The circadian rhythm regulates the 24-hour physiological and behavioral cycles through endogenous molecular clocks governed by core clock genes via the transcription-translation feedback loop (TTFL). In mammals, the suprachiasmatic nucleus (SCN) serves as the central pacemaker, coordinating the timing of physiological processes throughout the body by regulating clock genes such as CLOCK, BMAL1, PER, and CRY. The molecular clocks of peripheral tissues and cells are synchronized by the SCN through TTFLs to regulate metabolism, immunity, and energy homeostasis. Numerous studies indicate that circadian rhythm disruption is closely related to obesity, type 2 diabetes, metabolic syndrome and other diseases, and the mechanism involves the dysregulation of glucose and lipid metabolism, abnormal insulin signaling and low-grade inflammation. In recent years, small-molecule compounds targeting the core clock components such as CRY, REV-ERB, and ROR have been identified and shown potential to modulate metabolic diseases by stabilizing or inhibiting the activity of key clock proteins. This review summarizes the mechanisms and advances in these compounds, and explores the challenges and future directions for their clinical translation, providing insights for chronotherapy-based metabolic disease interventions.
Humans ; Metabolic Diseases/physiopathology* ; Animals ; Circadian Rhythm/physiology* ; Biological Clocks/drug effects* ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Suprachiasmatic Nucleus/physiology*

Circadian rhythms are driven by circadian oscillators, and these rhythms result in the biological phenomenon of 24-h oscillations. Previous studies suggest that learning and memory are affected by circadian rhythms. One of the genes responsible for generating the circadian rhythm is Rev-erbα. The REV-ERBα protein is a nuclear receptor that acts as a transcriptional repressor, and is a core component of the circadian clock. However, the role of REV-ERBα in neurophysiological processes in the hippocampus has not been characterized yet. In this study, we examined the time-dependent role of REV-ERBα in hippocampal synaptic plasticity using Rev-erbα KO mice. The KO mice lacking REV-ERBα displayed abnormal NMDAR-dependent synaptic potentiation (E-LTP) at CT12~CT14 (subjective night) when compared to their wild-type littermates. However, Rev-erbα KO mice exhibited normal E-LTP at CT0~CT2 (subjective day). We also found that the Rev-erbα KO mice had intact late LTP (L-LTP) at both subjective day and night. Taken together, these results provide evidence that REV-ERBα is critical for hippocampal E-LTP during the dark period.
Animals ; Biological Phenomena ; Circadian Clocks ; Circadian Rhythm ; Hippocampus ; Learning ; Long-Term Potentiation ; Memory ; Mice ; Neuronal Plasticity

BACKGROUND: Shift work disturbs workers' biological clocks and this condition can cause various health problems including cardiovascular disease. The elevated albuminuria level has been significantly associated with the risk of the cardiovascular disease even within a normal reference range. Therefore, this study aimed to investigate the association between shift work and microalbuminuria. METHODS: Workers aged over 20 years from the fifth and sixth Korea National Health and Nutrition Examination Survey(KNHANES 2012–2014; n = 3000) were included in this analysis. The multiple logistic regression analysis was performed to determine the association between shift work and microalbuminuria stratified by gender. RESULTS: The prevalence of microalbuminuria in male subjects was higher among day workers, but the difference was not significant. However, the prevalence of microalbuminuria among females was higher in shift workers with statistical significance. For female, the Odds ratio of microalbuminuria in shift workers was significantly higher with 1.86 (95% CI 1.02–3.39) compared with day workers. After dividing into 5 subgroups of the shift work pattern, the odds ratio of microalbuminuria for fixed night shift was significantly higher at 4.68 (95% CI 1.29–17.00) compared with day workers. CONCLUSIONS: This study showed that shift work was associated with microalbuminuria in female workers. Especially we found out the association between fixed night shift and microalbuminuria in female workers.
Albuminuria ; Biological Clocks ; Cardiovascular Diseases ; Female ; Humans ; Korea ; Logistic Models ; Male ; Odds Ratio ; Prevalence ; Reference Values

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. Circadian rhythm is controlled by the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and the peripheral clocks in various tissues. More importantly, the central clock can integrate photic/nonphotic signals to generate rhythmic outputs, and then drive the slave oscillators in peripheral tissues through neuroendocrine and behavioral signals. Human reproductive activities, as some other physiological functions, are controlled by the biological clocks. Accumulating lines of epidemiological and genetic evidence indicate that disruption of circadian clock can be directly involved in multiple pathological processes, including infertility. In this review, we mainly discuss the presence of a circadian clock in reproductive tissues and its roles in follicles development, ovulation, spermatogenesis, fertilization and embryo implantation, etc. As the increased shift work and assisted reproductive technologies possibly disrupt circadian rhythmicity to impact reproduction, the importance of circadian rhythms should be highlighted in the regulation of reproductive process.
Animals ; Biological Clocks ; Circadian Rhythm ; Hypothalamus ; Light ; Reproduction ; Suprachiasmatic Nucleus

Sinoatrial node (SAN) automaticity is jointly regulated by a voltage (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release). Using optical mapping in Langendorff-perfused canine right atrium, we previously demonstrated that the beta-adrenergic stimulation pushes the leading pacemaker to the superior SAN, which has the fastest activation rate and the most robust late diastolic intracellular calcium (Cai) elevation. Dysfunction of the superior SAN is commonly observed in animal models of heart failure and atrial fibrillation (AF), which are known to be associated with abnormal SAN automaticity. Using the 3D electroanatomic mapping techniques, we demonstrated that superior SAN served as the earliest atrial activation site (EAS) during sympathetic stimulation in healthy humans. In contrast, unresponsiveness of superior SAN to sympathetic stimulation was a characteristic finding in patients with AF and SAN dysfunction, and the 3D electroanatomic mapping technique had better diagnostic sensitivity than corrected SAN recovery time testing. However, both tests have significant limitations in detecting patients with symptomatic sick sinus syndrome. Recently, we reported that the location of the EAS can be predicted by the amplitudes of P-wave in the inferior leads. The inferior P-wave amplitudes can also be used to assess the superior SAN responsiveness to sympathetic stimulation. Inverted or isoelectric P-waves at baseline that fail to normalize during isoproterenol infusion suggest SAN dysfunction. P-wave morphology analyses may be helpful in determining the SAN function in patients at risk of symptomatic sick sinus syndrome.
Adrenergic beta-Agonists ; Atrial Fibrillation ; Biological Clocks ; Calcium ; Heart Atria ; Heart Failure ; Humans ; Isoproterenol ; Membranes ; Models, Animal ; Sarcoplasmic Reticulum ; Sick Sinus Syndrome ; Sinoatrial Node*

OBJECTIVETo explore the effects of feeding mode on biological clock and circadian expression of lipids metabolism-related genes in mice.

METHODSNinety healthy male ICR mice were divided into 3 groups with 30 in each: ad libitum-feeding, daytime-feeding and nighttime-feeding groups, in a 12 h to 12 h light-dark cycle. After two weeks of feeding the animals was sacrificed in batches (5 in each batch) at 4, 8, 12, 16, 20 and 24 h, the circadian expression of lipids metabolism-related genes in the liver and brain was detected by real time quantitative RT PCR at 6 time points.

RESULTSThe circadian oscillator in the brain was more sensitive to alteration of feeding mode than that in the liver, nighttime feeding decreased peak mRNA levels of Cry2, Per1, and Per2 (5.5, 4.3 and 7.1 folds, respectively) in the brain. However, there was no difference in the expression rhythm of hepatic clock genes between nighttime-feeding and ad libitum group. In addition, changed feeding mode significantly decreased the peak value of Rev erbα (2 folds for daytime feeding, 3.4 folds for nighttime feeding) and Dbp (10.6 folds for daytime feeding, 2.8 folds for nighttime feeding), which two had opposite expression mode in different feeding modes. Different expression rhythm of lipid metabolism related genes SREBP1-c, PPARα, FAS, and CPT was shown with decreased mRNA expression levels of SREBP1-c and PPARα in daytime feeding (5.5 folds, 4 folds) and nighttime feeding (4.4 folds, 4.8 folds).

CONCLUSIONChanging the feeding mode could entrain circadian oscillators both in the brain and liver. What is more, hepatic circadian oscillators couple with the feeding time.

Animals ; Biological Clocks ; Circadian Rhythm ; Feeding Methods ; Lipid Metabolism ; Liver ; metabolism ; Male ; Mice ; Mice, Inbred ICR ; RNA, Messenger ; Time Factors

The early cardiac biological pacemaker studies were mostly around HCN channel, and how to build a biological pacemaker through the enhanced If current. In recent years, however, people found that the genes of Tbx3 could play an important role in the development of cardiac conduction system, especially in processes of the maturity of the sinoatrial node and maintenance of its function. And the Tbx3 can further optimize the biological pacemaker. Therefore, it could be a new therapeutic focus in biological pacemaker and treatment of cardiac conduction system disease. This paper summarizes some of the latest research progress of the Tbx3 in biological pacemaker in recent years. We hope that this review could provide theoretical basis for the clinical applications of Tbx3.
Arrhythmias, Cardiac ; genetics ; Biological Clocks ; Brugada Syndrome ; Cardiac Conduction System Disease ; Heart ; physiopathology ; Heart Conduction System ; abnormalities ; Humans ; Sinoatrial Node ; T-Box Domain Proteins ; genetics

PURPOSE: Shift work disrupts the synchronization between the human biological clock and the environment. Sleep disturbances are common for shift work nurses, and may threaten patient safety. This study was done to investigate the sleep characteristics and medication errors (ME) of intensive care unit (ICU) nurses who work shifts, and ascertain if there is an association between these factors. METHODS: Data were collected using a self-report questionnaire from 126 ICU nurses on three shifts. Collected data included their sleep characteristics including sleep patterns and sleep disturbances, and ME for the past 2 weeks. RESULTS: There were significant differences in sleep duration and sleep latency according to shift. Day shift nurses had the shortest sleep duration, and their sleep latency was the longest (about 49 minutes) compared to nurses on evening and night shifts; 54% reported sleep disturbances, 16% experienced ME, and among these nurses 50% were on the night shift. Logistic regression analysis revealed significant associations between nurses' sleep duration and ME (adjusted OR 0.52 [95% CI 0.32-0.85]). CONCLUSIONS: The results confirmed that shift worknurses in the ICUs experience sleep disturbance, and that less sleep is associated with ME.
Biological Clocks ; Humans ; Intensive Care Units* ; Logistic Models ; Medication Errors* ; Patient Safety ; Surveys and Questionnaires ; Sleep Disorders, Circadian Rhythm

Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In this review, we briefly introduce circadian clocks and their organization in mammals. We then summarize known daily or circadian variations in urinary function. Importantly, recent findings by others as well as results obtained by us suggest an active role of circadian clock genes in various urinary functions. Finally, we discuss possible research avenues for the circadian control of urinary function.
Biological Clocks ; Circadian Clocks ; Circadian Rhythm ; Humans ; Mammals ; Physiological Processes ; Rodentia ; Urinary Bladder ; Urination

As a rhythmic neural activity, neural oscillation exists all over the nervous system, in structures as diverse as the cerebral cortex, hippocampus, subcortical nuclei and sense organs. This review firstly presents some evidence that synchronous neural oscillations in theta and gamma bands reveal much about the origin and nature of cognitive processes such as learning and memory. And then it introduces the novel analyzing algorithms of neural oscillations, which is a directionality index of neural information flow (NIF) as a measure of synaptic plasticity. An example of application used such an analyzing algorithms of neural oscillations has been provided.
Animals ; Biological Clocks ; Brain ; physiology ; Cognition ; physiology ; Humans ; Learning ; physiology ; Memory ; physiology ; Nervous System Physiological Phenomena ; physiology ; Neural Pathways ; physiology ; Neuronal Plasticity ; physiology ; Synapses ; physiology ; Theta Rhythm ; physiology