高脂肪食を16~24週間摂取させたとき、脂肪組織の線維化が現れるという報告がある(Hu,M et al.,Evidence-Based Complementary and Alternative Medicine,1-12,2018;Kwon,E.Y.,& Choi,M.S.,Nutrients,10(10),1415,2018;Nakazeki,F et al.,Scientific Reports,8(1),2018;Muniappan,L et al.,Scientific Reports,7(1),2017;Lancha,A et al.,PLoS ONE、9(5),e98398,2014;Velazquez,K.T et al.,Physiological Reports,5(18),e13412,2017;Wang,L.,Ye,X.,Hua,Y.,& Song,Y.,Biomedicine & Pharmacotherapy,105,121-129,2018)。高脂肪食を長期間摂取時、栄養過多によって脂肪細胞の拡張が起こることで、中性脂肪の蓄積、脂肪細胞死滅、アディポカインとサイトカインの生成、小胞体ストレス、脂肪組織低酸素症などが発生して、脂肪組織への免疫細胞の浸透が起こり、慢性炎症が起こる(Schenk S et al.,J Clin Invest,118:2992-3002,2008;Sun K,Kusminski CM,Scherer PE,J Clin Invest,121:2094-101,2011)。脂肪組織に蓄積された様々な炎症性免疫細胞とマクロファージ-脂肪細胞間の相互作用は、線維化の核心誘発因子であるTGFβを生成し、そのため、脂肪組織の変形が起こって、脂肪線維化が誘発される(Lee CG et al.,J Exp Med,194:809-21,2001;Fichtner-Feigl S et al.,Nat Med,12:99-106,2006;Pessin,J.E.,& Kwon,H,Journal of Investigative Medicine,60(8),1147-1150,2012)。脂肪組織の線維化は、正常脂肪組織に比べて増加する代表的線維化遺伝子マーカーの発現変化を通じて確認が可能である。
動物における脂肪線維症の実験のために、実施例4-1と同一の方法で脂肪線維化動物モデルを確立した。
マウスの麻酔と解剖に必要なイソフルレン(Isoflurane)をハナ製薬から購入し、Vetequip社のRC2 Rodent Circuit Controller Anesthesia Systemを準備した。リン酸緩衝生理食塩水(PBS)は、Hyclone社から購入した。マウスの脂肪組織分離のために、3~3.5%イソフルレンでマウスを呼吸麻酔させた。麻酔したマウスの心臓から血液を採取した後、副睾丸脂肪組織(EAT)を直ちに摘出して脂肪100mgを切り出し、RNA抽出および遺伝子発現分析は、実施例6-2と同一に行った。リアルタイムPCRのためのprimerは、表4のような塩基配列でBioneer社で合成して使用した。各遺伝子の発現値は、ハウスキーピング遺伝子であるGAPDHの発現値で割って補正した。
Claims (13)
- シクロ-ヒスプロまたはその薬学的に許容可能な塩を含む、線維症の予防または治療用薬学組成物。
- 前記線維症は、腎臓、肝、肺、皮膚、心臓、すい臓、泌尿器系、生殖器系、汗腺、神経、脳、骨髄、筋肉および関節からなる群から選択されたいずれか一つ以上で発生するものである、請求項1に記載の線維症の予防または治療用薬学組成物。
- 前記線維症は、肺線維症(Pulmonary Fibrosis)、特発性肺線維症(Idiopathic Pulmonary Fibrosis)、放射線誘発性肺損傷(Radiation-induced lung injury)または肺線維化、肺浮腫、嚢胞性線維症(Cystic Fibrosis)、肝線維化、心内膜心筋線維症(Endomyocardial Fibrosis)、心筋梗塞(Myocardial Infarction)、心房線維化(Atrial Fibrosis)、グリア性瘢痕(Glial scar)、腎線維症(Renal Fibrosis)、骨髄線維症(Myelofibrosis)、関節線維症(Arthrofibrosis)、脂肪線維症、皮膚線維症、神経線維腫症および筋線維症からなる群から選択されたいずれか一つ以上である、請求項1に記載の線維症の予防または治療用薬学組成物。
- シクロ-ヒスプロまたはその食品学的に許容可能な塩を含む、線維症の予防または改善用健康機能食品組成物。
- 前記線維症は、腎臓、肝、肺、皮膚、心臓、すい臓、泌尿器系、生殖器系、汗腺、神経、脳、骨髄、筋肉および関節からなる群から選択されたいずれか一つ以上で発生するものである、請求項4に記載の線維症の予防または改善用健康機能食品組成物。
- 前記線維症は、肺線維症(Pulmonary Fibrosis)、特発性肺線維症(Idiopathic Pulmonary Fibrosis)、放射線誘発性肺損傷(Radiation-induced lung injury)または肺線維化、肺浮腫、嚢胞性線維症(Cystic Fibrosis)、肝線維化、心内膜心筋線維症(Endomyocardial Fibrosis)、心筋梗塞(Myocardial Infarction)、心房線維化(Atrial Fibrosis)、グリア性瘢痕(Glial scar)、腎線維症(Renal Fibrosis)、骨髄線維症(Myelofibrosis)、関節線維症(Arthrofibrosis)、脂肪線維症、皮膚線維症、神経線維腫症および筋線維症からなる群から選択されたいずれか一つ以上である、請求項4に記載の線維症の予防または改善用健康機能食品組成物。
- シクロ-ヒスプロまたはその薬学的に許容可能な塩を含む、抗線維性組成物。
- シクロ-ヒスプロを有効量でこれを必要とする個体に投与する段階を含む、線維症を予防または治療する方法。
- 前記線維症は、腎臓、肝、肺、皮膚、心臓、すい臓、泌尿器系、生殖器系、汗腺、神経、脳、骨髄、筋肉および関節からなる群から選択されたいずれか一つ以上で発生するものである、請求項8に記載の線維症を予防または治療する方法。
- 前記線維症は、肺線維症(Pulmonary Fibrosis)、特発性肺線維症(Idiopathic Pulmonary Fibrosis)、放射線誘発性肺損傷(Radiation-induced lung injury)または肺線維化、肺浮腫、嚢胞性線維症(Cystic Fibrosis)、肝線維化、心内膜心筋線維症(Endomyocardial Fibrosis)、心筋梗塞(Myocardial Infarction)、心房線維化(Atrial Fibrosis)、グリア性瘢痕(Glial scar)、腎線維症(Renal Fibrosis)、骨髄線維症(Myelofibrosis)、関節線維症(Arthrofibrosis)、脂肪線維症、皮膚線維症、神経線維腫症および筋線維症からなる群から選択されたいずれか一つ以上である、請求項8に記載の線維症を予防または治療する方法。
- 線維症を予防または治療するための薬学組成物の製造時におけるシクロ-ヒスプロの用途。
- 前記線維症は、腎臓、肝、肺、皮膚、心臓、すい臓、泌尿器系、生殖器系、汗腺、神経、脳、骨髄、筋肉および関節からなる群から選択されたいずれか一つ以上で発生するものである、請求項11に記載のシクロ-ヒスプロの用途。
- 前記線維症は、肺線維症(Pulmonary Fibrosis)、特発性肺線維症(Idiopathic Pulmonary Fibrosis)、放射線誘発性肺損傷(Radiation-induced lung injury)または肺線維化、肺浮腫、嚢胞性線維症(Cystic Fibrosis)、肝線維化、心内膜心筋線維症(Endomyocardial Fibrosis)、心筋梗塞(Myocardial Infarction)、心房線維化(Atrial Fibrosis)、グリア性瘢痕(Glial scar)、腎線維症(Renal Fibrosis)、骨髄線維症(Myelofibrosis)、関節線維症(Arthrofibrosis)、脂肪線維症、皮膚線維症、神経線維腫症および筋線維症からなる群から選択されたいずれか一つ以上である、請求項11に記載のシクロ-ヒスプロの用途。
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KR10-2020-0037859 | 2020-03-27 | ||
PCT/KR2020/004354 WO2020197359A1 (ko) | 2019-03-28 | 2020-03-30 | 섬유증의 예방, 개선 또는 치료를 위한 chp (사이클로-히스프로)의 용도 |
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2022528857A (ja) * | 2019-03-28 | 2022-06-16 | ノブメタファーマ カンパニー リミテッド | 腹膜線維症の予防、改善または、治療のためのchp(シクロ-ヒスプロ)の用途 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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BR112022018707A2 (pt) | 2020-03-20 | 2022-11-01 | Novmetapharma Co Ltd | Composição farmacêutica, composição alimentícia funcional saudável e uso de ciclo-hispro ou um sal farmaceuticamente aceitável do mesmo |
US20220054541A1 (en) * | 2020-08-20 | 2022-02-24 | Novmetapharma Co., Ltd. | Method for treating inflammatory bowel diseases |
US20220193073A1 (en) * | 2020-12-18 | 2022-06-23 | NovMeta Pharma Co., Ltd. | Method of treating fibrosis |
WO2023249049A1 (ja) * | 2022-06-23 | 2023-12-28 | 学校法人 愛知医科大学 | 腹膜劣化抑制組成物、腹膜劣化抑制組成物キット、腹膜透析液、および腹膜透析液キット |
WO2024085325A1 (ko) * | 2022-10-19 | 2024-04-25 | 이화여자대학교 산학협력단 | 티플락스티닌을 포함하는 복막 섬유증의 개선, 예방 또는 치료용 조성물 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004518614A (ja) * | 2000-08-04 | 2004-06-24 | ディーエムアイ バイオサイエンシズ インコーポレイテッド | ジケトピペラジン類の使用方法とジケトピペラジン類を含む組成物 |
JP2007500747A (ja) * | 2003-05-15 | 2007-01-18 | ディーエムアイ バイオサイエンシズ インコーポレイテッド | T細胞媒介性疾患の処置 |
JP2011521956A (ja) * | 2008-05-27 | 2011-07-28 | ディエムアイ アクイジション コーポレイション | 治療方法および化合物 |
JP2013537195A (ja) * | 2010-09-07 | 2013-09-30 | ディエムアイ アクイジション コーポレイション | 疾患の治療 |
WO2018012901A1 (ko) * | 2016-07-13 | 2018-01-18 | 주식회사 노브메타파마 | 사이클로 히스티딘-프롤린을 유효성분으로 포함하는 세포 보호용 조성물 |
WO2020013974A1 (en) * | 2018-07-10 | 2020-01-16 | Novmetapharma Co., Ltd. | Novel polymorphic forms of cyclo (-his-pro) |
JP2022528857A (ja) * | 2019-03-28 | 2022-06-16 | ノブメタファーマ カンパニー リミテッド | 腹膜線維症の予防、改善または、治療のためのchp(シクロ-ヒスプロ)の用途 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5576287A (en) * | 1994-04-29 | 1996-11-19 | Wake Forest University | Method for treating acute renal disease and failure |
AU2000259049A1 (en) * | 2000-06-30 | 2002-01-14 | Chandan Prasad | Histidyl-proline diketopiperazine and method of use |
WO2008109445A1 (en) * | 2007-03-02 | 2008-09-12 | Preventive Nutrient Company, Inc. | Compositions and methods for treating alzheimer's disease and dementia |
US20120070520A1 (en) * | 2009-05-26 | 2012-03-22 | Hyun Jung Shin | Composition containing a bean extract for improving blood circulation and increasing vascular health |
KR101224685B1 (ko) * | 2010-11-23 | 2013-01-21 | 강릉원주대학교산학협력단 | 새우젓 분말, 새우젓 극성용매 가용 추출물 및 극성용매 불용성 추출 잔여물을 유효성분으로 함유하는 비만 또는 고지혈증 및 동맥경화성 혈관계 질환의 예방 및 치료용 조성물 |
KR101273163B1 (ko) * | 2010-11-23 | 2013-06-14 | 강릉원주대학교산학협력단 | 오징어젓 분말, 오징어젓 극성용매 가용 추출물 및 극성용매 불용성 추출 잔여물을 유효성분으로 함유하는 비만 또는 고지혈증 및 동맥경화성 혈관계 질환의 예방 및 치료용 조성물 |
WO2013006170A1 (en) * | 2011-07-06 | 2013-01-10 | Hewlett-Packard Development Company, L.P. | Telepresence portal system |
KR101418968B1 (ko) | 2011-07-08 | 2014-07-14 | 대구대학교 산학협력단 | CHP(cyclo(His-Pro))를 고농도로 함유한 대두 가수분해물을 포함하는 혈당 조절용 조성물 |
WO2016153363A1 (en) * | 2015-03-24 | 2016-09-29 | The New Zealand Institute For Plant And Food Research Limited | Water-soluble mussel extract |
KR101617584B1 (ko) * | 2015-05-13 | 2016-05-02 | 이화여자대학교 산학협력단 | 복막 섬유증의 예방 또는 치료용 약학적 조성물 |
KR102012554B1 (ko) * | 2016-07-13 | 2019-08-23 | 주식회사 노브메타파마 | 사이클로 히스티딘-프롤린을 유효성분으로 포함하는 세포 보호용 조성물 |
KR101734986B1 (ko) * | 2016-07-20 | 2017-05-12 | 부산대학교 산학협력단 | 아리스몰을 유효성분으로 포함하는 섬유화 질환의 예방 또는 치료용 조성물 |
CN107260730B (zh) * | 2017-05-31 | 2019-10-22 | 上海市东方医院 | 组蛋白去乙酰化酶hdac6的抑制剂在制备防治腹膜透析后腹膜纤维化的药物中的用途 |
-
2020
- 2020-03-27 KR KR1020200037858A patent/KR102133151B1/ko active IP Right Grant
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- 2020-03-30 JP JP2021557878A patent/JP7330471B2/ja active Active
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- 2020-03-30 WO PCT/KR2020/004343 patent/WO2020197356A1/ko unknown
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- 2020-03-30 WO PCT/KR2020/004354 patent/WO2020197359A1/ko unknown
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- 2020-03-30 JP JP2021557877A patent/JP7224006B2/ja active Active
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004518614A (ja) * | 2000-08-04 | 2004-06-24 | ディーエムアイ バイオサイエンシズ インコーポレイテッド | ジケトピペラジン類の使用方法とジケトピペラジン類を含む組成物 |
JP2007500747A (ja) * | 2003-05-15 | 2007-01-18 | ディーエムアイ バイオサイエンシズ インコーポレイテッド | T細胞媒介性疾患の処置 |
JP2011521956A (ja) * | 2008-05-27 | 2011-07-28 | ディエムアイ アクイジション コーポレイション | 治療方法および化合物 |
JP2013537195A (ja) * | 2010-09-07 | 2013-09-30 | ディエムアイ アクイジション コーポレイション | 疾患の治療 |
WO2018012901A1 (ko) * | 2016-07-13 | 2018-01-18 | 주식회사 노브메타파마 | 사이클로 히스티딘-프롤린을 유효성분으로 포함하는 세포 보호용 조성물 |
WO2020013974A1 (en) * | 2018-07-10 | 2020-01-16 | Novmetapharma Co., Ltd. | Novel polymorphic forms of cyclo (-his-pro) |
JP2022528857A (ja) * | 2019-03-28 | 2022-06-16 | ノブメタファーマ カンパニー リミテッド | 腹膜線維症の予防、改善または、治療のためのchp(シクロ-ヒスプロ)の用途 |
Non-Patent Citations (2)
Title |
---|
AMINO ACIDS, vol. 35, JPN7022005977, 2008, pages 283 - 289, ISSN: 0004961471 * |
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY :KIDNEY WEEK EDITION (ABSTRACT SUPPLEMENT), JPN7022005978, November 2019 (2019-11-01), pages 786, ISSN: 0004961472 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022528857A (ja) * | 2019-03-28 | 2022-06-16 | ノブメタファーマ カンパニー リミテッド | 腹膜線維症の予防、改善または、治療のためのchp(シクロ-ヒスプロ)の用途 |
JP7224006B2 (ja) | 2019-03-28 | 2023-02-17 | ノブメタファーマ カンパニー リミテッド | 腹膜線維症の予防、改善または、治療のためのchp(シクロ-ヒスプロ)の用途 |
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