Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health.
Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health.
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DOI：
10.12688/f1000research.126364.2
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发表时间：
2022
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生物钟是一种基本的生物机制，它协调基本的细胞和生理过程，以优化健康和健康。基本的功能单元是细胞自主振荡器，由相交的负反馈环路组成。虽然核心环主要负责节律的产生，但辅助环，尤其是次要或稳定环，在赋予时间精确度和分子稳健性方面发挥着关键作用。稳定环包含相反的核受体亚家族Rev-ERB和维甲酸受体相关孤儿受体(RORs)，竞争调节核心环中基本螺旋-环-螺旋Arntlike 1(BMal1)基因以及其他时钟控制基因的节律性表达。因此，REV-ERBS和ROR是连接振荡器和全球转录网络的战略位置，在整个生命周期中促进细胞内稳态和生理健康。REV-ERB和ROR功能的中断与疾病和衰老有关，这些因素的药理学操作在各种小鼠疾病模型中显示出希望。诺比莱汀是一种天然化合物，直接与RoRα/γ结合并激活，调节昼夜节律，并在体内显示出强大的抗击时钟相关的病理生理和与年龄相关的衰退的效果。几项研究的结果表明，nobiletin的疗效与时钟功能状态之间存在反向关系，其中nobiletin对年轻和健康的小鼠几乎没有影响，因为时钟受到环境和遗传挑战的干扰，导致效率不断增长。这种作用模式与稳定环促进昼夜节律和生理弹性的功能是一致的。未来的研究应该进一步研究REV-ERBS和RORS的功能和机制，并测试针对这些因素的抗病和抗衰老策略。
The circadian clock is a fundamental biological mechanism that orchestrates essential cellular and physiological processes to optimize fitness and health. The basic functional unit is the cell-autonomous oscillator, consisting of intersecting negative feedback loops. Whereas the core loop is primarily responsible for rhythm generation, auxiliary loops, most notably the secondary or stabilization loop, play pivotal roles to confer temporal precision and molecular robustness. The stabilization loop contains opposing nuclear receptor subfamilies REV-ERBs and retinoic acid receptor-related orphan receptors (RORs), competing to modulate rhythmic expression of the basic helix-loop-helix ARNT like 1 ( Bmal1) genes in the core loop as well as other clock-controlled genes. Therefore, REV-ERBs and RORs are strategically located to interface the oscillator and the global transcriptomic network, promoting cellular homeostasis and physiological fitness throughout lifespan. Disruption of REV-ERB and ROR functions has been linked with diseases and aging, and pharmacological manipulation of these factors has shown promise in various mouse disease models. Nobiletin is a natural compound that directly binds to and activates RORα/γ, modulating circadian rhythms, and shows robust in vivo efficacies to combat clock-associated pathophysiologies and age-related decline. Results from several studies demonstrate an inverse relation between nobiletin efficacy and clock functional state, where nobiletin elicits little effect in young and healthy mice with growing efficacy as the clock is perturbed by environmental and genetic challenges. This mode of action is consistent with the function of the stabilization loop to promote circadian and physiological resilience. Future studies should further investigate the function and mechanism of REV-ERBs and RORs, and test strategies targeting these factors against disease and aging.