Retinoic acid receptor agonist activity of naturally occurring diterpenes.
Retinoic acid receptor agonist activity of naturally occurring diterpenes.
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天然存在的二萜的视黄酸受体激动剂活性。
DOI：
10.1016/j.bmc.2014.03.047
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发表时间：
2014
影响因子：
3.5
通讯作者：
Makoto Inoue
中科院分区：
文献类型：
--
作者：
Hiroki Tanabe;Tomohisa Yasui;Hitoshi Kotani;Akito Nagatsu;Makoto Makishima;Sakae Amagaya;Makoto Inoue
近年来越来越多的证据表明，全反式维甲酸（ATRA）可用于预防或治疗炎症，过敏和自身免疫性疾病，尽管它有严重的副作用。本研究采用荧光素酶报告基因检测技术对99种生药中的视黄酸受体（RAR α）配体进行了筛选，结果表明，辽东木甲醇提取物对RARα的转录活性具有最强的激活作用。随后分离出匹马拉二烯酸（ent-pimara-8（14），15-dien-19-oic acid）作为能够激活RAR的成分。海松酸和松香酸，具有类似的结构，海松二烯酸，也被发现是新的RAR激动剂，虽然松香酸只有轻微激活过氧化物酶体增殖物激活受体γ。这三种具有二萜结构的天然RAR激动剂，虽然在结构上不同于ATRA，但能够增加HepG 2细胞中组成型雄烷受体的mRNA水平，诱导F9细胞分化，随后Cyp 26 a1 mRNA表达，并以不同于ATRA的方式通过RAR活化分化HL-60细胞。这些结果表明，一些二萜类化合物作为天然存在的RAR激动剂存在，ATRA和这些二萜类化合物之间的化学结构差异可能会诱导不同的基因激活和特定的细胞反应。
Recent accumulating evidence indicates that all-transretinoic acid (ATRA) may be useful for preventing or treating inflammation, allergy, and autoimmune diseases, despite its severe side effects. In this study, screening of 99 crude drugs for retinoic acid receptor (RAR) ligands by luciferase reporter assay demonstrated that the methanol extract ofAralia cordataRhizoma most effectively activates the transcriptional activity of RARα. Pimaradienoic acid (ent-pimara-8(14),15-dien-19-oic acid) was subsequently isolated as the constituent capable of activating RAR. Pimaric acid and abietic acid, which have similar structures to pimaradienoic acid, were also found to be novel RAR agonists, although abietic acid only slightly activated peroxisome proliferator-activated receptor gamma. These three natural RAR agonists with diterpene structures, while structurally different from ATRA, were able to increase the mRNA levels of the constitutive androstane receptor in HepG2 cells, induce F9 cell differentiation followed by Cyp26a1 mRNA expression, and differentiate HL-60 cells via RAR activation in a different manner from ATRA. These results demonstrate that some diterpenes exist as naturally occurring RAR agonists and that the differences in chemical structure between ATRA and these diterpenes may induce distinct gene activation and a specific cellular response.