Circadian regulation of cardiac metabolism

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.     

Model-based covariate pharmacokinetic analysis and lack of cortisol suppression by the new inhaled corticosteroid ciclesonide using a novel cortisol release model

Ciclesonide is a novel and effective inhaled corticosteroid for the treatment of asthma that is converted into the active metabolite C21-desisobutyryl-ciclesonide (des-CIC) in the lung. The objectives of this analysis were to characterize covariate effects on des-CIC pharmacokinetics (PK) and circadian cortisol release. In addition, the effect of systemic des-CIC exposure on circadian cortisol release was also evaluated. Data from 12 phase I and 3 phase III studies in adults and 2 phase III studies in children (ex-actuator dose of ciclesonide: 40-2880 microg) were pooled. There were 635 subjects in the analysis with 5238 and 4470 observations recorded for concentrations of des-CIC and cortisol, respectively. The des-CIC PK was described using a 1-compartment model with first-order absorption and no clinically relevant differences in des-CIC PK due to body weight, race, asthma severity, or gender. The mean PK parameters estimates of apparent clearance and apparent volume of distribution were 302 L/h and 1310 L, respectively. A 1-compartment model with first-order absorption, an endogenous "predose" cortisol concentration at dose interval and a lag time based on a fixed, hypothetical cortisol dosing time of 10:00 PM could adequately characterize the circadian rhythm of endogenous cortisol release. The potential effect of des-CIC on the circadian rhythm of endogenous cortisol release was evaluated using dose and AUC as covariates and applying the Emax model. Less than 1% of all observed des-CIC concentrations were higher than the EC50 for cortisol suppression, indicating negligible changes in cortisol concentrations at therapeutically relevant doses.     

CIRCULATING CATECHOLAMINES IN ASTHMA

Summary Circulating catecholamines are not abnormally elevated in asthmatics. The normal circadian fall in circulating adrenaline at night may contribute to nocturnal wheezing by facilitating release of bronchoconstrictor mast cell mediators. Asthmatics who develop exercise-induced wheezing show an impaired catecholamine response to exercise which may facilitate mediator release during exercise. Endogenous catecholamines in asthma may therefore play a modulatory role on the release of mast cell mediators.     

Measuring circadian temperature rhythm

Experimental control and mathematical techniques increase confidence that results of circadian temperature rhythm studies reflect true changes in the circadian timing system versus coupling with exogenous synchronizers. Masking effects represent confounding influences in studies that are concerned with the endogenous temperature rhythm. Because it is technically difficult to measure directly the behavior of the endogenous timing system, marker rhythms are used as proxy measures. However in addition to entraining, the external environment exerts a direct masking effect on the monitored rhythm. Methods for measuring circadian temperature rhythm are reviewed in this article. Constant routine, forced desynchrony, and purification methods represent attempts, at an experimental or mathematical level, to remove masking effects and more accurately capture the endogenous circadian temperature rhythm. Exogenous factors have not been subjected to the same scrutiny as the endogenous features of circadian temperature rhythm. But it is the environmental context, the extent to which the endogenous features are adaptively modified by the field environment, that will ultimately determine the biological value of circadian temperature rhythm to the organism. Thus, nurse investigators are encouraged to use rigorous methods to study both endogenous circadian temperature rhythm and exogenous rhythms.     

Interconnections between circadian clocks and metabolism

Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.

To adapt to daily environmental changes caused by our Earth’s rotation, most organisms on the planet evolved near-24-hour cycles of behavioral, physiological, and metabolic rhythms (1). In addition to the entrained environmental stimuli, the internal timekeeping system of the circadian clock has evolved to anticipate external changes (2, 3). These conserved rhythms synchronize internal biological and behavioral processes to the external temporal environment, presumably providing organisms with selective advantages for survival. However, over the past century, modern industrialized society has profoundly changed our external environment (4). For example, the boundaries between day and night have been blurred by electric light and travel across different time zones. Disrupted circadian rhythms are highly associated with metabolic disorders (5). Conversely, obesity induced by overeating or overnutritional environment leads to circadian remodeling (6, 7). Understanding the reciprocal regulation of circadian rhythm and metabolism may provide mechanistic insights into circadian physiology and advance new chronotherapy approaches and therapeutic targets for metabolic disorders.     

Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics.

The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.     

Cross-talk between the circadian clock and the cell cycle in cancer

Abstract

The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.     

Crosstalk between central and peripheral biological clocks

Mammalian circadian system is multi-oscillator system. Clock gene expression analysis revealed that central clock, suprachiasmatic nucleus, organizes and synchronizes the peripheral oscillators in the whole body cells. Similarly, human circadian system is considered to be dual oscillation system because of internal desynchronization between melatonin, body temperature rhythms(driven by oscillator I) and sleep-wake rhythm (driven by oscillator II) under temporal isolation of dim light conditions. These oscillators control their periods mutually which means there is crosstalk of oscillators. Although the effect from oscillator II to oscillator I is weak under experimental dim light conditions, sleep-wake behavior controls light input to light sensitive oscillator I and feedbacks to sleep-wake driving oscillator II under lighting condition we live. To understand these mechanisms is important for prevention of circadian rhythm related diseases.     

Rhythms in second messenger mechanisms.

In this chapter circadian rhythms in the beta-adrenoceptor/adenylate cyclase/phosphodiesterase system are presented and discussed. Daily variation in total number and affinity of beta-adrenoceptors in rat forebrain and rat heart ventricles seem to be of minor importance in the circadian regulation of the cAMP concentration in these tissues. Pronounced and significant circadian rhythms in cAMP formation by the adenylate cyclase and cAMP degradation by the phosphodiesterases could be demonstrated in either rat forebrain or heart ventricles. Also the accessibility of cardiac adenylate cyclase to different stimuli was circadian-phase-dependent. Furthermore, data are presented which indicate that the catalytic unit of the adenylate cyclase must undergo qualitative changes with age.     

Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people.

BACKGROUND: Morningness-eveningness refers to interindividual differences in preferred timing of behavior (i.e., bed and wake times). Older people have earlier wake times and rate themselves as more morning-like than young adults. It has been reported that the phase of circadian rhythms is earlier in morning-types than in evening types, and that older people have earlier phases than young adults. These changes in phase have been considered to be the chronobiological basis of differences in preferred bed and wake times and age-related changes therein. Whether such differences in phase are associated with changes in the phase relationship between endogenous circadian rhythms and the sleep-wake cycle has not been investigated previously. METHODS: We investigated the association between circadian phase, the phase relationship between the sleep-wake cycle and circadian rhythms, and morningness-eveningness, and their interaction with aging. In this circadian rhythm study, 68 young and 40 older subjects participated. RESULTS: Among the young subjects, the phase of the melatonin and core temperature rhythms occurred earlier in morning than in evening types and the interval between circadian phase and usual wake time was longer in morning types. Thus, while evening types woke at a later clock hour than morning types, morning types actually woke at a later circadian phase. Comparing young and older morning types we found that older morning types had an earlier circadian phase and a shorter phase-wake time interval. The shorter phase-waketime interval in older "morning types" is opposite to the change associated with morningness in young people, and is more similar to young evening types. CONCLUSIONS: These findings demonstrate an association between circadian phase, the relationship between the sleep-wake cycle and circadian phase, and morningness-eveningness in young adults. Furthermore, they demonstrate that age-related changes in phase angle cannot be attributed fully to an age-related shift toward morningness. These findings have important implications for understanding individual preferences in sleep-wake timing and age-related changes in the timing of sleep.     

Functional relationship between circadian rhythm and control of food intake

Living things on the earth including bacteria, plants and animals show circadian rhythms in their behaviors and physiological phenomena, and these circadian rhythms are usually synchronized with environmental changes having the period of 24 h on the earth. In mammals including human beings, the hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, and generates a circadian rhythm of food intake. Sometimes the circadian oscillation of the SCN is disturbed with physical and psychological stressors. This review describes the functional relationship in respect to connections between the circadian oscillator in the SCN and food regulatory centers and neurons in the brain focusing on its mechanism in human beings, and a possible involvement of the circadian oscillator of the SCN in the abnormality of the appetite control.     

Circadian gene variants in cancer

Abstract

Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment.     

Current status and approaches to developing press-coated chronodelivery drug systems

The past several decades have seen the development of many controlled-release preparations featuring constant release rates to maintain drug concentrations in the human body, regardless of the patient's physiological condition. However, long-term constant drug concentrations in the blood and tissue can cause problems such as resistance, tolerability, and drug side effects. People vary considerably in their physiological and biochemical conditions during any 24 h period, due to the circadian rhythm, and thus, the constant delivery of a drug into the body seems both unnecessary and undesirable. If the drug release profile mimics a living system's pulsatile hormone secretion, then it may improve drug efficacy, and reduce the toxicity of a specific drug administration schedule. Medication and treatments provided according to the body's circadian rhythms will result in better outcomes. This may be provided by a chronopharmaceutical dosage regimen with pulsatile release that matches the circadian rhythm resulting from a disease state, so optimizing the therapeutic effect while minimizing side effects. The press coating technique is a simple and unique technology used to provide tablets with a programmable lag phase, followed by a fast, or rate-controlled, drug release after administration. The technique offers many advantages, and no special coating solvent or coating equipment is required for manufacturing this type of tablet. The present review article introduces chronopharmaceutical press-coated products from a patient physiological needs perspective. The contents of this article include biological rhythms and pulsatile hormone secretion in humans, the reasons for using pulsatile drug delivery for disease treatment, recent chronopharmaceutical preparations appearing on the market, updated compilation of all research articles and press-coated delivery techniques, factors affecting the performance and drug release characteristics of press-coated delivery systems, and recent challenges for the press coating technique. We also provide a brief overview of press-coating approaches intended for chronotherapy.     

Circadian rhythm disruption in severe sepsis: the effect of ambient light on urinary 6-sulfatoxymelatonin secretion

Purpose  

Properly regulated circadian rhythm supports physical and immunologic function. This rhythm is disrupted in patients with critical illness. We assessed the association between ambient light and circadian melatonin release, measured by urinary 6-sulfatoxymelatonin (6-SMT), in medical intensive care unit (MICU) patients with severe sepsis.     

The correlates of subjective perception of identity and expression in the face network: an fMRI adaptation study

The recognition of facial identity and expression are distinct tasks, with current models hypothesizing anatomic segregation of processing within a face-processing network. Using fMRI adaptation and a region-of-interest approach, we assessed how the perception of identity and expression changes in morphed stimuli affected the signal within this network, by contrasting (a) changes that crossed categorical boundaries of identity or expression with those that did not, and (b) changes that subjects perceived as causing identity or expression to change, versus changes that they perceived as not affecting the category of identity or expression. The occipital face area (OFA) was sensitive to any structural change in a face, whether it was identity or expression, but its signal did not correlate with whether subjects perceived a change or not. Both the fusiform face area (FFA) and the posterior superior temporal sulcus (pSTS) showed release from adaptation when subjects perceived a change in either identity or expression, although in the pSTS this effect only occurred when subjects were explicitly attending to expression. The middle superior temporal sulcus (mSTS) showed release from adaptation for expression only, and the precuneus for identity only. The data support models where the OFA is involved in the early perception of facial structure. However, evidence for a functional overlap in the FFA and pSTS, with both identity and expression signals in both areas, argues against a complete independence of identity and expression processing in these regions of the core face-processing network.     

In situ electrolyte interactions in a disk-compressed configuration system for up-curving and constant drug delivery.

A new approach in drug delivery system design for meeting the needs that are associated with certain circadian variations is presented. The system is comprised of a pure compressed drug disk, which is encased by a polymeric coat using hydroxypropylmethylcellulose or polyethylene oxide. Within the polymeric coat, a physiologically acceptable binary electrolyte combination such as sodium deoxycholate and adipic acid is disposed. Through this process and upon exposure to dissolution media, ionic interactions occur and a texturally variable matrix is manifested in the form of peripheral stiffening' with self-correcting boundaries as demonstrated by texture analysis studies. The peripheral boundaries erode and progressively shift toward the disk-core, thus constantly reducing the diffusional pathlength with the resultant up-curving kinetics. Utilizing these mechanisms, a lag time is induced and drug is delivered over a 24-h period in one of two ways namely, in an up-curving or constant manner for drug models theophylline and diltiazem hydrochloride with water solubilities of 0.85% and > 50% at 25 degrees C, respectively. It appears that for both sparingly and highly soluble drugs, sum of the dissolution/diffusion rates, dynamics of diffusional pathlength and system erosion rate control the release process. The heterogeneous nature of changes in coat thickness, stiffening dynamics and erosion rate in relation to disk geometry is discussed. The developed technology has potential to provide release patterns, compatible with specific chronophysiological conditions, and overcome the absorption-limited capacity of the distal gastrointestinal tract     

Shifted sleep hours

This paper reviews the effects of suboptimal timing of the sleep/wake cycle on sleep, alertness and well-being. It is seen that shift work and rapid travel across time zones causes disturbed sleep and increased fatigue. These effects are mainly due to sleep being displaced to a rising phase of the circadian rhythm at which the interference with sleep is at its maximum. The process may also be reversed such that pathological changes of the circadian rhythm may require sleep patterns incompatible with those of the rest of society. The review concludes with a discussion of possible counter measures.     

Insomnia and circadian variation of attacks in episodic migraine

OBJECTIVES: To assess the influence of insomnia on the 24-hour temporal pattern of migraine. BACKGROUND: Migraine attacks have been reported to occur in a harmonic (monophasic) or a biphasic 24-hour cyclic manner, and in some studies to have preponderance in the morning hours. The influence of insomnia on the circadian pattern has not been evaluated. METHOD: Based on a previous study of the circadian variation in migraine, an explorative data analysis was made to compare the circadian pattern of insomnia-related migraine attacks to the circadian pattern of migraine attacks not related to insomnia. If the patients reported difficulties in falling asleep and/or maintaining sleep the night prior to the reported attack or the night the attack occurred, the attack was defined as insomnia-related. Relapses were not counted as distinctive attacks. RESULTS: Sixty-eight female migraineurs (mean +/- SD age: 35.5 +/- 7.0) prospectively recorded 1869 migraine attacks. Five hundred-and-thirty-three attacks (29%) were insomnia-related. Insomnia-related attacks had a biphasic temporal pattern with one peak in the morning hours and one peak after noon. They had a preponderance in the morning hours compared to attacks not related to insomnia (t= 3.27, df = 62, P= .002). In 79% of attacks insomnia was experienced prior to the headache. CONCLUSIONS: Episodic morning migraine is associated with insomnia. The cause and consequences of insomnia in migraine is not clarified, but sleep obviously protects against attacks rather than provokes them.     

松果体昼夜节律生物钟分子机制的研究进展

在下丘脑视交叉上核(SCN)的调控下，哺乳类松果体通过合成褪黑素(MEL)而表达输出效应。松果体作为一个神经内分泌器官，也在各种非哺乳类脊椎动物中起着中枢昼夜节律振荡器的作用。在多数情况下，松果体振荡器均保持与光信号输入通路和内分泌输出通路的密切联系。近来，在鸟类松果体中相继发现了几种钟基因，如Per、Cry、Clock和Bmal等，其表达的时间变化规律与哺乳类SCN的非常相似。钟的振荡由其自身调控反馈环路的转录和翻译组成，鸟类松果体和哺乳类SCN似乎具有共同的钟振荡基本分子构架；若干钟基因产物作为正向(CLOCK／BNAL)或负向(PER／CRY)调节子影响钟的振荡；昼夜性的控时机制同时也需要翻译后事件的参与，包括蛋白移位、降解和磷酸化等过程。这些过程对钟振荡器稳定的24小时周期和／或钟导引的光输入通路有着重要的调控作用。     

Energy Stores Are Not Altered by Long-Term Partial Sleep Deprivation in Drosophila melanogaster

Recent human studies reveal a widespread association between short sleep and obesity. Two hypotheses, which are not mutually exclusive, might explain this association. First, genetic factors that reduce endogenous sleep times might also impact energy stores, an assertion that we confirmed in a previous study. Second, metabolism may be altered by chronic partial sleep deprivation. Here we address the second assertion by measuring the impact of long-term partial sleep deprivation on energy stores using Drosophila as a model. We subjected flies to long-term partial sleep deprivation via two different methods: a mechanical stimulus and a light stimulus. We then measured whole-body triglycerides and glycogen, two important sources of energy for the fly, and compared them to un-stimulated controls. We also measured changes in energy stores in response to a random circadian clock shift. Sex and line-dependent alterations in glycogen and/or triglyceride levels occurred in response to the circadian clock shift and in flies subjected to a single night of sleep deprivation using light. Thus, consistent with previous studies, our findings suggest that acute sleep loss and changes to the circadian clock can alter metabolism. Significant changes in energy stores were also observed when flies were subjected to chronic sleep loss via the mechanical stimulus, although not the light stimulus. Interestingly, mechanical stimulation resulted in the same change in energy stores even when it was not associated with sleep deprivation, suggesting that the changes are caused by stress rather than sleep loss. These findings emphasize the importance of taking stress into account when evaluating the relationship between sleep loss and metabolism.