Withanolide Derivative 2,3-Dihydro-3β-methoxy Withaferin-A Modulates the Circadian Clock via Interaction with RAR-Related Orphan Receptor α (RORa)
Withanolide Derivative 2,3-Dihydro-3β-methoxy Withaferin-A Modulates the Circadian Clock via Interaction with RAR-Related Orphan Receptor α (RORa)
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DOI：
10.1021/acs.jnatprod.0c01276
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发表时间：
2021-06-21
影响因子：
5.1
通讯作者：
Onishi, Yoshiaki
中科院分区：
文献类型：
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作者：
Tomita, Tatsunosuke;Wadhwa, Renu;Onishi, Yoshiaki
紫丁香衍生物具有抗癌、抗炎和其他功能，是印度传统阿育吠陀医学的组成部分。在这里，我们发现，2，3-二氢-3 β-甲氧基醉茄素-A（3 β mWi-A），一种醉茄素-A（Wi-A）的衍生物，属于一类醉茄内酯，在Ashwagandha（Withania somnifera）中丰富，延长了昼夜节律钟的周期。该化合物剂量依赖性地延长了肉瘤180癌细胞和正常成纤维细胞（包括NIH 3 T3和自发永生化小鼠胚胎成纤维细胞（MEF））中的昼夜节律。此外，3 β mWi-A剂量依赖性地上调地塞米松刺激后Bmal 1和核孤儿受体Rora和Nr 1d 1的mRNA表达和启动子活性，这些受体包括Bmal 1振荡表达的稳定环。我们发现3 β mWi-A作为RORa的反向激动剂发挥作用，IC 50为11.3 μ M，3 β mWi-A直接但微弱地与RORa相互作用（估计解离常数[K-d]，5.9 μ M）。我们建议，3 β mWi-A是一种新的昼夜节律的调制器。
Withanolide derivatives have anticancer, anti-inflammatory, and other functions and are components of Indian traditional Ayurvedic medicine. Here, we found that 2,3-dihydro-3 beta-methoxy withaferin-A (3 beta mWi-A), a derivative of withaferin-A (Wi-A) belonging to a class of withanolides that are abundant in Ashwagandha (Withania somnifera), lengthened the period of the circadian clock. This compound dose-dependently elongated circadian rhythms in Sarcoma 180 cancer cells and in normal fibroblasts including NIH3T3 and spontaneously immortalized mouse embryonic fibroblasts (MEF). Furthermore, 3 beta mWi-A dose-dependently upregulated the mRNA expression and promoter activities of Bmal1 after dexamethasone stimulation and of the nuclear orphan receptors, Rora and Nr1d1, that comprise the stabilization loop for Bmal1 oscillatory expression. We showed that 3 beta mWi-A functions as an inverse agonist for RORa with an IC50 of 11.3 mu M and that 3 beta mWi-A directly, but weakly, interacts with RORa (estimated dissociation constant [K-d], 5.9 mu M). We propose that 3 beta mWi-A is a novel modulator of circadian rhythms.