Research Article: Potent Effects of Flavonoid Nobiletin on Amplitude, Period, and Phase of the Circadian Clock Rhythm in PER2::LUCIFERASE Mouse Embryonic Fibroblasts

Date Published: February 2, 2017

Publisher: Public Library of Science

Author(s): Ayako Shinozaki, Kenichiro Misawa, Yuko Ikeda, Atsushi Haraguchi, Mayo Kamagata, Yu Tahara, Shigenobu Shibata, Henrik Oster.


Flavonoids are natural polyphenols that are widely found in plants. The effects of flavonoids on obesity and numerous diseases such as cancer, diabetes, and Alzheimer’s have been well studied. However, little is known about the relationships between flavonoids and the circadian clock. In this study, we show that continuous or transient application of flavonoids to the culture medium of embryonic fibroblasts from PER2::LUCIFERASE (PER2::LUC) mice induced various modifications in the circadian clock amplitude, period, and phase. Transient application of some of the tested flavonoids to cultured cells induced a phase delay of the PER2::LUC rhythm at the down slope phase. In addition, continuous application of the polymethoxy flavonoids nobiletin and tangeretin increased the amplitude and lengthened the period of the PER2::LUC rhythm. The nobiletin-induced phase delay was blocked by co-treatment with U0126, an ERK inhibitor. In summary, among the tested flavonoids, polymethoxy flavones increased the amplitude, lengthened the period, and delayed the phase of the PER2::LUC circadian rhythm. Therefore, foods that contain polymethoxy flavones may have beneficial effects on circadian rhythm disorders and jet lag.

Partial Text

The daily circadian rhythm in mammals is adapted to the 24-h solar cycle. The main circadian oscillator is located in the suprachiasmatic nucleus (SCN) of the brain, and additional oscillators are found in other regions of the brain and in the peripheral organs [1]. It has also been reported that various in vitro cultures of peripheral tissues and cell lines exhibit circadian rhythms [2]. Circadian rhythms are entrained by environmental cycles, such as sunlight, food, and temperature, and by various drugs and chemicals [3–8].

In this study, we examined the effects of flavonoids on the amplitude, period, and phase of the PER2 circadian rhythm in vitro by monitoring the rhythm of bioluminescence in MEFs derived from PER2::LUC knock-in mice chronically or transiently exposed to flavonoids. The chemical structures of the flavonoids in each of the main classes are similar [39]. We hypothesized that the effects of flavonoids in the same subgroup would be similar. However, the present results demonstrated variations in the effects of flavonoids in the same subgroup. Many flavonoids showed negative amplitude-period correlations, and higher concentrations decreased the amplitudes of the PER2::LUC wave. However, the dose-dependency of amplitude and period differed even in the same flavonoid group, such as the flavone and catechin groups. At low concentrations (<10 μM), 5-OH flavone, 7-OH flavone, and luteolin showed effects similar to those of the flavones which lengthened the period but had no effect on amplitude. In contrast, bicalein and apigenin, which only differed from the aforementioned reagents, showed amplitude decreases. Baicalein showed period lengthening; however, apigenin did not. Galangin, a flavonol, induced no significant change in the amplitude, but its effect on the period differed from those of other flavonols. Quercetin was effective at a lower concentration than other flavonols. These results suggest that similarity in planar structure does not always translate to similar steric structure, and such steric differences may lead to different effects. In addition, the differences in the effects induced by these flavonoids may be because they affect different signaling pathways.   Source:


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