• Molecules and Cells
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• v.40 no.7
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• pp.450-456
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• 2017

Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-$erb{\alpha}$ induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson's disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.

• Journal of the Korean Wood Science and Technology
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• v.50 no.5
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• pp.338-352
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• 2022

Herein, water and ethanol extracts were obtained from the leaves, branches, kernels, and pericarp of Quercus gilva and subsequently analyzed for antioxidant activity and circadian rhythm regulation effects. Candidate components that may affect circadian rhythm and antioxidant activity were investigated to discover potential functional materials. Antioxidant activity was analyzed via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity assays, showing that the hot water extract exhibited higher activity than that of the ethanol extract. In particular, the branch extract showed high antioxidant activity. By measuring total contents of polyphenols, flavonoids, and tannins, the hot water branch extract showed the highest concentrations, highlighting their significant contribution to the antioxidant activity. Examination of the circadian rhythm regulation of each extract showed that the ethanol extract exhibited greater impacts on the circadian rhythm amplitude compared to the water extract. The branch ethanol extract induced circadian rhythm amplitude changes via clock gene Bmal1 expression regulation. Determination of 12 phenolic compound concentrations showed that the branch ethanol extract contained many phenolic compounds, including catechin. This suggests that these com- pounds affected circadian rhythm regulation. In conclusion, the hot water branch extract has potential as an natural antioxidant material, while the corresponding ethanol extract has potential as a functional material for regulating circadian rhythm.

• Animal cells and systems
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• v.16 no.1
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• pp.1-10
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• 2012

Most living organisms synchronize their physiological and behavioral activities with the daily changes in the environment using intrinsic time-keeping systems called circadian clocks. In mammals, the key molecular features of the internal clock are transcription- and translational-based negative feedback loops, in which clock-specific transcription factors activate the periodic expression of their own repressors, thereby generating the circadian rhythms. CLOCK and BMAL1, the basic helix-loop-helix (bHLH)/PAS transcription factors, constitute the positive limb of the molecular clock oscillator. Recent investigations have shown that various levels of posttranslational regulation work in concert with CLOCK/BMAL1 in mediating circadian and cellular stimuli to control and reset the circadian rhythmicity. Here we review how the CLOCK and BMAL1 activities are regulated by intracellular distribution, posttranslational modification, and the recruitment of various epigenetic regulators in response to circadian and cellular signaling pathways.

• Molecules and Cells
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• v.39 no.1
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• pp.6-19
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• 2016

Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redoxsensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian timekeeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological timekeeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping.

• Proceedings of the KSAR Conference
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• 2004.06a
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• pp.261-261
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• 2004

Circadian rhythms, which measure time about 24 hours, are generated by one of the most ubiquitous and well investigated timing system. More recently, circadian clock gene expression has been reported in various peripheral tissues. If a circadian clock is functioning in the testis, expression of clock genes should be observed in this tissue. To resolve this issue, we examined the expression of circadian clock genes in the testis. (omitted)

• Journal of Photoscience
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• v.9 no.2
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• pp.25-28
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• 2002

The chicken pineal gland has been used for studies on the circadian clock, because it retains an intracellular phototransduction pathway regulating the phase of the intrinsic clock oscillator. Previously, we identified chicken clock genes expressed in the gland (cPer2, cPer3, cBmal1, cBmal2, cCry1, cCry2, and cClock), and showed that a cBMALl/2-cCLOCK heteromer acts as a regulator transactivating cPer2 gene through the CACGTG E-box element found in its promoter. Notably, mRNA expression of cPer2 gene is up-regulated by light as well as is driven by the circadian clock, implying that light-dependent clock resetting may involve the up-regulation of cPer2 gene. To explore the mechanism of light-dependent gene expression unidentified in animals, we first focused on pinopsin gene whose mRNA level is also up-regulated by light. A pinopsin promoter was isolated and analyzed by transcriptional assays using cultured chicken pineal cells, resulting in identification of an 18-bp light-responsive element that includes a CACGTG E-box sequence. We also investigated a role of mitogen-activated protein kinase (MAPK) in the clock resetting, especially in the E-box-dependent transcriptional regulation, because MAPK is phospholylated (activated) in a circadian manner and is rapidly dephosphorylated by light in the gland. Both pulldown analysis and kinase assay revealed that MAPK directly associates with BMAL1 to phosphorylate it at several Ser/Thr residues. Transcriptional analyses implied that the MAPK-mediated phosphorylation may negatively regulate the BMAL-CLOCK-dependent transactivation through the E-box. These results suggest that the CACGTG E-box serves not only as a clock-controlled element but also as a light-responsive element.

• Journal of Life Science
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• v.27 no.10
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• pp.1225-1231
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• 2017

Disruptive expression patterns of the circadian clock genes are highly associated with many human diseases, including cancer. Cell cycle and proliferation is linked to a circadian rhythm; therefore, abnormal clock gene expression could result in tumorigenesis and malignant development. The molecular network of the circadian clock is based on transcriptional and translational feedback loops orchestrated by a variety of clock activators and clock repressors. The expression of 10~15% of the genome is controlled by the overall balance of circadian oscillation. Among the many clock genes, Period 1 (Per1) and Period 2 (Per2) are clock repressor genes that play an important role in the regulation of normal physiological rhythms. It has been reported that PER1 and PER2 are involved in the expression of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. In addition, correlation of the down-regulation of PER1 and PER2 with development of many cancer types has been revealed. In this review, we focused on the molecular function of PER1 and PER2 in the circadian clock network and the transcriptional and translational targets of PER1 and PER2 involved in cell cycle and tumorigenesis. Moreover, we provide information suggesting that PER1 and PER2 could be promising therapeutic targets for cancer therapies and serve as potential prognostic markers for certain types of human cancers.

• Journal of Life Science
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• v.23 no.8
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• pp.1064-1072
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• 2013

Circadian rhythm is controlled by hormonal oscillations governing the physiology of all living organisms. In mammals, the main function of the pineal gland is to transform the circadian rhythm generated in the hypothalamic suprachiasmatic nucleus into rhythmic signals of circulating melatonin characterized by a largely nocturnal increase that closely reflects the duration of night time. The pineal gland has lost direct photosensitivity, but responds to light via multi-synaptic pathways that include a subset of retinal ganglion cells. Rhythmic control is achieved through a tight coupling between environmental lighting and arylalkylamine-N-acetyltransferase (AANAT) expression, which is the rhythm-controlling enzyme in melatonin synthesis. Previous studies on the nocturnal expression of AANAT protein have described transcriptional, post-transcriptional, and post-translational regulatory mechanisms. Molecular mechanisms for dependent AANAT expression provide novel aspects for melatonin's circadian rhythmicity. Extensive animal research has linked pineal melatonin for the expression of seasonal rhythmicity in many mammalian species to the modulation of circadian rhythms and to sleep regulation. It has value in treating various circadian rhythm disorders, such as jet lag or shift-work sleep disorders. Melatonin, also, in a broad range of effects with a significant regulation influences many of the body's physiological functions. In addition, this hormone is known to influence reproductive, cardiovascular, and immunological regulation as well as psychiatric disorders.

• BMB Reports
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• v.48 no.12
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• pp.677-684
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• 2015

Cardiovascular function is regulated by the rhythmicity of circadian, infradian and ultradian clocks. Specific time scales of different cell types drive their functions: circadian gene regulation at hours scale, activation-inactivation cycles of ion channels at millisecond scales, the heart's beating rate at hundreds of millisecond scales, and low frequency autonomic signaling at cycles of tens of seconds. Heart rate and rhythm are modulated by a hierarchical clock system: autonomic signaling from the brain releases neurotransmitters from the vagus and sympathetic nerves to the heart's pacemaker cells and activate receptors on the cell. These receptors activating ultradian clock functions embedded within pacemaker cells include sarcoplasmic reticulum rhythmic spontaneous Ca²⁺ cycling, rhythmic ion channel current activation and inactivation, and rhythmic oscillatory mitochondria ATP production. Here we summarize the evidence that intrinsic pacemaker cell mechanisms are the end effector of the hierarchical brain-heart circadian clock system.

• Journal of Life Science
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• v.7 no.3
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• pp.205-211
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• 1997

The possibility of circadian production of plant hormone gibberellin (GA0 was examined in phytochrome B mutant (plyB-1) and wild-type sorghum. GA$_{12}$, GA$_{20}$ and GA$_{1}$ levels were found to cycle circadianly in both phyB-1 and wild-type. The periods (33 h) of GA$_{20}$ and GA$_{1}$ cycling in constant light were longer than normal photoperiods in both genotypes and typical average free running periods in plants of 22 to 28 h. The biological clock was thus shown to function properly in phyB-1. However, circadian regulation of GAs productions were not clear as compared to circadian ethylene regulation reported by Lee (1996). Although, in sorghum, EOD FR treatment hasten floral inititation, the differences in GA concentrations between treatments and untreated control were generally less dramatic than expected. Thus, it can be concluded that FR does not act primarily by changing absolute levels of GAs but rather by increasing flowering responsiveness to GAs.