Age-Induced Differential Changes in the Central and Colonic Human Circadian Oscillators

Aging modifies not only multiple cellular and homeostatic systems, but also biological rhythms. The circadian system is driven by a central hypothalamic oscillator which entrains peripheral oscillators, in both cases underlain by circadian genes. Our aim was to characterize the effect of aging in the circadian expression of clock genes in the human colon. Ambulatory recordings of the circadian rhythms of skin wrist temperature, motor activity and the integrated variable TAP (temperature, activity and position) were dampened by aging, especially beyond 74 years of age. On the contrary, quantitative analysis of genes expression in the muscle layer of colonic explants during 24 h revealed that the circadian expression of Bmal1, Per1 and Clock genes, was larger beyond that age. In vitro experiments showed that aging induced a parallel increase in the myogenic contractility of the circular colonic muscle. This effect was not accompanied by enhancement of Ca2+ signals. In conclusion, we describe here for the first time the presence of a molecular oscillator in the human colon. Aging has a differential effect on the systemic circadian rhythms, that are impaired by aging, and the colonic oscillator, that is strengthened in parallel with the myogenic contractility.

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THE ROLE OF CIRCADIAN REGULATION OF GHRELIN LEVELS IN PARKINSON’S DISEASE (LITERATURE REVIEW)

Wiadomości Lekarskie ◽

10.36740/wlek202107132 ◽

2021 ◽

Vol 74 (7) ◽

pp. 1750-1753

Author(s):

Kateryna A. Tarianyk ◽

Nataliya V. Lytvynenko ◽

Anastasiia D. Shkodina ◽

Igor P. Kaidashev

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clock Genes ◽

Biological Rhythms ◽

Circadian Regulation ◽

Diurnal Changes ◽

Dopaminergic Therapy ◽

Peripheral Oscillators ◽

Genes Expression

The paper is aimed at the analysis of the role of the circadian regulation of ghrelin levels in patients with Parkinson’s disease. Based on the literature data, patients with Parkinson’s disease have clinical fluctuations in the symptoms of the disease, manifested by the diurnal changes in motor activity, autonomic functions, sleep-wake cycle, visual function, and the efficacy of dopaminergic therapy. Biological rhythms are controlled by central and peripheral oscillators which links with dopaminergic neurotransmission – core of the pathogenesis of Parkinson`s disease. Circadian system is altered in Parkinson`s disease due to that ghrelin fluctuations may be changed. Ghrelin is potential food-entrainable oscillator because it is linked with clock genes expression. In Parkinson`s disease this hormone may induce eating behavior changing and as a result metabolic disorder. The “hunger hormone” ghrelin can be a biomarker of the Parkinson’s disease, and the study of its role in the pathogenesis, as well as its dependence on the period of the day, intake of levodopa medications to improve the effectiveness of treatment is promising.

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CORTISOL CIRCADIAN RHYTHM AND INSULIN RESISTANCE IN MUSCLE: EFFECT OF DOSING AND TIMING OF HYDROCORTISONE EXPOSURE ON INSULIN SENSITIVITY IN SYNCHRONIZED MUSCLE CELLS.

Neuroendocrinology ◽

10.1159/000512685 ◽

2020 ◽

Author(s):

Mariarosaria Negri ◽

Claudia Pivonello ◽

Chiara Simeoli ◽

Gilda Di Gennaro ◽

Mary Anna Venneri ◽

...

Keyword(s):

Skeletal Muscle ◽

Circadian Rhythm ◽

Insulin Sensitivity ◽

Circadian Clock ◽

Insulin Signaling ◽

Clock Genes ◽

Muscle Cells ◽

C2c12 Cells ◽

Circadian Expression

Introduction/Aim: Circadian rhythm disruption is emerging as a risk factor for metabolic disorders and particularly, alterations in clock genes circadian expression have been shown to influence insulin sensitivity. Recently, the reciprocal interplay between the circadian clock machinery and HPA axis has been largely demonstrated: the circadian clock may control the physiological circadian endogenous glucocorticoids secretion and action; glucocorticoids, in turn, are potent regulator of the circadian clock and their inappropriate replacement has been associated with metabolic impairment. The aim of the current study was to investigate in vitro the interaction between the timing-of-the-day exposure to different hydrocortisone (HC) concentrations on muscle insulin sensitivity. Methods: Serum-shock synchronized mouse skeletal muscle C2C12 cells were exposed to different HC concentrations recapitulating the circulating daily physiological cortisol profile (standard cortisol profile), the circulating daily cortisol profile that reached in adrenal insufficient (AI) patients treated with once-daily MR-HC (flat cortisol profile) and treated with thrice-daily of conventional IR-HC (steep cortisol profile). The 24 hrs spontaneous oscillation of the clock genes in synchronized C2C12 cells was used to align the timing for in vitro HC exposure (Bmal1 acrophase, midphase and bathyphase) with the reference times of cortisol peaks in AI treated with IR-HC (8 am, 1 pm, 6 pm). A panel of 84 insulin sensitivity related genes and intracellular insulin signaling proteins were analyzed by RT-qPCR and western blot, respectively. Results: Only the steep profile, characterized by a higher HC exposure during Bmal1 bathyphase, produced significant downregulation in 21 insulin sensitivity-related genes. Among these, Insr, Irs1, Irs2, Pi3kca and Adipor2 were downregulated when compared the flat to the standard or steep profile. Reduced intracellular IRS1 Tyr608, AKT Ser473, AMPK Thr172 and ACC Ser79 phosphorylations were also observed. Conclusions: The current study demonstrated that is late-in-the-day cortisol exposure that modulates insulin sensitivity-related genes expression and intracellular insulin signaling in skeletal muscle cells.

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Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4613.4613 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4613-4613

Author(s):

Ming-Yu Yang ◽

Pai-Mei Lin ◽

Jui-Feng Hsu ◽

Wen-Chi Yang ◽

Yi-Chang Liu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Circadian Rhythms ◽

Circadian Clock ◽

Myeloid Leukemia ◽

Clock Genes ◽

Expression Patterns ◽

Healthy Individuals ◽

Daily Pattern ◽

Genes Expression ◽

Circadian Clock Genes

Abstract Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Intercellular coupling between peripheral circadian oscillators by TGF-β signaling

Science Advances ◽

10.1126/sciadv.abg5174 ◽

2021 ◽

Vol 7 (30) ◽

pp. eabg5174

Author(s):

Anna-Marie Finger ◽

Sebastian Jäschke ◽

Marta del Olmo ◽

Robert Hurwitz ◽

Adrián E. Granada ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Clock Genes ◽

Ex Vivo ◽

Three Dimensional ◽

Transforming Growth Factor Β ◽

Molecular Clocks ◽

Peripheral Oscillators ◽

Circadian Oscillators

Coupling between cell-autonomous circadian oscillators is crucial to prevent desynchronization of cellular networks and disruption of circadian tissue functions. While neuronal oscillators within the mammalian central clock, the suprachiasmatic nucleus, couple intercellularly, coupling among peripheral oscillators is controversial and the molecular mechanisms are unknown. Using two- and three-dimensional mammalian culture models in vitro (mainly human U-2 OS cells) and ex vivo, we show that peripheral oscillators couple via paracrine pathways. We identify transforming growth factor–β (TGF-β) as peripheral coupling factor that mediates paracrine phase adjustment of molecular clocks through transcriptional regulation of core-clock genes. Disruption of TGF-β signaling causes desynchronization of oscillator networks resulting in reduced amplitude and increased sensitivity toward external zeitgebers. Our findings reveal an unknown mechanism for peripheral clock synchrony with implications for rhythmic organ functions and circadian health.

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Circadian rhythms of locomotor activity and hippocampal clock genes expression are dampened in vitamin A–deficient rats

Nutrition Research ◽

10.1016/j.nutres.2014.02.002 ◽

2014 ◽

Vol 34 (4) ◽

pp. 326-335 ◽

Cited By ~ 9

Author(s):

Lorena S. Navigatore-Fonzo ◽

Silvia M. Delgado ◽

Rebeca S. Golini ◽

Ana C. Anzulovich

Keyword(s):

Locomotor Activity ◽

Circadian Rhythms ◽

Vitamin A ◽

Clock Genes ◽

Genes Expression

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Clock genes SNP array identifies a key role of the PER1/HES7 gene in the risk of cannabis addiction and psychiatric comorbidities

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.1739 ◽

2017 ◽

Vol 41 (S1) ◽

pp. s867-s868

Author(s):

G. Lafaye ◽

A. Benyamina

Keyword(s):

Large Scale ◽

Clock Genes ◽

Strong Association ◽

Snp Array ◽

Biological Rhythms ◽

Cell Types ◽

Predisposing Factor ◽

Circadian Expression ◽

Potential Biomarker

The existence of biological rhythms disruption in addicted subjects has been described including disturbances in their sleep-wake pattern, rest-activity rhythms, and feeding schedules. Circadian rhythms have also been related to psychiatric diseases, including mood and anxiety disorders and the regulation of dopaminergic transmission, especially in reward circuitry in substance abusers. The relationship between them remained enigmatic and no data on the role of clock genes variants on cannabis dependence have been documented. We aimed at exploring the role of clock gene genotypes as potential predisposing factor to cannabis addiction, using a high throughput mass spectrometry methodology that enables the large-scale analysis of all the known clinically-relevant polymorphisms of the core human clock genes. We have conducted a case-control study on 177 Caucasians categorizing between cannabis-addicted subjects (n = 83) and casual cannabis consumers (n = 94). We report here a strong association between the TT* genotype RS1442849 in PER1/HES7 gene and a significantly higher risk of vulnerability to be dependent to cannabis. Moreover, this SNP was overrepresented in the subsets of cannabis users with more severe characteristics like personal psychiatric history, unemployed status, and beginning of cannabis use early in lifetime as well as large weekly consumption. HES7 gene is a newly described gene with a circadian expression regulated by reactive oxygen species in many cell types including neural stem cells. The HES7 TT* genotype RS1442849 gene could intervene on the dopamine reward systems. This genotype thus represents the first potential biomarker for stratification of cannabis consumers for the risk to develop a true dependence.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Cancer clocks in tumourigenesis: the p53 pathway and beyond

Endocrine Related Cancer ◽

10.1530/erc-20-0475 ◽

2021 ◽

Vol 28 (4) ◽

pp. R95-R110

Author(s):

Ewan M Stephenson ◽

Laura E J Usselmann ◽

Vinay Tergaonkar ◽

David M Virshup ◽

Robert Dallmann

Keyword(s):

Circadian Rhythms ◽

Circadian Clock ◽

Cancer Biology ◽

Cell Cycle Progression ◽

Clock Genes ◽

Human Cancer ◽

Epidemiologic Studies ◽

Current Evidence

Circadian rhythms regulate a vast array of physiological and cellular processes, as well as the hormonal milieu, to keep our cells synchronised to the light–darkness cycle. Epidemiologic studies have implicated circadian disruption in the development of breast and other cancers, and numerous clock genes are dysregulated in human tumours. Here we review the evidence that circadian rhythms, when altered at the molecular level, influence cancer growth. We also note some common pitfalls in circadian-cancer research and how they might be avoided to maximise comparable results and minimise misleading data. Studies of circadian gene mutant mice, and human cancer models in vitro and in vivo, demonstrate that clock genes can impact tumourigenesis. Clock genes influence important cancer-related pathways, ranging from p53-mediated apoptosis to cell cycle progression. Confusingly, clock dysfunction can be both pro- or anti-tumourigenic in a model and cell type-specific manner. Due to this duality, there is no canonical mechanism for clock interaction with tumourigenic pathways. To understand the role of the circadian clock in patients’ tumours requires analysis of the molecular clock status compared to healthy tissue. Novel mathematical approaches are under development, but this remains largely aspirational, and is hampered by a lack of temporal information in publicly available datasets. Current evidence broadly supports the notion that the circadian clock is important for cancer biology. More work is necessary to develop an overarching model of this connection. Future studies would do well to analyse the clock network in addition to alterations in single clock genes.

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A Circadian Clock Entrained by Melatonin Is Ticking in the Rat Fetal Adrenal

Endocrinology ◽

10.1210/en.2010-1260 ◽

2011 ◽

Vol 152 (5) ◽

pp. 1891-1900 ◽

Cited By ~ 87

Author(s):

C. Torres-Farfan ◽

N. Mendez ◽

L. Abarzua-Catalan ◽

N. Vilches ◽

G. J. Valenzuela ◽

...

Keyword(s):

Adrenal Gland ◽

Circadian Clock ◽

Clock Genes ◽

Regulatory Protein ◽

Fetal Life ◽

Early Growth Response ◽

Circadian Expression ◽

Steroidogenic Acute Regulatory

The adrenal gland in the adult is a peripheral circadian clock involved in the coordination of energy intake and expenditure, required for adaptation to the external environment. During fetal life, a peripheral circadian clock is present in the nonhuman primate adrenal gland. Whether this extends to the fetal adrenal gland like the rat is unknown. Here we explored in vivo and in vitro whether the rat fetal adrenal is a peripheral circadian clock entrained by melatonin. We measured the 24-h changes in adrenal content of corticosterone and in the expression of clock genes Per-2 and Bmal-1 and of steroidogenic acute regulatory protein (StAR), Mt1 melatonin receptor, and early growth response protein 1 (Egr-1) expression. In culture, we explored whether oscillatory expression of these genes persisted during 48 h and the effect of a 4-h melatonin pulse on their expression. In vivo, the rat fetal adrenal gland showed circadian expression of Bmal-1 and Per-2 in antiphase (acrophases at 2200 and 1300 h, respectively) as well as of Mt1 and Egr-1. This was accompanied by circadian rhythms of corticosterone content and of StAR expression both peaking at 0600 h. The 24-h oscillatory expression of Bmal-1, Per-2, StAR, Mt1, and Egr-1 persisted during 48 h in culture; however, the antiphase between Per-2 and Bmal-1 was lost. The pulse of melatonin shifted the acrophases of all the genes studied and restored the antiphase between Per-2 and Bmal-1. Thus, in the rat, the fetal adrenal is a strong peripheral clock potentially amenable to regulation by maternal melatonin.

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Organ-specific development characterizes circadian clock gene Per2 expression in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00063.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. R67-R74 ◽

Cited By ~ 23

Author(s):

Shin-ya Nishide ◽

Kazuaki Hashimoto ◽

Takuya Nishio ◽

Ken-ichi Honma ◽

Sato Honma

Keyword(s):

Circadian Rhythms ◽

Clock Gene ◽

Developmental Stages ◽

Phase Relationship ◽

Developmental Changes ◽

Circadian Phase ◽

Peripheral Oscillators ◽

Clock Gene Expression ◽

Organ Specific

To explore developmental changes in circadian organization of central and peripheral oscillators, circadian rhythms in clock gene expression were examined in 12 organs in transgenic rats carrying a bioluminescence reporter for Per2. Organ slices were obtained from different developmental stages starting at postnatal day 5 and tissue was cultured for more than 6 days. In addition, four organs were examined from embryonic day 20. Robust circadian rhythms in bioluminescence were detected in all organs examined. The circadian period in vitro was specific to each organ and remained essentially the same during development. The circadian peak phase on the first day of culture was significantly different not only among organs but also in the same organ. Three patterns in circadian phase were detected during development. Thus, during development, circadian phase did not change in the suprachiasmatic nucleus, adrenal gland, and liver, whereas delay shifts were seen in the pineal, lung, heart, kidney, spleen, thymus, and testis. Finally, circadian phase advanced at postnatal day 10–15 and subsequently delayed in skeletal muscle and stomach.Circadian amplitude also showed developmental changes in several organs. These findings indicate that the temporal orders of physiological functions of various organs change during development. Such age-dependent and organ-specific changes in the phase relationship among circadian clocks most likely reflect entrainment to organ-specific time cues at different developmental stages.

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