生物钟信号调控的营养学

近日节律是生物界普遍存在的一种生理现象,而内源性生物钟是产生近日节律的物质基础,它能使生物体感知并适应环境中的光、温度和食物等周期信号,从而使生物体与外界环境保持周期同步。研究表明,葡萄糖、胆固醇、腺苷、咖啡因、维生素A和视黄酸等营养物质能通过各自不同的方式调控哺乳动物的生物钟,影响其近日节律的信号输出。本文概述了至今为止研究发现的各类与生物钟信号调控相关的营养物质及功能的相关研究进展。     

生物钟基因与哺乳动物生殖

近日节律是生物节律中最重要的一种。它是一种以近似24 h为周期的自主振荡器,普遍存在于生物界中。近日节律主要受生物钟基因的调控,在哺乳动物中已发现时钟基因(Clock)、周期基因(Period,Per)家族、隐花色素基因(Cryptochrome1,Cry)家族、Bmal1(Brain and muscle ARNT-like 1)在内的多种重要的生物钟基因。这些基因及其蛋白质产物构成的反馈调节环是生物钟运行的分子基础。研究表明,生物钟基因不仅仅在近日节律的中枢系统中存在表达,在外周组织中也存在表达。而且生物钟基因与哺乳动物生殖密切相关,提示可能在生殖领域中具有重要的调控作用。主要从几个关键生物钟基因的发现、在近日节律和非近日节律中的调节作用、以及与哺乳动物生殖的关系做一综述。     

蓝藻生物节律性分子调控机制的研究进展

生物钟现象是一种普遍存在于生物界细胞的内源节律性保持机制。生物钟机制的存在可以使生物体的代谢行为产生并维持以24 h为周期的昼夜节律,从而更好地适应于地球自转所产生的环境条件昼夜间节律性变化。蓝藻是目前生物钟分子机制研究中的模式生物,其依赖于k ai基因家族成员的核心生物钟调控模式已经被众多研究者详细阐明。蓝藻生物钟的核心振荡器是由蓝藻k aiA/B/C的编码产物来调控的,Kai蛋白的表达模式具有节律性。KaiC蛋白磷酸化状态的节律性循环及输入、输出途径相关组成蛋白的翻译后修饰状态节律性循环共同组成其反馈回路,负责维持生物钟节律性振荡的持续进行并与环境周期保持同步。传统的蓝藻生物钟分子机制模型认为,节律性表达基因翻译产物的转录/翻译负反馈抑制环是生物节律性维持和输出的关键。遗憾的是,在其它物种生物钟分子机制研究中未发现由kai基因家族成员同源基因组成的节律性标签,这表明以k aiA/B/C为核心振荡器的生物钟系统并不是一种跨物种保守的生物钟系统。近期,人们发现非转录/翻译依赖的振荡器(NTO)也具有成为生物节律性产生和维持的“源动力”的可能。过氧化物氧化还原酶(PRX)氧化还原状态节律性是第一种被报道的跨物种保守的NTO节律性标签,这也日渐成为蓝藻生物钟分子机制研究新的热点。     

生物钟基因3及其表达的调节机制

众所周知 ,生物体的新陈代谢过程 ,细胞和细胞器官的生理功能 ,以及心理行为等生命活动往往随着昼夜循环而发生规律性的变化。就是在实验室恒定的条件下 ,消除一切环境因子的影响 ,生命活动仍表现出昼夜节律性的变化。这说明昼夜节律受体内的测时系统——生物钟的控制。从 5 0年代至今 ,人们对生物的昼夜节律及其调控机制进行了深入地研究 ,特别是应用生物化学和分子生物学的方法 ,使人们逐步了解了生物节律的特点 ,生物钟基因及其表达的调控机制。1　生物钟基因存在于不同生物体中的昼夜节律时钟都表现出 3个共同的特点 :1 )在恒定的环境条…     

节律性转录因子驱动哺乳动物昼夜节律生物钟简

生物体通过内在的昼夜节律生物钟调整生理行为和代谢生化反应来适应昼夜环境周期性变化。哺乳动物的昼夜节律生物钟核心连锁环通过驱动特异性的转录因子来维持整个基因组转录的节律性。生物钟与代谢的内稳态密切相关,生物钟的紊乱会引起各种疾病,该领域的研究能够促进时间疗法的发展来维持生命的健康,甚至可以延缓衰老。     

节律性转录因子驱动哺乳动物昼夜节律生物钟

生物体通过内在的昼夜节律生物钟调整生理行为和代谢生化反应来适应昼夜环境周期性变化。哺乳动物的昼夜节律生物钟核心连锁环通过驱动特异性的转录因子来维持整个基因组转录的节律性。生物钟与代谢的内稳态密切相关,生物钟的紊乱会引起各种疾病,该领域的研究能够促进时间疗法的发展来维持生命的健康,甚至可以延缓衰老。     

哺乳动物生物钟与能量代谢的相关研究进展

生物钟广泛存在于各种生物体中,是生命体的一种内源调节机制。哺乳动物生物钟系统与机体营养代谢和能量平衡有着密切的关系。概述了生物钟系统通过营养途径、限速酶途径、核受体途径对哺乳动物机体代谢活动和能量平衡的调控,以及哺乳动物代谢稳态对生物钟系统的影响,从而为从生物钟调控的角度治疗和防控代谢综合征提供新的思路。     

生物节律影响巨核细胞发育和血小板产生的研究进展

自然界中生物体的生命活动、生活习性都存在着一定的周期性变化。生物昼夜节律的产生是以内源性的生物钟系统为基础的。生物钟不仅易受到外界环境的影响,而且可以通过调控一系列特定的下游基因的表达,影响生物体的生理生化过程。巨核细胞是生成血小板的前体细胞,经过分化、增殖、成熟和裂解,最终生成血小板。血小板是一种没有细胞核的特殊细胞,在生理性止血和器官修复上发挥着重要作用,同时参与血栓等多种疾病的发生。近几年借助现代分子生物学和细胞生物学手段,证实了哺乳动物的巨核细胞和血小板的生成呈现明显的周期性的变化,利用生物钟基因缺失模型进一步发现了生物钟基因对巨核细胞和血小板的影响。本文概述了生物节律对巨核细胞和血小板的影响,为进一步研究巨核细胞的发育和血小板生成机制提供了参考。     

生物节律影响巨核细胞发育和血小板产生的研究进展

自然界中生物体的生命活动、生活习性都存在着一定的周期性变化。生物昼夜节律的产生是以内源性的生物钟系统为基础的。生物钟不仅易受到外界环境的影响,而且可以通过调控一系列特定的下游基因的表达,影响生物体的生理生化过程。巨核细胞是生成血小板的前体细胞,经过分化、增殖、成熟和裂解,最终生成血小板。血小板是一种没有细胞核的特殊细胞,在生理性止血和器官修复上发挥着重要作用,同时参与血栓等多种疾病的发生。近几年借助现代分子生物学和细胞生物学手段。证实了哺乳动物的巨核细胞和血小板的生成呈现明显的周期性的变化,利用生物钟基因缺失模型进一步发现了生物钟基因对巨核细胞和血小板的影响。本文概述了生物节律对巨核细胞和血小板的影响,为进一步研究巨核细胞的发育和血小板生成机制提供了参考。     

Melatonin and sleep

Sleep-wake cycle is the predominant example of circadian rhythms. Melatonin is commonly used to treat insomnia and in additional neurodevelopmental disorders in which sleep disturbance is frequent. In mammals, melatonin receptors are present in the membrane and cell nucleus of many tissues and systems where it exhibits various actions, including the regulation of circadian rhythms. The rhythmic pattern of melatonin secretion is imperative since it endows with vital information to the organism concerning time, which permits for alterations of a number of physiological functions consistent with daily and seasonal variations. Melatonin as well has sleep promoting effects demonstrated in changes in brain activation patterns and tiredness generation. The SCN’s (suprachiasmatic nuclei) function and melatonin production capability turns down with age consequently depriving the brain from an important time cue and sleep regulator.     

Biorhythms and pineal gland

Endocrine biorhythms are classified according to the period time, as one of the most characteristic properties of biorhythms. Each endocrine organ has parallel more than one biorhythms with different period time (e. g. circadian and circannual rhythms). The time of acrophase of the biorhythms at the different endocrine organs is fairly variant. This review summarizes the rhythmic function of the THS-thyroid, gonadotrophic-gonadal and ACTH-adrenocortical systems. Pineal gland plays an integrative role in the regulation of rhythmic function of the endocrine system. The melatonin secretion of this gland also reveals conspicuous circadian and circannual rhythms both in mammals and in birds. Mammalian pineal is functional only if its peripheral sympathetic innervation from the superior cervical ganglion is intact. In contrast, melatonin secretion and its circadian rhythm is also maintained in birds under isolated conditions (explanted into an in vitro superfusion system). The 24 hours period time of melatonin circadian rhythm can not be changed by light impulses. The phases of the circadian rhythm, however, can be turned by changing the time of environmental light-dark phases. The wavelength of the artificial light used for reversal of circadian rhythm is an important factor. The development of the entrainment and synchronization of the circadian melatonin rhythm in birds is independent of the rhythmic day-night changes in environmental lighting condition. The differences in the main elements of the biological clock between mammals and birds are discussed.     

Circadian rhythms of indoleamines and serotonin N-acetyltransferase activity in the pineal gland

Conclusion The circadian rhythm of melatonin synthesis in the pineal glands of various species has been summarized. The night-time elevation of melatonin content is in most if not all cases regulated by the change of N-acetyltransferase activity. In mammals, the N-acetyltransferase rhythm is controlled by the central nervous system, presumably by suprachiasmatic nuclei in hypothalamus through the superior cervical ganglion. In birds, the circadian oscillator that regulates the N-acetyltransferase rhythm is located in the pineal glands. The avian pineal gland may play a biological clock function to control the circadian rhythms in physiological, endocrinological and biochemical processes via pineal hormone melatonin.     

微小RNA和长链非编码RNA介导的昼夜节律调控

非编码RNA(ncRNA)是生物体细胞内一类重要的调控分子,其介导的昼夜节律调控日益受到研究者的重视。本文主要以黑腹果蝇Drosophila melanogaster和哺乳动物的相关研究为背景,阐述了微小RNA(miRNA)和长链非编码RNA(lncRNA)对昼夜节律的调控。miRNA介导的昼夜节律调控包括:生物体内(尤其是钟神经元中)具有节律性表达的miRNA;输入系统和miRNA存在相互调控,这主要是通过光照这个授时因子起作用;miRNA可直接调控核心振荡器,还可以调控其他基因而间接影响到核心振荡器;miRNA对输出系统的调控主要集中在代谢取食节律、运动节律、睡眠节律等。昼夜节律可调控lncRNA的表达,同时lncRNA也可调控昼夜节律,且lncRNA对基因调控范围广,作用机制复杂,这些都具有广阔的研究前景。本文将有助于进一步深入研究ncRNA对昼夜节律的调控。     

The circadian timing system and reproduction in mammals.

Circadian systems in a wide variety of organisms all appear to include three basic components: 1) biological oscillators that maintain a self-sustained circadian periodicity in the absence of environmental time cues; 2) input pathways that convey environmental information, especially light cues, that can entrain the circadian oscillations to local time; and 3) output pathways that drive overt circadian rhythms, such as the rhythms of locomotor activity and a variety of endocrine rhythms. In mammals, the circadian system is employed in the regulation of reproductive physiology and behavior in two very important ways. 1) In some species, there is a strong circadian component in the timing of ovulation and reproductive behavior, ensuring that these events will occur at a time when the animal is most likely to encounter a potential mate. 2) Many mammals exhibit seasonal reproductive rhythms that are largely under photoperiod regulation; in these species, the circadian system and the pineal gland are crucial components of the mechanism that is used to measure day length. The rhythm of pineal melatonin secretion is driven by a neural pathway that includes the circadian oscillator(s) in the suprachiasmatic nuclei. Melatonin is secreted at night in all mammals, and the duration of each nocturnal episode of melatonin secretion is inversely related to day length. The pineal melatonin rhythm appears to serve as an internal signal that represents day length and that is capable of regulating a variety of seasonal variations in physiology and behavior.     

The Avian Pineal Gland

The pineal gland plays a key role in the control of the daily and seasonal rhythms in most vertebrate species. In mammals, rhythmic melatonin (MT) release from the pineal gland is controlled by the suprachiasmatic nucleus via the sympathetic nervous system. In most non‐mammalian species, including birds, the pineal gland contains a self‐sustained circadian oscillator and several input channels to synchronize the clock, including direct light sensitivity. Avian pineal glands maintain rhythmic activity for days under in vitro conditions. Several physical (light, temperature, and magnetic field) and biochemical (Vasoactive intestinal polypeptide (VIP), norepinephrine, PACAP, etc.) input channels, influencing release of melatonin are also functional in vitro, rendering the explanted avian pineal an excellent model to study the circadian biological clock. Using a perifusion system, we here report that the phase of the circadian melatonin rhythm of the explanted chicken pineal gland can be entrained easily to photoperiods whose length approximates 24 h, even if the light period is extremely short, i.e., 3L:21D. When the length of the photoperiod significantly differs from 24 h, the endogenous MT rhythm becomes distorted and does not follow the light‐dark cycle. When explanted chicken pineal fragments were exposed to various drugs targeting specific components of intracellular signal transduction cascades, only those affecting the cAMP‐protein kinase‐A system modified the MT release temporarily without phase‐shifting the rhythm in MT release. The potential role of cGMP remains to be investigated.     

Melatonin: characteristics, concerns, and prospects

Melatonin is of great importance to the investigation of human biological rhythms. Its rhythm in plasma or saliva provides the best available measure of the timing of the internal circadian clock. Its major metabolite 6-sulphatoxymelatonin is robust and easily measured in urine. It thus enables long-term monitoring of human rhythms in real-life situations where rhythms may be disturbed, and in clinical situations where invasive procedures are difficult. Melatonin is not only a "hand of the clock"; endogenous melatonin acts to reinforce the functioning of the human circadian system, probably in many ways. Most is known about its relationship to sleep and the decline in core body temperature and alertness at night. Current perspectives also include a possible influence on major disease risk, arising from circadian rhythm disruption. Melatonin clearly has the ability to induce sleepiness and lower core body temperature during "biological day" and to change the timing of human rhythms when treatment is appropriately timed. It can entrain free-running rhythms and maintain entrainment in most blind and some sighted people. Used therapeutically it has proved a successful treatment for circadian rhythm disorder, particularly the non-24-h sleep wake disorder of the blind. Numerous other clinical applications are under investigation. There are, however, areas of controversy, large gaps in knowledge, and insufficient standardization of experimental conditions and analysis for general conclusions to be drawn with regard to most situations. The future holds much promise for melatonin as a therapeutic treatment. Most interesting, however, will be the dissection of its effects on human genes.     

The avian pineal gland

The pineal gland plays a key role in the control of the daily and seasonal rhythms in most vertebrate species. In mammals, rhythmic melatonin (MT) release from the pineal gland is controlled by the suprachiasmatic nucleus via the sympathetic nervous system. In most non-mammalian species, including birds, the pineal gland contains a self-sustained circadian oscillator and several input channels to synchronize the clock, including direct light sensitivity. Avian pineal glands maintain rhythmic activity for days under in vitro conditions. Several physical (light, temperature, and magnetic field) and biochemical (Vasoactive intestinal polypeptide (VIP), norepinephrine, PACAP, etc.) input channels, influencing release of melatonin are also functional in vitro, rendering the explanted avian pineal an excellent model to study the circadian biological clock. Using a perifusion system, we here report that the phase of the circadian melatonin rhythm of the explanted chicken pineal gland can be entrained easily to photoperiods whose length approximates 24 h, even if the light period is extremely short, i.e., 3L:21D. When the length of the photoperiod significantly differs from 24 h, the endogenous MT rhythm becomes distorted and does not follow the light-dark cycle. When explanted chicken pineal fragments were exposed to various drugs targeting specific components of intracellular signal transduction cascades, only those affecting the cAMP-protein kinase-A system modified the MT release temporarily without phase-shifting the rhythm in MT release. The potential role of cGMP remains to be investigated.     

Role of Sleep Restriction in Daily Rhythms of Expression of Hypothalamic Core Clock Genes in Mice

Lack of sleep time is a menace to modern people, and it leads to chronic diseases and mental illnesses. Circadian processes control sleep, but little is known about how sleep affects the circadian system. Therefore, we performed a 28-day sleep restriction (SR) treatment in mice. Sleep restriction disrupted the clock genes’ circadian rhythm. The circadian rhythms of the Cry1 and Per1/2/3 genes disappeared. The acrophase of the clock genes (Bmal1, Clock, Rev-erbα, and Rorβ) that still had a circadian rhythm was advanced, while the acrophase of negative clock gene Cry2 was delayed. Clock genes’ upstream signals ERK and EIFs also had circadian rhythm disorders. Accompanied by changes in the central oscillator, the plasma output signal (melatonin, corticosterone, IL-6, and TNF-α) had an advanced acrophase. While the melatonin mesor was decreased, the corticosterone, IL-6, and TNF-α mesor was increased. Our results indicated that chronic sleep loss could disrupt the circadian rhythm of the central clock through ERK and EIFs and affect the output signal downstream of the core biological clock.