Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice.

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A1/A2A receptor signalling through the activation of the Ca2+ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.

Removal of melatonin receptor type 1 signalling induces dyslipidaemia and hormonal changes in mice subjected to environmental circadian disruption.

Background: Melatonin is a hormone secreted by the pineal gland in a circadian rhythmic manner with peak synthesis at night. Melatonin signalling was suggested to play a critical role in metabolism during the circadian disruption. Methods: Melatonin-proficient (C3H-f+/+ or WT) and melatonin receptor type 1 knockout (MT1 KO) male and female mice were phase-advanced (6 hours) once a week for 6 weeks. Every week, we measured weight, food intake and basal glucose levels. At the end of the experiment, we sacrificed the animals and measured the blood's plasma for lipids profile (total lipids, phospholipids, triglycerides and total cholesterol), metabolic hormones profiles (ghrelin, leptin, insulin, glucagon, glucagon-like-peptide and resistin) and the body composition. Results: Environmental circadian disruption (ECD) did not produce any significant effects in C3H-f+/+, while it increased lipids profile in MT1 KO with the significant increase observed in total lipids and triglycerides. For metabolic hormones profile, ECD decreased plasma ghrelin and increased plasma insulin in MT1 KO females. Under control condition, MT1 KO females have significantly different body weight, fat mass, total lipids and total cholesterol than the control C3H-f+/+ females. Conclusion: Our data show that melatonin-proficient mice are not affected by ECD. When the MT1 receptors are removed, ECD induced dyslipidaemia in males and females with females experiencing the most adverse effect. Overall, our data demonstrate that MT1 signalling is an essential modulator of lipid and metabolic homeostasis during ECD.

Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans.

Circadian disruption has been identified as a risk factor for health disorders such as obesity, cardiovascular disease, and cancer. Although epidemiological studies suggest an increased risk of various cancers associated with circadian misalignment due to night shift work, the underlying mechanisms have yet to be elucidated. We sought to investigate the potential mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased cancer risk in shift workers. In a controlled laboratory study, we investigated the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in circulating leukocytes obtained from healthy young adults during a 24-hour constant routine protocol following 3 days of simulated day shift or night shift. The simulated night shift schedule significantly altered the normal circadian rhythmicity of genes involved in cancer hallmark pathways. A DNA repair pathway showed significant enrichment of rhythmic genes following the simulated day shift schedule, but not following the simulated night shift schedule. In functional assessments, we demonstrated that there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift. Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers.

Internal clock and the surgical ICU patient.

PURPOSE OF REVIEW: The alteration of circadian rhythms in the postoperative period has been demonstrated to influence the outcomes. With this narrative review we would revise how anesthesia, surgery and intensive care can interfere with the circadian clock, how this could impact on the postsurgical period and how to limit the disruption of the internal clock. RECENT FINDINGS: Anesthesia affects the clock in relation to the day-time administration and the type of anesthetics, N-methyl-D-aspartate receptor antagonists or gamma-aminobutyric acid receptors agonists. Surgery causes stress and trauma with consequent alteration in the circadian release of cortisol, cytokines and melatonin. ICU represents a further challenge for the patient internal clock because of sedation, immobility, mechanical ventilation and alarms noise. SUMMARY: The synergic effect of anesthesia, surgery and postoperative intensive care on circadian rhythms require a careful approach to the patient considering a role for therapies and interventions aimed to re-establish the normal circadian rhythms. Over time, approach like the Awakening and Breathing Coordination, Delirium Monitoring and Management, Early Mobility and Family engagement and empowerment bundle can implement the clinical practice.

Maternal circadian disruption is associated with variation in placental DNA methylation.

Circadian disruption is a common environmental and occupational exposure with public health consequences, but not much is known about whether circadian disruption affects in utero development. We investigated whether maternal circadian disruption, using night shift work as a proxy, is associated with variations in DNA methylation patterns of placental tissue in an epigenome-wide association study (EWAS) of night shift work. Here, we compared cytosine-guanosine dinucleotide (CpG) specific methylation genome-wide of placental tissue (measured with the Illumina 450K array) from participants (n = 237) in the Rhode Island Child Health Study (RICHS) who did (n = 53) and did not (n = 184) report working the night shift, using robust linear modeling and adjusting for maternal age, pre-pregnancy smoking, infant sex, maternal adversity, and putative cell mixture. Statistical analyses were adjusted for multiple comparisons and results presented with Bonferroni or Benjamini and Hochberg (BH) adjustment for false discovery rate. Night shift work was associated with differential methylation in placental tissue, including CpG sites in the genes NAV1, SMPD1, TAPBP, CLEC16A, DIP2C, FAM172A, and PLEKHG6 (Bonferroni-adjusted p<0.05). CpG sites within NAV1, MXRA8, GABRG1, PRDM16, WNT5A, and FOXG1 exhibited the most hypomethylation, while CpG sites within TDO2, ADAMTSL3, DLX2, and SERPINA1 exhibited the most hypermethylation (BH q<0.10). Functional analysis indicated GO-terms associated with cell-cell adhesion and enriched GWAS results for psoriasis. Night shift work was associated with differential methylation of the placenta, which may have implications for fetal health and development. This is the first study to examine the epigenetic impacts of night shift exposure, as a proxy for circadian disruption, on placental methylation in humans, and, while results should be interpreted with caution, suggests circadian disruption may have epigenetic impacts.

[Surgery and circadian disturbances].

Circadian disturbances in relation to surgery have been extensively researched through the latest couple of decades. Surgery has been shown to affect melatonin rhythm, core body temperature, cortisol rhythm, activity rhythm and sleep in the perioperative period. The changes translate into both subjective patients' discomfort, prolonging convalescence and clinical effects on morbidity and mortality. Future research should be performed to show effect across different surgical procedures and to investigate potential interventions to alleviate harmful effects of circadian disturbances.

Depressive symptoms and actigraphy-measured circadian disruption predict head and neck cancer survival.

OBJECTIVE: Depressive symptoms have demonstrated prognostic significance among head and neck cancer patients. Depression is associated with circadian disruption, which is prognostic in multiple other cancer types. We hypothesized that depressive symptoms would be associated with circadian disruption in head and neck cancer, that each would be related to poorer 2-year overall survival, and that relationships would be mediated by tumor response to treatment. METHODS: Patients (N = 55) reported on cognitive/affective and somatic depressive symptoms (PHQ-9) and wore an actigraph for 6 days to continuously record rest and activity cycles prior to chemoradiation. Records review documented treatment response and 2-year survival. Spearman correlations tested depressive symptoms and circadian disruption relationships. Cox proportional hazard models tested the predictive capability of depressive symptoms and circadian disruption, separately, on survival. RESULTS: Depressive symptoms were significantly associated with circadian disruption, and both were significantly associated with shorter survival (somatic: hazard ratio [HR] = 1.325, 95% confidence interval [CI] = 1.089-1.611, P = .005; rest/activity rhythm: HR = 0.073, 95% CI = 0.009-0.563, P = .012; nighttime restfulness: HR = 0.910, 95% CI = 0.848-0.977, P = .009). Tumor response to treatment appeared to partly mediate the nighttime restfulness-survival relationship. CONCLUSIONS: This study replicates and extends prior work with new evidence linking a subjective measure of depression and an objective measure of circadian disruption-2 known prognostic indicators-to shortened overall survival among head and neck cancer patients. Continued examination should elucidate mechanisms by which depressive symptomatology and circadian disruption translate to head and neck cancer progression and mortality.

Spinal Cord Injury in Rats Disrupts the Circadian System.

Spinal cord injury (SCI) perturbs many physiological systems. The circadian system helps maintain homeostasis throughout the body by synchronizing physiological and behavioral functions to predictable daily events. Whether disruption of these coordinated daily rhythms contributes to SCI-associated pathology remains understudied. Here, we hypothesized that SCI in rats would dysregulate several prominent circadian outputs including glucocorticoids, core temperature, activity, neuroinflammation, and circadian gene networks. Female and male Sprague Dawley rats were subjected to clinically relevant thoracic 9 moderate contusion SCI (or laminectomy sham surgery). Diurnal measures-including rhythms of plasma corticosterone (CORT), body temperature, and activity (using small implanted transmitters), and intraspinal circadian and inflammatory gene expression-were studied prior to and after surgery. SCI caused overall increases and disrupted rhythms of the major rodent glucocorticoid, CORT. Presurgery and sham rats displayed expected rhythms in body temperature and activity, whereas rats with SCI had blunted daily rhythms in body temperature and activity. In parallel, SCI disrupted intraspinal rhythms of circadian clock gene expression. Circadian clock genes can act as transcriptional regulators of inflammatory pathways. Indeed, SCI rats also showed dysregulated rhythms in inflammatory gene expression in both the epicenter and distal spinal cord. Our data show that moderate SCI in rats causes wide-ranging diurnal rhythm dysfunction, which is severe at acute time points and gradually recovers over time. Normalizing post-SCI diurnal rhythms could enhance the recovery of homeostasis and quality of life.

Disruption of normal circadian clock function in a mouse model of tauopathy.

Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to ß-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention.

Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ < 20 h), circadian (20 h > τ < 28 h) and infradian (τ > 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker - the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase "circadian disruption" (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson's disease; Smith-Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain ß-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it.

[Temporal order deterioration and circadian disruption with age. 2. Systemic mechanisms and correction].

Part 2 of the present review highlights the impact of aging on mechanisms involved in response of the circadian system to different photic and non-photic factors, especially zeitgebers. Promising strategies to prevent age-dependent circadian disruption using internal and external factors that may entrain circadian rhythms are presented. In particular, benefits of bright light, melatonin and other chronobiotics, the circadian body temperature rhythm, physical activity and regular feeding schedules to preserve the temporal order of aged organisms are discussed, emphasizing especially a personalized approach based on the assessment of individual overt rhythms parameters.

The ticking clock of Cayo Santiago macaques and its implications for understanding human circadian rhythm disorders.

The circadian clock disorders in humans remain poorly understood. However, their impact on the development and progression of major human conditions, from cancer to insomnia, metabolic or mental illness becomes increasingly apparent. Addressing human circadian disorders in animal models is, in part, complicated by inverse temporal relationship between the core clock and specific physiological or behavioral processes in diurnal and nocturnal animals. Major advantages of a macaque model for translational circadian research, as a diurnal vertebrate phylogenetically close to humans, are further emphasized by the discovery of the first familial circadian disorder in non-human primates among the rhesus monkeys originating from Cayo Santiago. The remarkable similarity of their pathological phenotypes to human Delayed Sleep Phase Disorder (DSPD), high penetrance of the disorder within one branch of the colony and the large number of animals available provide outstanding opportunities for studying the mechanisms of circadian disorders, their impact on other pathological conditions, and for the development of novel and effective treatment strategies.

Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer's Disease Mouse Model.

It is unclear whether pre-symptomatic Alzheimer's disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2-/- model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.

Chronobesity: role of the circadian system in the obesity epidemic.

Although obesity is considered to result from an imbalance between energy uptake and energy expenditure, the strategy of dietary changes and physical exercise has failed to tackle the global obesity epidemic. In search of alternative and more adequate treatment options, research has aimed at further unravelling the mechanisms underlying this excessive weight gain. While numerous studies are focusing on the neuroendocrine alterations that occur after bariatric Roux-en-Y gastric bypass surgery, an increasing amount of chronobiological studies have started to raise awareness concerning the pivotal role of the circadian system in the development and exacerbation of obesity. This internal timekeeping mechanism rhythmically regulates metabolic and physiological processes in order to meet the fluctuating demands in energy use and supply throughout the 24-h day. This review elaborates on the extensive bidirectional interaction between the circadian system and metabolism and explains how disruption of body clocks by means of shift work, frequent time zone travelling or non-stop consumption of calorie-dense foods can evoke detrimental metabolic alterations that contribute to obesity. Altering the body's circadian rhythms by means of time-related dietary approaches (chrononutrition) or pharmacological substances (chronobiotics) may therefore represent a novel and interesting way to prevent or treat obesity and associated comorbidities.

[CHRONOBIOLOGICAL ASPECTS OF THE USE OF PROLIT SUPER SEPTO IN PATIENTS WITH INFECTIOUS AND INFLAMMATORY DISEASES OF THE URINARY SYSTEM].

This paper presents results of a study involving 120 patients with infectious and inflammatory diseases of the urinary system, divided into four groups. Groups 1 and 3 included patients with acute serous non-obstructive pyelonephritis, groups 2 and 4--patients with exacerbation of chronic recurrent bacterial cystitis. Patients in groups 3 and 4 received a 10 day course of antibiotic therapy combined with Prolit super septo while patients in groups 1 and 2--only the standard antibiotic therapy. The authors studied changes in the clinical presentation, chronorhythms and psycho-emotional condition of the patients. At baseline, all patients showed signs of severe desynchronosis and psycho-emotional disorders. Combination therapy with Prolit super septo more effectively suppressed inflammation, improved clinical symptoms, corrected patient psycho-emotional status and restored normal chronorhythms regardless of the inflammation location.

Mitomycin C modulates the circadian oscillation of clock gene period 2 expression through attenuating the glucocorticoid signaling in mouse fibroblasts.

Clock gene regulates the circadian rhythm of various physiological functions. The expression of clock gene has been shown to be attenuated by certain drugs, resulting in a rhythm disorder. Mitomycin C (MMC) is often used in combination with ophthalmic surgery, especially in trabeculectomy, a glaucoma surgical procedure. The purpose of this study was to investigate the influence of MMC on clock gene expression in fibroblasts, the target cells of MMC. Following MMC treatment, Bmal1 mRNA levels was significantly decreased, whereas Dbp, Per1, and Rev-erbα mRNA levels were significantly increased in the mouse fibroblast cell line NIH3T3 cells. Microarray analysis was performed to explore of the gene(s) responsible for MMC-induced alteration of clock gene expression, and identified Nr3c1 gene encoding glucocorticoid receptor (GR) as a candidate. MMC suppressed the induction of Per1 mRNA by dexamethasone (DEX), ligand of GR, in NIH3T3 cells. MMC also modulated the DEX-driven circadian oscillations of Per2::Luciferase bioluminescence in mouse-derived ocular fibroblasts. Our results demonstrate a previously unknown effect of MMC in GR signaling and the circadian clock system. The present findings suggest that MMC combined with trabeculectomy could increase the risk for a local circadian rhythm-disorder at the ocular surface.

Disruption of Circadian Rhythms in Critical Illness - A Role of Hyperoxia-Induced Lung Injury.

With the current high rates of associated morbidity and mortality, proper management of critical illness is vital in the treatment of severely ill patients. Disruptions of key body systems stemming from these illnesses may be attributed to their severity and limited treatment options. Disruption in circadian rhythms caused by critical illnesses may lead to a decreased patient prognosis, as the biological clocks stemming from circadian rhythms play several key roles in regulating our internal pathways. This review will highlight how the occurrence of hyperoxic injury during the progression of critical illness may severely damage circadian rhymicity, and lead to an increased risk of infection, development of disease, severity of symptoms, morbidity and mortality, and dysregulation of multiple body systems. Overall, there is strong evidence suggesting that the disruption of circadian rhythms may be caused by critical illness. Studies performed on several animal models have shown alterations of key genes associated with circadian clock function may heavily contribute to the increased severity of critical illness linked to circadian disruption. This review will aid in further understanding the link between circadian disruption and critical illness.

Light at night pollution of the internal clock, a public health issue.

Light is the major synchronizer of the internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus. Retinal ganglion cells contain melanopsin, a photoreceptor with a peak sensitivity to blue wavelength (460-480 nm). Light signal is transmitted from the eye to the clock, then to the pineal gland which produces melatonin, considered as the hand of the clock. Even a weak intensity of light (LEDs, tablets, mobile phones, computers...) is able to block the secretion of melatonin, the hormone of darkness. Light is also able to phase advance or phase delay the circadian system according to the timing of exposure. This Phase Response Curve (PRC) is used to resynchronize the clock in various situations of circadian desynchronization. Exposure to Light at Night (LAN) results in a disruption of the circadian system which is deleterious to health. In industrialized countries, including France, 75 % of the total workforce is estimated to be involved in atypical hours, far from the classical diurnal hours of work. Of interest, shift work and night work involve 15.4 % of the French workforce. A number of epidemiologic studies, peiformed mainly on nurses, showed an association between sustained night work (3 to 20 years) and an increased risk of breast cancer Health problems faced by flight attendants have also been reported, though other causes like exposure to radiations cannot be ruled out. Other deleterious effects are reported in this paper. The potential mechanisms of the deleterious effects of LAN on health are suppression of melatonin andsleep deprivation. The International Agencyfor Cancer Research (IARC) classified shift work that involves circadian disruption as ( probably carcinogenic to humans". Countermeasures (e.g melatonin, bright light, use of psychotropic drugs) have been proposed as a means to improve adaptation to shift work and night work and to fight " clock pollution " and circadian desynchronization by LAN.