Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic ...suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called “clock genes”. Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between “oral clocks” and diseases such as head and neck cancer and Sjögren’s syndrome.
Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, ...sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in tissue- and locus-specific manners. These molecular rhythms modulate several key aspects of cellular and tissue function with profound implications in public health, disease prevention, and disease management. In modern societies light at night disrupts circadian rhythms, leading to further disruption of sleep-activity and eating-fasting cycles. While acute circadian disruption may cause transient discomfort or exacerbate chronic diseases, chronic circadian disruption can enhance risks for numerous diseases. The molecular understanding of circadian rhythms is opening new therapeutic frontiers placing the circadian clock in a central role. Here, we review recent advancements on how to enhance our circadian clock through behavioral interventions, timing of drug administration, and pharmacological targeting of circadian clock components that are already providing new preventive and therapeutic strategies for several diseases, including metabolic syndrome and cancer.
Although circadian rhythm disruption (CRD) was typically considered to be a risk for chronic diseases solely for shift workers (∼20% of workforce), new epidemiological data suggest more than 80% of the population may be living a shift work lifestyle and thus are at elevated risk for chronic diseases.
Acute CRD compromises health with temporary physical challenges and may be a trigger for underlying latent diseases. Chronic CRD raises the risk for cancer along with a range of diseases affecting the central nervous system, immune and reproductive systems, metabolic organs, endocrine functions, and cardiovascular health.
Recent progress in understanding the molecular mechanisms of circadian timing and diurnal rhythms of tissue-specific gene products has generated testable hypotheses for how the circadian timing system optimizes health and, conversely, how circadian disruption leads to diseases.
Leveraging circadian rhythms to prevent, manage, and treat diseases involves three major strategies: optimizing the circadian lifestyle (‘training the clock’), optimizing timing of therapies (‘clocking the drugs’), and targeting specific circadian clock components (‘drugging the clock’).
Properties of the circadian and annual timing systems are expected to vary systematically with latitude on the basis of different annual light and temperature patterns at higher latitudes, creating ...specific selection pressures. We review literature with respect to latitudinal clines in circadian phenotypes as well as in polymorphisms of circadian clock genes and their possible association with annual timing. The use of latitudinal (and altitudinal) clines in identifying selective forces acting on biological rhythms is discussed, and we evaluate how these studies can reveal novel molecular and physiological components of these rhythms.
Dendritic cells play a key role in processing and presenting antigens to naïve T cells to prime adaptive immunity. Circadian rhythms are known to regulate many aspects of immunity; however, the role ...of circadian rhythms in dendritic cell function is still unclear. Here, we show greater T cell responses when mice are immunised in the middle of their rest versus their active phase. We find a circadian rhythm in antigen processing that correlates with rhythms in both mitochondrial morphology and metabolism, dependent on the molecular clock gene, Bmal1. Using Mdivi-1, a compound that promotes mitochondrial fusion, we are able to rescue the circadian deficit in antigen processing and mechanistically link mitochondrial morphology and antigen processing. Furthermore, we find that circadian changes in mitochondrial Ca
are central to the circadian regulation of antigen processing. Our results indicate that rhythmic changes in mitochondrial calcium, which are associated with changes in mitochondrial morphology, regulate antigen processing.
Neutral Beam Injector (NBI) is one of the main plasma heating and plasma current driving methods for Experimental Advanced Superconducting Tokomaks. In order to monitor the NBI experiment, control ...all the power supply, realize data acquisition and network, the control system is designed. As an important part of NBI control system, timing system (TS) provides a unified clock for all subsystems of NBI. TS controls the input/output services of digital signals and analog signals. It sends feedback message to the control server which is the function of alarm and interlock protection. The TS software runs on a Windows system and uses Labview language code while using client/server mode, multithreading and cyclic redundancy check technology. The experimental results have proved that TS provides a stability and reliability clock to the subsystems of NBI and contributed to the safety of the whole NBI system.
The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells ...through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1α-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1α. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild-type but not of HIF1α-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1α activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag.
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•O2 levels exhibit daily rhythms in blood and tissue of rodents•Physiological O2 rhythms reset clocks in cultured cells in HIF1α-dependent manner•Several core clock genes respond to changes in O2 levels in HIF1α-dependent fashion•Modulation of O2 levels accelerates the recovery of mice in a jet lag protocol
Adamovich et al. uncover daily oscillations in blood and tissue oxygenation and find that physiological oxygen rhythms synchronize clocks in cultured cells in a HIF1α-dependent manner. Modulation of oxygen levels accelerates the recovery of wild-type but not of HIF1α-deficient mice to the new time in a jet lag protocol.
Resveratrol (RES) possesses anti-inflammatory and anti-oxidant activities, and it can prevent liver lipid metabolism disorders in obese and diabetic individuals. This study elucidated the mechanisms ...of brain and muscle Arnt-like protein-1 (Bmal1) in the protective effects of RES against liver lipid metabolism disorders. The results indicated that RES ameliorated free fatty acid (FFA)-induced (oleic acid (OA): palmitic acid (PA) = 2:1) glycolipid metabolic disorders in hepatocytes. Simultaneously, RES partially reverted the relatively shallow daily oscillations of FFA-induced circadian clock gene transcription and protein expression in HepG2 cells. RES also attenuated FFA-triggered reactive oxygen species (ROS) secretion and restored mitochondrial membrane potential consumption, as well as the restoration of mitochondrial respiratory complex expression. This study provides compelling evidence that RES controls intracellular lipid metabolic imbalance in a Bmal1-dependent manner. Overall, RES may serve as a promising natural nutraceutical for the regulation of lipid metabolic disorders relevant to the circadian clock.
Microbial infection poses a threat to organismal homeostasis and therefore must be efficiently counteracted by host defense mechanisms. It has been recently demonstrated that the immune system may ...anticipate an emerging pathogenic exposure through a heightened inflammatory state. Such anticipatory responses to fluctuating environmental conditions are typically orchestrated by the circadian clock, an intrinsic time-keeping system that adapts tissue physiology to diurnal variations in external influences. Here, we review current knowledge about the interplay between the circadian clock and antimicrobial responses. We summarize the molecular strategies employed by the circadian system against specific pathogens, the core-clock proteins as well as cells in which they are expressed that mediate host defense, and the consequences of circadian variations on immune function. Furthermore, we highlight the possible implications of such circadian gating in immune reactions against pathogenic infections for the chronopharmacology of antibacterial and antiviral therapies.
Tognini et al. review evidence showing how the circadian clock regulates the immune response to multiple infectious agents in different tissues, and the importance of the daily control of immune system functions to maximize the host defense against a pathogenic attack.
Circadian clocks are cell autonomous timekeepers that regulate ∼24-h oscillations in the expression of many genes and control rhythms in nearly all our behavior and physiology. Almost every cell in ...the human body has a molecular clock and networks of cells containing clock proteins orchestrate daily rhythms in many physiological processes, from sleep–wake cycles to metabolism to immunity. All eukaryotic circadian clocks are based on transcription–translation delayed negative feedback loops in which activation of core clock genes is negatively regulated by their cognate protein products. Our current understanding of circadian clocks has been accumulated from decades of genetic and biochemical experiments, however, what remains poorly understood is how clock proteins, genes, and mRNAs are spatiotemporally organized within live clock cells and how such subcellular organization affects circadian rhythms at the single cell level. Here, we review recent progress in understanding how clock proteins and genes are spatially organized within clock cells over the circadian cycle and the role of such organization in generating circadian rhythms and highlight open questions for future studies.
In plants, the spatiotemporal expression of circadian oscillators provides adaptive advantages in diverse species. However, the molecular basis of circadian clock in soybean is not known. In this ...study, we used soybean hairy roots expression system to monitor endogenous circadian rhythms and the sensitivity of circadian clock to environmental stimuli. We discovered in experiments with constant light and temperature conditions that the promoters of clock genes GmLCLb2 and GmPRR9b1 drive a self‐sustained, robust oscillation of about 24‐h in soybean hairy roots. Moreover, we demonstrate that circadian clock is entrainable by ambient light/dark or temperature cycles. Specifically, we show that light and cold temperature pulses can induce phase shifts of circadian rhythm, and we found that the magnitude and direction of phase responses depends on the specific time of these two zeitgeber stimuli. We obtained a quadruple mutant lacking the soybean gene GmLCLa1, LCLa2, LCLb1, and LCLb2 using CRISPR, and found that loss‐of‐function of these four GmLCL orthologs leads to an extreme short‐period circadian rhythm and late‐flowering phenotype in transgenic soybean. Our study establishes that the morning‐phased GmLCLs genes act constitutively to maintain circadian rhythmicity and demonstrates that their absence delays the transition from vegetative growth to reproductive development.
We investigated the molecular characteristics and the physiological function of circadian oscillators in soybean. We found that soybean circadian clock is very sensitive to ambient light/temperature signals, and GmLCL genes are required for self‐sustained circadian period length and the timing of flowering.
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