Synchronization Of Circadian Rhythms Research Articles

Steven A. Brown and the synchronization of circadian rhythms by body temperature cycles.

The mammalian circadian timing system has a hierarchical architecture, with a central pacemaker located in the brain's suprachiasmatic nucleus orchestrating rhythms in behaviour and physiology. In cooperation with environmental cycles, it synchronizes the phases of peripheral oscillators operating in most cells of the body. Even cells kept in tissue culture harbour self-sustained and cell-autonomous circadian clocks that keep ticking throughout their lifespan. The master pacemaker in the suprachiasmatic nucleus is synchronized primarily by light-dark cycles, whereas peripheral oscillators are phase entrained by a multitude of systemic signalling pathways. These include pathways depending on feeding-fasting cycles, cellular actin polymerization dynamics, endocrine rhythms and, surprisingly, body temperature oscillations. Using tissue culture and murine models, Steve Brown was the first one to demonstrate that shallow rhythms of mammalian body temperature are timing cues (zeitgebers) for peripheral circadian clocks.

Biological Rhythms, Chrono-Nutrition, and Gut Microbiota: Epigenomics Insights for Precision Nutrition and Metabolic Health.

Circadian rhythms integrate a finely tuned network of biological processes recurring every 24 h, intricately coordinating the machinery of all cells. This self-regulating system plays a pivotal role in synchronizing physiological and behavioral responses, ensuring an adaptive metabolism within the environmental milieu, including dietary and physical activity habits. The systemic integration of circadian homeostasis involves a balance of biological rhythms, each synchronically linked to the central circadian clock. Central to this orchestration is the temporal dimension of nutrient and food intake, an aspect closely interwoven with the neuroendocrine circuit, gut physiology, and resident microbiota. Indeed, the timing of meals exerts a profound influence on cell cycle regulation through genomic and epigenetic processes, particularly those involving gene expression, DNA methylation and repair, and non-coding RNA activity. These (epi)genomic interactions involve a dynamic interface between circadian rhythms, nutrition, and the gut microbiota, shaping the metabolic and immune landscape of the host. This research endeavors to illustrate the intricate (epi)genetic interplay that modulates the synchronization of circadian rhythms, nutritional signaling, and the gut microbiota, unravelling the repercussions on metabolic health while suggesting the potential benefits of feed circadian realignment as a non-invasive therapeutic strategy for systemic metabolic modulation via gut microbiota. This exploration delves into the interconnections that underscore the significance of temporal eating patterns, offering insights regarding circadian rhythms, gut microbiota, and chrono-nutrition interactions with (epi)genomic phenomena, thereby influencing diverse aspects of metabolic, well-being, and quality of life outcomes.

Increased glutamatergic neurotransmission between the retinohypothalamic tract and the suprachiasmatic nucleus of old mice.

Circadian rhythms synchronize to light through the retinohypothalamic tract (RHT), which is a bundle of axons coming from melanopsin retinal ganglion cells, whose synaptic terminals release glutamate to the ventral suprachiasmatic nucleus (SCN). Activation of AMPA-kainate and NMDA postsynaptic receptors elicits the increase in intracellular calcium required for triggering the signaling cascade that ends in phase shifts. During aging, there is a decline in the synchronization of circadian rhythms to light. With electrophysiological (whole-cell patch-clamp) and immunohistochemical assays, in this work, we studied pre- and postsynaptic properties between the RHT and ventral SCN neurons in young adult (P90-120) and old (P540-650) C57BL/6J mice. Incremental stimulation intensities (applied on the optic chiasm) induced much lesser AMPA-kainate postsynaptic responses in old animals, implying a lower recruitment of RHT fibers. Conversely, a higher proportion of old SCN neurons exhibited synaptic facilitation,and variance-mean analysis indicated an increase in the probability of release in RHT terminals. Moreover, both spontaneous and miniature postsynaptic events displayed larger amplitudes in neurons from aged mice, whereas analysis of the NMDA and AMPA-kainate components (evoked by RHT electrical stimulation) disclosed no difference between the two ages studied. Immunohistochemistry revealed a bigger size in the puncta of vGluT2, GluN2B, and GluN2A of elderly animals, and the number of immunopositive particles was increased, but that of PSD-95 was reduced. All these synaptic adaptations could be part of compensatory mechanisms in the glutamatergic signaling to ameliorate the loss of RHT terminals in old animals.

Changes in RBM47 expression based on the timing of melatonin administration and its effects on Nrf2 activity in the hippocampus

Melatonin is an endogenous indoleamine that plays a significant role in various physiological processes, including the sleep-wake cycle, anxiety, immunity, and circadian rhythms. However, it is important to clarify that melatonin does not directly control circadian rhythms. Circadian rhythms are primarily synchronized by light, which acts on the suprachiasmatic nucleus (SCN) and subsequently regulates melatonin production. This light-mediated synchronization of circadian rhythms is essential for maintaining the alignment of the body with the light-dark cycle. In this study, we investigated the efficacy of melatonin administration during different times of the day or night and explored its neuroprotective effects. Furthermore, we aimed to apply these findings to rodent models of dementia, aging, and neuro-inflammation for potential therapeutic applications. Our study uncovered novel evidence suggesting the involvement of RNA-binding motif protein (RBM)-47 and Nrf2 in the signaling pathways associated with melatonin administration during both day and night. We examined the role of RBM47 in Nrf2 activity through siRNA or CRISPR-mediated knockdown experiments using hippocampal neuronal cells and lentivirus injections in mice. In 5xFAD/aging/neuroinflammatory mouse models, antioxidant effects were enhanced when melatonin was administered during the day compared to nighttime administration. Furthermore, mRNA analysis and molecular biology experiments revealed the differential expression of RBM47 depending on the timing of melatonin administration. These findings suggest that a decrease in RBM47 expression may improve the antioxidant defense system in the hippocampus. Consequently, administering melatonin during the day rather than at night may present a plausible therapeutic strategy as an antioxidant.

Circadian Rhythm Effect in Depression Management: A Psychosocial Approach

Depression is a kind of mental disorder. It is a risk factor for many diseases. Recently, it has been suggested to contribute to the high mortality rate, especially for young-middle ages. The incidence of depression is studied to be associated with sleep-style change that leads to internal circadian rhythm disruption. The circadian rhythm is related to the light-dark cycle of the sun. Dusk and dawn twilight are an important part of internal circadian rhythm synchronization. These moments correlate with the praying time of Muslims. A socio-spiritual approach could be a potential treatment for depressive disorder. At praying time for Muslims, the synchronization process of circadian rhythm is happening so that, hopefully, circadian disruption will resolve. This review aims to understand the impact of circadian rhythm on depression and its potential for depression treatment in the future.

A novel study of melatonin diffusion in a 3D cell culture model

Melatonin is now considered a major physiological regulator of many different functions including synchronization of circadian rhythms, antioxidant defense at different levels, immunomodulation, cell growth control, neuroprotector and anti-tumor agent. In addition to its membrane receptor-dependent actions, it has been classically assumed that its diffusion through lipid bilayers contribute to its intracellular actions, including direct and indirect free radical scavenging activities. While pineal gland is the major site of nocturnal production of the indolamine, skin is considered an important source of melatonin synthesis. Here, using a 3-D culture model of HaCaT cells in an artificial scaffold (epidermal equivalents), we have quantified diffusion of melatonin in these cells and compared it to 2-D or spheroid cultures. Diffusion in 3-D scaffold cultures was similar to that found in 2-D culture and proportion of intracellular melatonin was low. AFMK, a major oxidative metabolite of melatonin, was also found and quantified. Redox parameters including total ROS, superoxide or mitochondrial mass were also assayed. We also report the effect of melatonin on the cytoskeleton of normal human keratinocyte HaCaT cells. We propose HaCaT epidermal equivalents as an affordable, easy-to-use, 3-D cell culture tool to test diffusion rates of melatonin but also other similar small molecules. This 3-D models can also be studied at cellular and molecular level, including redox parameters, and can provide important information regarding molecules that can be topically added to skin. Similarly, mechanisms of transportation can also be approached with this methodology.

Physical activity as a promising alternative for young people with juvenile idiopathic arthritis: Towards an evidence-based prescription.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in young people. Although biologics now enable most children and adolescents with JIA to enjoy clinical remission, patients present lower physical activity and spend more time in sedentary behavior than their healthy counterparts. This impairment probably results from a physical deconditioning spiral initiated by joint pain, sustained by apprehension on the part of both the child and the child's parents, and entrenched by lowered physical capacities. This in turn may exacerbate disease activity and lead to unfavorable health outcomes including increased risks of metabolic and mental comorbidities. Over the past few decades, there has been growing interest in the health benefits of increased overall physical activity as well as exercise interventions in young people with JIA. However, we are still far from evidence-based physical activity and / or exercise prescription for this population. In this review, we give an overview of the available data supporting physical activity and / or exercise as a behavioral, non-pharmacological alternative to attenuate inflammation while also improving metabolism, disease symptoms, poor sleep, synchronization of circadian rhythms, mental health, and quality of life in JIA. Finally, we discuss clinical implications, identify gaps in knowledge, and outline a future research agenda.

Müller glial cell photosensitivity: A novel function bringing higher complexity to vertebrate retinal physiology

The retina of vertebrates is responsible for detecting and capturing ambient light for image and non-image forming (NIF) functions through diverse projections to the brain which regulate visual processing, pupillary light responses, photic synchronization of circadian rhythms and suppression of pineal melatonin, among others. For this, vertebrates have retained through evolution at least two sets of photoreceptors specialized primarily in such visual and NIF tasks: visual photoreceptors cones and rods responsible for day/night vision, and intrinsically photosensitive retinal ganglion cells (ipRGC) together with horizontal cells in some vertebrates, expressing melanopsin (Opn4). Interestingly, Opn4 as well as encephalopsin (Opn3) and neuropsin (Opn5), responding to blue and UV light, respectively, are expressed in the inner retina and command light detection in the blue range of the visible spectra; they are responsible for a number of NIF functions still lacking characterization. Though most retinal photoreceptors are derived from ciliary or neuronal progenitor cells, in recent years Müller glial cells (MCs), the most abundant retinal glial cell type, have been shown to express different blue opsins (Opn3 and Opn5) and the photoisomerase retinal G protein-coupled receptor (RGR), and to respond directly to light. MCs display different essential functions to maintain the homeostasis and cell survival of the whole retina, contributing to glutamate metabolism and chromophore recycling. The novel photoreceptive capacity of MCs, mainly in the blue region, offers several highly intriguing possibilities that increase the complexity levels for light detection in the retina and its light-activated circuits, calling for further investigation. The goal of the present review is to discuss the state of the art of research on the principal macroglial cells in the retina, focusing mainly on the novel photic responses driven by MCs, the biochemical mechanisms triggered after light stimulation and their putative functions and implications.

The role of melatonin in the pathogenesis of alcohol dependence in rats that survived separation from their mother

Chronic alcohol consumption is the leading cause of chronic disease. Currently, both alcohol dependence and the consequences of chronic alcohol consumption are growing in the population. According to the liter-ature, one of the main causes of alcohol dependence is the stress effect on the body. Melatonin, as a hormone with a large number of biological effects, plays an essen-tial role in normalizing the post-stress state of the body. This is primarily due to its effect on neurotransmitter sys-tems and the impact on the synchronization of circadian rhythms. By acting simultaneously on the immune and neuroendocrine systems, melatonin optimizes homeo-stasis and increases resistance to stress.The aim of this study was to study the effect of me-latonin on the development of alcohol dependence in laboratory rats exposed to stress in the early postnatal period.The experiment reproduced early postnatal stress in newborn laboratory rats, which was a predictor of the development of alcohol dependence in experimental an-imals. The alcohol dependence that developed against the background of stress was pharmacologically correct-ed with the introduction of melatonin.Oral and intraventricular administration of me-latonin reduces voluntary alcohol consumption in a group of animals with more pronounced alcohol depen dence.Further study of the clinical effect of melatonin in the pathogenesis of alcohol dependence seems promising. The question remains whether melatonin has a signifi-cant effect on the craving for alcohol and on its amount in the developed alcohol dependence.

Invitro cell models merging circadian rhythms and brain waves for personalized neuromedicine.

New evidence is emerging about the dynamics of interaction between circadian rhythms and brain waves, whose coordination occurs through the entrainment process. The so-called "oscillopathies" or dysfunctions in synchronization of neuronal oscillation in key brain networks lead to the onset of neurodegenerative diseases. A typical example of alteration is insomnia, a risk factor for the oscillopathies, increasingly widespread worldwide. Recently, synchronization of circadian rhythms in cell cultures has allowed an improvement in the physiological relevance of responses to stimuli. Furthermore, brain organoids and neurons cultured in microfluidic systems are the latest frontiers for invitro reproduction of rhythmic electrical signals. In this review, the combination of these invitro experimental approaches is proposed as suitable for a more direct investigation on the common mechanisms and neurophysiological substrates underlying brain waves and circadian oscillations, and useful to evaluate the effects of "oscillotherapeutic" drugs for personalized neuromedicine.

Developmental light deprivation transiently reduces the expression of vGluT2 and GluN2B in the rat ventral suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is the most important circadian clock in mammals. The SCN synchronizes to environmental light via the retinohypothalamic tract (RHT), which is an axon cluster derived from melanopsin-expressing intrinsic photosensitive retinal ganglion cells. Investigations on the development of the nonimage-forming pathway and the RHT are scarce. Previous studies imply that light stimulation during postnatal development is not needed to make the RHT functional at adult stages. Here, we examined the effects of light deprivation (i.e., constant darkness (DD) rearing) during postnatal development on the expression in the ventral SCN of two crucial proteins for the synchronization of circadian rhythms to light: the presynaptic vesicular glutamate transporter type 2 (vGluT2) and the GluN2B subunit of the postsynaptic NMDA receptor. We found that animals submitted to DD conditions exhibited a transitory reduction in the expression of vGluT2 (at P12-19) and of GluN2B (at P7-9) that was compensated at older stages. These findings support the hypothesis that visual stimulation during early ages is not decisive for normal development of the RHT-SCN pathway.

The Effect of Exogenous Melatonin on Eating Habits of Female Night Workers with Excessive Weight.

Background and Aims: Melatonin is a pineal hormone that plays an important role as an endogenous synchronizer of circadian rhythms and energy metabolism. As this circadian component has been closely related to eating behavior, an important question on this topic would be whether melatonin administration could influence eating habits. However, this topic has been rarely studied in the literature in individuals with excessive weight and chronic circadian misalignment, such as shift workers. Therefore, the present study aims to evaluate the effects of exogenous melatonin administration on the quali/quantitative aspects and temporal distribution of food intake in female night workers with excessive weight (overweight and obesity). An additional aim is to evaluate the association of the referred outcomes with circadian misalignment and chronotype. Methods: A randomized, double-blind, placebo-controlled, crossover clinical trial was conducted with 27 female nursing professionals with excessive weight who worked permanent night shifts. The protocol was implemented under real-life conditions for 24 weeks, in two randomly allocated conditions (12 weeks of melatonin and 12 weeks of placebo). The quali/quantitative aspects of food intake (NOVA classification, total energy intake and the proportion of calories from macronutrients) and meal timing were assessed using food diaries. Timing for every meal recorded in the diaries was assessed to evaluate the temporal distribution of food intake. Generalized estimating equations were performed for each dependent variable. Results: No significant modifications in total energy intake, macronutrient distribution, types of foods consumed, and meal timing were observed after melatonin administration. Different levels of circadian misalignment and chronotype did not interfere with these results. Conclusion: Eating habits of female night workers with excessive weight remained unchanged after melatonin administration, and no association of these results with circadian misalignment and chronotype was found. These results suggest that the metabolic effects of melatonin may occur independently of food intake.

Circadian parameter as a possible indicator of gait performance and daily activity levels in chronic stroke survivors.

Stroke recovery is a critical public health problem. It involves cognitive and physical impairments leading to physical inactivity. In addition, there are also sleep problems and disruption of the circadian rhythm. In this paper, we analyze the relation between cognitive impairments level, walking performance, sleep and circadian parameters of a group of chronic stroke survivors. Five stroke survivors enrolled in the study. The clinical assessments were: cognitive function (MoCA), the 10 meter-walking test (10MWT), and the 6 minutes walking test (6MWT). The circadian rhythm parameters were obtained for at least one week wearing the actimeters. There was a positive correlation between the duration of the main sleep episode and the MoCA scores. There were significant correlations between the 10MWT and 6MWT and the circadian parameters that were positive for most active period (M10), Interdaily stability (IS), Mesor and Amplitude and negative for intradaily variability (IV). Our results indicate that gait speed and resistance are correlated to circadian rhythm synchronization, lower rhythm variability and more defined activity-rest episodes. This preliminary study underscores the importance of including a continuous measure of sleep and activity cycles in the assessment of stroke survivors.

Time Restricted Feeding to the Light Cycle Dissociates Canonical Circadian Clocks and Physiological Rhythms in Heart Rate.

Circadian rhythms are approximate 24-h biological cycles that optimize molecular and physiological functions to predictable daily environmental changes in order to maintain internal and organismal homeostasis. Environmental stimuli (light, feeding, activity) capable of altering the phase of molecular rhythms are important tools employed by circadian biologists to increase understanding of the synchronization of circadian rhythms to the environment and to each other within multicellular systems. The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus is largely responsive to light and is thought to entrain the phase of peripheral clocks via neurohumoral signals. Mice are nocturnal and consume most of their food during the dark cycle. Early studies demonstrated that altered metabolic cues in the form of time restricted feeding, specifically, feeding mice during the light cycle, resulted in an uncoupling of molecular clocks in peripheral tissues with those from the SCN. These studies showed as much as a 12-h shift in gene expression in some peripheral tissues but not others. The shifts occurred without corresponding changes in the central clock in the brain. More recent studies have demonstrated that changes in cardiac physiology (heart rate, MAP) in response to time of food intake occur independent of the cardiac molecular clock. Understanding differences in the physiology/function and gene expression in other organs both independently and in relation to the heart in response to altered feeding will be important in dissecting the roles of the various clocks throughout the body, as well as, understanding their links to cardiovascular pathology.

Abstract MP31: Bmal1 Regulates Production Of Larger Lipoproteins By Modulating Crebh And Apolipoprotein A 4

High plasma lipid and lipoprotein levels are risk factors for various metabolic diseases, such as diabetes, obesity, metabolic syndrome, and atherosclerosis. We previously showed that circadian rhythms regulate plasma lipids, and deregulation of these rhythms cause hyperlipidemia and atherosclerosis in mice. Here, we show that global and liver-specific Bmal1-deficient mice maintained on a chow or a Western diet developed hyperlipidemia, which was denoted by the presence of higher amounts of triglyceride- and apoAIV-rich larger chylomicron and very-low-density lipoprotein, due to overproduction. Bmal1 deficiency decreased Shp and increased MTP, a key protein that facilitates primordial lipoprotein assembly and secretion. Moreover, we show that Bmal1 regulates Crebh to modulate apoAIV expression and the assembly of larger lipoproteins. This is supported by the observation that Crebh- and apoAIV-deficient mice, along with Bmal1-deficient mice with knockdown of Crebh, had smaller lipoproteins. Further, overexpression of Bmal1 in Crebh-deficient mice had no effect on apoAIV expression and lipoprotein size. These studies indicate that regulation of apoAIV and assembly of larger lipoproteins by Bmal1 requires Crebh. Mechanistic studies showed that Bmal1 regulates Crebh expression by two mechanisms. First, Bmal1 interacts with the Crebh promoter to control circadian regulation. Second, Bmal1 increases Rev-erbα expression, and Rev-erbα interacts with the Crebh promoter to repress expression. In short, Bmal1 modulates both the synthesis of primordial lipoproteins and their subsequent expansion into larger lipoproteins by regulating two different proteins, MTP and apoAIV, via two different transcription factors, Shp and Crebh. It is likely that disruptions in circadian mechanisms contribute to hyperlipidemia, and synchronization of circadian rhythms may limit/prevent hyperlipidemia and atherosclerosis.

Social synchronization of circadian rhythms with a focus on honeybees.

Many animals benefit from synchronizing their daily activities with conspecifics. In this hybrid paper, we first review recent literature supporting and extending earlier evidence for a lack of clear relationship between the level of sociality and social entrainment of circadian rhythms. Social entrainment is specifically potent in social animals that live in constant environments in which some or all individuals do not experience the ambient day-night cycles. We next focus on highly social honeybees in which there is good evidence that social cues entrain the circadian clocks of nest bees and can override the influence of conflicting light-dark cycles. The current understanding of social synchronization in honeybees is consistent with self-organization models in which surrogates of forager activity, such as substrate-borne vibrations and colony volatiles, entrain the circadian clocks of bees dwelling in the dark cavity of the nest. Finally, we present original findings showing that social synchronization is effective even in an array of individually caged callow bees placed on the same substrate and is improved for bees in connected cages. These findings reveal remarkable sensitivity to social time-giving cues and show that bees with attenuated rhythms (weak oscillators) can nevertheless be socially synchronized to a common phase of activity.This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.

The importance of melatonin in the regulation of metabolism, eating behavior, sleep, and the prospects for the use of melatonin drugs for obesity treatment

Melatonin is a special hormone that act as an internal synchronizer of circadian rhythms, the organism physiology and behavior to the environmental day and night and seasons of the year. The present urban society and the industrial production processes as organized should be considered, as both depend on the presence of indoor lights during the night and include the profuse use of electronic devices whose screens are rich in blue wavelength light. Light during the night delays the beginning of the secretory episode of melatonin and blunts its peak, causing chronic hypomelatoninemia. Hypomelatonemia, that causes deprivation of sleep and eating behavior disorders, along with low physical activity, can be the reason of the obesity, «non-infectious epidemic of the 21st century». According to this, the use of melatonin drugs for obesity treatment can be effective. Further prospective, controlled, randomized trials in this area are required to confirm this hypothesis.

Effect of periodic social interaction and odour presentation of same and opposite-sex conspecifics on free-running mice

ABSTRACT Social interaction, a non-photic cue, plays a role in the synchronization of circadian rhythm under constant environmental conditions. However, little is known about the effect of sex-specific interaction and sex-specific odor on the free-running circadian clock of mice. Hence, in the present study, we investigated the effect of social interaction and odor presentation of same and opposite-sex conspecifics on the free-running rhythm of mice. In this investigation, stranger and dummy mice (saturated with either male- or female-associated odor) were separately exposed to the same and opposite-sex conspecifics of male and female runners and receivers, respectively for 30 min at CT15 for 10–12 d. The results showed that the daily exposure of runners with same and opposite-sex strangers entrained the free-running locomotor activity rhythm in a gender-specific manner. However, daily exposure of same and opposite-sex conspecific odors masked the circadian rhythm of receiver animals by increasing the activity. Further, social interaction and odor presentation caused lengthened and shortened period length, respectively. These results suggest that periodic social interactions can produce entrainment and conspecific odor can produce only masking on free-running circadian locomotor activity rhythm in mice.

Behavioural effects of early‐life exposure to parabens in zebrafish larvae

AbstractParabens are classified as endocrine disrupting chemicals due to their ability to activate several nuclear receptors causing changes in hormones‐dependent signalling pathways. Central nervous system of developing organisms is particularly vulnerable to changes in hormonal pathways, which could lead to altered brain function, abnormal behaviour and even diseases later in life. The aim of the present study was to investigate the effects of exposure to butylparaben (BuP), ethylparaben (EtP) and methylparaben (MeP) during early development on nervous system using zebrafish larvae's behavioural models. Zebrafish were exposed until 4 days post fertilization (dpf) to three concentrations of each paraben chosen considering the environmentally realistic concentrations of human exposure and the benchmark‐dose lower bound calculated for zebrafish larvae (BuP: 5, 50 and 500 μg/L; EtP: 50, 500 and 5000 μg/L; MeP: 100, 1000 and 10,000 μg/L). Activity in novel and in familiar environment, thigmotaxis, visual startle response and photic synchronization of the behavioural circadian rhythms were analysed at 4, 5 and 6 dpf. Zebrafish larvae exposed to BuP 500 μg/L and EtP 5000 μg/L revealed increased anxiety‐like behaviour in novel environment. Larvae treated with 500 μg/L of BuP showed reduced activity in familiar and marginally in unfamiliar environment, and larvae exposed to 5000 μg/L of EtP exhibited hyperactivity in familiar environment. Parabens exposure did not influence the visual startle response and the photic synchronization of circadian rhythms in zebrafish larvae. This research highlighted as the exposure to parabens has the potential to interfere with behavioural development of zebrafish.

PER2 Circadian Oscillation Sensitizes Esophageal Cancer Cells to Chemotherapy.

Simple SummaryThere are growing evidences that the circadian rhythm modulates key cellular processes in physiological and pathological conditions. Here, we characterized the consequences of the daily oscillations of the clock-related gene PER2 in esophageal cancer cells and found that chemotherapy is more efficient when PER2 expression is low. These results suggest that chronotherapy might be used to potentiate the impact of current chemotherapy regimen.Esophageal squamous cell carcinoma (eSCC) accounts for more than 85% cases of esophageal cancer worldwide and the 5-year survival rate associated with metastatic eSCC is poor. This low survival rate is the consequence of a complex mechanism of resistance to therapy and tumor relapse. To effectively reduce the mortality rate of this disease, we need to better understand the molecular mechanisms underlying the development of resistance to therapy and translate that knowledge into novel approaches for cancer treatment. The circadian clock orchestrates several physiological processes through the establishment and synchronization of circadian rhythms. Since cancer cells need to fuel rapid proliferation and increased metabolic demands, the escape from circadian rhythm is relevant in tumorigenesis. Although clock related genes may be globally repressed in human eSCC samples, PER2 expression still oscillates in some human eSCC cell lines. However, the consequences of this circadian rhythm are still unclear. In the present study, we confirm that PER2 oscillations still occur in human cancer cells in vitro in spite of a deregulated circadian clock gene expression. Profiling of eSCC cells by RNAseq reveals that when PER2 expression is low, several transcripts related to apoptosis are upregulated. Consistently, treating eSCC cells with cisplatin when PER2 expression is low enhances DNA damage and leads to a higher apoptosis rate. Interestingly, this process is conserved in a mouse model of chemically-induced eSCC ex vivo. These results therefore suggest that response to therapy might be enhanced in esophageal cancers using chronotherapy.