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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.

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.

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.

Along evolution, living organisms developed a precise timekeeping system, circadian clocks, to adapt life to the 24-h light/dark cycle and temporally regulate physiology and behavior. The transcriptional molecular circadian clock and metabolic/redox oscillator conforming these clocks are present in organs, tissues, and even in individual cells, where they exert circadian control over cellular metabolism. Disruption of the molecular clock may cause metabolic disorders and higher cancer risk. The synthesis and degradation of glycerophospholipids (GPLs) is one of the most highly regulated metabolisms across the 24-h cycle in terms of total lipid content and enzyme expression and activity in the nervous system and individual cells. Lipids play a plethora of roles (membrane biogenesis, energy sourcing, signaling, and the regulation of protein-chromatin interaction, among others), making control of their metabolism a vital checkpoint in the cellular organization of physiology. An increasing body of evidence clearly demonstrates an orchestrated and sequential series of events occurring in GPL metabolism across the 24-h day in diverse retinal cell layers, immortalized fibroblasts, and glioma cells. Moreover, the clock gene Per1 and other circadian-related genes are tightly involved in the regulation of GPL synthesis in quiescent cells. However, under proliferation, the metabolic oscillator continues to control GPL metabolism of brain cancer cells even after molecular circadian clock disruption, reflecting the crucial role of the temporal metabolism organization in cell preservation. The aim of this review is to examine the control exerted by circadian clocks over GPL metabolism, their synthesizing enzyme expression and activities in normal and tumorous cells of the nervous system and in immortalized fibroblasts. Graphical abstract

Background Disturbances in clock genes affect almost all patients with Alzheimer’s disease (AD), as evidenced by their altered sleep/wake cycle, thermoregulation, and exacerbation of cognitive impairment. As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, in this study, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. Methods In this study, the expression of clock genes and inflammatory-related genes was examined in MACS microglia isolated from 2-month-old amyloid precursor protein knock-in (APP-KI) and wild-type (WT) mice using cap analysis gene expression (CAGE) deep sequencing and RT-PCR. The effects of clock gene disturbance on neuroinflammation and relevant memory changes were examined in 2-month-old APP-KI and WT mice after injection with SR9009 (a synthetic agonist for REV-ERB). The microglia morphology was studied by staining, neuroinflammation was examined by Western blotting, and cognitive changes were examined by Y-maze and novel object recognition tests. Results CLOCK/BMAL1-driven transcriptional negative feedback loops were impaired in the microglia from 2-month-old APP-KI mice. Pro-inflammatory genes in microglia isolated from APP-KI mice were significantly higher than those isolated from WT mice at Zeitgeber time 14. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in 2-month-old APP-KI mice. Conclusion Clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation, which may be a new target for preventing or slowing AD.

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.

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.

Background Chronodisruption, marked by circadian rhythm misalignment, is linked to inflammatory diseases like obesity. Chronotypes, reflecting individual circadian behavior, include morning, intermediate, and evening types, with evening chronotypes showing worse body composition and higher metabolic risk. This study evaluated the inflammatory profile of visceral adipose tissue (VAT) across chronotypes in individuals with obesity and examined clock gene expression. Methods Twenty-five participants with obesity (11/14 F/M, BMI 41.59 ± 7.69 kg/m², age 41.13 ± 11.08 years) candidates for bariatric surgery were classified using the Morningness-Eveningness Questionnaire (MEQ): morning (36%), intermediate (28%), or evening (36%) chronotypes. VAT biopsies were analyzed for cytokines, chemokines, and growth factors via multiplex ELISA, and clock genes (PER1, CLOCK, BMAL1) were assessed using qPCR. Results Body composition and biochemical parameters were similar across groups, but evening chronotypes had higher triglyceride levels ( p  = 0.012) and lower phase angle ( p  = 0.035). VAT inflammatory markers, including IL-1β ( p  = 0.04), IL-8 ( p  = 0.03), bFGF ( p  = 0.01), MCP-1 ( p  = 0.01), and MIP-1β ( p  = 0.05), were highest in evening and lowest in morning chronotypes. Evening chronotypes had significantly elevated bFGF levels compared to other groups ( p  = 0.04). PER1 mRNA expression was also higher in evening chronotypes ( p  = 0.02) and correlated with VAT-released bFGF ( p  = 0.03) and IL-1β ( p  = 0.03). MEQ scores negatively correlated with VAT bFGF ( p  = 0.02), MCP-1 ( p  = 0.02), and PER1 expressions. Conclusion Despite similar metabolic profiles, evening chronotypes exhibit heightened VAT inflammation and altered clock gene expression, potentially worsening their metabolic risk.

Circadian clocks evolved to allow plants and animals to adapt their behaviors to the 24-hr change in the external environment due to the Earth's rotation. While the first scientific observation of circadian rhythm in the plant leaf movement may be dated back to the early 18th century, it took 200 years to realize that the leaf movement is controlled by an endogenous circadian clock. The cloning and characterization of the first Drosophila clock gene period in the early 1980s, independently by Jeffery C. Hall and Michael Rosbash at Brandeis University and Michael Young at Rockefeller University, paved the way for their further discoveries of additional genes and proteins, culminating in establishing the so-called transcriptional translational feedback loop (TTFL) model for the generation of autonomous oscillator with a period of ∼24 h. The 2017 Nobel Prize in Physiology or Medicine was awarded to honor their discoveries of molecular mechanisms controlling the circadian rhythm.

The circadian timing system of mammals is synchronized in concert with a central clock, but is also influenced by additional stimuli, including nutrients. However, little research has been done on polyphenols other than resveratrol and there seem to be no studies on their influence on young and old cells. The purpose of this study was to analyse the potential effects of quercetin, caffeic acid, and resveratrol on young and old fibroblast cells in the expressions of different clock genes and aging-related genes, and further investigate the mechanism. The mRNA expression of different clock genes and aging-related genes was assessed by quantitative real-time PCR. The protein levels of clock genes (BMAL1, PER1 and SIRT1) and glucocorticoid receptor α (GRα) were assessed by ELISA. Quercetin and caffeic acid in old fibroblast cells showed higher clock gene expression than resveratrol, quercetin increased Sirt1 expression, and caffeic acid increased Sirt6 expression indicating the possibility of an anti-aging effect. Also, quercetin and caffeic acid showed higher clock-controlled gene (Sirt1 and NR1D1) expression than resveratrol in young fibroblast cells. It appears that caffeic acid acts on NRF2 expression, and in turn to the actions of GRα, GDF11, Sirt1, and Sirt6. Regarding the increased expression of Per1, the activation effect on NR1D1 was confirmed only for caffeic acid in young fibroblast cells. Our results have confirmed the interplay of the circadian clock genes and cellular aging.