Circadian rhythm disorders are common characteristics of neurodegenerative diseases. The pathological aggregation of transactive response DNA-binding protein 43 (TDP-43) is associated with multiple neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the relationship between TDP-43 and circadian rhythm remains unknown. Here, we found that TDP-43 is rhythmically expressed both in vivo and in vitro. TDP-43 knockdown affected the expression of circadian genes, including BMAL1, CLOCK, CRY1, and PER2, and impaired autonomous circadian wheel behavior, cognitive functions, and balance abilities in mice. Furthermore, TDP-43 knockdown induced aberrant splicing of ubiquitin-specific peptidase 13 (USP13) and blocked USP13 rhythmic expression, enhancing the ubiquitination of BMAL1. Meanwhile, TDP-43 knockdown altered the rhythmic expression of phospho-AMPKα (Thr172) and platelet-type phosphofructokinase (PFKP), which may change cellular glucose uptake and ATP production. Our findings further the understanding of the role of TDP-43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidence supporting the interaction between circadian rhythm disruption and neurodegeneration.

Hepatic fibrosis, a precursor to chronic liver diseases, is linked to circadian rhythm disruptions. This study investigates the anti-fibrotic effects of saikosaponin D (SSd) from Bupleurum falcatum L. and its regulation of circadian genes. Transcriptomic and single-cell analyses revealed circadian gene dysregulation, particularly Period 2 (Per2), in liver fibrosis and hepatic stellate cells. SSd upregulated Per2 transcription via estrogen receptor 1 (Esr1), as confirmed by siRNA, real-time quantitative polymerase chain reaction, and Western blot analyses. In vivo, SSd alleviated fibrosis and hepatitis, increasing Esr1 but not Per2 protein levels. These findings suggest SSd exerts anti-fibrotic effects by modulating Esr1-mediated Per2 transcription.

We reviewed the connections among Alzheimer's disease (AD), sleep deprivation, and circadian rhythm disorders. Evidence is mounting that disrupted sleep and abnormal circadian rhythms are not merely symptoms of AD, but are also involved in accelerating the disease. Amyloid-beta (Aβ) accumulates, a feature of AD, and worsens with sleep deprivation because glymphatic withdrawal is required to clear toxic proteins from the brain. In addition, disturbances in circadian rhythm can contribute to the induction of neuroinflammation and oxidative stress, thereby accelerating neurodegenerative processes. While these interactions are bidirectional, Alzheimer's pathology further disrupts sleep and circadian function in a vicious cycle that worsens cognitive decline, which is emphasized in the review. The evidence that targeting sleep and circadian mechanisms may serve as therapeutic strategies for AD was strengthened by this study through the analysis of the molecular and physiological pathways. Further work on this nexus could help unravel the neurobiological mechanisms common to the onset of Alzheimer's and disrupted sleep and circadian regulation, which could result in earlier intervention to slow or prevent the onset of the disease.

Obstructive sleep apnea (OSA) is associated with circadian rhythm dysregulation plausibly through affecting clock genes. The study's purpose was to investigate the effect of one-night continuous positive airway pressure treatment (CPAP treatment) on circadian clock genes: BMAL1, CLOCK, CRY1, and PER1 at mRNA and protein levels. The study included 30 OSA patients, who underwent diagnostic polysomnography (PSG) and next a one-night effective CPAP treatment with PSG monitoring (CPAP). The blood was collected in the evening before and the morning after PSG and CPAP. Protein levels and mRNA expression were measured using ELISA and qRT-PCR, respectively. The increase in PER1 expression was observed in the morning after compared to the evening before CPAP (p = 0.005); additionally, PER1 protein level decreased in the morning after CPAP compared to the morning after PSG (p = 0.035). In CLOCK protein levels significant changes were observed: an increase in the morning after CPAP compared to the morning after PSG (p = 0.049), an increase in the morning after CPAP compared to the evening before (p = 0.006), and an increase in difference between the morning after and evening before CPAP vs. difference between morning after and evening before PSG (p = 0.012). Obtained results suggest that even short-term effective CPAP treatment might reverse circadian clock signaling pathway disruption in OSA.

The dawn phenomenon (DP), characterized by early morning hyperglycemia, poses a significant challenge in diabetes management and is associated with increased glycemic variability and long-term complications. Despite its clinical impact, effective therapeutic strategies remain limited. Chiglitazar, a novel pan-PPAR agonist, has demonstrated benefits in improving lipid metabolism and insulin sensitivity, but its potential role in mitigating DP remains unexplored. This study evaluates the regulatory effect of chiglitazar on DP and investigates its possible mechanisms beyond lipid modulation.

This retrospective observational study included 22 hospitalized diabetic patients who received chiglitazar (20 mg). Blood glucose levels at 3:00 a.m. and fasting glucose levels over three consecutive days were measured pre- and post-treatment, and the dawn phenomenon intensity was calculated. Lipid profiles were assessed to explore potential correlations with glucose changes.

Following chiglitazar administration, significant reductions were observed in LDL-C (43.82 ± 18.27 vs. 36.97 ± 16.90, p < 0.05), FFA (6.00 ± 2.38 vs. 5.06 ± 1.77, p < 0.05), mean 3:00 a.m. blood glucose (Z = - 2.03, p < 0.05), and fasting blood glucose (Z = - 2.96, p < 0.05). DP intensity also significantly improved (Z = - 3.48, p < 0.01). However, no significant correlation was found between glucose improvements and lipid profile changes (p > 0.05), suggesting an alternative mechanism of action.

Chiglitazar effectively reduces DP intensity and improves glycemic control, independent of its effects on lipid metabolism. These findings suggest a potential link between chiglitazar's mechanism and circadian rhythm regulation, possibly through the modulation of REV-ERB nuclear receptors. Further research is needed to confirm this hypothesis and evaluate the long-term clinical benefits of chiglitazar in diabetes management.

Circadian rhythms, the 24-h oscillations of biological activities guided by the molecular clock, play a pivotal role in regulating various physiological processes in organisms. The intricate relationship between the loss of circadian rhythm and its influence on the tolerability and pharmacokinetic properties of anticancer drugs is poorly understood. In our study, we investigated the effects of oxaliplatin, a commonly used anticancer drug, on Cry1-/- and Cry2-/- mice (Cry DKO mice) under darkness conditions, where they exhibit free-running phenotype. We administered oxaliplatin at a dosage of 12 mg/kg/day at two distinct circadian times, CT8 and CT16, under constant darkness conditions to Cry DKO mice and their wild type littermates. Our results revealed a striking disparity in oxaliplatin tolerance between Cry DKO mice and their wild-type counterparts. Oxaliplatin exhibited severe toxicity in Cry DKO mice at both CT8 and CT16, in contrast to the wild type mice. Pharmacokinetic analyses suggested that such toxicity was a result of high concentrations of oxaliplatin in the serum and liver of Cry DKO mice after repeated dose injections. To understand the molecular basis of such intolerance, we performed RNA-seq studies using mouse livers. Our findings from the RNA-seq analysis highlighted the substantial impact of circadian rhythm disruption on gene expression, particularly affecting genes involved in detoxification and xenobiotic metabolism, such as the Gstm gene family. This dysregulation in detoxification pathways in Cry DKO mice likely contributes to the increased toxicity of oxaliplatin. In conclusion, our study highlights the crucial role of an intact molecular clock in dictating the tolerability of oxaliplatin. These findings emphasize the necessity of considering circadian rhythms in the administration of anticancer drugs, providing valuable insights into optimizing treatment strategies for cancer patients.

This paper presents a comprehensive framework that traces the evolution of consciousness through a continuum of recursive processes spanning reaction, temporogenesis, symbiogenesis, and cognogenesis. By integrating biological cooperation, temporal structuring, and self-referential processing, our model provides a novel perspective on how complexity emerges and scales across evolutionary time. Reaction is established as the foundational mechanism that enables adaptive responses to environmental stimuli, which, through recursive refinement, transitions into temporogenesis-the synchronization of internal processes with external temporal rhythms. Symbiogenesis further enhances this process by fostering cooperative interactions at multiple biological levels, facilitating the emergence of higher-order cognitive functions. Cognogenesis represents the culmination of these recursive processes, where self-awareness and intentionality arise through iterative feedback loops. Our framework offers a biologically grounded pathway to addressing the "hard problem" of consciousness by proposing that subjective experience emerges as a result of progressively complex recursive interactions rather than as a static or isolated phenomenon. In comparing our approach with established theories such as Integrated Information Theory, Global Workspace Theory, and enactive cognition, we highlight its unique contributions in situating consciousness within a broader evolutionary and biological context. This work aims to provide a foundational model that bridges the gap between reaction and reflection, offering empirical avenues for further exploration in neuroscience, evolutionary biology, and artificial intelligence.

Redox imbalance induced by the accumulation of reactive oxygen species (ROS) accelerates age-related processes, often accompanied by a decrease in circadian rhythm amplitude. However, the underlying mechanisms by which ROS modulate circadian rhythms remain poorly understood. In this study, we found that ROS disrupt circadian rhythms in both zebrafish, as indicated by changes in diurnal behavior and clock gene expression, and in a human cell model. Using weighted gene co-expression network analysis (WGCNA) and machine learning approaches (RF, LASSO, SVM), EZH2 was identified as a key gene involved in regulating circadian rhythms under oxidative stress conditions. To further investigate the role of EZH2, we employed ezh2-/- mutants, Morpholino injection, and overexpression treatment and discovered that EZH2 is crucial in mediating the effect of ROS on circadian rhythms. Furthermore, EZH2 interacts with the CLOCK-BMAL1 complex to regulate the transcription of clock genes, as demonstrated through co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. Our study revealed that ROS disrupt circadian rhythms by regulating the interaction between EZH2 and the CLOCK-BMAL1 complex, shedding light on the molecular mechanisms of circadian rhythm disruption under oxidative stress and suggesting potential targets for age-related and circadian disorders.

The adenosine 1 receptor (A1R) is a G protein-coupled receptor that transduces signals to regulate sleep-wake cycles and circadian rhythms. Plastic products contain thousands of chemicals, known to disrupt physiological function. Recent research has demonstrated that some of these chemicals are also A1R agonists, however, the extent to which such activation propagates downstream and results in cellular alterations remains unknown. Thus, we investigate whether chemicals extracted from polyurethane (PUR) and polyvinyl chloride (PVC) plastics disrupt circadian rhythms via agonism of A1R. We confirm that plastic chemicals in both plastics activate A1R and inhibit intracellular cAMP in U2OS cells. Notably, this inhibition is comparable to that induced by the highly specific A1R agonist 2'-MeCCPA. To assess circadian disruption, we quantify temporal expression patterns of the clock genes PER2 and CRY2 at 4-h intervals over 48 h. Here, exposure to plastic chemicals shifts the phase in the oscillatory expression cycles of both clock genes by 9-17 min. Importantly, these effects are dose-dependent and reversible when A1R is inhibited by a pharmacological antagonist. This demonstrates that plastic chemicals can disrupt circadian processes by interfering with A1R signaling and suggests a novel mechanism by which these and other chemicals may contribute to non-communicable diseases.

Fibrosis-related disorders represent an increasing medical and economic burden on a worldwide scale, accounting for one-third of all disease-related deaths with limited therapeutic options. As central mediators in fibrosis development, myofibroblasts have been gaining increasing attention in the last 20 years as potential targets for fibrosis attenuation and reversal. While various aspects of myofibroblast physiology have been proposed as treatment targets, many of these approaches have shown limited long-term efficacy so far. However, ongoing research is uncovering new potential strategies for targeting myofibroblast activity, offering hope for more effective treatments in the future. The circadian molecular clock is a feature of almost every cell in the human body that dictates the rhythmic nature of various aspects of human physiology and behavior in response to changes in the surrounding environment. The dysregulation of these rhythms with aging is considered to be one of the underlying reasons behind the development of multiple aging-related chronic disorders, with fibrotic tissue scarring being a common pathological complication among the majority of them. Myofibroblast dysregulation due to skewed circadian clockwork might significantly contribute to fibrotic scar persistence. In the current review, we highlight the role of the circadian clock in the context of myofibroblast activation and deactivation and examine its dysregulation as a driver of fibrogenesis.

While there is extensive literature on both the neuronal circuitry of rhythms and the intracellular molecular clock, there is a large component of signaling that has been understudied: interstitial fluid (ISF)-fluid that surrounds the cells in the extracellular space of tissue. In this review, we highlight evidence in the circadian literature supporting ISF signaling as key to circadian synchronization and entrainment and propose new mechanisms of how fluid movement between the brain and periphery may act as zeitgebers by examining the main ISF pathways of the body, focusing on circadian regulation of the glymphatic and lymphatic systems. We identify key pieces of circadian research that point to ISF as an important timing medium, expand on the basics of cerebrospinal fluid (CSF) and ISF production, and outline the basic structure and function of the glymphatic and lymphatic systems.

The basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) proteins BMAL1 and CLOCK heterodimerize to form the master transcription factor governing rhythmic gene expression. Owing to connections between circadian regulation and numerous physiological pathways, targeting the BMAL1-CLOCK complex pharmacologically is an attractive entry point for intervening in circadian-related processes. In this study, we developed a small molecule, Core Circadian Modulator (CCM), that targets the cavity in the PASB domain of BMAL1, causing it to expand, leading to conformational changes in the PASB domain and altering the functions of BMAL1 as a transcription factor. Biochemical, structural and cellular investigations validate the high level of selectivity of CCM in engaging BMAL1, enabling direct access to BMAL1-CLOCK cellular activities. CCM induces dose-dependent alterations in PER2-Luc oscillations and orchestrates the downregulation of inflammatory and phagocytic pathways in macrophages. These findings collectively reveal that the BMAL1 protein architecture is inherently configured to enable the binding of chemical ligands for functional modulation.

The circadian rhythm is a phenomenon in which physiological, behavioral, and biochemical processes within an organism naturally fluctuate over a period of approximately 24 hours. This phenomenon is ubiquitous in living organisms. Disruption of circadian rhythms in mammals leads to different diseases, such as cancer, and neurodegenerative and metabolic disorders. In specific tissues, numerous genes have been found to have circadian oscillations, suggesting a broad role for rhythm genes in the regulation of gene expression. This review systematically summarizes the role of cryptochromes (CRYs) in the initiation and progression of different types of cancer and discusses the relationships between Clock genes and the tumor microenvironment (TME), as well as clock-based therapeutic strategies.

Cells of the body rely on the circadian clock to orchestrate daily changes in physiology that impact both homeostatic and pathological conditions, such as the inflammatory autoimmune disease rheumatoid arthritis (RA). In RA, high levels of proinflammatory cytokines peak early in the morning hours, reflected by daily changes in joint stiffness. Chronotherapy (or circadian medicine) seeks to delivery drugs at optimal times to maximize their efficacy. However, chronotherapy remains a largely unexplored approach for disease modifying, antirheumatic treatment, particularly for cell-based therapies. In this study, we developed autonomous chronogenetic gene circuits that produce the biologic drug interleukin-1 receptor antagonist (IL-1Ra) with desired phase and amplitude. We compared expression of IL-1Ra from circuits that contained different circadian promoter elements (E'-boxes, D-boxes, or RREs) and their ability to respond to inflammatory challenges in murine pre-differentiated induced pluripotent stem cells (PDiPSC) or engineered cartilage pellets. We confirmed that each circuit reliably peaked at a distinct circadian time over multiple days. Engineered cells generated significant amounts of IL-1Ra on a circadian basis, which protected them from circadian dysregulation and inflammatory damage. These programmable chronogenetic circuits have the potential to align with an individual's circadian rhythm for optimized, self-regulated daily drug delivery.

The atmospheric oxygen concentration is significantly reduced in highland regions compared to lowland areas. The first entering the plateau can induce sleep disorders in individuals, primarily attributed to insufficient oxygen supply. This study used Drosophila melanogaster as a model organism to better understand the molecular mechanism of acute hypoxia-induced sleep disorders. The Drosophila activity monitoring system (DAMS) was employed to observe the sleep-wake in adult (w1118, simaKG07607, and clockjrk) female flies. Quantifying the relative mRNA expression levels of sima and circadian clock genes in the head of flies was accomplished by utilizing qRT-PCR. Acute hypoxia caused sleep disorders in w1118 flies, such as shortened sleep duration and length, and prolonged sleep latency. PCR results showed that sima and clock genes were up-regulated in ZT6 and ZT12 and down-regulated in ZT0 and ZT18 in acute hypoxic w1118 flies compared to normoxic w1118 flies. Under normoxic conditions, sleep indexes in simaKG07607 flies were not substantially different from w1118 flies. However, clockjrk flies demonstrated a reduced sleep duration, decreased sleep bout length, and increased sleep latency and activities. Sleep and gene expression in simaKG07607 flies under acute hypoxic conditions were not significantly different from those under normoxic conditions. Surprisingly, sleep and gene expression in clockjrk flies showed opposite trends to w1118 flies. The present study indicates that acute hypoxia disrupt circadian rhythms through the activation of sima/HIF-1α, leading to the onset of sleep disorders, with Clock signaling potentially serving as a contributing factor.

Lung cancer is a malignant tumor with a high morbidity and mortality rate worldwide, causing an increasing disease burden. Of these, the most common type is non-small cell lung cancer (NSCLC), which accounts for 80-85% of all lung cancer cases. Genetic research is crucial for continuously discovering susceptibility genes related to lung cancer for in-depth study. The role of genetic predisposition in the development of NSCLC, particularly within circadian rhythm pathways known to govern various physiological processes, is increasingly acknowledged. Yet, the association between genetic variants of circadian rhythm-related genes and NSCLC susceptibility among Chinese populations is not fully understood. This study carried out a two-phase (discovery and validation stages) research design to identify genetic variants associated with NSCLC risk within the circadian rhythm pathway. We employed extensive whole-genome sequencing (WGS) for 1,104 NSCLC cases and 9,635 controls. FastGWA-GLMM was used for single-locus risk association analysis of NSCLC, and we screened candidate SNPs in the validation set that comprised 4,444 cases and 174,282 controls from the Biobank Japan Project (BBJ). Furthermore, GCTA-COJO conditional analysis was utilized to confirm SNPs related to NSCLC risk. Finally, potential genetic variations that may regulate gene expression were explored in GTEx and QTLbase. RNA sequencing data were utilized for transcriptomic verification. Our study identified eight candidate SNPs associated with NSCLC susceptibility within the circadian rhythm pathway that met the requirement with P < 0.05 in both the discovery and validation populations. After conditional analysis, five of these SNPs remained. The A allele of CUL1 rs78524436 (ORmeta = 1.18, 95%CI: 1.09-1.29, Pmeta = 7.99e-5) and the A allele of TEF rs9611588 (ORmeta = 1.06, 95%CI: 1.02-1.10, Pmeta = 1.28e-3) were associated with an increased risk of NSCLC. The A allele of FBXL21 rs2069868 (ORmeta = 0.86, 95%CI: 0.80-0.96, Pmeta = 4.78e-4), the T allele of CSNK1D rs147316973 (ORmeta = 0.76, 95%CI: 0.65-0.88, Pmeta = 5.93e-4), and the A allele of RORA rs1589701 (ORmeta = 0.94, 95%CI: 0.91-0.98, Pmeta = 3.40e-3) were associated with a lower risk of NSCLC, separately. The eQTL results revealed an association between RORA rs1589701 and TEF rs9611588 with the expression levels of RORA and TEF, respectively. Transcriptome data indicated that RORA and TEF showed lower expression levels in tumor tissues compared to normal tissues (P < 0.001). Moreover, poorer survival was observed in patients with lower RORA and TEF expressions (log-rank P < 0.05). Our findings spotlight potential susceptibility loci within circadian rhythm pathway genes that modulate NSCLC carcinogenesis, which enriches the understanding of the genetic susceptibility of NSCLC in the Chinese population and provides a more solid basis for exploring the biological mechanism of circadian rhythm genes in NSCLC.

To satisfy the needs of sleeping underwater, marine mammals, including cetaceans, sirenians, and pinnipeds, have evolved an unusual form of sleep, known as unihemispheric slow-wave sleep (USWS), in which one brain hemisphere is asleep while the other is awake. All aquatic cetaceans have only evolved USWS without rapid eye movement (REM) sleep, whereas aquatic sirenians and amphibious pinnipeds display both bihemispheric slow-wave sleep (BSWS) and USWS, as well as REM sleep. However, the molecular genetic changes underlying USWS remain unknown. The present study investigated the evolution of eight canonical circadian genes and found that positive selection occurred mainly within cetacean lineages. Furthermore, convergent evolution was observed in lineages with USWS at three circadian clock genes. Remarkably, in vitro assays showed that cetacean-specific mutations increased the nuclear localization of zebrafish clocka, and enhanced the transcriptional activation activity of Clocka and Bmal1a. In vivo, transcriptome analysis showed that the overexpression of the cetacean-specific mutant clocka (clocka-mut) caused the upregulation of the wakefulness-promoting glutamatergic genes and the differential expression of multiple genes associated with sleep regulation. In contrast, the GABAergic and cholinergic pathways, which play important roles in promoting sleep, were downregulated in the bmal1a-mut-overexpressing zebrafish. Concordantly, sleep time of zebrafish overexpressing clocka-mut and bmal1a-mut were significantly less than the zebrafish overexpressing the wild-type genes, respectively. These findings support our hypothesis that canonical circadian clock genes may have evolved adaptively to enhance circadian regulation ability relating to sleep in cetaceans and, in turn, contribute to the formation of USWS.

The circadian clock generates and maintains ∼24-hour oscillations in almost all organs. The testis, however, remains mysterious, without a clear understanding of its circadian functions. Our time-series transcriptome analysis reveals more than 1000 rhythmically expressed genes in the zebrafish and mouse testes, respectively. Canonical circadian clock genes are rhythmically expressed in Sertoli cells and regulate retinoic acid (RA) production, which is also evidenced by their co-expression with RA synthesis genes in single Sertoli cells. Genetic and pharmacological manipulations and temporal desynchronization revealed that the circadian clock-regulated RA signaling synchronizes spermatogonial differentiation via zbtb16a and promotes fertilization via izumo1 in zebrafish. Our findings indicate that the testicular circadian clock contributes to reproduction in a cell-specific manner through RA signaling, highlighting circadian roles in male fertility.

This study investigates the connection of Obstructive Sleep Apnea (OSA) with the expression and daily oscillation patterns of core circadian clock genes and related genes. OSA, a sleep disorder characterized by repetitive airway occlusion leading to nocturnal arousals, sleep fragmentation, and intermittent hypoxemia (IH), shares sleep dysfunction as an overlapping phenotype with circadian clock genes. The research involved 40 subjects (30 OSA patients and 10 normal controls), categorized into four groups based on Polysomnography (PSG) results: normal, mild, moderate, and severe. Peripheral blood samples were collected twice from each participant in the evening before and the morning after PSG examination. Using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR), the study measured the expression levels of target genes in leukocytes. Results revealed changes in diurnal expression patterns of several genes (PER1, PER3, CRY1, BMAL1, CLOCK, HIF-1α, IL-1β, TNFα) in OSA groups compared to normal controls. While PER2, CRY2, and NPAS2 genes did not show diurnal patterns, their expression was significantly elevated in severe OSA. Notably, the expression levels of HIF-1α, IL-1β, and TNFα increased with OSA severity, consistent with the roles of IH and inflammation as clinical indicators in OSA. These findings not only demonstrate that circadian clock-related gene expression fluctuates with OSA but also provide potential molecular markers for early diagnosis and personalized treatment. By identifying biomarkers parallel to clinical indicators in OSA, this innovative study paves the way for future research and clinical applications in the field.

Microglia, the brain's resident macrophages, are key mediators of neuroinflammation, responding to immune pathogens and toxins. They play a crucial role in clearing cellular debris, regulating synaptic plasticity, and phagocytosing amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Recent studies indicate that microglia not only exhibit intrinsic circadian rhythms but are also regulated by circadian clock genes, influencing specific functions such as phagocytosis and the modulation of neuroinflammation. Disruption of the circadian rhythm is closely associated with AD pathology. In this review, we will provide an overview of how circadian rhythms regulate microglia-mediated neuroinflammation in the progression of AD, focusing on the pathway from the central nervous system (CNS) and the peripheral immune system. We also discuss potential therapeutic targets, including hormone modulation, lifestyle interventions, and anti-inflammatory therapies, aimed at maintaining brain health in AD. This will shed light on the involvement of circadian rhythm in AD and explore new avenues for AD treatment.

Identifying the circadian clock first provided the genetic basis for behaviour, and our understanding of circadian rhythms has since expanded to provide molecular insight into disease and physiology. The synchronization of central and peripheral clocks and robust daily rhythms can be achieved in a wide range of physiological systems and homeostatic responses can be supplemented. The rhythmical epigenome, which works as a central regulator, determines the circadian transcription of cell types. The rhythmical epigenome imposes oscillation on biological systems that momentarily split metabolism within 24 h. Interactions between the endogenous circadian system govern blood pressure, sleep, obesity and postural variations. Human health is dependent on the circadian rhythm. It can depict disease dynamics as well as overall drug efficacy monitoring to optimize the therapy effect. Circadian rhythms can collectively drive various metabolic activities, but dietary habits, sleep patterns, and other factors can also influence the circadian rhythm. The synergy of circadian rhythm and metabolism can bring new insights and personalized analysis for disease development causes and prevention. The understanding of the molecular clock and disease relationship can be exploited to determine treatment timing as well as new therapy targets.

The suprachiasmatic nucleus (SCN), locus of a circadian clock, is a small nucleus of approximately 20,000 neurons that oscillate with a period of about 24 hours. While individual neurons produce circadian oscillations even when dispersed in culture, the coherence and robustness of oscillation of the SCN as a whole is dependent on its circuitry. Surprisingly, the individual neurons of the intact SCN do not all oscillate in phase with each other. To understand the oscillatory dynamics across the intact nucleus, we develop a model of the relation of the phase of neurons to their PER2 expression at a particular subjective time (CT1900) using time series data from SCN slice preparations. Next, we use the model, which produces a surprisingly good fit in the SCN slice data, to estimate oscillator phase at a single time point (CT1900) in snapshot data from PER2 expression measurements in intact, unsliced SCN-wide tissue. To monitor temporal changes in phase in time series data, we use PER2::LUC imaging in an ex vivo SCN slice preparation. To study phase in the intact SCN at a fixed time point we use data generated by PER2 staining and a tissue clearing protocol. Because PER2 expression, as measured in the time series slices and the snapshot intact SCN are not directly comparable, the model estimated from time series slices to the snapshot intact SCN data requires a calibrating constant. The results indicate that our model provides a surprisingly good fit to the SCN slice data and is therefore a meaningful method for estimating phase in the intact SCN snapshot data, permitting the study of virtual interventions such as virtual tissue slicing. We next compare oscillation in circuits in the SCN-wide tissue to those that have been disrupted by virtual slicing using a Kuramoto model to simulate the dynamics. The results support prior evidence that the damage done by coronal slicing has the most disruptive impact on SCN oscillation, while horizontal slicing has the least damage. The results point to the importance of connectivity along the caudal-to-rostral axis and indicate that SCN circuit organization depends on the caudal-to-rostral flow of information. In summary, the construction of this model is a major finding of the paper. Our modeling allows us to perform the previously impossible analysis of oscillatory dynamics in static data in an intact SCN captured at a single time point.

Calcium ions (Ca2+) play crucial role in tooth development, particularly in maintaining enamel density during amelogenesis. Ameloblasts require specific proteins such as amelogenin, ameloblastin, enamelin, kallikrein, and collagen for enamel growth. Recent research has highlighted the importance of calcium and fluoride ions, as well as the TRPM7, STIM, and SOCE pathways, in regulating various stages of enamel formation. This review synthesizes current knowledge, focusing on preclinical data elucidating the molecular mechanisms of calcium transport in ameloblasts, during normal tooth development and in response to external stimuli.

This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search, conducted in December 2023, spanned multiple databases including PubMed (8.363 records), Google Scholar (5.630 records), and Science Direct (21.810 records). The primary aim was to examine the influence of calcium ion regulation on ameloblast development, with a focus on preclinical studies.

After an initial screening of 396 titles and abstracts, 11 full-text articles (four in vitro studies and seven animal studies) met the inclusion and exclusion criteria. The studies, assessed for quality using the CAMRADES tool, ranged from low to moderate. Calcium deficiency, nutritional supplements, fluoride exposure, TRPM7, STIM proteins, and the SOCE pathway were found to influence amelogenesis.

Calcium transport mechanisms play a critical role in enamel formation, with factors such as TRPM7, Kir 4.2, CRAC channels, and the SOCE pathway supporting enamel mineralization, while disruptions like hypoxia, fluoride exposure, and circadian imbalances negatively impact amelogenesis. Understanding the interplay between calcium, environmental, and nutritional factors provides valuable insights into ameloblast function and offers potential avenues for improving enamel quality and addressing defects.

Endothermic animals expend significant energy to maintain high body temperatures, which offers adaptability to varying environmental conditions. However, this high metabolic rate requires increased food intake. In conditions of low environmental temperature and scarce food resources, some endothermic animals enter a hypometabolic state known as torpor to conserve energy. Torpor involves a marked reduction in body temperature, heart rate, respiratory rate, and locomotor activity, enabling energy conservation. Despite their biological significance and potential medical applications, the neuronal mechanisms regulating torpor still need to be fully understood. Recent studies have focused on fasting-induced daily torpor in mice due to their suitability for advanced neuroscientific techniques. In this review, we highlight recent advances that extend our understanding of neuronal mechanisms regulating torpor. We also discuss unresolved issues in this research field and future directions.

The circadian clock orchestrates a broad spectrum of physiological processes, crucially modulating human biology across an approximate 24-hour cycle. The circadian disturbances precipitated by modern lifestyle contribute to the occurrence of low back pain (LBP), mainly ascribed to intervertebral disc degeneration (IVDD). The intervertebral disc (IVD) exhibits rhythmic physiological behaviors, with fluctuations in osmotic pressure and hydration levels that synchronized with the diurnal cycle of activity and rest. Over recent decades, advanced molecular biology techniques have shed light on the association between circadian molecules and IVD homeostasis. The complex interplay between circadian rhythm disruption and IVDD is becoming increasingly evident, with the sympathetic nervous system (SNS) emerging as a potential mediator. Synchronized with circadian rhythm through suprachiasmatic nucleus, the SNS regulates diverse physiological functions and metabolic processes, profoundly influences the structural and functional integrity of the IVD. This review synthesizes the current understanding of circadian regulation and sympathetic innervation of the IVD, highlighting advancements in the comprehension of their interactions. We elucidate the impact of circadian system on the physiological functions of IVD through the SNS, advocating for the adoption of chronotherapy as a brand-new and effective strategy to ameliorate IVDD and alleviate LBP.

Exposure to light at night and meal time misaligned with the light/dark (LD) cycle-typical features of daily life in modern 24/7 society-are associated with negative effects on health. To understand the mechanism, we developed a novel protocol of complex chronodisruption (CD) in which we exposed female rats to four weekly cycles consisting of 5-day intervals of constant light and 2-day intervals of food access restricted to the light phase of the 12:12 LD cycle.

We examined the effects of CD on behavior, estrous cycle, sleep patterns, glucose homeostasis and profiles of clock- and metabolism-related gene expression (using RT qPCR) and liver metabolome and lipidome (using untargeted metabolomic and lipidomic profiling).

CD attenuated the rhythmic output of the central clock in the suprachiasmatic nucleus via Prok2 signaling, thereby disrupting locomotor activity, the estrous cycle, sleep patterns, and mutual phase relationship between the central and peripheral clocks. In the periphery, CD abolished Per1,2 expression rhythms in peripheral tissues (liver, pancreas, colon) and worsened glucose homeostasis. In the liver, it impaired the expression of NAD+, lipid, and cholesterol metabolism genes and abolished most of the high-amplitude rhythms of lipids and polar metabolites. Interestingly, CD abolished the circadian rhythm of Cpt1a expression and increased the levels of long-chain acylcarnitines (ACar 18:2, ACar 16:0), indicating enhanced fatty acid oxidation in mitochondria.

Our data show the widespread effects of CD on metabolism and point to ACars as biomarkers for CD due to misaligned sleep and feeding patterns.

Noctuid moths provide prime examples of species in various stages of allochronic speciation, where reproductive barriers are mediated by genetic divergence in daily or seasonal timing. Theory indicates that allochronic divergence might be one of the most plausible mechanisms of adaptive speciation, especially when timing is subject to divergent ecological selection. Here, we show that the validity of this theoretical expectation is entirely contingent on species characteristics of the mating system. Our analysis focuses on the moth Spodoptera frugiperda (Lepidoptera, Noctuidae), which occurs as two strains that differ in circadian reproductive activity. Unlike in generic models of assortative mating, where chronotypes diverge under mild assumptions, individual-based evolutionary simulations of the mating system and life cycle of S. frugiperda fail to recover allochronic diversification, even under conditions highly conducive to speciation. Instead, we observe that both chronotypes advance their activity schedule toward the early night, resulting in a rapid loss of allochronic variation. This outcome is caused by the fact that mating in S. frugiperda takes considerable time and potential mates are encountered sequentially, so that early males enjoy a systematic advantage. The undermining effect of male mate competition can be overcome when circadian genes evolve sex-specific expression, enabling early and late chronotypes to be maintained or even to diversify in sympatry. These results give new significance to sex differences in biological rhythms and suggest that species characteristics of the mating system and genetic architecture are key to understanding the scope for allochronic speciation across diverse species exhibiting variation in timing.

There is growing evidence that individuals with cardiovascular disease (CVD) are more likely to develop depression. The timing of food intake can significantly alter the body's circadian rhythm and affect the occurrence of depression. Currently, it is unknown whether and how energy or macronutrient intake times are associated with depression in adults with CVD.

To evaluate dietary energy or macronutrient intake (across three meals) associations with depression in adults with CVD in a nationally representative sample.

The study population consisted of 3,490 U.S. adults with CVD (including 554 with depression) from the National Health and Nutrition Examination Survey 2003-2018. Energy and macronutrient intake was measured by a 24-h dietary recall, and depression was diagnosed by the Patient Health Questionnaire (PHQ-9, score ≥ 10). According to dietary energy or macronutrient intake across three meals, adults with CVD were divided into five groups. Logistic regression analysis was performed to examine associations between energy or macronutrient intake and depression after adjusting for a series of confounding factors, including age, gender, education level, household income, smoking status, drinking status, physical activity, marital status, skipping breakfast/lunch/dinner, total energy, carbohydrate, protein, dietary fiber, SFA, MUFA, and PUFA intake, T2DM and hypertension status, and BMI. Dietary substitution models were used to explore changes in depression risk when 5% dietary energy intake at dinner or lunch was substituted with energy intake at breakfast.

When compared with participants in the lowest quintile of breakfast energy intake, those who received energy intake in the highest quintile at breakfast were associated with lower depression risk in those with CVD, and the adjusted odds ratio (OR) was 0.71 (95% CI, 0.51 to 0.91). When compared with participants in the lowest quintile of lunch or dinner energy intake, the risk of depression did not exhibit statistical significance when lunch or dinner energy intake was in the highest quintile, and the adjusted ORs were 1.08 (95% CI, 0.65 to 1.83) and 0.92 (95% CI, 0.62 to 1.37), respectively. Isocalorically replacing 5% of total energy at dinner or lunch with breakfast was associated with 5% (OR: 0.95, 95% CI 0.93 to 0.97) and 5% (OR: 0.95, 95% CI 0.93 to 0.96) lower risk of depression, respectively.

High energy intake at breakfast may be associated with a lower risk of depression in those with CVD. We should focus on the potential role of breakfast energy intake in preventing the onset of depression.

Melatonin, a molecule with diverse biological functions, is ubiquitously present in living organisms. There is significant interest in understanding melatonin signal transduction pathways in humans, particularly due to its critical role in regulating the sleep-wake cycle. However, a knowledge gap remains in fully elucidating the mechanisms by which melatonin influences circadian regulation. To bridge this gap, there is a growing need for a model system to study the role of melatonin in circadian clocks, with Neurospora crassa being a promising candidate. As a first step in this investigation, we focused on identifying melatonin receptors in N. crassa. Given the lack of sequence similarity between potential receptors in this fungus and known human melatonin receptors, we utilized structural similarity analysis through AlphaFold2. This approach led to the identification of a strong candidate gene, gpr-3, which shares structural similarities with human melatonin receptors. Experimental validation confirmed that the removal of GPR-3 from cells results in the absence of melatonin signaling. This proof-of-concept study underscores the potential of N. crassa as a model organism for circadian research and demonstrates the broader applicability of using AlphaFold2, especially when sequence similarity does not lead to candidate genes, for identifying novel receptors across different species.

The within-host environment changes over circadian time and influences the replication and severity of viruses. Genetic knockout of the circadian transcription factors CRYPTOCHROME 1 and CRYPTOCHROME 2 (CRY1-/-/CRY2-/-; CKO) leads to altered protein homeostasis and chronic activation of the integrated stress response (ISR). The adaptive ISR signalling pathways help restore cellular homeostasis by downregulating protein synthesis in response to endoplasmic reticulum overloading or viral infections. By quantitative mass spectrometry analysis, we reveal that many viral recognition proteins and type I interferon (IFN) effectors are significantly upregulated in lung fibroblast cells from CKO mice compared with wild-type (WT) mice. This basal 'antiviral state' restricts the growth of influenza A virus and is governed by the interaction between proteotoxic stress response pathways and constitutive type I IFN signalling. CKO proteome composition and type I IFN signature were partially phenocopied upon sustained depletion of CRYPTOCHROME (CRY) proteins using a small-molecule CRY degrader, with modest differential gene expression consistent with differences seen between CKO and WT cells. Our results highlight the crosstalk between circadian rhythms, cell-intrinsic antiviral defences and protein homeostasis, providing a tractable molecular model to investigate the interface of these key contributors to human health and disease.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Daily rhythms in the activities of PERIOD proteins are critical to the temporal regulation of mammalian physiology. While the molecular partners and genetic circuits that allow PERIOD to effect auto-repression and regulate transcriptional programmes are increasingly well understood, comprehension of the time-resolved mechanisms that allow PERIOD to conduct this daily dance is incomplete. Here, we consider the character and controversies of this central mammalian clock protein with a focus on its intrinsically disordered nature.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Circadian rhythms in mammals are tightly regulated through phosphorylation of Period (PER) proteins by Casein Kinase 1 (CK1, subtypes δ and ε). CK1 acts on at least two different regions of PER with opposing effects: phosphorylation of phosphodegron (pD) regions leads to PER degradation, while phosphorylation of the Familial Advanced Sleep Phase (FASP) region leads to PER stabilization. To investigate how substrate selectivity is encoded by the conformational dynamics of CK1, we performed a large set of independent molecular dynamics (MD) simulations of wildtype CK1 and the tau mutant (R178C) that biases kinase activity toward a pD. We used Markovian State Models (MSMs) to integrate the simulations into a single model of the conformational landscape of CK1 and used Gaussian accelerated molecular dynamics (GaMD) to build the first molecular model of CK1 and the unphosphorylated FASP motif. Together, these findings provide a mechanistic view of CK1, establishing how the activation loop acts as a key molecular switch to control substrate selectivity. We show that the tau mutant favors an alternative conformation of the activation loop and significantly accelerates the dynamics of CK1. This reshapes the binding cleft in a way that impairs FASP binding and would ultimately lead to PER destabilization and shorter circadian periods. Finally, we identified an allosteric pocket that could be targeted to bias this molecular switch. Our integrated approach offers a detailed model of CK1's conformational landscape and its relevance to normal, mutant, and druggable circadian timekeeping.

The complex interaction between circadian rhythms and physiological functions is essential for maintaining human health. At the heart of this interaction lies the PERIOD proteins (PERs), pivotal to the circadian clock, influencing the timing of physiological and behavioral processes and impacting oxidative stress, immune functionality, and tumorigenesis. PER1 orchestrates the cooperation of the enzyme GPX1, modulating mitochondrial dynamics in sync with daily rhythms and oxidative stress, thus regulating the mechanisms managing energy substrates. PERs in innate immune cells modulate the temporal patterns of NF-κB and TNF-α activities, as well as the response to LPS-induced toxic shock, initiating inflammatory responses that escalate into chronic inflammatory conditions. Crucially, PERs modulate cancer cell behaviors including proliferation, apoptosis, and migration by influencing the levels of cell cycle proteins and stimulating the expression of oncogenes c-Myc and MDM2. PER2/3, as antagonists in cancer stem cell biology, play important roles in differentiating cancer stem cells and in maintaining their stemness. Importantly, the expression of Pers serve as a significant factor for early cancer diagnosis and prognosis. This review delves into the link between circadian rhythm regulator PERs, disruptions in circadian rhythm, and oncogenesis. We examine the evidence that highlights how dysfunctions in PERs activities initiate cancer development, aid tumor growth, and modify cancer cell metabolism through pathways involved in oxidative stress and immune system. Comprehending these connections opens new pathways for the development of circadian rhythm-based therapeutic strategies, with the aims of boosting immune responses and enhancing cancer treatments.

Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms.

Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging.

The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups.

This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis.

The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15th, 2017).

The circadian clock protein reverse erythroblastosis virus (REV)-ERBα is implicated in the pathogenesis of various diseases, including cancer and myocardial infarction. Emerging evidence suggests that SR9009, an agonist of REV-ERBα, regulates multiple signaling molecules independent or dependent of REV-ERBα. However, the impact of SR9009 on renal fibrosis remains largely unevaluated. In this study, we investigated the effects of SR9009 on transforming growth factor (TGF)-β1-induced fibrotic responses and elucidated the mechanisms involved. Masson's trichome staining revealed that in the unilateral ureteral obstruction groups, there was a decrease in REV-ERBα expression, accompanied by increased levels of the profibrotic factor TGF-β1 and the fibrosis marker α-smooth muscle actin (α-SMA). REV-ERBα knockdown significantly increased α-SMA expression in NRK-49F cells. SR9009 significantly attenuated unilateral ureteral obstruction-induced fibrosis and TGF-β1-induced fibrotic responses in normal rat kidney fibroblasts (NRK-49F cells). Conversely, the REV-ERBα antagonist SR8278 did not affect TGF-β1-induced fibrotic responses. Mechanistic studies revealed that SR9009 significantly inhibited the phosphorylation of ERK and p38, concomitant with reduced α-SMA levels, suppressing TGF-β1-induced NADPH oxidase 4 (NOX4) mRNA expression in NRK-49F cells. Notably, SR9009 did not influence the expression of dual specificity phosphatase 4, which dephosphorylates MAPKs, including p38. Furthermore, REV-ERBα knockdown did not affect the ability of SR9009 to inhibit TGF-β1-induced fibrotic responses and NOX4 expression in NRK-49F cells. In conclusion, SR9009 exerts a protective role against renal fibrosis independent of REV-ERBα. Therefore, SR9009 is a promising therapeutic agent for the prevention and treatment of renal fibrosis associated with renal failure.

Interleukin-17 plays a major role in controlling adipose tissue homeostasis. In a recent study published in Nature, Douglas et al. demonstrate that time-of-day-dependent expression of interleukin-17 by tissue-resident innate lymphocytes in the adipose tissue drives circadian regulation of adipose tissue homeostasis and function.

Cryptochromes (CRYs) are blue-light receptors that regulate diverse aspects of plant growth. However, whether and how non-photoexcited CRYs function in darkness or non-blue-light conditions is unknown. Here, we show that CRY2 affects the Arabidopsis transcriptome even in darkness, revealing a non-canonical function. CRY2 suppresses cell division in the root apical meristem to downregulate root elongation in darkness. Blue-light oligomerizes CRY2 to de-repress root elongation. CRY2 physically interacts with FORKED-LIKE 1 (FL1) and FL3, and these interactions are inhibited by blue light, with only monomeric but not dimeric CRY2 able to interact. FL1 and FL3 associate with the chromatin of cell division genes to facilitate their transcription. This pro-growth activity is inhibited by CRY2's physical interaction with FLs in darkness. Plants have evolved to perceive both blue-light and dark cues to coordinate activation and repression of competing developmental processes in above- and below-ground organs through economical and dichotomous use of ancient light receptors.

Almost all organisms, from the simplest bacteria to advanced mammals, havea near 24 h circadian rhythm. Circadian rhythms are highly conserved across different life forms and are regulated by circadian genes as well as by related transcription factors. Transcription factors are fundamental to circadian rhythms, influencing gene expression, behavior in plants and animals, and human diseases. This review examines the foundational research on transcriptional regulation of circadian rhythms, emphasizing histone modifications, chromatin remodeling, and Pol II pausing control. These studies have enhanced our understanding of transcriptional regulation within biological circadian rhythms and the importance of circadian biology in human health. Finally, we summarize the progress and challenges in these three areas of regulation to move the field forward.

Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD+) or reduced (NADH) states, which together form a key NADH/NAD+ redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts total cellular NAD levels and provides some therapeutic benefits in human clinical trials. However, supplementation studies cannot determine tissue-specific effects of an altered NADH/NAD+ ratio. Here, we created transgenic Drosophila expressing a genetically encoded xenotopic tool LbNOX to directly manipulate the cellular NADH/NAD+ ratio. We found that LbNOX expression in Drosophila impacts both NAD(H) and NADP(H) metabolites in a sex-specific manner. LbNOX rescues neuronal cell death induced by the expression of mutated alpha-B crystallin in the Drosophila eye, a widely used system to study reductive stress. Utilizing LbNOX, we demonstrate that targeting redox NAD metabolism in different tissues may have drastically different outcomes, as the expression of LbNOX solely in the muscle is much more effective for rescuing paraquat-induced oxidative stress compared to whole-body expression. Excitingly, we demonstrate that perturbing NAD(P) metabolism in non-neuronal tissues is sufficient to rejuvenate sleep profiles in aged flies to a youthful state. In summary, we used xenotopic tool LbNOX to identify tissues and metabolic processes which benefited the most from the modulation of the NAD metabolism thereby highlighting important aspects of rebalancing the NAD and NADP pools, all of which can be translated into novel designs of NAD-related human clinical trials.

Chronic jet lag (CJL) is known to disrupt circadian rhythms, which regulate various physiological processes, including ocular surface homeostasis. However, the specific effects of CJL on lacrimal gland function and the underlying cellular mechanisms remain poorly understood.

A CJL model was established using C57BL/6J mice. Extraorbital lacrimal glands (ELGs) were collected at 3-hour intervals for RNA extraction and high-throughput RNA sequencing. Circadian transcriptomic profiles were analyzed, and functional annotations were performed. Hydrogen peroxide levels and total antioxidant capacity in tear fluid were measured using chemometric assays. Immunofluorescence was used to assess cell proliferation, apoptosis, immune cell infiltration in ELGs, and reactive oxygen species (ROS) accumulation. The potential therapeutic effects of alpha-lipoic acid (ALA) on CJL-induced oxidative stress and pathological changes in ELGs were also investigated.

CJL significantly disrupted locomotor activity, altered body temperature rhythms, and modified diurnal oscillations in ELGs. Transcriptomic analysis revealed extensive changes in rhythmic gene expression, phase shifts, and pathway clustering in response to CJL. The disruption of the core circadian clock transcription was associated with ELG hyperproliferation and increased ROS accumulation. tert-Butyl hydroperoxide promoted ELG cell proliferation, and ALA effectively reduced ROS levels and mitigated CJL-induced hyperproliferation.

These findings uncover novel molecular pathways affected by CJL and highlight the potential of antioxidant therapies, such as ALA, in preserving ocular surface health under conditions of circadian rhythm disruption.

Brain and muscle ARNT-Like 1 (BMAL1) is a circadian clock transcription factor that regulates physiological functions. Male adrenal-specific Bmal1 (ASCre/+::Bmal1) KO mice displayed blunted serum corticosterone rhythms, altered blood pressure rhythm, and altered timing of eating, but there is a lack of knowledge in females. This study investigates the role of adrenal BMAL1 in renal electrolyte handling and urinary aldosterone levels in response to low salt in male and female mice. Mice were placed in metabolic cages to measure 12-h urinary aldosterone after a standard diet and 7 days low-salt diet, as well as daily body weight, 12-h food and water intake, and renal sodium and potassium balance. Adrenal glands and kidneys were collected at ZT0 or ZT12 to measure the expression of aldosterone synthesis genes and clock genes. Compared with littermate controls, ASCre/+::Bmal1 KO male and female mice displayed increased urinary aldosterone in response to a low-salt diet, although mRNA expression of aldosterone synthesis genes was decreased. Timing of food intake was altered in ASCre/+::Bmal1 KO male and female mice, with a blunted night/day ratio. ASCre/+::Bmal1 KO female mice displayed decreases in renal sodium excretion in response to low salt, but both male and female KO mice had changes in sodium balance that were time-of-day-dependent. In addition, sex differences were found in adrenal and kidney clock gene expression. Notably, this study highlights sex differences in clock gene expression that could contribute to sex differences in physiological functions.NEW & NOTEWORTHY Our findings highlight the importance of sex as well as time-of-day in understanding the role of the circadian clock in the regulation of homeostasis. Time-of-day is a key biological variable that is often ignored in research, particularly in preclinical rodent studies. Our findings demonstrate important differences in several measures at 6 AM compared with 6 PM. Consideration of time-of-day is critical for the translation of findings in nocturnal rodent physiology to diurnal human physiology.

The developmental origins of health and disease theory suggests that environmental exposures during early life, particularly during prenatal life, can greatly influence health status later in life. Irregular light-dark cycles, such as those experienced during shift work, result in the repeated disruption of circadian rhythms, which negatively impacts physiological and behavioral cycles. The purpose of our study was to assess parameters in the developing mouse embryo and fetus using high frequency ultrasound when exposed to circadian disruption. Pregnant female mice were subjected to a seven-hour advanced circadian disrupted protocol or remained on a normal 12/12 light-dark cycle throughout pregnancy. Significant differences were observed in placental length (p = 0.00016), placental thickness (p = 0.0332), and stomach diameter (p = 0.0186) at E14.5-18.5. These findings suggest that circadian disruption in pregnant dams, mimicking shift work, alters embryonic and fetal development in specific organs in utero.

Sleep disturbances are more prevalent among women with infertility. Current research increasingly highlights the significant relationship between sleep disturbances and female infertility, suggesting that sleep may be a key factor in reproductive health. In this review, we aim to delve into the complex interplay between sleep disturbances and female infertility, as well as to assess the underlying mechanisms involved, and seek to illuminate the causes of sleep-related fertility issues. The understanding of these contents may help clinicians enhance clinical strategies for managing sleep disturbances in women facing infertility challenges and provide timely support to those seeking fertility treatments.

A comprehensive literature search was conducted in the PubMed and EMBASE databases. Studies that described sleep patterns or any type of sleep disturbance, sleep breathing disorders and their associations with female infertility or female fecundity, published between January 1, 2010, and November 1, 2023, were identified and extracted. The screening, data extraction, and quality assessment processes were independently performed by paired reviewers. The quality of the included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal tools for observational and cohort studies.

A total of 1,179 articles were initially identified from the search strategy (PubMed, n = 377; EMBASE, n = 802). After removing duplicates (n = 83) and screening for eligibility (n = 75), 19 studies were reviewed and determined to be eligible for inclusion. Infertile women generally report poorer sleep quality and exhibit more evening sleep chronotypes. Sleep disorders are significantly associated with infertility. Poor sleep quality, extreme sleep durations, and certain sleep chronotypes are associated with poorer fertility treatment outcomes, such as a reduced number of retrieved oocytes, decreased embryo quality, and lower fertilization rates. Obstructive sleep apnea (OSA) is also more prevalent in women with fertility issues, especially those with polycystic ovary syndrome (PCOS), and may negatively impact reproductive outcomes. The circadian rhythms of the Clock gene system, melatonin and hormone dysregulation, oxidative stress and immune response are considered to be potential mechanisms explaining how sleep disturbance impairs reproductive function, remain to be fully elucidated, and therefore, require further investigation.

Sleep disturbances are negatively associated with female infertility and poor fertility treatment outcomes. Longitudinal studies are expected to substantiate these findings and inform more nuanced approaches to prior sleep management and lifestyle advisement for infertile women, especially those undergoing fertility treatments.

This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO, #CRD42024498443).

Circadian rhythms, intrinsic cycles spanning approximately 24 h, regulate numerous physiological processes, including sleep-wake cycles, hormone release, and metabolism. These rhythms are orchestrated by the circadian clock, primarily located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Disruptions in circadian rhythms, whether due to genetic mutations, environmental factors, or lifestyle choices, can significantly impact health, contributing to disorders such as sleep disturbances, metabolic syndrome, and cardiovascular diseases. Additionally, there is a profound link between the disruption of circadian rhythms and development of various cancer, the influence on disease incidence and progression. This incurred regulation by circadian clock on pathways has its implication in tumorigenesis, such as cell cycle control, DNA damage response, apoptosis, and metabolism. Furthermore, the circadian timing system modulates the efficacy and toxicity of cancer treatments. In cancer treatment, the use of chronotherapy to optimize the timing of medical treatments, involves administering chemotherapy, radiation, or other therapeutic interventions at specific intervals to enhance efficacy and minimize side effects. This approach capitalizes on the circadian variations in cellular processes, including DNA repair, cell cycle progression, and drug metabolism. Preclinical and clinical studies have demonstrated that chronotherapy can significantly improve the therapeutic index of chemotherapeutic agents like cisplatin and 5-fluorouracil by enhancing anticancer activity and reducing toxicity. Further research is needed to elucidate the mechanisms underlying circadian regulation of cancer and to develop robust chronotherapeutic protocols tailored to individual patients' circadian profiles, potentially transforming cancer care into more effective and personalized treatment strategies.