2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/651287摘要：糖尿病人口逐年攀升，但目前藥物對血糖控制情形仍不理想，因此尋找新的糖尿病候選藥物是迫切的任務。先前研究發現赤芍粗萃取物在糖尿病小鼠模式下可改善高血糖、胰島素抗性及β細胞功能。赤芍的四種活性成分：P1、P2、P3與富含多酚的部分純化物(此部分純化物稱 PEF)中，P1-P3在小鼠體內具有增進葡萄糖利用與改善葡萄糖耐受性等活性，PEF在活體實驗中具抑制 PEPCK基因表現之活性。P1、P2、P3與 PEF依特定比例混合的配方(此配方稱為 PRM)活性與粗萃取物相當，表示化合物間具協同作用。此外，此配方且比僅含 P1-P3配方之活性增強許多，顯示 PEF扮演關鍵角色。核磁共振譜及透析結果得知 PEF含分子量超過 3,000的大分子多酚。為發展赤芍為抗糖尿病之新候選藥物，本計畫擬延續上述研究成果，以三年的時間進行以下工作： 第一年 − 進行 PEF 之分離、化學特性描述以及降解以釐清化學組成與結構活性之關係，並建立 PEF之指紋圖譜。 第二年 − 進行 PEF 六個批次樣品製備與各批次間化學指紋特徵之比較，合併後進行大規模(> 10克)之大分子芍藥多酚(MPPs)純化及動物活性測試；與已知成分化學指紋圖譜之比對，鑑定出新穎化合物。 第三年 − 進行單一組成剔除方法以評估指紋圖譜與活性之關係；完成化合物 P1-P3 與MPPs 之配方最佳化；此外，將以液相層析-固相萃取-核磁共振串聯技術(LC-SPE-NMR)分析大鼠口服MPPs之尿液代謝物。 本研究將建立大分子芍藥多酚(MPPs)化合物化學指紋特徵、製造控管、以及組成與活性之關係，並決定活性最佳化之配方；了解其在動物體內之活性以及尿液代謝物之特徵，並獲知所含之新穎活性成分。上述成果對後續開發赤芍為抗糖尿病之新穎植物藥具相當助益。 <br> Abstract: Population with diabetes is increasing year-by-year, however, blood control by the current drugs is still not satisfactory. Thus, to look for new antidiabetic drug candidates has become a mission of great urgency. Previous investigations revealed that the Paeoniae Rubra Radix (PRR) extract alleviated hyperinsulinemia, ameliorate the insulin resistance of peripheral tissues and β-cell function. Among the four active compounds P1-P3 and a partial-purified fraction polyphenol-enriched fraction (PEF) of PRR, P1-P3 showed activities such as to ameliorate utilization and tolerance of glucose, and the PEF inhibited PEPCK gene expression in vitro. Combination of P1-P3 and PEF in a specific ratio (PRM) showed comparable potency to that of PRR extract, representative of their synergistic effect. In addition, this combination showed superior activity than that of a combination of P1-P3, suggestive of the key role of the PEF. Nuclear magnetic resonance and dialysis results indicated that the PEF contained macromolecular polyphenols with molecular weights more than 3,000. To develop PRR as a novel anti-diabetic drug candidate, the present project plans to extend the aforementioned research outcomes and carry out the following tasks in the three years. First year — Separation and characterization, and degradation of the MPPs from PRR will be undertaken for clarification of chemical composition and structure-activity relationship. In addition, fingerprinting of the PEF will also be accomplished. Second year — Batch-to-batch chemical profiles of the PEF will be compared. Large-scale (> 10 g) preparation and in vivo antidiabetic activity tests of the macromolecular paeonia polyphenols (MPPs) will be performed; identification of novel compounds by matching their chemical profiles will also be undertaken. Third year — The profile-activity relationship of individual polyphenol by single-component knockout method will be evaluated; optimization of a formula of P1-P3 and the MPPs will be accomplished. Furthermore, analysis of the metabolites from the MPPs in rat urine by LC-SPE-NMR will be performed. Accomplishment of the project will establish chemical profiles, chemical manufacturing control, chemical composition-activity relationship for MPPs from PRR, and determination of activity-optimized formula; have a profound understanding of the in vivo activities, characteristics of MPPs metabolite in rat urine, and new anti-diabetic compounds from PRR. All of the above-mentioned achievements will be very helpful for developing PRR as a new herbal drug.毛茛科抗糖尿病大分子芍藥多酚赤芍Ranunculaceaeantidiabetesmacromolecular paeonia polyphenolsPaeonia Rubra Radix