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There are significant bioperiodicities for hormonal, neural, cellular, and humoral factors as well as for mediators. A combination of these findings is an explanation for the increased hyperreactivity in patients with allergic diseases during the night. In the morning hours between 2 and 6 a.m., the histamine concentration shows a peak, adrenaline and cyclic AMP have their minimum, while cortisol secretion is just ascending. Circadian variations are also seen with respect to the density of beta-receptors. Thromboxane A2 shows a peak during the night, PGE2 is depressed, a finding also in favour of bronchial constriction. Total plasma protein IgA, IgM, IgG and IgE show a distinct bioperiodicity with a minimum during the night, cellular elements like T11, T4 and B-lymphocytes, and Leu8 have a maximum. The nocturnal symptom exacerbation must be given the fullest attention in choosing the time of administration of the appropriate medication.
Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian programme exhibits unique features, including a divergent group of rhythmic genes and metabolites compared with the basal state and a distinct periodicity and phase distribution. At the cellular level, endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex re-organization of cellular and molecular circadian rhythms that are relevant to early events in lung injury.
Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
Artificial light has been increasingly in use for the past 70 years. The aberrant light exposure and round-the-clock nature of work lead to the disruption of biological clock. Circadian rhythm disruption (CRD) contributes to multiple metabolic and neurodegenerative diseases. However, its effect on vision is not understood. Moreover, the mammalian retina possesses an autonomous clock that could be reset with light exposure. We evaluated the impact of CRD on retinal morphology, physiology, and vision after housing mice in a disruption inducing shorter light/dark cycle (L10:D10). Interestingly, the mice under L10:D10 exhibited three different entrainment behaviors; "entrained," "free-running," and "zigzagging." These behavior groups under CRD exhibited reduced visual acuity, retinal thinning, and a decrease in the number of photoreceptors. Intriguingly, the electroretinogram response was decreased only in the mice exhibiting "entrained" behavior. The retinal proteome showed distinct changes with each entrainment behavior, and there was a dysfunctional oxidative stress-antioxidant mechanism. These results demonstrate that CRD alters entrainment behavior and leads to visual dysfunction in mice. Our studies uniquely show the effect of entrainment behavior on retinal physiology. Our data have broader implications in understanding and mitigating the impact of CRD on vision and its potential role in the etiology of retinal diseases.
Circadian rhythms are controlled at the cellular level by a molecular clock consisting of several genes/proteins engaged in a transcription-translation-degradation feedback loop. These core clock proteins regulate thousands of tissue-specific genes. Regarding circadian control in neoplastic tissues, reports to date have demonstrated anomalous circadian function in tumor models and cultured tumor cells. We have extended these studies by analyzing circadian rhythmicity genome-wide in a mouse model of liver cancer, in which mice treated with diethylnitrosamine at 15 days develop liver tumors by 6 months. We injected tumor-bearing and control tumor-free mice with cisplatin every 2 h over a 24-h cycle; 2 h after each injection mice were sacrificed and gene expression was measured by XR-Seq (excision repair sequencing) assay. Rhythmic expression of several core clock genes was observed in both healthy liver and tumor, with clock genes in tumor exhibiting typically robust amplitudes and a modest phase advance. Interestingly, although normal hepatic cells and hepatoma cancer cells expressed a comparable number of genes with circadian rhythmicity (clock-controlled genes), there was only about 10% overlap between the rhythmic genes in normal and cancerous cells. "Rhythmic in tumor only" genes exhibited peak expression times mainly in daytime hours, in contrast to the more common pre-dawn and pre-dusk expression times seen in healthy livers. Differential expression of genes in tumors and healthy livers across time may present an opportunity for more efficient anticancer drug treatment as a function of treatment time.
Transcriptomic analysis showed that the central circadian pathway genes had significantly altered expression in fracture calluses from mice fed a low phosphate diet. This led us to hypothesize that phosphate deficiency altered the circadian cycle in peripheral tissues. Analysis of the expression of the central clock genes over a 24-36 hour period in multiple peripheral tissues including fracture callus, proximal tibia growth plate and cardiac tissues after 12 days on a low phosphate diet showed higher levels of gene expression in the hypophosphatemia groups (p < 0.001) and a 3 to 6 hour elongation of the circadian cycle. A comparative analysis of the callus tissue transcriptome genes that were differentially regulated by hypophosphatemia with published data for the genes in bone that are diurnally regulated identified 1879 genes with overlapping differential regulation, which were shown by ontology assessment to be associated with oxidative metabolism and apoptosis. Network analysis of the central circadian pathway genes linked their expression to the up regulated expression of the histone methyltransferase gene EZH2, a gene that when mutated in both humans and mice controls overall skeletal growth. These data suggest that phosphate is an essential metabolite that controls circadian function in both skeletal and non skeletal peripheral tissues and associates its levels with the overall oxidative metabolism and skeletal growth of animals.
Circadian rhythms regulate the body's homeostasis through the temporal control of tissue-specific circadian rhythm control genes. Circadian rhythm disorders (CRD) affect the expression levels of circadian rhythms-associated genes in brain and muscle aryl hydrocarbon receptor nuclear translocator-like-1(BMAL1), which is thought to contribute to metabolic disorders and an altered immune system. However, the relationship between CRD and the development of periodontitis was poorly reported. Therefore, this study aimed to investigate the role played by BMAL1 in periodontitis. We used a modified multi-platform approach (MMPM) to induce circadian rhythm disturbances in rats to investigate the role of BMAL1 in periodontitis. Our results showed significant downregulation of BMAL1 in the CRD with periodontitis group, significant resorption of alveolar bone, increased osteoclast differentiation, and upregulation of the inflammatory signaling molecule NF-κB. In addition, apoptosis and oxidative stress levels were increased in periodontal tissues. Collectively, our study suggests that BMAL1 is a key regulator in periodontitis exacerbated by CRD and that CRD may lead to the downregulation of BMAL1, thereby exacerbating oxidative stress and apoptosis in periodontal tissues. Our study found that BMAL1 may be associated with the progression of periodontitis and provides a new perspective on the treatment of periodontitis.
The circadian oscillator is based on transcription-translation feedback loops that generate 24 h oscillations in gene expression. Although circadian regulation of mRNA expression at the transcriptional level is one of the most important steps for the generation of circadian rhythms within the cell, multiple lines of evidence point to a disconnect between transcript oscillation and protein oscillation. This can be explained by regulatory RNA-binding proteins acting on the nascent transcripts to modulate their processing, export, translation and degradation rates. In this chapter we will review what is known about the different steps involved in circadian gene expression from transcription initiation to mRNA stability and translation efficiency. The role of ribonucleoprotein particles in the generation of rhythmic gene expression is only starting to be elucidated, but it is likely that they cooperate with the basal transcriptional machinery to help to maintain the precision of the clock under diverse cellular and environmental conditions.
Circadian clocks are fundamental machinery in organisms ranging from archaea to humans. Disruption of the circadian system is associated with premature aging in mice, but the molecular basis underlying this phenomenon is still unclear. In this study, we found that telomerase activity exhibits endogenous circadian rhythmicity in humans and mice. Human and mouse TERT mRNA expression oscillates with circadian rhythms and are under the control of CLOCK-BMAL1 heterodimers. CLOCK deficiency in mice causes loss of rhythmic telomerase activities, TERT mRNA oscillation, and shortened telomere length. Physicians with regular work schedules have circadian oscillation of telomerase activity while emergency physicians working in shifts lose the circadian rhythms of telomerase activity. These findings identify the circadian rhythm as a mechanism underlying telomere and telomerase activity control that serve as interconnections between circadian systems and aging.
The circadian rhythm regulation plays a crucial role in people's healthy lives affected by factors consisting of cosmic events related to the universe and earth, environmental factors (light, night and day duration, seasons) and lifestyles. These factors changes lead to disturbance of circadian rhythm and it causes increasing the incidence of mental diseases like depression and physiological problems like cancers, cardiovascular disease and diabetes.
We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.
Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments. An important part of this process is the presence of the well-known hormone, melatonin. This compound assists in the governing of sleep and circadian rhythms. Previous studies have postulated that dysregulation of melatonin rhythms is the driving force behind sleep and circadian disorders. A computer-aided search spanning the years of 2015-2020 using the search terms melatonin, circadian rhythm, disorder yielded 52 full text articles that were analyzed. We explored the mechanisms behind melatonin dysregulation and how it affects various disorders. Additionally, we examined associated therapeutic treatments including bright light therapy (BLT) and exogenous forms of melatonin. We found that over the past 5 years, melatonin has not been widely investigated in clinical studies thus there remains large gaps in its potential utilization as a therapy.
Disturbances in the sleep/wake cycle are prevalent in patients with Rett syndrome (RTT). We sought to determine whether the circadian system is disrupted in a RTT model, Mecp2(-/y) mice. We found that MeCP2 mutants showed decreased strength and precision of daily rhythms of activity coupled with extremely fragmented sleep. The central circadian clock (suprachiasmatic nucleus) exhibited significant reduction in the number of neurons expressing vasoactive intestinal peptide (VIP) as well as compromised spontaneous neural activity. The molecular clockwork was disrupted both centrally in the SCN and in peripheral organs, indicating a general disorganization of the circadian system. Disruption of the molecular clockwork was observed in fibroblasts of RTT patients. Finally, MeCP2 mutant mice were vulnerable to circadian disruption as chronic jet lag accelerated mortality. Our finds suggest an integral role of MeCP2 in the circadian timing system and provides a possible mechanistic explanation for the sleep/wake distrubances observed in RTT patients. The work raises the possibility that RTT patients may benefit from a temporally structured environment.
The current model of the mammalian circadian clock describes cell-autonomous and negative feedback-driven circadian oscillation of Cry and Per transcription as the core circadian rhythm generator. However, the actual contribution of this oscillation to circadian rhythm generation remains undefined. Here we perform targeted disruption of cis elements indispensable for cell-autonomous Cry oscillation. Mice lacking overt cell-autonomous Cry oscillation show robust circadian rhythms in locomotor activity. In addition, tissue-autonomous circadian rhythms are robust in the absence of overt Cry oscillation. Unexpectedly, although the absence of overt Cry oscillation leads to severe attenuation of Per oscillation at the cell-autonomous level, circadian rhythms in Per2 accumulation remain robust. As a mechanism to explain this counterintuitive result, Per2 half-life shows cell-autonomous circadian rhythms independent of Cry and Per oscillation. The cell-autonomous circadian clock may therefore remain partially functional even in the absence of overt Cry and Per oscillation because of circadian oscillation in Per2 degradation.
In addition to responding to environmental entrainment with diurnal variation, metabolism is also tightly controlled by cell-autonomous circadian clock. Extensive studies have revealed key roles of transcription in circadian control. Post-transcriptional regulation for the rhythmic gating of metabolic enzymes remains elusive. Here, we show that arginine biosynthesis and subsequent ureagenesis are collectively regulated by CLOCK (circadian locomotor output cycles kaput) in circadian rhythms. Facilitated by BMAL1 (brain and muscle Arnt-like protein), CLOCK directly acetylates K165 and K176 of argininosuccinate synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of arginine biosynthesis. ASS1 acetylation by CLOCK exhibits circadian oscillation in human cells and mouse liver, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the circadian regulation of ASS1 and ureagenesis. Furthermore, we also identified NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 (NDUFA9) and inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as acetylation substrates of CLOCK. Taken together, CLOCK modulates metabolic rhythmicity by acting as a rhythmic acetyl-transferase for metabolic enzymes.
Modern lifestyles, such as shift work, nocturnal social activities, and jet lag, disturb the circadian rhythm. The interaction between mammals and the co-evolved intestinal microbiota modulates host physiopathological processes. Radiotherapy is a cornerstone of modern management of malignancies; however, it was previously unknown whether circadian rhythm disorder impairs prognosis after radiotherapy. To investigate the effect of circadian rhythm on radiotherapy, C57BL/6 mice were housed in different dark/light cycles, and their intestinal bacterial compositions were compared using high throughput sequencing. The survival rate, body weight, and food intake of mice in diverse cohorts were measured following irradiation exposure. Finally, the enteric bacterial composition of irradiated mice that experienced different dark/light cycles was assessed using 16S RNA sequencing. Intriguingly, mice housed in aberrant light cycles harbored a reduction of observed intestinal bacterial species and shifts of gut bacterial composition compared with those of the mice kept under 12 h dark/12 h light cycles, resulting in a decrease of host radioresistance. Moreover, the alteration of enteric bacterial composition of mice in different groups was dissimilar. Our findings provide novel insights into the effects of biological clocks on the gut bacterial composition, and underpin that the circadian rhythm influences the prognosis of patients after radiotherapy in a preclinical setting.
Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm(2) eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling.
The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (<0.1 lux), rather than completely dark nights, permits expression of an altered circadian waveform wherein mice in light/dark/light/dark (LDLD) cycles "bifurcate" their rhythms into two rest and activity intervals per 24 h. Secondly, this bifurcated state enables mice to adopt stable activity rhythms under 15 or 30 h days (LDLD T15/T30), well beyond conventional limits of entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions.
Diurnal oscillations in gene expression are a hallmark of the liver internal clock and can be regulated by a variety of environmental stimuli. The circadian rhythm and liver regeneration (LR) are intimately linked. However, how they affect each other at the transcriptomic level is mainly unknown. Here, we revealed that partial hepatectomy (PHx)-induced LR led to reprogramming of rhythmic gene expression profiles as a consequence of disrupted BMAL1 occupation on the chromatin, while the rhythm of core clock genes remained robust. Furthermore, we demonstrated retarded LR when PHx was carried out in the evening, possibly due to the accumulation of DEC1. In summary, our data offer a broad perspective of the relationship between circadian rhythm and LR and suggest that the timing of PHx should be considered in the clinic application.
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