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After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.

Objectives Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression. Materials and Methods Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single‐cell RNA‐Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony‐forming assay and flow cytometry. Results The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high‐risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high‐risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase. Conclusions Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan‐cancer. Dysregulated circadian clock genes were associated with glioma grades and the IDH status. Prognostic model suggests circadian clock genes affect glioma progression. The GO and GSEA enrichment analysis suggested dysregulated circadian clock genes can affect glioma through interfering cell cycle and influencing immunocytes infltration.

Objective Impairment of clock gene expression and changes in melatonin and 17-ß-estradiol levels may constitute biological alterations underlying the increased risk of breast cancer among shift workers. The aim of this study was to compare levels of selected core clock gene expression, 6-sulfatoxymelatonin (aMT6s), and 17-ß-estradiol between rotational shift work (SW) and daytime (DT) workers after a day off. Methods The cross-sectional study comprised 60 nurses with>2 years of SW and 56 permanent DT nurses. Transcript levels of circadian genes BMAL1, CLOCK, NPAS2, CRY1, CRY2, PERI, PER2, PER3, and REVERBa were determined by quantitative real-time polymerase chain reaction (PCR) in lymphocytes. All participants were tested in the early follicular phase of the menstrual cycle. Samples were collected at the beginning of the morning-shift after a regular night's sleep on a day off. Chronotype and sociodemographic characteristics were also evaluated. Results We found a significantly higher expression of BMAL1, CLOCK, NPAS2, PERI, PER2, and REVERBa and a lower expression of PER3, CRY1 and CRY2 among SW compared to DT nurses. SW participants did not demonstrate a significant difference in aMT6s levels, but they did show significantly higher 17-ß-estradiol levels compared to DT nurses. Multiple linear regression analysis confirmed the role of SW on expression of BMAL1 (ß0.21, P=0.040), CLOCK(ß0.35, P=0.008), NPAS2 (ß0.30, P=0.012), PERI (ß0.33, P=0.008), PER2 (ß0.19, P=0.047), PER3 (ß-0.27, P=0.012), CRY1 (ß-0.33, P=0.002), CRY2 (ß-0.31, P=0.005), REVERBa (ß0.19, P=0.045), and on 17-ß-estradiol levels (ß0.32, P=0.003). The analysis also confirmed the role of chronotype as an independent factor for PERI (ß0.48, P=0.001) and PER2 (ß-0.22, P=0.022) expression, and 17-ß-estradiol levels (ß0.26, P=0.011). Conclusions Rotating SW nurses show alterations in peripheral clock gene expression and 17-ß-estradiol levels at the beginning of the morning shift after a day off.

Metabolism is one of the most complex cellular biochemical reactions, providing energy and substances for basic activities such as cell growth and proliferation. Early studies have shown that glucose is an important nutrient in osteoblasts. In addition, amino acid metabolism and fat metabolism also play important roles in bone reconstruction. Mammalian circadian clocks regulate the circadian cycles of various physiological functions. In vertebrates, circadian rhythms are mediated by a set of central clock genes: muscle and brain ARNT like-1 ( Bmal1), muscle and brain ARNT like-2 (Bmal2), circadian rhythmic motion output cycle stagnates (Clock), cryptochrome 1 (Cry1), cryptochrome2 (Cry2), period 1 (Per1), period 2 (Per2), period 3 (Per3) and neuronal PAS domain protein 2 ( Npas2) . Negative feedback loops, controlled at both the transcriptional and posttranslational levels, adjust these clock genes in a diurnal manner. According to the results of studies on circadian transcriptomic studies in several tissues, most rhythmic genes are expressed in a tissue-specific manner and are affected by tissue-specific circadian rhythms. The circadian rhythm regulates several activities, including energy metabolism, feeding time, sleeping, and endocrine and immune functions. It has been reported that the circadian rhythms of mammals are closely related to bone metabolism. In this review, we discuss the regulation of the circadian rhythm/circadian clock gene in osteoblasts/osteoclasts and the energy metabolism of bone, and the relationship between circadian rhythm, bone remodeling, and energy metabolism. We also discuss the therapeutic potential of regulating circadian rhythms or changing energy metabolism on bone development/bone regeneration.

RationaleSleep disturbances was associated with numerous adverse health outcomes. Many studies have reported that long-term exposure to job stress can lead to sleep disturbances, which may be influenced by genetic and environmental factors.ObjectivesThis cross-sectional study investigated whether circadian clock gene polymorphisms modulated the influence of job stress on sleep disturbances in a Chinese Han population, which to our best knowledge has not been explored.MethodsThe Effort-Reward Imbalance (ERI) scale and the Pittsburgh Sleep Quality Index (PSQI) were both used to access job stress and sleep disturbances. The SNaPshot SNP assay was carried out by screening for circadian clock gene polymorphisms in every participant. Interactions associated with sleep disturbances were assessed by linear hierarchical regression analysis and SPSS macros (PROCESS).ResultsLinear hierarchical regression analysis showed that job stress was significantly related to sleep disturbances. Likewise, our study found a significant effect of PER2 rs2304672 polymorphisms on sleep disturbances (p < 0.01), after controlling for confounding factors. In addition, the PER2 rs2304672 genotype modulated the relationship between job stress and sleep disturbances (β = 0.414, p = 0.007). Interestingly, further analysis of the results of the PER2 gene rs2304672 × job stress interaction showed that rs2304672 G-allele carriers had a high-risk effect on sleep disturbances under high job stress.ConclusionsOur results suggest that the PER2 rs2304672 polymorphism may modulate the influence of job stress on sleep disturbances. These findings contribute to the field of sleep disturbances prevention and treatment.

Main conclusionMolecular mechanisms of biological rhythms provide opportunities to harness functional allelic diversity in core (and trait- or stress-responsive) oscillator networks to develop more climate-resilient and productive germplasm.The circadian clock senses light and temperature in day–night cycles to drive biological rhythms. The clock integrates endogenous signals and exogenous stimuli to coordinate diverse physiological processes. Advances in high-throughput non-invasive assays, use of forward- and inverse-genetic approaches, and powerful algorithms are allowing quantitation of variation and detection of genes associated with circadian dynamics. Circadian rhythms and phytohormone pathways in response to endogenous and exogenous cues have been well documented the model plant Arabidopsis. Novel allelic variation associated with circadian rhythms facilitates adaptation and range expansion, and may provide additional opportunity to tailor climate-resilient crops. The circadian phase and period can determine adaptation to environments, while the robustness in the circadian amplitude can enhance resilience to environmental changes. Circadian rhythms in plants are tightly controlled by multiple and interlocked transcriptional–translational feedback loops involving morning (CCA1, LHY), mid-day (PRR9, PRR7, PRR5), and evening (TOC1, ELF3, ELF4, LUX) genes that maintain the plant circadian clock ticking. Significant progress has been made to unravel the functions of circadian rhythms and clock genes that regulate traits, via interaction with phytohormones and trait-responsive genes, in diverse crops. Altered circadian rhythms and clock genes may contribute to hybrid vigor as shown in Arabidopsis, maize, and rice. Modifying circadian rhythms via transgenesis or genome-editing may provide additional opportunities to develop crops with better buffering capacity to environmental stresses. Models that involve clock gene‒phytohormone‒trait interactions can provide novel insights to orchestrate circadian rhythms and modulate clock genes to facilitate breeding of all season crops.

The circadian clock confers daily rhythmicity on many biochemical and physiological functions and its disruption is associated with increased risks of developing obesity, diabetes, heart disease and cancer. Although, there are studies on the role of Bmal1 in carcinogenesis using germline, conditional or tissue-specific knockouts, it is still not well understood how BMAL1 gene affects cancer-related biological events at the molecular level. We, therefore, took an in vitro approach to understand the contribution of BMAL1 in this molecular mechanism using human breast epithelial cell lines by knocking out BMAL1 gene with CRISPR technology. We preferred epithelial cells over fibroblasts as the most of cancers originate from epithelial cells. After obtaining BMAL1 knockouts by targeting the gene at two different sites from non-tumorigenic MCF10A and invasive tumorigenic MDA-MB-231 cells, we analysed apoptosis and invasion properties of the cell lines as representative events in tumor development. BMAL1 disruption sensitized both cell lines to a bulky-DNA adduct forming agent (cisplatin) and a double-strand break-inducing agent (doxorubicin), while it enhanced the invasive properties of MDA-MB-231 cells. These results show that the disruption of clock genes may have opposing carcinogenic effects.

Prenatal alcohol-exposed (AE) infants and children often demonstrate disrupted sleep patterns, including more frequent awakenings, reduced total sleep time, and more night-to-night sleep variability. Despite the strong connection between sleep patterns and circadian rhythmicity, relatively little is known about circadian rhythm disruptions in individuals with AE. Recently, several reports demonstrated that evaluating the expression patterns of human clock genes in biological fluids could reveal an individual’s circadian phenotype. Human saliva offers an emerging and easily available physiological sample that can be collected non-invasively for core-clock gene transcript analyses. We compared the expression patterns of core-clock genes and their regulatory genes in salivary samples of children aged 6–10 years-old with and without AE during the light cycle between ZT0-ZT11. We isolated the RNA from the samples and measured the expression patterns of core clock genes and clock regulating genes using the human specific primers with quantitative real-time PCR. Analysis of core clock genes expression levels in saliva samples from AE children indicates significantly altered levels in expression of core-clock BMAL1, CLOCK , PER1-3 and CRY1,2, as compared to those in age-matched control children. We did not find any sex difference in levels of clock genes in AE and control groups. Cosinor analysis was used to evaluate the rhythmic pattern of these clock genes, which identified circadian patterns in the levels of core clock genes in the control group but absent in the AE group. The gene expression profile of a salivary circadian biomarker ARRB1 was rhythmic in saliva of control children but was arhythmic in AE children. Altered expression patterns were also observed in clock regulatory genes: NPAS2, NFL3 , NR1D1 , DEC1 , DEC2 , and DBP , as well as chromatin modifiers: MLL1, P300, SIRT1, EZH2, HDAC3, and ZR1D1, known to maintain rhythmic expression of core-clock genes. Overall, these findings provide the first evidence that AE disturbs the circadian patten expression of core clock genes and clock-regulatory chromatin modifiers in saliva.

ABSTRACT Background Circadian clock coordinates the physiologic and behavioral activities with a 24‐hour solar rhythm to maintain the temporal homeostasis of the body. In the mammalian retina, the circadian system regulates the physiological function of this organ. The realm of ocular circadian rhythm has earned kinds of research interest as the circadian rhythms dysfunction will disrupt the retinal homeostasis. Bmal1 functions as a major transcriptional regulator of the circadian clock. Results In the retina, Bmal1 mediates the processing of light information, sustains photoreceptor viability and governs neurotransmitter release. Moreover, Bmal1 gene is believed to be a pathologic cofactor of the diabetic retinopathy (DR), age‐related macular degeneration (AMD), premature aging and refractive myopia. To date, the precise mechanisms underlying the pathological effects mediated by Bmal1 remain incompletely elucidated. Conclusions This review presents recent findings and evidence regarding the contributory role of Bmal1 in retinal degeneration and its deficits, while exploring its therapeutic potential. And th review provides a comprehensive analysis of the underlying mechanisms of the clock gene Bmal1 in other diseases, with the aim of offering insights into innovative therapeutic strategies for retinopathy. Circadian rhythm is offering novel insights into the pathogenesis of retinopathy. Bmal1, a key transcriptional regulator of the circadian clock, serves as a critical pathologic cofactor in retinal degeneration. Deficiency in Bmal1 contributes to a broad spectrum of retinal pathological alterations, and modulating the clock gene Bmal1 could potentially inform innovative treatment strategies for retinal diseases.

Variations in circadian rhythm-related genes influence the individual chronotype. Here, we hypothesize that the peak of clock gene expression at 7 a.m. differs between young adults with a late chronotype and young adults with an early chronotype. Participants of the Chronotype and Nutrition nutritional trial (ChroNu study) were selected for their chronotype assessed by the Munich Chronotype questionnaire (MCTQ) and actigraphy. Total RNA was isolated from CD14 + monocytes of participants at 7 a.m. on the run-in day. Expression levels of seven clock genes ( PER1 , PER2 , PER3 , NR1D1 , NR1D2 , CRY1 and CRISPLD2 ) of individuals with early ( n  = 11) or late chronotypes ( n  = 19) were analysed by reverse transcription quantitative polymerase chain reaction. Difference in expression levels was tested by Mann Whitney-U test. The relative expression levels of the selected genes were not significantly different between individuals with early and late chronotypes (all p  > 0.07). Contrary to expectation, clock gene expression levels at 7 a.m. was similar in individuals with early and late chronotypes. Further studies on larger sample sizes with multiple sampling time points should elucidate whether gene expression is altered at other day times underscoring the biological difference between individuals with early or late chronotypes.