Search Results (891)

The protein SNAIL has been widely studied for its roles in promoting cancer invasion and resistance to apoptosis. There are multiple contributors to its expression, including self- and circadian regulation, and it has been posited that SNAIL oscillates in a circadian manner. Given the multiple factors involved, we sought to determine whether this is indeed the case. We developed a luciferase reporter that was used to demonstrate SNAIL’s rhythmic nature (SNAIL:luc) in the circadian model cell line, U2OS. Considering SNAIL’s relevance in breast cancer, we also assessed its oscillations in cellular models representing different levels of aggression. We incorporated the SNAIL:luc reporter in MCF10A breast epithelial cells, and MCF7 and MDA-MB-231 breast cancer cell lines, which are less and more aggressive, respectively. We found that SNAIL oscillations were present but weak in MCF7 and arrhythmic in MDA-MB-231 cells, correlating with those of core clock genes (BMAL1 and PER2) in these models. Surprisingly, MCF10A cells, whose core clock genes possess robust circadian expression patterns, did not have rhythmic oscillations of SNAIL. Our findings suggest that SNAIL is under circadian control, but this is cell line/tissue dependent, setting the stage for additional studies to better understand the impacts of various factors contributing to its expression. Full article

In fish cells, light exposure elevates levels of reactive oxygen species (ROS) and stress-activated MAP kinase activity and thereby induces gene transcription. However, we lack a complete understanding of the function and evolution of this regulatory mechanism. Here, we reveal that a set of mitochondrial and heme metabolism genes is transcriptionally induced in zebrafish cells upon exposure to light or elevated ROS. The integrity of D-box and E-box enhancers in these gene promoters is essential for their transcriptional activation. Furthermore, light-induced transcription of mitochondrial and heme metabolism genes is absent in a cell line derived from the blind Somalian cavefish (Phreatichthys andruzzii). This fish species has evolved in perpetual darkness and lacks light-dependent circadian and DNA repair responses as well as D-box-mediated and light- and ROS-induced transcription. PAR-bZip transcription factors bind to and activate transcription via the D-box. Cavefish homologs of these factors share extensive homology with their zebrafish counterparts and lack the deletion mutations that characterize other light-dependent genes in this species. These results extend the role of the D-box as a key regulator of light- and ROS-driven transcription in fish, beyond the circadian clock and DNA repair systems, to also encompass metabolic and mitochondrial function. Full article

Cortisol follows a 24 h circadian rhythm that plays a pivotal role in maintaining the optimal function of various physiological systems in alignment with behavioural cycles. Its synthesis and secretion are regulated by the hypothalamic–pituitary–adrenal (HPA) axis. The 24 h fluctuations of cortisol may result from physiological changes influencing its regulation, or conversely, hormone-mediating physiological changes within the body. This review mainly aims to synthesize current evidence on methods for detecting cortisol. In addition, it focuses on evaluating cortisol’s potential as a biomarker for circadian disruption and related health impacts. A literature search was conducted across databases, including Google Scholar, PubMed, and Scopus, using search terms such as “circadian rhythm OR circadian clock OR circadian disruption OR circadian dysregulation” and “cortisol OR hydrocort* OR corticoid OR corticosteroid”. A total of 47 articles were included on methods of cortisol detection, and 41 articles were reviewed for their health implications. Cortisol measured via saliva, blood serum, urine, interstitial fluid (ISF), and sweat has been reported as suitable for 24 h monitoring, reflecting circadian regulation. In contrast, hair cortisol is suitable for identifying chronic changes and prolonged elevations in cortisol levels. This review highlights the stability, suitability, and challenges of each detection method, including reported cortisol levels across studies. Additionally, it provides a comprehensive overview of health implications associated with changes in cortisol, offering insights into its potential as a marker for circadian disruption and related health outcomes. Full article

Skeletal muscle plays vital roles in locomotion, metabolic regulation and endocrine signalling. Critically, it undergoes structural and functional decline with age, leading to a progressive loss of muscle mass and strength (sarcopenia) and contributing to a systemic loss of tissue resilience to stressors of multiple tissue systems (frailty). Emerging evidence implicates misalignments in both the circadian molecular clock and redox homeostasis as major drivers of age-related skeletal muscle deterioration. The circadian molecular clock, through core clock components such as BMAL1 and CLOCK, orchestrates rhythmic gene, protein and myokine expression impacting diurnal regulation of skeletal muscle structure and metabolism, mitochondrial function, antioxidant defence, extracellular matrix organisation and systemic inter-tissue communication. In parallel, the master redox regulator, NRF2, maintains cellular antioxidant defence, tissue stress resistance and mitochondrial health. Disruption of either system impairs skeletal muscle contractility, metabolism, and regenerative capacity as well as systemic homeostasis. Notably, NRF2-mediated redox signalling is clock-regulated and, in turn, affects circadian clock regulation. Both systems are responsive to external cues such as exercise and hormones, yet studies do not consistently include circadian timing or biological sex as key methodological variables. Given that circadian regulation shifts with age and differs between sexes, aligning exercise interventions with one’s own chronotype may enhance health benefits, reduce adverse side effects, and overcome anabolic resistance with ageing. This review highlights the essential interplay between circadian and redox systems in skeletal muscle homeostasis and systemic health and argues for incorporating personalised chrono-redox approaches and sex-specific considerations into future experimental research and clinical studies, aiming to improve functional outcomes in age-related sarcopenia and broader age-related metabolic and musculoskeletal conditions. Full article

The increasing interest in the presence of contaminants of emerging concern (CEC) in aquatic environments has driven research into biological mechanisms capable of eliminating pharmaceutical compounds like paracetamol, considering different plant species as model systems. Thus, the use of hairy roots (HRs) has become an interesting tool. This study explores the ability of tobacco HRs to remove paracetamol, with an emphasis on elucidating the main metabolism steps and key enzymes involved in the green liver detoxification process, as well as the antioxidant response. The deepening of these aspects has been carried out through gene expression and biochemical analysis under circadian regulation. Our results reveal that HRs efficiently removed paracetamol (100 mg L⁻¹) from the culture medium, achieving around 99% removal at ZT16 h (Zeitgeber Time 16). The early activation of antioxidant defense mechanisms, demonstrated by enhanced peroxidase (POD) activity and total antioxidant capacity (TAA) during the light phase, has been observed. Furthermore, glutathione S-transferase (GSTs) activity and glutathione (GSH) levels, potentially linked to paracetamol conjugation, were also assessed. Gene expression analyses confirmed GST gene upregulation in response to paracetamol treatment, with GSTF6-like and GSTF8-like maintaining circadian rhythms as in the control, and GSTZ1-like only displayed rhythmic expression upon treatment. Additionally, the modulation of core circadian clock genes (NtLHY1 and NtTOC1) suggests that the plant response to paracetamol is tightly regulated by the circadian system. Together, these findings shed light on the complex molecular and biochemical mechanisms underlying paracetamol detoxification in tobacco HRs and underscore the significant role of circadian regulation in orchestrating these responses. Full article

The circadian rhythm controls the sleep/wake cycle and a wide variety of metabolic and physiological functions. Clock genes regulate it in response to both external and endogenous stimuli, and their expression may change because of aging, leading to an increased risk of health problems. Despite the well-described benefits of physical exercise as a circadian synchronizer, there is a lack of literature regarding the role of chronic exercise intensity in clock gene expression during aging. This article aims to analyze the differential expression of genes that regulate the biological clock under the effects of variable-intensity aerobic swimming training in aging mice, determining whether these exercise regimens interfere with the genomic regulation of the circadian rhythm. For this purpose, the mice were exposed to low- and high-intensity exercise and had their heart and gastrocnemius tissues molecularly analyzed by cDNA synthesis and qPCR to determine the expression levels of the selected genes: Clock, Arntl, Per1, Per2, Cry1, Cry2, and Nr1d1. The results showed that low-intensity exercise, performed at workloads below the anaerobic threshold, significantly changed their expression in the gastrocnemius muscle (p < 0.05), while high-intensity exercise had no statistically significant effects (p > 0.05), with the heart being immune to exercise influence except when it comes to the Per1 gene, for which expression was increased (p = 0.031) by low-intensity exercise. Additionally, both body weight and lactate thresholds had no change during the experiment (p > 0.05), while the maximum supported workload was maintained for high-intensity exercise (p > 0.05) and increased for low-intensity exercise (p < 0.01), with the control group experiencing a decay instead (p < 0.05). Thus, the present study highlights the importance of chronic exercise in modulating clock genes and opens exciting possibilities for circadian medicine, such as improvements in exercise capacity, heart condition, and lipid metabolism for subjects of low-intensity regimens. Full article

The large, white paired bract is a unique trait, as well as the most intriguing feature of the dove tree (Davidia involucrata). However, the mechanisms underlying bract development remain unclear. Our previous comparative transcriptome analysis concerning Davidia bracts at different developmental stages has identified a number of bract-specific genes. Among these, the genes encoding PRPs (proline-rich proteins) show dramatic expression variation, indicating the participation of this gene family in bract development. In this study, we screened the whole Davidia genome and identified twelve Davidia PRP (DiPRP) genes, showing obvious expression variation during bract development, with some upregulated up to 100-fold at the fast-developing stage. These PRP genes are evenly distributed on seven Davidia chromosomes. The cis-element composition of the promoter regions of the DiPRPs demonstrates that these genes might be controlled by phytohormones (especially ABA, GA, and MeJA), light, and the circadian clock, which is consistent with the environmental cues during Davidia bract development. Synteny analysis indicated that the PRP genes from the Davidia genome have higher collinearity with naturally bracted plants, such as Antirhonum majus and Bougainvillea glabra, but lower collinearity with non-bracted species. Our results suggest that high expression of certain PRP genes, specifically in bracts, might be critical for leaf metamorphosis. Full article

Background: Mood disorders, including anxiety, depression, and seasonal affective disorder (SAD), are often comorbid and can be exacerbated by the misalignment of an individual’s circadian rhythm with their social timing. Single-nucleotide polymorphisms (SNPs) in circadian clock genes have been associated with both internalizing disorders and sleep disturbances, and some clock polymorphisms, including those in the Period3 (PER3) gene, likely function via delaying or advancing circadian period and affecting sleep–wake patterns. Methods: Here, we explore associations of multiple SNP haplotypes in the PER3 gene with anxiety, depression, internalizing disorder (ID), chronotype, and sleep disturbance in young adults (n = 1109 individuals). Results: We report novel, sex-specific associations of single PER3 SNPs with mood and sleep disorders and highlight strong multi-SNP haplotype associations, revealing a greater risk of mood and sleep disorders in university students with specific PER3 haplotypes. Conclusions: Our results suggest that the additive effects of multiple risk variants amplify the prevalence of mood disorders and sleep disruptions in young adults. Understanding how polymorphisms within circadian genes interact to alter clock function, sleep-wake behavior and downstream physiological changes in the brain may help explain the comorbidity of mood and sleep syndromes and provide future therapeutic targets to combat these debilitating disorders. Full article

In mammals, the suprachiasmatic nucleus (SCN), located in the hypothalamus serves as the master biological clock and precisely regulates circadian rhythms through a complex network structure. As a central pacemaker, the SCN has two primary functions: one is to synchronize the daily rhythms in physiological and behavioral activities; the other is to entrain the endogenous rhythms to the external light–dark cycle. A deep understanding of the SCN network structure is crucial for elucidating the functional mechanisms of the biological clock system. In this review, we systematically summarized the impact of the SCN network structure on functional regulation under light stimulation based on mathematical models. Studies have shown that the coupling between the light-sensitive subgroups in the left and right nuclei of the SCN can enhance the entrainment ability. As an integrated network structure, the SCN may have the characteristics of the small-world network or the scale-free network, as these properties are more conducive to the realization of functions. Additionally, the higher-order coupling mechanism within the SCN can effectively expand the entrainment range. These theoretical research results offer new insights into the relationship between the SCN network and functions and provide crucial theoretical guidance and validation directions for subsequent experimental research. Full article

Background: Ozone (O₃) pollution disrupts pulmonary circadian rhythms, yet the molecular mechanisms remain elusive. The Notch signaling pathway, critical for lung homeostasis, may crosstalk with the circadian clock system. Objective: This study elucidates the role of the Notch signaling pathway in O₃-induced lung circadian rhythm disruption. Methods: C57BL/6J mice were acutely exposed to O₃ (1.0 ppm, 3 h). Lung tissues were collected 24 h post exposure. Transcriptome sequencing coupled with GSEA identified dysregulated pathways; IHC and RT-qPCR validated core genes; GEO dataset (GSE58244) reanalysis assessed Notch3/4 knockout effects. Results: O₃ activated Notch signaling (NES = 1.85, FDR = 0.034) and disrupted the circadian pathway (NES = 1.84, FDR = 0.029), downregulating Bmal1 while upregulating Per2/3 and Notch3/4 (p < 0.05). Strong correlations (r > 0.8) existed between core genes of both pathways. Notch3/4 knockout exacerbated circadian disruption in a time-dependent manner upon O₃ exposure. Conclusion: O₃ induces lung circadian disruption via Notch3/4 activation, which provides novel mechanistic insights into pollutant-induced lung injury. Full article

The relationship between sleep and epilepsy involves complex interactions between thalamocortical circuits, circadian mechanisms, and sleep architecture that fundamentally influence seizure susceptibility and cognitive outcomes. Epileptic activity disrupts essential sleep oscillations, particularly sleep spindles generated by thalamic circuits. Thalamic epileptic spikes actively compete with physiological sleep spindles, impairing memory consolidation and contributing to cognitive dysfunction in epileptic encephalopathy. This disruption explains why patients with epilepsy often experience learning difficulties despite adequate seizure control. Sleep stages show differential seizure susceptibility. REM sleep provides robust protection through enhanced GABAergic inhibition and motor neuron suppression, while non-REM sleep, particularly slow-wave sleep, increases seizure risk. These observations reveal fundamental mechanisms of seizure control within normal brain physiology. Circadian clock genes (BMAL1, CLOCK, PER, CRY) play crucial roles in seizure modulation. Dysregulation of these molecular timekeepers creates permissive conditions for seizure generation while being simultaneously disrupted by epileptic activity, establishing a bidirectional relationship. These mechanistic insights are driving chronobiological therapeutic approaches, including precisely timed antiseizure medications, sleep optimization strategies, and orexin/hypocretin system interventions. This understanding enables a paradigm shift from simple seizure suppression toward targeted restoration of physiological brain rhythms, promising transformative epilepsy management through sleep-informed precision medicine. Full article

The circadian rhythm of the central brain clock in the suprachiasmatic nucleus (SCN) is synchronized by light. White adipose tissue (WAT) is one of the metabolic endocrine organs containing a molecular clock, and it is synchronized by the SCN. Excess WAT is a risk factor for health issues including type 2 diabetes mellitus (DM2). We hypothesized that bright-light exposure would affect the human WAT transcriptome. Therefore, we analyzed WAT biopsies from two previously performed randomized cross-over trials (trial 1: n = 8 lean, healthy men, and trial 2: n = 8 men with obesity and DM2). From 7:30 h onwards, all the participants were exposed to either bright or dim light. Five hours later, we performed a subcutaneous abdominal WAT biopsy. RNA-sequencing results showed major group differences between men with obesity and DM2 and lean, healthy men as well as a differential effect of bright-light exposure. For example, gene sets encoding proteins involved in oxidative phosphorylation or respiratory chain complexes were down-regulated under bright-light conditions in lean, healthy men but up-regulated in men with obesity and DM2. In addition to evident group differences between men with obesity and DM2 and healthy lean subjects, autonomic or neuroendocrine signals resulting from bright-light exposure also differentially affect the WAT transcriptome. Full article

Mammalian circadian rhythms, governing ~24 h oscillations in behavior, physiology, and hormone levels, are orchestrated by transcriptional–translational feedback loops centered around the core clock protein cryptochrome 1 (CRY1). While CRY1 ubiquitination is known to regulate clock function, the roles of specific ubiquitination sites remain unclear. Here, we identify lysine 151 (K151) as a critical residue modulating the circadian period through non-canonical mechanisms. Using site-directed mutagenesis, we generated CRY1-K151Q/R mutants mimicking constitutive deubiquitination. Circadian rescue assays in Cry1/2-deficient cells revealed period shortening (K151Q: −2.25 h; K151R: −1.4 h; n = 3, p < 0.01, Student’s t-test), demonstrating K151’s functional importance. Despite normal nuclear localization kinetics, K151Q/R mutants exhibited reduced transcriptional repression in luciferase assays, a weakened interaction with BMAL1 by the luciferase complementation assay, and enhanced binding to E3 ligase FBXL12 (but not FBXL3) while showing more stability than wild-type CRY1. Notably, the absence of ubiquitination-linked degradation or altered FBXL3 engagement suggests a ubiquitination-independent mechanism. We propose that CRY1-K151 serves as a structural hub fine-tuning circadian periodicity by modulating core clock protein interactions rather than through traditional ubiquitin-mediated turnover. These findings redefine the mechanistic landscape of post-translational clock regulation and offer new therapeutic avenues for circadian disorders. Full article

Background/Objectives: Gender Medicine addresses how sex- and gender-based differences influence people’s health. Blood pressure (BP), which is the leading global risk factor for cardiovascular disease, shows a sexual dimorphism. This is seen also in case of shift work, as shift work is associated with hypertension in the male sex. It is not clear if this may be extended also to night-shift work, as data for this are limited. Based on this background, the aim of this study was to evaluate whether there were sex differences in the 24 h BP profile during a day with a day shift and a day with a night shift. Methods: This study is a post hoc analysis of a previous study where we evaluated ambulatory blood pressure monitoring data for two days, in a day with a day shift (and night of rest) and in a day with a night shift. Results: Overall, 25 subjects (physicians) were included in the analysis, of whom 10 were (40%) males and 15 were (60%) females. No differences were recorded in terms of age, years of work, number of steps, admissions, and calls during the recordings between the two sexes. Subjects worked on average 1.2 night per month, indicating that this population had a low exposure to night-shift work. BP patterns did not differ between sexes, but BP levels were always higher in males than females. Nevertheless, only females showed a significant increase of SBP during the night shift as compared to the night of rest. Both males and females showed a significant reduction in BP dipping during the night shift, but only in females, the significant reduction in BP dipping was maintained after the night-shift work. Interestingly, BMAL1 gene expression, which is a gene of the circadian rhythm, increased significantly after the night shift only in females, suggesting that females display an earlier acrophase than males after night-shift work, which may be associated with tolerance to shiftwork. Conclusions: Our data are consistent with the concept that blood pressure display several sex/gender differences. Males had higher BP values, but females showed signs of lower tolerance to shift work. This might be due to sex differences in the circadian rhythm regulation, which, in turns, regulate physiological functions, such as blood pressure. Full article

There is evidence that bone health is closely linked to a functioning circadian rhythm. Most of the evidence comes from mice, which may exhibit some species-specific differences from humans due to their nocturnal lifestyle. To address the current lack of human model systems, the present study aimed to develop an in vitro model system that can represent diurnal changes in bone metabolism. The model is based on co-cultured SCP-1 and THP-1 cells that serve as osteoblast and osteoclast precursors, respectively. Diurnal effects were induced by replacing the FCS in the differentiation medium with human serum pools (HSPs) obtained in the morning, noon, or evening. The model system was tested for cell viability, gene expression, and osteoblast and osteoclast function. The replacement of the FCS with the HSPs increased viability and induced expression changes in circadian clock genes in the model system. Resulting alterations in osteoblast and osteoclast function led to a gradual increase in mineral density and stiffness when 3D co-cultures were differentiated in the presence of the HSPs collected in the morning, noon, or evening, respectively. Here, we present for the first time an in vitro model that can present diurnal changes in bone metabolism in the form of a snapshot. With the simple use of HSPs, this model can be used as a platform technique to investigate bone function in various situations, taking into account the time of day. Full article