Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Division of Health Chemistry, Department of Clinical Pharmaceutical Sciences, School of Pharmacy, Iwate Medical University, Morioka, Japan.
J Nat Med. 2019 Jun;73(3):497-503. doi: 10.1007/s11418-019-01290-y. Epub 2019 Feb 21.
The capitula of Chrysanthemum morifolium and C. indicum are used to prepare Chrysanthemi Flos in traditional Japanese Kampo medicine. In our previous study, we reported on the agonistic effect of methanol extract of C. indicum capitulum on peroxisome proliferator-activated receptor (PPAR)-γ. We further isolated (E)-tonghaosu from C. indicum capitulum as one of the active ingredients. In the present study, we aimed to evaluate the PPAR-γ agonistic activity of a methanol extract of C. morifolium capitulum (MCM) in which (E)-tonghaosu could not be detected. MCM exhibited PPAR-γ agonistic activity in a concentration-dependent manner, and at a dose of 100 µg/ml, it showed similar activity to pioglitazone (30 µM), a standard PPAR-γ agonist. Through activity-guided fractionation, we isolated two geometric isomers, (E)- (1) and (Z)-B-ring-homo-tonghaosu (2), as the active ingredients of MCM. Both compounds exerted concentration-dependent PPAR-γ agonistic effects, and 1 had higher activity than 2. At 1.4 µM, 1 had similar activity to pioglitazone (30 µM), which was achieved by 2 at a concentration of 140 µM. Thus, 1 has the potential to become a lead compound for the drug discovery of PPAR-γ agonists. We compared the activities and the contents of (E)-, (Z)-tonghaosu, 1, and 2 among 13 commercial samples of Chrysanthemi Flos, including those derived from both C. morifolium and C. indicum. Their PPAR-γ agonistic activities were not related to the contents of these compounds. 1 and 2 were detected in the samples derived from both species but (E)- and (Z)-tonghaosu were not detected in the samples derived from C. morifolium; hence (E)- and (Z)-tonghaosu can serve as marker compounds to identify the capitula of C. indicum in Chrysanthemi Flos samples.
菊花的头状花序被用于制备传统日本汉方药中的菊花。在我们之前的研究中，我们报道了野菊花头状花序甲醇提取物对过氧化物酶体增殖物激活受体（PPAR）-γ的激动作用。我们进一步从野菊花头状花序中分离出（E）-tonghaosu 作为一种活性成分。在本研究中，我们旨在评估（E）-tonghaosu 无法检测到的菊花头状花序甲醇提取物（MCM）对 PPAR-γ 的激动作用。MCM 以浓度依赖的方式表现出 PPAR-γ 激动活性，在 100µg/ml 的剂量下，其活性与吡格列酮（30µM）相当，吡格列酮是一种标准的 PPAR-γ 激动剂。通过活性导向的分离，我们分离出两种几何异构体，（E）-（1）和（Z）-B-环同tonghaosu（2），作为 MCM 的活性成分。这两种化合物均表现出浓度依赖性的 PPAR-γ 激动作用，1 的活性高于 2。在 1.4µM 时，1 的活性与吡格列酮（30µM）相当，而 2 则需要 140µM 的浓度才能达到相同的效果。因此，1 有可能成为 PPAR-γ 激动剂药物发现的先导化合物。我们比较了 13 种菊花的 Chrysanthemi Flos 商业样本中（E）-、（Z）-tonghaosu、1 和 2 的活性和含量，包括来自 C. morifolium 和 C. indicum 的样品。它们的 PPAR-γ 激动活性与这些化合物的含量无关。1 和 2 存在于来自两种植物的样品中，但（E）-和（Z）-tonghaosu 不存在于来自 C. morifolium 的样品中；因此，（E）-和（Z）-tonghaosu 可以作为鉴定 Chrysanthemi Flos 样品中 C. indicum 头状花序的标记化合物。
