JP2012116763A - Cgrp応答性促進剤 - Google Patents
Cgrp応答性促進剤 Download PDFInfo
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- JP2012116763A JP2012116763A JP2010265230A JP2010265230A JP2012116763A JP 2012116763 A JP2012116763 A JP 2012116763A JP 2010265230 A JP2010265230 A JP 2010265230A JP 2010265230 A JP2010265230 A JP 2010265230A JP 2012116763 A JP2012116763 A JP 2012116763A
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Abstract
【解決手段】ニンジン又はその抽出物を有効成分とする細胞のCGRP応答性促進剤。
【選択図】なし
Description
(1)ニンジン又はその抽出物を有効成分とする細胞のCGRP応答性促進剤。
(2)細胞が血管平滑筋細胞である、(1)の促進剤。
(3)抽出物が水抽出物又はエタノール水溶液抽出物である、(1)又は(2)の促進剤。
(4)ニンジン又はその抽出物を有効成分とする歯周病の予防及び/又は改善剤。
(5)細胞のCGRP応答性を促進する方法であって、CGRP受容体を有し且つCGRP応答性を促進させたい細胞を、ニンジン又はその抽出物の存在下で培養する工程を含む方法。
(6)細胞が血管平滑筋細胞である、(5)の方法。
(7)抽出物が水抽出物又はエタノール水溶液抽出物である、(5)又は(6)の方法。
本発明による細胞のCGRP応答性促進剤は、CGRPにより惹起される細胞におけるこれらの一連のプロセスを促進し得る。例えば、本発明のCGRP応答性促進剤の作用としては、CGRPとその受容体との結合の促進、Gタンパク質活性の増強、アデニレートシクラーゼ活性の増強、細胞内cAMPの増加、プロテインキナーゼA活性の増強、NO産生又はcGMP活性の増強、及びK+チャネル開口促進等が挙げられる。好ましくは、「細胞のCGRP応答性」は、CGRPにより引き起こされる細胞内cAMPの増加の程度を指標として決定され得る。従って、本発明のCGRP応答性促進剤は、好ましくは、CGRPにより惹起される細胞内cAMPの増加を促進する。
あるいは、当該「細胞」は、上記で挙げた細胞の細胞片または細胞分画物であってもよく、上記で挙げた細胞を含む組織又は上記で挙げた細胞に由来する培養物であってもよい。
溶剤の使用量としては、ニンジン(乾燥質量換算)1gに対して1〜100mLが好ましい。抽出条件は、充分な抽出が行える条件であれば特に限定されないが、抽出時間としては、3分間〜30日間が好ましく、60分間〜14日間がより好ましく、抽出温度は、0℃〜溶媒沸点が好ましく、5〜70℃がより好ましい。通常、低温なら長時間、高温なら短時間の抽出を行う。
抽出物を得る抽出手段は、具体的には、固液抽出、液液抽出、浸漬、煎出、浸出、還流抽出、超音波抽出、マイクロ波抽出、攪拌等の手段を用いることができる。
抽出条件の例として、15〜25℃で7日間〜14日間、約70℃で5時間、等が挙げられる。
また、抽出時間を短縮する場合には、攪拌を伴う固液抽出が望ましい。この固液抽出の好適な条件の一例としては、40〜100℃(好ましくは50〜70℃)下、100〜1000rpmで30〜300分間の攪拌が挙げられる。
抽出物の酸化を防止するため、煮沸脱気や窒素ガス等の不活性ガスを通気して溶存酸素を除去しつつ、いわゆる非酸化的雰囲気下で抽出する手段を併用してもよい。
好ましくは、上記医薬又は医薬部外品は、ニンジン若しくはその抽出物又は本発明のCGRP応答性促進剤を有効成分として含有する、歯磨剤、マウスウォッシュ、マウススプレー、口腔洗浄剤、口腔用の軟膏、クリームや塗布剤等の口腔用組成物であり得る。
好ましい形態として、本発明の飲食品は、歯周病予防及び/又は改善をコンセプトトとしたガム、飴、タブレット、飲料、ペット用ガム等であり得る。
上記飲食品等におけるニンジン若しくはその抽出物の含有量は、乾燥重量として、0.00001〜100質量%とするのが好ましく、0.00002〜75質量%とするのがより好ましく、0.00005〜50質量%とするのがさらに好ましく、0.0001〜30質量%とするのがさらにより好ましく、0.0005〜20重量%とするのがなお好ましい。
一態様において、当該投与は、健康促進又は美容目的での皮膚循環の改善、皮膚代謝改善、又は血行促進を企図して、非治療的に行われる。
あるいは、投与対象は、動物由来の組織、器官、細胞、又はそれらの分画物であり得る。当該組織、器官、細胞、又はそれらの分画物は、CGRP受容体を発現するか又はCGRP受容体を有する、天然由来又は生物学的若しくは生物工学的に改変された組織、器官、細胞、又はそれらの分画物である。
チョウセンニンジンPanax ginsengの根(中国産)100gに50%エタノール水溶液1000mLを加え、室温で7日間浸漬抽出した後、ろ過してニンジンエキス840mLを得た(蒸発残分2.8 w/v%)。
ニンジンエキスによる細胞のCGRP応答性促進効果を調べた。
(1)方法
1.細胞培養
正常ヒト冠状動脈平滑筋細胞(HCASMC;クラボウ社、細胞lot# 625723)を増殖用培地(基礎培地HuMedia-SB2 500mlにFBS 25ml、hEGF 0.5ml、hFGF-B 0.5ml、インスリン 0.5ml、抗菌剤 0.5mlを添加したもの;クラボウ社)で培養した。継代には0.025%トリプシン/0.01%EDTAを用いた。
正常ヒト冠状動脈平滑筋細胞を4000個/cm2の密度で増殖用培地を用いて48ウェルプレートに播種し、翌日分化用培地(基礎培地HuMedia-SB2 500mlにFBS 5ml、ヘパリン 0.5ml、抗菌剤 0.5mlを添加したもの;クラボウ社)に交換した。培地を1日おきに交換して7日間培養した。最後の2日間は表1記載の濃度のニンジンエキス(一丸ファルコス株式会社 シンホングギニシン LV、エキス分2.8 w/v%)を含む分化培地にて培養し、CGRP応答性の測定に供した。
細胞を、ホスホジエステラーゼ阻害剤(PDI)IBMX(3-Isobutyl-1-methylxanthine、500μM;シグマ社)及びRo-20-1724(100μM;和光純薬工業株式会社)、所定の濃度のニンジンエキスを含む基礎培地(Humedia-SB2;クラボウ社)で2回洗浄し、さらに同培地を200μl添加して37℃にて60分間培養し、細胞内に阻害剤を浸透させた。培地を除去して表1記載の濃度のニンジンエキス、0.5nM CGRP、ホスホジエステラーゼ阻害剤を含む基礎培地を添加し、15分間37℃にて培養した。反応の停止は、cAMP測定EIAキット(cAMP EIA (non-acetylation);GEヘルスケアバイオサイエンス株式会社)に付属の細胞溶解液を添加することにより行い、取扱説明書に記載の方法に従って細胞内cAMP濃度([cAMP]i)を測定した。ニンジンエキスのCGRP応答性促進能は、0.5nM CGRPのみで刺激したときの[cAMP]iを基準(コントロール)とし、これに対する百分率をImprove Indexとして表した。
CGRP応答性の測定結果を図1に示す。Improve Index 100% は、893.5 fmol/wellの[cAMP]iに相当する。ニンジンエキスの濃度に従ってImprove Indexが増加した。
ニンジンエキスの添加条件を様々に変更して細胞のCGRP応答性を調べた。
(1)方法
実施例1と同様の条件でHCASMC(クラボウ社、細胞lot# 625723)を調製した。分化培地での培養の最後の2日間は、表1に記載の条件下にて培養し、その後、実施例1と同様の方法で細胞のCGRP応答性を測定した。
CGRP応答性の測定結果を図2に示す。Improve Index 100% は、893.5 fmol/wellの[cAMP]iに相当する。分化培地での培養の最後の2日間〜CGRP刺激時にニンジンエキスを添加することにより、Improve Indexは増加した(条件2〜4)。一方、CGRP非存在下ではImprove Indexは有意に低かった(条件5)ことから、ニンジンエキスによる作用は、CGRPを代替するもの(例えば、CGRP受容体アゴニスト)ではなく、CGRPとその受容体との結合により惹起される一連の応答を促進するものであることが示された。
Claims (7)
- ニンジン又はその抽出物を有効成分とする細胞のCGRP応答性促進剤。
- 細胞が血管平滑筋細胞である、請求項1記載の促進剤。
- 抽出物が水抽出物又はエタノール水溶液抽出物である、請求項1又は2記載の促進剤。
- ニンジン又はその抽出物を有効成分とする歯周病の予防及び/又は改善剤。
- 細胞のCGRP応答性を促進する方法であって、CGRP受容体を有し且つCGRP応答性を促進させたい細胞を、ニンジン又はその抽出物の存在下で培養する工程を含む方法。
- 細胞が血管平滑筋細胞である、請求項5記載の方法。
- 抽出物が水抽出物又はエタノール水溶液抽出物である、請求項5又は6記載の方法。
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