JP2017101010A - 糖取り込み促進剤 - Google Patents
糖取り込み促進剤 Download PDFInfo
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- JP2017101010A JP2017101010A JP2015238090A JP2015238090A JP2017101010A JP 2017101010 A JP2017101010 A JP 2017101010A JP 2015238090 A JP2015238090 A JP 2015238090A JP 2015238090 A JP2015238090 A JP 2015238090A JP 2017101010 A JP2017101010 A JP 2017101010A
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Abstract
Description
で表される化合物群から選ばれる1種又は2種以上の化合物を有効成分として含有する、筋肉細胞への糖取り込み促進剤、
[2] 前記糖が、グルコースである、[1]に記載の糖取り込み促進剤、
[3] 以下の式(I)〜(VI):
で表される化合物群から選ばれる1種又は2種以上の化合物を有効成分として含有する、筋肉細胞へのグルコース輸送体4(GLUT4)トランスロケーション活性化剤、
[4] 以下の式(Ic)で表される5−(3,5−ジヒドロキシフェニル)−γ−バレロラクトンを有効成分として含有する、[3]に記載の筋肉細胞へのグルコース輸送体4トランスロケーション活性化剤、
[5] [1]又は[2]に記載の糖取り込み促進剤、及び[3]又は[4]に記載のグルコース輸送体4トランスロケーション活性化剤の少なくとも一種を有効成分として含有する医薬品、
[6] [1]又は[2]に記載の糖取り込み促進剤、及び[3]又は[4]に記載のグルコース輸送体4トランスロケーション活性化剤の少なくとも一種を有効成分として含有するサプリメント、である。
本発明によれば優れた糖取り込み促進作用により、高血糖を改善し、糖尿病の予防もしくは改善する機能性食品や医薬品を提供することが出来る。さらに本発明によればGLUT4を活性化し、GLUT4のトランスロケーションを誘導するGLUT4活性化剤を提供することが出来る。
カテキン代謝物として、上記式(I)〜(VI)で表される化合物を以下製造例1から18の方法で製造した。表1にそれぞれの化合物の化合物名を示す。
(化合物の製造例)
製造例1:エガーテラ・レンタJCM9979株とフラボニフラクター・プラウティ(クロストリジウム・オルビスシンデンス)ATCC49531株および大腸菌K12株の共存下での(S)−5−(3−ヒドロキシフェニル)−γ−バレロラクトン(化合物Ib)の製造方法
カラム:CAPCELLPAK C18 MG(2.0i.d.×100.0mm、5μm、((株)資生堂社製)、流速:0.2mL/分、カラム温度:40℃、溶媒A;水:アセトニトリル:酢酸(100:2.5:0.1 容量比(v/v/v))、溶媒B;水:アセトニトリル:メタノール:酢酸(35:2.5:65:0.1 容量比(v/v/v/v)、グラジエント;0分:A100% B0%、3分:A100% B0%、25分:A0% B100%、25.1分:A100% B0%、33分:A100% B0%、検出:PDA及び質量分析計、インターフェース:ESI、ポラリティ:ネガティブとした。
分取後に分画した画分を、製造例1記載のLC/MS分析と同条件で分析し、目的とする(S)−1−(3,4−ジヒドロキシフェニル)−3−(2,4,6−トリヒドロキシフェニル)−プロパン−2−オールが含まれる画分を確認した。その後、分取液をエバポレーターで濃縮乾固し、乾固物に5mLの純水を加えて再度濃縮乾固する操作を3回繰り返して画分中の酸を完全除去した。乾固物に少量の純水を加えて溶解後、凍結乾燥を行い、(S)−1−(3,4−ジヒドロキシフェニル)−3−(2,4,6−トリヒドロキシフェニル)−プロパン−2−オール(化合物VIc)を110mg得た。
1H−NMR(400MHz,重水素化メタノール):δ7.14(1H,t,J=7.6Hz),6.70(3H,d,J=1.1Hz),3.70(2H,s),2.78(2H,t,J=6.3Hz),2.52(2H,t,J=6.5Hz)
試験例:ラット骨格筋由来L6筋管細胞を用いた2−デオキシグルコース細胞内取り込み量測定試験
まず、ラット骨格筋由来L6細胞(住友大日本製薬株式会社より購入)を、10%(v/v)ウシ胎児血清(FBS、シグマアルドリッチジャパン合同会社より購入)含有イーグル最小必須培地(MEM培地、シグマアルドリッチジャパン合同会社より購入)中で、37℃、5%(v/v)CO2条件下において培養した。つぎに、L6細胞を96穴マルチプレートに播種し、2%(v/v)ウシ胎児血清MEM培地中で5〜6日間インキュベーションし、L6筋管細胞に分化誘導した。そして、培地を無血清MEM培地に置き換え、16〜18時間脱感作させた。
製造例1〜製造例18で製造した各化合物をジメチルスルホキシド(DMSO)にそれぞれ溶解後、L6筋管細胞を培養した無血清MEM培地に添加し(終濃度3μM)、L6筋管細胞に化合物を4時間作用させた。陰性対照としてDMSO、陽性対照としての0.1μMインスリンを同様に作用させた。L6筋管細胞を0.1%(w/v)ウシ血清アルブミン(BSA)含有Krebs Ringer HEPES緩衝液(KRH;50mM HEPES、pH7.4、37mM NaCl、4.8mM KCl、1.85mM CaCl2、1.3mM MgSO4)を用いて2回洗浄した後、0.1%(w/v)BSA含有KRH緩衝液中に溶解した1mMの2−デオキシグルコース(2DG)を加え、37℃で20分間加温した。
図2A、図2B、図2Cに示した様に、本発明の化合物で、L6筋管細胞のグルコース取り込み活性を有意に促進したことが確認できた。
図2Aに記載した化合物の中では、(R)−5−(3,5−ジヒドロキシフェニル)−γ−バレロラクトン(Ic)、(R)−5−(3,4、5−トリヒドロキシフェニル)−γ−バレロラクトン(Id)、5−(3−ヒドロキシフェニル)吉草酸(IIa)、(R)−5−(3,4,5−トリヒドロキシフェニル)−4−ヒドロキシ吉草酸(IVd)において、コントロールと比較して特に高い糖取り込み活性が見られた(有意水準**p<0.01)。
また、図2Bに記載した化合物においては3−(3−ヒドロキシフェニル)−プロピオン酸(IIIa)、(S)−1−(3,4−ジヒドロキシフェニル)−3−(2,4,6−トリヒドロキシフェニル)−プロパン−2−オール(VIc)でコントロールと比較して、特に高い糖取り込み活性が見られた(有意水準**p<0.01)。
また、図2Cに記載した化合物においては(S)−5−(3−ヒドロキシフェニル)−γ−バレロラクトン(Ib)、(S)−5−(3−ヒドロキシフェニル)−4−ヒドロキシ吉草酸(IVa)でコントロールと比較して、特に高い糖取り込み活性が見られた(有意水準**p<0.01)。
ウエスタンブロット法による細胞膜におけるGLUT4発現量の測定
ラット骨格筋由来L6細胞を、10%(v/v)のウシ胎児血清(FBS)含有MEM培地中で、37℃、5%(v/v)CO2条件下において培養した。次に、L6細胞を60mmディッシュに播種し、2%(v/v)ウシ胎児血清MEM培地中で7〜8日間インキュベーションし、L6筋管細胞に分化誘導した。そして、培地を無血清MEM培地に置き換え、16〜18時間脱感作させた。
上記無血清MEM培地に、無血清MEM培地に、終濃度0.3μM、1μM、3μMとなるように(R)−5−(3,5−ジヒドロキシフェニル)−γ−バレロラクトン(化合物Ic)、および比較として既に糖取り込み促進作用を有することが明らかとなっている(−)−エピガロカテキンガレート(EGCg)1μM(終濃度)を添加し、L6筋管細胞に15分作用させた。陰性対照として溶媒として使用したDMSO、陽性対照としての0.1μMインスリンも同様に添加し、L6筋管細胞に15分作用させた。
上清を除き、再び沈殿にKRH緩衝液を200μL加え、3,000rpm、10分間、4℃で遠心分離した。さらに、上清を除き、1%NP−40含有緩衝液Aを40μL加え、細胞膜画分とした。画分を1時間放置し、15,000rpm、20分間、4℃で遠心分離し、得られた上清を細胞膜タンパク質画分として、下記するウエスタンブロッティングに供した。
L6筋管細胞を培養させた無血清MEM培地に、終濃度0.3μM、1μM、3μMとなるように(R)−5−(3,5−ジヒドロキシフェニル)−γ−バレロラクトン(化合物Ic)、及び比較として1μM EGCgをそれぞれ添加し、L6筋管細胞に上記物質を15分作用させた。陰性対照として溶媒として使用したDMSO、陽性対照としての0.1μM インスリンも同様に添加し、L6筋管細胞に15分作用させた。L6筋管細胞を、KRH緩衝液を用いて2回洗浄した後、RIPAバッファー(10 mM Tris−HCl、pH8.0、150mM塩化ナトリウム、1% NP−40、0.5%デオキシコール酸ナトリウム、0.1%ドデシル硫酸ナトリウム(SDS)、10mM NaF、1mM Na3VO4、5 μg/mLアプロチニン、1mM PMSF、500μM DTT、5μg/mLロイペプチン)120μLを加えてセルスクレーパーで剥ぎ、マイクロチューブに回収した。そしてこれをマイクロチューブホモジナイザーで摩砕し、1時間氷冷の後に、15000rpm、20分間、4℃で遠心分離し、得られた上清を細胞全タンパク質画分として、下記のウエスタンブロッティングに供した。
上記の回収した画分を、250mM Tris−HCl、20%(v/v)の2−メルカプトエタノール、140mMSDS、44%(v/v)グリセロール、750μMブロモフェノールブルーを含む4×SDSバッファーにて希釈した後、タンパク質のSDS化及びタンパク質中のジスルフィド結合の還元処理を効率よく行わせるために100℃で5分間加熱した。
Claims (6)
- 以下の式(I)〜(VI):
で表される化合物群から選ばれる1種又は2種以上の化合物を有効成分として含有する、筋肉細胞への糖取り込み促進剤。 - 前記糖が、グルコースである、請求項1に記載の糖取り込み促進剤。
- 以下の式(I)〜(VI):
で表される化合物群から選ばれる1種又は2種以上の化合物を有効成分として含有する、筋肉細胞へのグルコース輸送体4トランスロケーション活性化剤。 - 以下の式(Ic)で表される5−(3,5−ジヒドロキシフェニル)−γ−バレロラクトンを有効成分として含有する、請求項3に記載の筋肉細胞へのグルコース輸送体4トランスロケーション活性化剤。
- 請求項1又は請求項2に記載の糖取り込み促進剤、及び請求項3又は請求項4に記載のグルコース輸送体4トランスロケーション活性化剤の少なくとも一種を有効成分として含有する医薬品。
- 請求項1又は請求項2に記載の糖取り込み促進剤、及び請求項3又は4に記載のグルコース輸送体4トランスロケーション活性化剤の少なくとも一種を有効成分として含有するサプリメント。
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CN111989318A (zh) * | 2018-02-08 | 2020-11-24 | 医疗法人圣光医疗财团 | Dhpv的新合成方法 |
CN111989318B (zh) * | 2018-02-08 | 2023-04-04 | 医疗法人圣光医疗财团 | Dhpv的新合成方法 |
WO2023120425A1 (ja) * | 2021-12-22 | 2023-06-29 | 国立大学法人大阪大学 | 脳機能改善剤 |
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