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In addition to circadian rhythms, circadian genes play pivotal roles in myriad signaling pathways. Consequently, their dysregulation contributes to the onset and progression of various diseases. Identifying SNPs in clock genes offers an exciting avenue to predict the predisposition of an individual to different pathologies/variations in phenotype. Experimental models and human trials have confirmed that SNPs in core circadian genes are associated with pathologies. Given the inherent complexity of diseases, that are often polygenic traits influenced by gene–environment interactions, robust statistical approaches utilizing large and diverse sample sizes is crucial when identifying disease-linked SNPs. Furthermore, recognizing the key role of population stratification in minimizing confounding effects ensures the reliability of associations between SNPs and diseases. Circadian rhythms, ~24 h cycles of physiological and behavioral processes, can be synchronized by external signals (e.g., light) and persist even in their absence. Consequently, dysregulation of circadian rhythms adversely affects the well-being of the organism. This timekeeping system is generated and sustained by a genetically encoded endogenous mechanism composed of interlocking transcriptional/translational feedback loops that generate rhythmic expression of core clock genes. Genome-wide association studies (GWAS) and forward genetic studies show that SNPs in clock genes influence gene regulation and correlate with the risk of developing various conditions. We discuss genetic variations in core clock genes that are associated with various phenotypes, their implications for human health, and stress the need for thorough studies in this domain of circadian regulation. [ABSTRACT FROM AUTHOR]

Circadian clocks are inherent to most organisms, including cryptozoic animals that seldom encounter direct light, and regulate their daily activity cycles. A conserved suite of clock genes underpins these rhythms. In this study, we explore the circadian behaviors of the red flour beetle Tribolium castaneum, a significant pest impacting stored grain globally. We report on how daily light and temperature cues synchronize distinct activity patterns in these beetles, characterized by reduced morning activity and increased evening activity, anticipating the respective environmental transitions. Although less robust, rhythmicity in locomotor activity is maintained in constant dark and constant light conditions. Notably, we observed more robust rhythmic behaviors in males than females with individual variation exceeding those previously reported for other insect species. RNA interference targeting the Clock gene weakened locomotor activity rhythms. Our findings demonstrate the existence of a circadian clock and of clock-controlled behaviors in T. castaneum. Furthermore, they highlight substantial individual differences in circadian activity, laying the groundwork for future research on the relevance of individual variation in circadian rhythms in an ecological and evolutionary context. [ABSTRACT FROM AUTHOR]

SUMMARY: Translation initiation is a critical, rate‐limiting step in protein synthesis. The eukaryotic translation initiation factor 4E (eIF4E) plays an essential role in this process. However, the mechanisms by which eIF4E‐dependent translation initiation regulates plant growth and development remain not fully understood. In this study, we found that Arabidopsis eIF4E proteins are distributed in both the nucleus and cytoplasm, with only the cytoplasmic eIF4E being involved in the control of photoperiodic flowering. Genome‐wide translation profiling using Ribo‐tag sequencing reveals that eIF4E may regulate plant flowering by maintaining the homeostatic translation of components in the photoperiodic flowering pathway. eIF4E not only regulates the translation of flowering genes such as FLOWERING LOCUS T (FT) and FLOWERING LOCUS D (FLD) but also influences the translation of circadian genes like CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and PSEUDO‐RESPONSE REGULATOR 9 (PRR9). Consistently, our results show that the eIF4E modulates the rhythmic oscillation of the circadian clock. Together, our study provides mechanistic insights into how the protein translation regulates multiple developmental processes in Arabidopsis, including the circadian clock and photoperiodic flowering. Significance Statement: The cytoplasmic fraction of eukaryotic translation initiation factor 4E (eIF4E) regulates photoperiodic flowering in Arabidopsis by controlling the homeostatic translation of regulators in the photoperiodic flowering pathway, including light signaling factors, clock components, and photoperiodism flowering genes. Our study provides new insights into how photoperiodic flowering and the circadian clock are regulated at the translational level in plants. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the expression of core molecular clock genes/proteins in penile cavernous tissue from healthy male subjects and to determine whether their expression has circadian variation. Materials and Methods: Corpus cavernosum biopsy samples were obtained from 10 healthy males with penile deviation or fracture who underwent surgical intervention during the day and night. The daytime group (n=5) underwent corpus cavernosum tissue sampling during zeitgeber time (ZT) 8–12, while the nighttime group (n=5) underwent sampling during ZT 20–24. The expression and localization of BMAL1, CLOCK, PER1, PER2, PER3, CRY1, and CRY2 proteins were analyzed using immunohistochemistry and quantified using H-score analysis. RT-qPCR analysis was performed to assess the expression of core molecular clock genes in the corpus cavernosum tissue of 5 additional daytime patients. Results: The expression of core molecular clock proteins was detected in vascular endothelial cells (VECs) and smooth muscle cells (SMCs) in corpus cavernosum during daytime and nighttime. BMAL1 exhibited the most significant nuclear expression during daytime in both cell types, whereas its expression decreased significantly at night. In VECs, a significant decrease in the nuclear expression of CRY1 was observed at night. In SMCs, a significant decrease in the cytoplasmic expression of PER3 was observed at night. The expression patterns of the core molecular clock genes were ascertained through a RT-qPCR analysis. Conclusions: Our research provides compelling evidence that core molecular clock genes are distinctly expressed in penile tissue in humans. Furthermore, we observed the expression of molecular clock proteins within the VECs and SMCs of the corpus cavernosum, with BMAL1 being the most prominently expressed. The discovery of core molecular clock genes in penile tissue, as well as proteins within the SMCs and VECs of the corpus cavernosum, introduces the potential significance of the molecular clock mechanism in the physiology of penile erection. [ABSTRACT FROM AUTHOR]

Seasonal rhythms are gaining attention given their impact on metabolic disorders development such as obesity gut microbiota is emerging as a key factor in mediating this link. However, the underlying mechanisms are still poorly understood. In this regard, corticosterone may play a role as it has been shown to be affected by gut bacteria and seasonal rhythms, and has been linked to obesity. Thus, this study aimed to investigate if seasonal rhythms effects on corticosterone are influenced by gut microbiota in obese rats and whether this may be related to seasonal and clock genes expression in the pituitary gland and colon. Fischer 344 male rats fed with cafeteria diet (CAF) were housed under different photoperiods for 9 weeks and treated with an antibiotic cocktail (ABX) in drinking water during the last 4 weeks. Rats fed with standard chow and CAF-fed rats without ABX were included as controls. ABX altered gut microbiota, corticosterone levels and seasonal clock expression in the pituitary depending on photoperiod conditions. These results suggest a link between gut bacteria, seasonal rhythms and corticosterone and a novel nutrigenomic target for obesity. [ABSTRACT FROM AUTHOR]

The advancement in extraterrestrial exploration has highlighted the crucial need for studying how the human cardiovascular system adapts to space conditions. Human development occurs under the influence of gravity, shielded from space radiation by Earth's magnetic field, and within an environment characterized by 24-hour day-night cycles resulting from Earth's rotation, thus deviating from these conditions necessitates adaptive responses for survival. With upcoming manned lunar and Martian missions approaching rapidly, it is essential to understand the impact of various stressors induced by outer-space environments on cardiovascular health. This comprehensive review integrates insights from both actual space missions and simulated experiments on Earth, to analyze how microgravity, space radiation, and disrupted circadian affect cardiovascular well-being. Prolonged exposure to microgravity induces myocardial atrophy and endothelial dysfunction, which may be exacerbated by space radiation. Mitochondrial dysfunction and oxidative stress emerge as key underlying mechanisms along with disturbances in ion channel perturbations, cytoskeletal damage, and myofibril changes. Disruptions in circadian rhythms caused by factors such as microgravity, light exposure, and irregular work schedules, could further exacerbate cardiovascular issues. However, current research tends to predominantly focus on disruptions in the core clock gene, overlooking the multifactorial nature of circadian rhythm disturbances in space. Future space missions should prioritize targeted prevention strategies and early detection methods for identifying cardiovascular risks, to preserve astronaut health and ensure mission success. [ABSTRACT FROM AUTHOR]

The European corn borer (Ostrinia nubilalis) is an agricultural pest and burgeoning model for research on speciation, seasonal adaptation and insect resistance management. Although previous work in O. nubilalis has identified genes associated with differences in life cycle, reproduction, and resistance to Bt toxins, the general lack of a robust gene‐editing protocol for O. nubilalis has been a barrier to functional validation of candidate genes. Here, we demonstrate an efficient and practical methodology for heritable gene mutagenesis in O. nubilalis using the CRISPR/Cas9 genome editing system. Precise loss‐of‐function (LOF) mutations were generated at two circadian clock genes, period (per) and pigment‐dispersing factor receptor (pdfr), and a developmental gene, prothoracicotropic hormone (ptth). Precluding the need for a visible genetic marker, gene‐editing efficiency remained high across different single guide RNAs (sgRNA) and germline transmission of mutations to F1 offspring approached 100%. When single or dual sgRNAs were injected at a high concentration, gene‐specific phenotypic differences in behaviour and development were identified in F0 mutants. Specifically, F0 gene mutants demonstrated that PER, but not PDFR, is essential for normal timing of eclosion. PTTH F0 mutants were significantly heavier and exhibited a higher incidence of diapause. This work will accelerate future studies of gene function in O. nubilalis and facilitate the development of similar screens in other Lepidopteran and non‐model insects. [ABSTRACT FROM AUTHOR]

The core clock gene Period2 (PER2) is associated with mammary gland development and lipid synthesis in rodents and has recently been found to have a diurnal variation in the process of lactation, but has not yet been demonstrated in bovine mammary epithelial cells (BMECs). To explore the regulatory function of PER2 on milk fat synthesis in bovine mammary epithelial cells, we initially assessed the expression of clock genes and milk fat metabolism genes for 24 h using real-time quantitative PCR and fitted the data to a cosine function curve. Subsequently, we overexpressed the PER2 in BMECs using plasmid vector (pcDNA3.1-PER2), with empty vector pcDNA3.1-myc as the control. After transfecting BMECs for 48 h, we assessed the protein abundance related to milk fat synthesis by Western blot, the expression of genes coding for these proteins using real time-quantitative PCR, the production of triacylglycerol, and the fatty acid profile. The findings indicated that a total of nine clock genes (PER1/2, CRY1/2, REV-ERBα, BMAL1, NCOR1, NR2F2, FBXW11), seven fatty acid metabolism genes (CD36, ACSS2, ACACA, SCD, FADS1, DGAT1, ADFP), and six nuclear receptor-related genes (INSIG1, SCAP, SREBF1, C/EBP, PPARG, LXR) exhibited oscillation with a period close to 24 h in non-transfected BMECs (R2 ≥ 0.7). Compared to the control group (transfected with empty pcDNA3.1-myc), the triglyceride content significantly increased in the PER2 overexpression group (p < 0.05). The lipogenic genes for fatty acid transport and triglyceride synthesis (ACACA, SCD, LPIN1, DGAT1, and SREBF1) were upregulated after PER2 overexpression, along with the upregulation of related protein abundance (p < 0.05). The contents and ratios of palmitic acid (C16:0), oleic acid (C18:1n9c), and trans-oleic acid (C18:1n9t) were significantly increased in the overexpression group (p < 0.05). Overall, the data supported that PER2 participated in the process of milk fat metabolism and is potentially involved in the de novo synthesis and desaturation of fatty acid in bovine mammary epithelial cells. [ABSTRACT FROM AUTHOR]

Key points In mammals, the central circadian oscillator is located in the suprachiasmatic nucleus (SCN). Hypothalamus–pituitary–thyroid axis components exhibit circadian oscillation, regulated by both central clock innervation and intrinsic circadian clocks in the anterior pituitary and thyroid glands. Thyroid disorders alter the rhythmicity of peripheral clocks in a tissue‐dependent response; however, whether these effects are influenced by alterations in the master clock remains unknown. This study aimed to characterize the effects of hypothyroidism on the rhythmicity of SCN, body temperature (BT) and metabolism, and the possible mechanisms involved in this signalling. C57BL/6J adult male mice were divided into Control and Hypothyroid groups. Profiles of spontaneous locomotor activity (SLA), BT, oxygen consumption (V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$) and respiratory quotient (RQ) were determined under free‐running conditions. Clock gene expression, and neuronal activity of the SCN and medial preoptic nucleus (MPOM) area were investigated in light–dark (LD) conditions. Triiodothyronine (T3) transcriptional regulation of Bmal1 promoter activity was evaluated in GH3‐transfected cells. Hypothyroidism delayed the rhythmicity of SLA and BT, and altered the expression of core clock components in the SCN. The activity of SCN neurons and their outputs were also affected, as evidenced by the loss of circadian rhythmicity in V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ and RQ and alterations in the neuronal activity pattern of MPOM. In GH3 cells, T3 increased Bmal1 promoter activity in a time‐dependent manner. Thyroid hormone may act as a temporal cue for the central circadian clock, and the uncoupling of central and peripheral clocks might contribute to a wide range of metabolic and thermoregulatory impairments observed in hypothyroidism. Hypothyroidism alters clock gene expression in the suprachiasmatic nucleus (SCN). Thyroid hypofunction alters the phase of spontaneous locomotor activity and body temperature rhythms. Thyroid hormone deficiency alters the daily pattern of SCN and medial preoptic nucleus neuronal activities. Hypothyroidism alterations are extended to daily oscillations of oxygen consumption and metabolism, which might contribute to the development of metabolic syndrome. Triiodothyronine increases Bmal1 promoter activity acting as temporal cue for the central circadian clock. [ABSTRACT FROM AUTHOR]

Background: The rate of NAFLD in the general population is estimated to be 25.2%. NAFLD is affected by lifestyle, diet, and inflammation. In this study, the use of probiotics, prebiotics, and synbiotics was aimed to modulate the circadian clock in the liver and improve metabolic disorder through the gut–liver axis. Methods: Six-week-old, healthy, 43 Wistar albino rats were included in the study and their average weight was determined as 140.50 g (95.00–177.00) at the beginning of the study. Before the study, the rats were randomly divided into 5 groups, 8 animals were placed in the 1st, 3rd, 4th, and 5th groups and 11 animals were placed in the 2nd group. Rats in group 1 were fed standard food for 13 weeks. Rats in the 2nd, 3rd, 4th, and 5th groups were fed with 10% fructose water during the 1-week adaptation period and then 20% fructose water. After the 7th week, probiotic treatment (2 × 109 CFU/ml Lactobacillus rhamnosus GG) was administered to rats in group 3rd via gavage for 6 weeks, and prebiotic treatment was administered to rats in group 4th with feed containing 10% grape seed extract. Rats in the 5th group were given a feed consisting of 10% grape seed extract and 2 × 109 CFU/ml Lactobacillus rhamnosus GG via gavage. Results: It was determined that the use of prebiotics as a treatment option in fatty liver had a more positive effect on glucose, ALT, melatonin, and ZO-1 values. In addition, it was observed that synbiotic use had more positive effects on histopathological findings, NAS score, and the expression level of circadian clock genes. While there was no significant difference between the mRNA levels of circadian clock genes, it was observed that gene expression levels increased with fructose consumption and decreased especially with synbiotic treatment. Conclusion: It has been observed that fructose modulates the circadian rhythm by affecting some biochemical and genomic pathways as a result of synbiotic use in order to prevent the negative effects of fructose on fatty liver. [ABSTRACT FROM AUTHOR]

Marine microbes that have for eons been adapted to stable salinity regimes are confronted with sudden decreases in salinity in the Arctic Ocean. The episodic freshening is increasing due to climate change with melting multi-year sea-ice and glaciers, greater inflows from rivers, and increased precipitation. To investigate algal responses to lowered salinity, we analyzed the responses and acclimatation over 24 h in a non-model Arctic marine alga (pelagophyte CCMP2097) following transfer to realistic lower salinities. Using RNA-seq transcriptomics, here we show rapid differentially expressed genes related to stress oxidative responses, proteins involved in the photosystem and circadian clock, and those affecting lipids and inorganic ions. After 24 h the pelagophyte adjusted to the lower salinity seen in the overexpression of genes associated with freezing resistance, cold adaptation, and salt tolerance. Overall, a suite of ancient widespread pathways is recruited enabling the species to adjust to the stress of rapid salinity change. The authors analyzed the response of an Arctic pelagophyte to lowered salinity. They observed that several ancient and widespread pathways were activated, allowing the species to adjust to the stress of rapid salinity change. [ABSTRACT FROM AUTHOR]

Circadian rhythm (CR) disturbances are among the most commonly observed symptoms during major depressive disorder, mostly in the form of disrupted sleeping patterns. However, several other measurable parameters, such as plasma hormone rhythms and differential expression of circadian clock genes (ccgs), are also present, often referred to as circadian phase markers. In the recent years, CR disturbances have been recognized as an essential aspect of depression; however, most of the known animal models of depression have yet to be evaluated for their eligibility to model CR disturbances. In this study, we investigate the potential of adrenocorticotropic hormone (ACTH)‐treated animals as a disease model for research in CR disturbances in treatment‐resistant depression. For this purpose, we evaluate the changes in several circadian phase markers, including plasma concentrations of corticosterone, ACTH, and melatonin, as well as gene expression patterns of 13 selected ccgs at 3 different time points, in both peripheral and central tissues. We observed no impact on plasma corticosterone and melatonin concentrations in the ACTH rats compared to vehicle. However, the expression pattern of several ccgs was affected in the ACTH rats compared to vehicle. In the hippocampus, 10 ccgs were affected by ACTH treatment, whereas in the adrenal glands, 5 ccgs were affected and in the prefrontal cortex, hypothalamus and liver 4 ccgs were regulated. In the blood, only 1 gene was affected. Individual tissues showed changes in different ccgs, but the expression of Bmal1, Per1, and Per2 were most generally affected. Collectively, the results presented here indicate that the ACTH animal model displays dysregulation of a number of phase markers suggesting the model may be appropriate for future studies into CR disturbances. [ABSTRACT FROM AUTHOR]

Substance use disorder is a major global health concern, with a high prevalence among adolescents and young adults. The most common substances of abuse include alcohol, marijuana, cocaine, nicotine, and opiates. Evidence suggests that a mismatch between contemporary lifestyle and environmental demands leads to disrupted circadian rhythms that impair optimal physiological and behavioral function, which can increase the vulnerability to develop substance use disorder and related problems. The circadian system plays an important role in regulating the sleep–wake cycle and reward processing, both of which directly affect substance abuse. Distorted substance use can have a reciprocal effect on the circadian system by influencing circadian clock gene expression. Considering the detrimental health consequences and profound societal impact of substance use disorder, it is crucial to comprehend its complex association with circadian rhythms, which can pave the way for the generation of novel chronotherapeutic treatment approaches. In this narrative review, we have explored the potential contributions of disrupted circadian rhythms and sleep on use and relapse of different substances of abuse. The involvement of circadian clock genes with drug reward pathways is discussed, along with the potential research areas that can be explored to minimize disordered substance use by improving circadian hygiene. [ABSTRACT FROM AUTHOR]

With aging populations in many countries, including Japan, efforts to mitigate the aging-related decline in physical function have gained importance not only for improving individual quality of life but also for mitigating the effects of this loss of function on society. Impaired glucose tolerance, muscle weakness, and cognitive decline are well-known effects of aging. These interrelated factors can create a vicious cycle because impaired glucose tolerance can accelerate muscle weakness and cognitive decline. Unmodulated 40 Hz (u40Hz) stimulation is imperceptible to the human ear and has been reported to improve cognitive function in humans and mice. However, research on the effects of u40Hz stimulation is still limited. This study aimed to report the effects of u40Hz stimulation on glucose tolerance and muscle strength in senescence-accelerated prone (SAMP)-10 mice, a model of accelerated aging. SAMP-10 mice underwent five weeks of u40Hz stimulation followed by glucose-tolerance tests, cognitive and behavioral assessments, and frailty evaluations. In comparison with the control group, the u40Hz-stimulation group showed mitigation of age-related decline in glucose tolerance, a better frailty index (FI), and notably preserved muscle strength. Microarray analysis of stimulated muscle tissue revealed significant upregulation of β-oxidation genes and genes functioning downstream of peroxisome proliferator-activated receptor gamma, and significant downregulation of clock genes. These findings indicate the beneficial effects of u40Hz stimulation on glucose tolerance, muscle strength, and cognitive function, warranting further research in this area. [ABSTRACT FROM AUTHOR]

Mechanotransduction, which is the integration of mechanical signals from the external environment of a cell to changes in intracellular signaling, governs many cellular functions. Recent studies have shown that the mechanical state of the cell is also coupled to the cellular circadian clock. To investigate possible interactions between circadian rhythms and cellular mechanotransduction, we have developed a computational model that integrates the two pathways. We postulated that translocation of the transcriptional regulators MRTF (herein referring to both MRTF-A and MRTF-B), YAP and TAZ (also known as YAP1 and WWTR1, respectively; collectively denoted YAP/TAZ) into the nucleus leads to altered expression of circadian proteins. Simulations from our model predict that lower levels of cytoskeletal activity are associated with longer circadian oscillation periods and higher oscillation amplitudes, which is consistent with recent experimental observations. Furthermore, accumulation of YAP/TAZ and MRTF in the nucleus causes circadian oscillations to decay in our model. These effects hold both at the single-cell level and within a population-level framework. Finally, we investigated the effects of mutations in YAP or lamin A, the latter of which result in a class of diseases known as laminopathies. In silico, oscillations in circadian proteins are substantially weaker in populations of cells with mutations in YAP or lamin A, suggesting that defects in mechanotransduction can disrupt the circadian clock in certain disease states; however, reducing substrate stiffness in the model restores normal oscillatory behavior, suggesting a possible compensatory mechanism. Thus, our study identifies that mechanotransduction could be a potent modulatory cue for cellular clocks and that this crosstalk can be leveraged to rescue the circadian clock in disease states. [ABSTRACT FROM AUTHOR]

Circadian clocks are biochemical timers regulating many physiological and molecular processes according to the day/night cycles. The function of the oscillator relies on negative transcriptional/translational feedback loops operated by the so-called clock genes and the encoded clock proteins. Previously, we identified the small GTPase LIGHT INSENSITIVE PERIOD 1 (LIP1) as a circadian-clock-associated protein that regulates light input to the clock in the model plant Arabidopsis thaliana. We showed that LIP1 is also required for suppressing red and blue light-mediated photomorphogenesis, pavement cell shape determination and tolerance to salt stress. Here, we demonstrate that LIP1 is present in a complex of clock proteins GIGANTEA (GI), ZEITLUPE (ZTL) and TIMING OF CAB 1 (TOC1). LIP1 participates in this complex via GUANINE EX-CHANGE FACTOR 7. Analysis of genetic interactions proved that LIP1 affects the oscillator via modulating the function of GI. We show that LIP1 and GI independently and additively regulate photomorphogenesis and salt stress responses, whereas controlling cell shape and photoperiodic flowering are not shared functions of LIP1 and GI. Collectively, our results suggest that LIP1 affects a specific function of GI, possibly by altering binding of GI to downstream signalling components. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a heritable disorder characterized by shifts in mood that manifest in manic or depressive episodes. Clinical studies have identified abnormalities of the circadian system in BD patients as a hallmark of underlying pathophysiology. Fibroblasts are a well-established in vitro model for measuring circadian patterns. We set out to examine the underlying genetic architecture of circadian rhythm in fibroblasts, with the goal to assess its contribution to the polygenic nature of BD disease risk. We collected, from primary cell lines of 6 healthy individuals, temporal genomic features over a 48 h period from transcriptomic data (RNA-seq) and open chromatin data (ATAC-seq). The RNA-seq data showed that only a limited number of genes, primarily the known core clock genes such as ARNTL, CRY1, PER3, NR1D2 and TEF display circadian patterns of expression consistently across cell cultures. The ATAC-seq data identified that distinct transcription factor families, like those with the basic helix-loop-helix motif, were associated with regions that were increasing in accessibility over time. Whereas known glucocorticoid receptor target motifs were identified in those regions that were decreasing in accessibility. Further evaluation of these regions using stratified linkage disequilibrium score regression analysis failed to identify a significant presence of them in the known genetic architecture of BD, and other psychiatric disorders or neurobehavioral traits in which the circadian rhythm is affected. In this study, we characterize the biological pathways that are activated in this in vitro circadian model, evaluating the relevance of these processes in the context of the genetic architecture of BD and other disorders, highlighting its limitations and future applications for circadian genomic studies. [ABSTRACT FROM AUTHOR]

Purpose: To explore whether circadian clock genes contribute to elicit inflammation in experimental dry eye (EDE). Methods: RNA sequencing analyzed mRNA expression patterns in EDE model. RT-qPCR and/or Western blot determined the expression of inflammatory factors and circadian genes during EDE. MethylTarget™ assays determined the promoter methylation levels of Per genes in vivo. Per2 or Per3 knockdown assessed their effects on inflammatory factors in vitro. Results: We utilized an intelligently controlled environmental system (ICES) to establish a mouse EDE model. The significant upregulated genes were enriched for circadian rhythms. Therein lied oscillatory and time-dependent upregulation of PER2 and PER3, as well as their promoter hypomethylation during EDE. Silencing PER2 or PER3 significantly decreased inflammatory factor expression and also reversed such increased inflammatory response in azacitidine (AZA) treatment in vitro model. Conclusions: Our findings suggest that DNA methylation mediated the upregulation of PER2 and PER3, leading to inflammatory response in EDE. [ABSTRACT FROM AUTHOR]

Light/dark (LD) cycles are responsible for oscillations in gene expression, which modulate several aspects of plant physiology. Those oscillations can persist under constant conditions due to regulation by the circadian oscillator. The response of the transcriptome to light regimes is dynamic and allows plants to adapt rapidly to changing environmental conditions. We compared the transcriptome of Arabidopsis under LD and constant light (LL) for 3 days and identified different gene co‐expression networks in the two light regimes. Our studies yielded unforeseen insights into circadian regulation. Intuitively, we anticipated that gene clusters regulated by the circadian oscillator would display oscillations under LD cycles. However, we found transcripts encoding components of the flavonoid metabolism pathway that were rhythmic in LL but not in LD. We also discovered that the expressions of many stress‐related genes were significantly increased during the dark period in LD relative to the subjective night in LL, whereas the expression of these genes in the light period was similar. The nocturnal pattern of these stress‐related gene expressions suggested a form of "skotoprotection." The transcriptomics data were made available in a web application named Cyclath, which we believe will be a useful tool to contribute to a better understanding of the impact of light regimes on plants. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

N6‐methyladenosine (m6A) is the most abundant epitranscriptomic mark that regulates the fate of RNA molecules. Recent studies have revealed a bidirectional interaction between m6A modification and the circadian clock. However, the precise temporal dynamics of m6A global enrichment in the central circadian pacemaker have not been fully elucidated. Our study investigates the relationship between FTO demethylase and molecular clocks in primary cells of the suprachiasmatic nucleus (SCN). In addition, we examined the effects of lipopolysaccharide (LPS) on Fto expression and the role of FTO in LPS‐induced reactive oxygen species (ROS) production in primary SCN cell culture. We observed circadian rhythmicity in the global m6A levels, which mirrored the rhythmic expression of the Fto demethylase. Silencing FTO using siRNA reduced the mesor of Per2 rhythmicity in SCN primary cells and extended the period of the PER2 rhythm in SCN primary cell cultures from PER2::LUC mice. When examining the immune response, we discovered that exposure to LPS upregulated global m6A levels while downregulating Fto expression in SCN primary cell cultures. Interestingly, we found a loss of circadian rhythmicity in Fto expression following LPS treatment, indicating that the decrease of FTO levels may contribute to m6A upregulation without directly regulating its circadian rhythm. To explore potential protective mechanisms against neurotoxic inflammation, we examined ROS production following LPS treatment in SCN primary cell cultures pretreated with FTO siRNA. We observed a time‐dependent pattern of ROS induction, with significant peak at 32 h but not at 20 h after synchronization. Silencing the FTO demethylase abolished ROS induction following LPS exposure, supporting the hypothesis that FTO downregulation serves as a protective mechanism during LPS‐induced neuroinflammation in SCN primary cell cultures. [ABSTRACT FROM AUTHOR]

Introduction. This study aimed to investigate the relationship between obstructive sleep apnea (OSA), circadian rhythms, and individual sleep–wake preferences, as measured by chronotype, and to assess the association between circadian clock gene expression and subjective sleep-related variables. Methods: A total of 184 individuals were recruited, underwent polysomnography (PSG), and completed questionnaires including a chronotype questionnaire (CQ), insomnia severity index (ISI), and Epworth sleepiness scale (ESS). Blood samples were collected in the evening before and morning after PSG. Gene expression analysis included BMAL1, CLOCK, PER1, CRY1, NPAS2, and NR1D1. Results: In the OSA group, the subjective amplitude (AM score of CQ) positively correlated with all circadian clock genes in the morning (R ≥ 0.230 and p < 0.05 for each one), while the morningness–eveningness (ME score of CQ) was only associated with the evening BMAL1 level (R = 0.192; p = 0.044). In healthy controls, insomnia severity correlated with evening expression of BMAL1, PER1, and CRY1. Conclusions: The findings highlight the complex interplay between OSA, circadian rhythms, and sleep-related variables, suggesting potential determinants of morning chronotype in OSA and implicating disrupted circadian clock function in subjective feelings of energy throughout the day. Further research is warranted to elucidate underlying mechanisms and guide personalized management strategies. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the leading cause of cancer death among women worldwide. Women employed in shift jobs face heightened BC risk due to prolonged exposure to night shift work (NSW), classified as potentially carcinogenic by the International Agency for Research on Cancer (IARC). This risk is linked to disruptions in circadian rhythms governed by clock genes at the cellular level. However, the molecular mechanisms are unclear. This study aimed to assess clock genes as potential BC biomarkers among women exposed to long-term NSW. Clock gene expression was analysed in paired BC and normal breast tissues within Nurses' Health Studies I and II GEO datasets. Validation was performed on additional gene expression datasets from healthy night shift workers and women with varying BC susceptibility, as well as single-cell sequencing datasets. Post-transcriptional regulators of clock genes were identified through miRNA analyses. Significant alterations in clock gene expression in BC compared to normal tissues were found. BHLHE40, CIART, CLOCK, PDPK1, and TIMELESS were over-expressed, while HLF, NFIL3, NPAS3, PER1, PER3, SIM1, and TEF were under-expressed. The downregulation of PER1 and TEF and upregulation of CLOCK correlated with increased BC risk in healthy women. Also, twenty-six miRNAs, including miR-10a, miR-21, miR-107, and miR-34, were identified as potential post-transcriptional regulators influenced by NSW. In conclusion, a panel of clock genes and circadian miRNAs are suggested as BC susceptibility biomarkers among night shift workers, supporting implications for risk stratification and early detection strategies. [ABSTRACT FROM AUTHOR]

Light-at-night is known to produce a wide variety of behavioral outcomes including promoting anxiety, depression, hyperactivity, abnormal sociability, and learning and memory deficits. Unfortunately, we all live in a 24-h society where people are exposed to light-at-night or light pollution through nightshift work - the need for all-hours emergency services - as well as building and street-lights, making light-at-night exposure practically unavoidable. Additionally, the increase in screentime (tvs and smart devices) during the night also contributes to poorer sleep and behavioral impairments. Compounding these factors is the fact that adolescents tend to be "night owls" and prefer an evening chronotype compared to younger children and adults, so these teenagers will have a higher likelihood of being exposed to light-at-night. Making matters worse is the prevalence of high-school start times of 8 am or earlier - a combination of too early school start times, light exposure during the night, and preference for evening chronotypes is a recipe for reduced and poorer sleep, which can contribute to increased susceptibility for behavioral issues for this population. As such, this mini-review will show, using both human and rodent model studies, how light-at-night affects behavioral outcomes and stress responses, connecting photic signaling and the circadian timing system to the hypothalamic-pituitary adrenal axis. Additionally, this review will also demonstrate that adolescents are more likely to exhibit abnormal behavior in response to light-at-night due to changes in development and hormone regulation during this time period, as well as discuss potential interventions that can help mitigate these negative effects. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the most common and fatal malignancies among women worldwide. Circadian rhythms have emerged in recent studies as being involved in the pathogenesis of breast cancer. In this paper, we reviewed the molecular mechanisms by which the dysregulation of the circadian genes impacts the development of BC, focusing on the critical clock genes, brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK). We discussed how the circadian rhythm disruption (CRD) changes the tumor microenvironment (TME), immune responses, inflammation, and angiogenesis. The CRD compromises immune surveillance and features and activities of immune effectors, including CD8+ T cells and tumor-associated macrophages, that are important in an effective anti-tumor response. Meanwhile, in this review, we discuss bidirectional interactions: age and circadian rhythms, aging further increases the risk of breast cancer through reduced vasoactive intestinal polypeptide (VIP), affecting suprachiasmatic nucleus (SCN) synchronization, reduced ability to repair damaged DNA, and weakened immunity. These complex interplays open new avenues toward targeted therapies by the combination of clock drugs with chronotherapy to potentiate the immune response while reducing tumor progression for better breast cancer outcomes. This review tries to cover the broad area of emerging knowledge on the tumor-immune nexus affected by the circadian rhythm in breast cancer. [ABSTRACT FROM AUTHOR]

Obesity during pregnancy has been escalating, becoming a huge problem that poses consequences not only for the health of the offspring but also for the maternal well-being. Women's adipose and hepatic tissue metabolism undergoes significant changes during the gestational period. During pregnancy, obesity is a primary instigator of steatosis, increasing the risk of non-alcholic fatty liver disease (NAFLD), now recognized under the updated nomenclature metabolic dysfunction-associated steatotic liver disease (MASLD). Pregnant women with obesity present higher levels of free fatty acids and glucose, reduction in insulin sensitivity, and adipose tissue endocrine dysregulation. Furthermore, obesity-induced modifications in clock genes and lipid-associated gene expression within adipose tissue disrupt crucial metabolic adaptations, potentially culminating in adipose tissue dysfunction. Thus, the liver experiences increased exposure to free fatty acids through the portal vein. Higher uptake of free fatty acids into the liver disrupts hepatic lipid oxidation while enhances lipogenesis, thereby predisposing to ectopic fat deposition within the liver. This review focuses on the obesity-induced changes during pregnancy in both liver and adipose tissue metabolism, elucidating how the metabolic crosstalk between these two organs can be dysregulated in pregnant women living with obesity. [ABSTRACT FROM AUTHOR]

First, significantly higher mate-finding success was found under light condition than under constant darkness condition in Phauda flammans, a typical diurnal moth. We speculate that mate-finding behavior in P. flammans may be influenced by the light-sensitive opsin genes Long wavelength opsin (PfLW), Ultraviolet opsin (PfUV) and Blue opsin (PfBL), which are potentially regulated by both light-cues and endogenous circadian rhythms. Second, the circadian clock genes Period (PfPer), Timeless (PfTim), Cryptochrome1 (PfCry1), Cryptochrome2 (PfCRY2), Cryptochrome3 (PfCry-like), Clock (PfClk), Cycle (PfCyc), Vrille (PfVri), and Slimb (PfSli) were identified in P. flammans. Third, circadian rhythms in the relative expression levels of opsin and circadian clock genes were demonstrated via quantitative real-time PCR analysis, with peak expression coinciding with the mate-finding peak. Notably, the relative expression of PfLW in males P. flammans was significantly higher than that in females P. flammans at the mate-finding peaks Zeitgeber time (ZT) 8 and ZT 10 under light, while the expression of the opsin gene PfBL showed a similar pattern at ZT 10 under light. Additionally, the expression of the clock gene PfCry-like was significantly higher in males than in females at ZT 8 and ZT 10 under light, while PfPer, PfTim, PfClk and PfCyc exhibited similar male-biased expression patterns at ZT 10 under light. Conversely, PfCry1 and PfVri expression was significantly higher in females than in male at ZT 8 under light. In conclusion, sex differences were detected in the expression of opsin and circadian clock genes, which indicated that light-mediated regulation of these genes may contribute to the daytime mate-finding behavior of P. flammans. [ABSTRACT FROM AUTHOR]

The Diederik cuckoo, Chrysococcyx caprius, is a small Afrotropical bird in the family Cuculidae. It is taxonomically related to 13 other species within the genus Chrysococcyx and is migratory in sub‐Saharan Africa. It has a unique breeding behaviour of being a brood parasite: Breeding pairs lay their eggs in the nests of a host species and hatchlings expel the eggs of the host species. The aim of the present study was to investigate diversity in two circadian clock genes, Clock and Adcyap1, to probe for a relationship between genetic polymorphisms and their role in circannual timing and habitat selection (phenology) in intra‐African migrants. DNA extracted from blood was used for the PCR amplification and sequencing of clock genes in 30 Diederik cuckoos. Three alleles were detected for Clock with similar genotypes between individuals from the Northern and Southern breeding ranges while 10 alleles were detected for Adcyap1, having shorter alleles in the North and longer alleles in the South. Population genetic analyses, including allele frequency and zygosity analysis, showed distinctly higher frequencies for the most abundant Clock allele, containing 10 polyglutamine repeats, as well as a high degree of homozygosity. In contrast, all individuals were heterozygous for Adcyap1 and alleles from both regions showed distinct differences in abundance. Comparisons between both clock genes and phenology found several phenotypic correlations. This included evidence of a relationship between the shorter alleles and habitat selection as well as a relationship between longer alleles and timing. In both instances, evidence is provided that these effects may be sex‐specific. Given that these genes drive some of the synchronicity between environments and the life cycles of birds, they provide valuable insight into the fitness of species facing global challenges including climate change, urbanisation and expanding agricultural practices. [ABSTRACT FROM AUTHOR]

Plants possess the remarkable ability to integrate the circadian clock with various signalling pathways, enabling them to quickly detect and react to both external and internal stress signals. However, the interplay between the circadian clock and biological processes in orchestrating responses to environmental stresses remains poorly understood. TOC1, a core component of the plant circadian clock, plays a vital role in maintaining circadian rhythmicity and participating in plant defences. Here, our study reveals a direct interaction between TOC1 and the promoter region of MYB44, a key gene involved in plant defence. TOC1 rhythmically represses MYB44 expression, thereby ensuring elevated MYB44 expression at dawn to help the plant in coping with lowest temperatures during diurnal cycles. Additionally, both TOC1 and MYB44 can be induced by cold stress in an Abscisic acid (ABA)‐dependent and independent manner. TOC1 demonstrates a rapid induction in response to lower temperatures compared to ABA treatment, suggesting timely flexible regulation of TOC1‐MYB44 regulatory module by the circadian clock in ensuring a proper response to diverse stresses and maintaining a balance between normal physiological processes and energy‐consuming stress responses. Our study elucidates the role of TOC1 in effectively modulating expression of MYB44, providing insights into the regulatory network connecting the circadian clock, ABA signalling, and stress‐responsive genes. Summary statement: We present initial evidence that MYB44, a key player in the ABA signalling pathway, is directly targeted by the circadian clock. Additionally, our findings offer a comprehensive understanding of the TOC1‐MYB44 module, elucidating its crucial role under both ABA‐dependent and ABA‐independent conditions during cold stress. [ABSTRACT FROM AUTHOR]

• Microglia display transcriptional and protetype adaptations to light and dark phases • Molecular differences in microglia between light and dark phases affect their response to LPS and synaptic pruning in vivo • The timing of microglial sample collection infleunces the transcriptomic changes in a mouse model of maternal immune activation Microglia are increasingly recognized to contribute to brain health and disease. Preclinical studies using laboratory rodents are essential to advance our understanding of the physiological and pathophysiological roles of these cells in the central nervous system. Rodents are nocturnal animals, and they are mostly maintained in a defined light–dark cycle within animal facilities, with many laboratories investigating the molecular and functional profiles of microglia exclusively during the animals' light (sleep) phase. However, only a few studies have considered possible differences in microglial functions between the active and sleep phases. Based on initial evidence suggesting that microglial intrinsic clock genes can affect their phenotypes, we sought to investigate differences in transcriptional, proteotype and functional profiles of microglia between light (sleep) and dark (active) phases, and how these changes are affected in pathological models. We found marked transcriptional and proteotype differences between microglia harvested from male mice during the light or dark phase. Amongst others, these differences related to genes and proteins associated with immune responses, motility, and phagocytosis, which were reflected by functional alterations in microglial synaptic pruning and response to bacterial stimuli. Possibly accounting for such changes, we found RNA and protein regulation in SWI/SNF and NuRD chromatin remodeling complexes between light and dark phases. Importantly, we also show that the time of microglial sample collection influences the nature of microglial transcriptomic changes in a model of immune-mediated neurodevelopmental disorders. Our findings emphasize the importance of considering diurnal factors in studying microglial cells and indicate that implementing a circadian perspective is pivotal for advancing our understanding of their physiological and pathophysiological roles in brain health and disease. [ABSTRACT FROM AUTHOR]

Summary: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ‐aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS‐derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS‐derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ‐estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep‐related disorders and neurodegenerative conditions associated with glymphatic dysfunction. [ABSTRACT FROM AUTHOR]

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5‐day‐old larvae over a 24‐h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1a and per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine‐deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish. [ABSTRACT FROM AUTHOR]

The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semimechanistic mathematical model to delineate SCN's capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation revealed a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag as well as to an elongation of the circadian period. These phenomena are well replicated by our model, which suggests that both the swift re-entrainment and prolonged period can be ascribed to a reduced robustness in neuronal oscillators. Our model also offers insights into phase shifts induced by acute physiological stress and the alignment/misalignment of physiological stress with external light-dark cues. Such understanding aids in strategizing responses to stressful events, such as nutritional status changes and jetlag. NEW & NOTEWORTHY: This study is the first theoretical work to investigate the complex interaction between integrated stress response (ISR) sensing and central circadian rhythm regulation, encompassing the suprachiasmatic nucleus (SCN) and hypothalamus-pituitary-adrenal (HPA) axis. The findings carry implications for the development of dietary or pharmacological interventions aimed at facilitating recovery from stressful events, such as jetlag. Moreover, they provide promising prospects for potential therapeutic interventions that target circadian rhythm disruption and various stress-related disorders. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes’ involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD.

Substance use disorder is a major global health concern, with a high prevalence among adolescents and young adults. The most common substances of abuse include alcohol, marijuana, cocaine, nicotine, and opiates. Evidence suggests that a mismatch between contemporary lifestyle and environmental demands leads to disrupted circadian rhythms that impair optimal physiological and behavioral function, which can increase the vulnerability to develop substance use disorder and related problems. The circadian system plays an important role in regulating the sleep–wake cycle and reward processing, both of which directly affect substance abuse. Distorted substance use can have a reciprocal effect on the circadian system by influencing circadian clock gene expression. Considering the detrimental health consequences and profound societal impact of substance use disorder, it is crucial to comprehend its complex association with circadian rhythms, which can pave the way for the generation of novel chronotherapeutic treatment approaches. In this narrative review, we have explored the potential contributions of disrupted circadian rhythms and sleep on use and relapse of different substances of abuse. The involvement of circadian clock genes with drug reward pathways is discussed, along with the potential research areas that can be explored to minimize disordered substance use by improving circadian hygiene.

Abstract 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.

Circadian rhythms are driven by an internal molecular clock which controls physiological and behavioral processes. Disruptions in these rhythms have been associated with health issues. Therefore, studying circadian rhythms is crucial for understanding physiology, behavior, and pathophysiology. However, it is challenging to study circadian rhythms over gene expression data, due to a scarcity of time labels. In this paper, we propose a novel approach to predict the phases of un-timed samples based on a deep neural network (DNN) architecture. This approach addresses two challenges: (1) prediction of sample phases and reliable identification of cyclic genes from high-dimensional expression data without relying on conserved circadian genes and (2) handling small sample-sized datasets. Our algorithm begins with initial gene screening to select candidate cyclic genes using a Minimum Distortion Embedding framework. This stage is then followed by greedy layer-wise pre-training of our DNN. Pre-training accomplishes two critical objectives: First, it initializes the hidden layers of our DNN model, enabling them to effectively capture features from the gene profiles with limited samples. Second, it provides suitable initial values for essential aspects of gene periodic oscillations. Subsequently, we fine-tune the pre-trained network to achieve precise sample phase predictions. Extensive experiments on both animal and human datasets show accurate and robust prediction of both sample phases and cyclic genes. Moreover, based on an Alzheimer's disease (AD) dataset, we identify a set of hub genes that show significant oscillations in cognitively normal subjects but had disruptions in AD, as well as their potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that disturbance of the clock genes, which leads to systemic endocrine perturbation, plays a crucial role in the pathogenesis of metabolic and liver diseases. Fluorene-9-bisphenol (BHPF) is utilized in the manufacturing of plastic materials but its biological effects on liver homeostasis remain unknown. The impacts and involved mechanisms of BHPF on the liver diseases, metabolism, and circadian clock were comprehensively studied by zebrafish and mouse models. The therapeutic effect of melatonin (MT) was also verified. Zebrafish and mouse models with either acute exposure (0.5 and 1 µmol/L, 1-4 days post-fertilization) or chronic oral exposure (0.5 and 50 mg/(kg·2 days), 30 days) were established with various BHPF concentrations. Herein, we identified a crucial role for estrogenic regulation in liver development and circadian locomotor rhythms damaged by BHPF in a zebrafish model. BHPF mice showed chaos in circadian activity through the imbalance of circadian clock component Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 in the liver and brain. The liver sexual dimorphic alteration along with reduced growth hormone and estrogens played a critical role in damaged glucose metabolism, hepatic inflammation, and fibrosis induced by BHPF. Besides, sleep improvement by exogenous MT alleviated BHPF‐related glucose metabolism and liver injury in mice. We proposed the pathogenesis of metabolic and liver disease resulting from BHPF and promising targeted therapy for liver metabolism disorders associated with endocrine perturbation chemicals. These results might play a warning role in the administration of endocrine-disrupting chemicals in everyday life and various industry applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome‐wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English‐language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross‐sectional studies, 13.4% animal studies, 4.8% genome‐wide studies, 5.8% epigenome‐wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long‐term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early‐life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome‐wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long‐term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW‐associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Background: Energy allocation between growth and reproduction determines puberty onset and fertility. In mammals, peripheral hormones such as leptin, insulin and ghrelin signal metabolic information to the higher centres controlling gonadotrophin-releasing hormone neurone activity. However, these observations could not be confirmed in lower vertebrates, suggesting that other factors may mediate the energetic trade-off between growth and reproduction. A bioinformatic and experimental study suggested co-regulation of the circadian clock, reproductive axis and growth-regulating genes in zebrafish. While loss-of-function of most of the identified co-regulated genes had no effect or only had mild effects on reproduction, no such information existed about the co-regulated somatostatin, well-known for its actions on growth and metabolism. Results: We show that somatostatin signalling is pivotal in regulating fecundity and metabolism. Knock-out of zebrafish somatostatin 1.1 (sst1.1) and somatostatin 1.2 (sst1.2) caused a 20–30% increase in embryonic primordial germ cells, and sst1.2−/− adults laid 40% more eggs than their wild-type siblings. The sst1.1−/− and sst1.2−/− mutants had divergent metabolic phenotypes: the former had 25% more pancreatic α-cells, were hyperglycaemic and glucose intolerant, and had increased adipocyte mass; the latter had 25% more pancreatic β-cells, improved glucose clearance and reduced adipocyte mass. Conclusions: We conclude that somatostatin signalling regulates energy metabolism and fecundity through anti-proliferative and modulatory actions on primordial germ cells, pancreatic insulin and glucagon cells and the hypothalamus. The ancient origin of the somatostatin system suggests it could act as a switch linking metabolism and reproduction across vertebrates. The results raise the possibility of applications in human and animal fertility. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the effects of long day and night shifts on immune cells in a population of nurses. This cross-sectional study in December 2019 was based on a group of nurses. 1568 physically healthy caregivers were included, including 1540 women and 28 men. 1093 nurses had long-term shift work (working in a rotating system for > 1 year). The receiver operating characteristic curve, Ensemble Learning, and Logistic regression analyses were used to evaluate factors related to long-term shift work. The night shift group nurses had significantly higher MPV, PLCR, and WBC and significantly lower BASO%, ELR, MCHC, PLR, RDW-CV, and RDW-SD (P < 0.01). ROC curves showed that WBC, PLR, ELR, RDW_CV, and BASO% were more related to the night shift. Ensemble Learning, combined with the LASSO model, finally filtered out three indicators of night shifts related to ELR, WBC, and RDW_SD. Finally, logistic regression analysis showed that the nurses' night shift situation greatly influenced two peripheral blood ELR and WBC indicators (ELR: log (OR) = − 3.9, 95% CI: − 5.8– − 2.0; WBC: log (OR) = 0.25, 95% CI: 0.18–0.32). Finally, we showed that, unlike WBC, the relative riskiness of ELR showed opposite results among junior nurses and middle-senior nurses (log (OR) 6.5 (95% CI: 1.2, 13) and − 7.1 (95% CI: − 10, − 3.8), respectively). Our study found that prolonged night shifts were associated with abnormal WBC and ELR, but after strict age matching, WBC remained significantly different. These findings help to confirm that COVID-19 and tumorigenesis (e.g., breast cancer) are significantly associated with circadian rhythm disruption. However, more detailed studies are needed to confirm this. [ABSTRACT FROM AUTHOR]

The study explored the role of circadian rhythm genes (CRGs) in lower grade glioma (LGG) development and found that certain genes, such as CRY1, NPAS2, and RORB, were associated with increased or decreased risk of LGG. The study also investigated the correlation between CRGs and immune cell infiltration, revealing a negative association with macrophage infiltration and a positive correlation with B cell and CD8 + T cell infiltration. Additionally, the study identified major mutated CRGs, including PER2, BMAL1, CLOCK, and BMAL2, and their potential interaction with other CNS-associated genes. The study suggests that CRGs play a crucial role in immune response and tumorigenesis in LGG patients and warrants further investigation. [ABSTRACT FROM AUTHOR]

• prenatal LPS and early-life LL affect the expression profiles of genes at P30. • impact of combined interventions is smaller than that of individual interventions. • combined interventions increase the amplitude of expression rhythms in some genes. Exposure to lipopolysaccharide (LPS) during prenatal development leads to various changes in neurobiological and behavioural patterns. Similarly, continuous exposure to constant light (LL) during the critical developmental period of the circadian system affects gene expression in various tissues in adulthood. Given the reciprocal nature of the interaction between the circadian and the immune systems, our study primarily investigated the individual effects of both interventions and, more importantly, their combined effect. We aimed to explore whether there might be a potential synergistic effect on circadian rhythms and their parameters, focussing on the expression of clock genes, immune-related genes, and specific genes in the hippocampus, pineal gland, spleen and adrenal gland of rats at postnatal day 30. Our results show a significant influence of prenatal LPS and postnatal LL on the expression profiles of all genes assessed. However, the combination of prenatal LPS and postnatal LL only revealed an enhanced negative effect in a minority of the comparisons. In most cases, it appeared to attenuate the changes induced by the individual interventions, restoring the measured parameters to values closer to those of the control group. In particular, genes such as Nr1d1 , Aanat and Tph1 showed increased amplitude in the pineal gland and spleen, while the kynurenine enzymes Kynu and KatII developed circadian rhythmicity in the adrenal glands only after the combined interventions. Our data suggest that a mild immunological challenge during prenatal development may play a critical role in triggering an adaptive response of the circadian clock later in life. [ABSTRACT FROM AUTHOR]

Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells. [ABSTRACT FROM AUTHOR]

Light/dark (L/D) cycle plays a crucial role in controlling the production and quality of vegetables. However, the mechanism of L/D cycle on vegetable growth and quality is scarce studied. To investigate the impact of L/D cycle on lettuce growth and quality, we designed three diel scenarios, including 16 hours of light and 8 hours of darkness (L16/D8), 12 hours of light and 6 hours of darkness (L12/D6), and 8 hours of light and 4 hours of darkness (L8/D4). By phenotypic analysis, we found that lettuce grew taller under the L8/D4 scenario than under L16/D8 light cycle scenarios. The physiological indexes showed that the lettuce leaves grown in the L8/D4 scenario exhibited greater enhancements in the levels of soluble protein, soluble sugar, and carotenoid content compared to the other scenarios. By comparing the expression levels under different diel scenarios (L16/D8 vs L12/ D6, L16/D8 vs L8/D4, and L12/D6 vs L8/D4), we identified 7,209 differentially expressed genes (DEGs). Additionally, 3 gene modules that were closely related to L/D cycle of lettuce were selected by WGCNA analysis. The eigengenes of three gene modules were enriched in plant hormone signal transduction, sphingolipid metabolism, and nucleocytoplasmic transport pathways. Through network analysis, we identified six hub genes (CIP1, SCL34, ROPGEF1, ACD6, CcmB, and Rps4) in the three gene modules, which were dominant in plant circadian rhythms and greatly affected lettuce growth. qRT-PCR analysis confirmed the diurnal response patterns of the 6 hub genes in different treatments were significant. This study intensively enhanced our comprehension of the L/D cycle in the growth morphology, nutritional quality, and metabolic pathways of lettuce. [ABSTRACT FROM AUTHOR]

Coral exhibits diel rhythms in behavior and gene transcription. However, the influence of elevated temperature, a key factor causing coral bleaching, on these rhythms remains poorly understood. To address this, we examined physiological, metabolic, and gene transcription oscillations in the Acropora tenuis-Cladocopium sp. holobiont under constant darkness (DD), light-dark cycle (LD), and LD with elevated temperature (HLD). Under LD, the values of photosystem II efficiency, reactive oxygen species leakage, and lipid peroxidation exhibited significant diel oscillations. These oscillations were further amplified during coral bleaching under HLD. Gene transcription analysis identified 24-hour rhythms for specific genes in both coral and Symbiodiniaceae under LD. Notably, these rhythms were disrupted in coral and shifted in Symbiodiniaceae under HLD. Importantly, we identified over 20 clock or clock-controlled genes in this holobiont. Specifically, we suggested CIPC (CLOCK-interacting pacemaker-like) gene as a core clock gene in coral. We observed that the transcription of two abundant rhythmic genes encoding glycoside hydrolases (CBM21) and heme-binding protein (SOUL) were dysregulated by elevated temperature. These findings indicate that elevated temperatures disrupt diel gene transcription rhythms in the coral-Symbiodiniaceae holobiont, affecting essential symbiosis processes, such as carbohydrate utilization and redox homeostasis. These disruptions may contribute to the thermal bleaching of coral. Significant differences in rhythmic gene expression between the coral host and its symbiont under elevated temperature are revealed, suggesting the host is dependent on its endogenous molecular clock, while the symbiont's rhythmic expression is more influenced by environmental stimuli. [ABSTRACT FROM AUTHOR]

Introduction: Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA). Methods: We conducted a two-sample two-way Mendelian randomization (MR) study to investigate the causal relationship between walking and EAA. Walking and Leisure sedentary behavior data were sourced from UK Biobank, while EAA data were gathered from a total of 28 cohorts. The MR analysis was carried out using several methods, including the inverse variance weighted (IVW), weighted median, MR-Egger, and robust adjusted profile score (RAPS). To ensure the robustness of our findings, we conducted sensitivity analyses, which involved the MR-Egger intercept test, Cochran's Q test, and MR-PRESSO, to account for and mitigate potential pleiotropy. Results: The IVW MR results indicate a significant impact of usual walking pace on GrimAge (BETA = − 1.84, 95% CI (− 2.94, − 0.75)), PhenoAge (BETA = − 1.57, 95% CI (− 3.05, − 0.08)), Horvath (BETA = − 1.09 (− 2.14, − 0.04)), and Hannum (BETA = − 1.63, 95% CI (− 2.70, − 0.56)). Usual walking pace is significantly associated with a delay in epigenetic aging acceleration (EAA) (P < 0.05). Moreover, the direction of effect predicted by the gene remained consistent across RAPS outcomes and sensitivity MR analyses. There is a lack of robust causal relationships between other walking conditions, such as walking duration and walking frequency, on EAA (P > 0.05). Conclusion: Our evidence demonstrates that a higher usual walking pace is associated with a deceleration of the acceleration of all four classical epigenetic clocks acceleration. Key messages: In recent years, observational studies have found that there is a correlation between walking and aging, but the specific relationship is not clear We used a Mendelian randomization approach to test the causal effect of walking and sedentarism on epigenetic clock acceleration Mendelian randomization studies have found that faster walking speed may delay physiological aging through causal analysis at the genetic level [ABSTRACT FROM AUTHOR]

In mammals, intrinsic 24 h or circadian rhythms are primarily generated by the suprachiasmatic nuclei (SCN). Rhythmic daily changes in the transcriptome and proteome of SCN cells are controlled by interlocking transcription‐translation feedback loops (TTFLs) of core clock genes and their proteins. SCN cells function as autonomous circadian oscillators, which synchronize through intercellular neuropeptide signalling. Physiological and behavioural rhythms can be severely disrupted by genetic modification of a diverse range of genes and proteins in the SCN. With the advent of next generation sequencing, there is unprecedented information on the molecular profile of the SCN and how it is affected by genetically targeted alteration. However, whether the expression of some genes is more readily affected by genetic alteration of the SCN is unclear. Here, using publicly available datasets from recent RNA‐seq assessments of the SCN from genetically altered and control mice, we evaluated whether there are commonalities in transcriptome dysregulation. This was completed for four different phases across the 24 h cycle and was augmented by Gene Ontology Molecular Function (GO:MF) and promoter analysis. Common differentially expressed genes (DEGs) and/or enriched GO:MF terms included signalling molecules, their receptors, and core clock components. Finally, examination of the JASPAR database indicated that E‐box and CRE elements in the promoter regions of several commonly dysregulated genes. From this analysis, we identify differential expression of genes coding for molecules involved in SCN intra‐ and intercellular signalling as a potential cause of abnormal circadian rhythms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Temporomandibular joint osteoarthritis (TMJOA) has a high incidence rate, but its pathogenesis remains unclear. Circadian rhythm is an important oscillation in the human body and influences various biological activities. However, it is still unclear whether circadian rhythm affects the onset and development of TMJOA. Methods: We disrupted the normal rhythm of rats and examined the expression of core clock genes in the mandibular condylar cartilage of the jaw and histological changes in condyles. After isolating rat mandibular condylar chondrocytes, we upregulated or downregulated the clock gene Per1, examined the expression of cartilage matrix-degrading enzymes, tested the activation of the GSK3β/β-CATENIN pathway and verified it using agonists and inhibitors. Finally, after downregulating the expression of Per1 in the mandibular condylar cartilage of rats with jet lag, we examined the expression of cartilage matrix-degrading enzymes and histological changes in condyles. Results: Jet lag led to TMJOA-like lesions in the rat mandibular condyles, and the expression of the clock gene Per1 and cartilage matrix-degrading enzymes increased in the condylar cartilage of rats. When Per1 was downregulated or upregulated in mandibular condylar chondrocytes, the GSK3β/β-CATENIN pathway was inhibited or activated, and the expression of cartilage matrix-degrading enzymes decreased or increased, which can be rescued by activator and inhibitor of the GSK3β/β-CATENIN pathway. Moreover, after down-regulation of Per1 in mandibular condylar cartilage in vivo, significant alleviation of cartilage degradation, cartilage loss, subchondral bone loss induced by jet lag, and inhibition of the GSK3β/β-CATENIN signaling pathway were observed. Circadian rhythm disruption can lead to TMJOA. The clock gene Per1 can promote the occurrence of TMJOA by activating the GSK3β/β-CATENIN pathway and promoting the expression of cartilage matrix-degrading enzymes. The clock gene Per1 is a target for the prevention and treatment of TMJOA. [ABSTRACT FROM AUTHOR]