Abstract
The aim of this study is to compare the regulatory abilities of citrus flavonoids on the oscillating expression of circadian genes. Seven varieties of citrus fruits and twenty-five citrus flavonoids were selected and evaluated. Per2 luciferase bioluminescence report system and serum shock were used to induce circadian gene expression in mouse microglia BV-2 cells. In vivo experiments were carried out using C57BL6/J mice to evaluate the regulation of flavonoids on the oscillatory expression of liver biorhythm genes. Lipopolysaccharide was used to interfere the gene oscillating expression. QRT-PCR was performed to detect the expression of circadian rhythm-related genes, including Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, Rev-erbα, Rev-erbβ, Rorα, Dbp, and Npas2. The results show that the polymethoxyflavones (PMFs) exerted stronger circadian gene regulatory capability, while the flavonoids containing glycosides showed no biological activity. Also, all tested flavonoids decreased LPS-induced nitric oxide release, but only polymethoxyflavones inhibited circadian rhythm disorder. PMFs inhibited Nlrp3 inflammasome-related genes and proteins, including Nlrp3, IL-1β, ASC, and Caspase1, while other flavonoids only affected IL-1β and Caspase1 expression. This mechanism was preliminarily verified using the Nlrp3 inhibitor INF39.
Highlights
The circadian rhythm, called the circadian clock, is the intrinsic rhythm of the life activity of organisms determined by the temporal structure, as well as specific genes and proteins [1]
The biological clock is in a dynamic equilibrium state, and it can be affected by many factors, such as photoperiod [5], inflammatory factors [6], and nutrient intake [7]
Quantitative analysis of 9 flavonoid compounds with high content found that citrus flavonoids were mainly composed of flavanones and PMFs, which was consistent with previous reports [9]
Summary
The circadian rhythm, called the circadian clock, is the intrinsic rhythm of the life activity of organisms determined by the temporal structure, as well as specific genes and proteins [1]. Homeostasis of the circadian rhythm is vital to the organism. The functional patterns of the circadian genes, such as expression and phase, affect basal metabolism [2], organ function [3], and system homeostasis [4]. The biological clock is in a dynamic equilibrium state, and it can be affected by many factors, such as photoperiod [5], inflammatory factors [6], and nutrient intake [7]. Studying the effects of environmental factors on the circadian rhythm, especially the interaction of ubiquitous inflammatory factors and natural products with the circadian clock, would contribute to revealing the mechanism of circadian clock regulation and guide the consumption of natural products
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