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Effect of rotating light:dark regimen with phase advances on per2 (A), bmal1 (B) and rev-erba (C) mRNA expression in rat hearts. The solid line represents the control group and the broken line shows data from the experimental group (n=4-8). The black bar on the bottom of the graph represents the dark part of the 24 h cycle. Time scale is given in relative units: Zeitgeber time (ZT0 = beginning of the light part of the light:dark cycle).
Source publication
Under physiological conditions the mammalian circadian system is synchronized to a cyclic environment. The central oscillator in the suprachiasmatic nuclei (SCN) responds predominantly to an external light (L) dark (D) cycle. Peripheral oscillators are more efficiently synchronized by metabolic cues. When the circadian system is exposed to opposing...
Contexts in source publication
Context 1
... regimen with phase advances caused a significant decrease in mesor and amplitude of per2 expression and the per2 acrophase was shifted by 2 h compared with the control (Figs 2A, 3; Table 1). ...
Context 2
... rotating phase advance LD regimen strongly influenced the daily profile of bmal1 expression. The expression of bmal1 showed a significant decrease in mesor and amplitude, and the acrophase shifted by 4 h compared with the control (Figs 2B, 3; Table 1). ...
Context 3
... of rev-erba was significantly suppressed in the group exposed to the LD regimen with rotating advances compared with the control. The daily profile of rev-erba showed a decreased mesor and amplitude with no significant influence on the acrophase (Figs 2C, 3; Table 1) compared with the control group. ...
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The activity/rest rhythm of mammals reflects the output of an endogenous circadian oscillator entrained to the solar day by light. Despite detailed understanding of the neural and molecular bases of mammalian rhythms, we still lack practical tools for achieving rapid and flexible adjustment of clocks to accommodate shift-work, trans-meridian jet tr...
Citations
... Also similarly to humans, cortisol, neurohormones, renin, and aldosterone cycle in a way to raise HR and blood in the active phase. 4,9,[26][27][28][29] Created with biorender.com. ...
... The effect of light on the rhythmic expression of cardiac clock genes is well established. [9][10][11][12] Stimulated by light, the SCN acts as the central clock and synchronizer of all peripheral clocks. The SCN induces melatonin secretion by the pineal gland which influences clock gene expression in the heart. ...
... 9,30 ANP (atrial natriuretic peptide) gene expression in rats was seen to be arrhythmic throughout the day. 9 However, ANP protein quantification in perfused rat hearts demonstrated rhythmic levels of expression. 114 ANP concentrations oscillate rhythmically in humans, increasing at night and peaking before morning in an opposite trend to blood pressure. ...
Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.
... However, we thought it is important to investigate substances that shorten the circadian clock period as many humans show longer endogenous circadian periods than 24 h (Brown et al. 2008). In addition, mammals, including mice and humans, find it more difficult to adjust to a short period length than a long period length as delaying the onset of activity rhythms is easier than accelerating them (Herichov a et al. 2014;West et al. 2017). Therefore, in this study, we focussed on crude drug candidates capable of shortening clock gene expression rhythms. ...
Context
The mammalian circadian clock system regulates physiological function. Crude drugs, containing Polygalae Radix, and Kampō, combining multiple crude drugs, have been used to treat various diseases, but few studies have focussed on the circadian clock.
Objective
We examine effective crude drugs, which cover at least one or two of Kampō, for the shortening effects on period length of clock gene expression rhythm, and reveal the mechanism of shortening effects.
Materials and methods
We prepared 40 crude drugs. In the in vitro experiments, we used mouse embryonic fibroblasts from PERIOD2::LUCIFERASE knock-in mice (background; C57BL/6J mice) to evaluate the effect of crude drugs on the period length of core clock gene, Per2, expression rhythm by chronic treatment (six days) with distilled water or crude drugs (100 μg/mL). In the in vivo experiments, we evaluated the free-running period length of C57BL/6J mice fed AIN-93M or AIN-93M supplemented with 1% crude drug (6 weeks) that shortened the period length of the PERIOD2::LUCIFERASE expression rhythm in the in vitro experiments.
Results
We found that Polygalae Radix (ED50: 24.01 μg/mL) had the most shortened PERIOD2::LUCIFERASE rhythm period length in 40 crude drugs and that the CaMKII pathway was involved in this effect. Moreover, long-term feeding with AIN-93M+Polygalae Radix slightly shortened the free-running period of the mouse locomotor activity rhythm.
Discussion and conclusions
Our results indicate that Polygalae Radix may be regarded as a new therapy for circadian rhythm disorder and that the CaMKII pathway may be regarded as a target pathway for circadian rhythm disorders.
... Insomnia is associated with a 68 % increased incidence of myocardial infarction and an 85 % increase in risk of stroke (Somers et al. 2008). In one experimental model, the circadian rhythm of natriuretic peptide was altered by rotating the light-dark regimen (Herichová et al. 2014). ...
Obesity is linked to a wide range of serious illnesses. In addition to the important impact on the health of the individual, obesity also has a substantial impact on the economy. Disruption of physiological day-night cycles could contribute to the increased incidence of obesity. According to the American National Sleep Federation, the percentage of the people who reported a sleep duration of six hours or less increased from 12 to 37 % over ten years. Insufficient sleep leads not only to an increase of the total calorie intake but changes the meal preference in favor of palatable foods and meals with high carbohydrate content. A decrease of leptin and increase of ghrelin levels caused by sleep deficiency can also play a role. In addition to the higher caloric intake, the timing of food consumption should be taken into account. The same meal eaten during the night versus the day is associated with increased postprandial glucose and triglyceride levels. The gut microbiome has also been recently understood as an endocrine system, with links between the gut microbiome and circadian rhythm changes possibly influencing increased obesity.
... The present study extends our previous results, which demonstrated that chronic phase advance and delay shifts disturb circadian system functioning based on changed temporal organisation of locomotor activity, cardiovascular parameters and clock gene expression [23,25]. In the current study, we analysed effects of repeated phase shifts of LD cycle on behaviour and the activity of autonomic nervous system (ANS) in response to different behavioural tests. ...
... Recent studies have shown that rapid shifts of LD cycle may prevent entrainment to such light schedules and induce a free-running like pattern of activity rhythm in animals [18] suggesting that SHIFT rats could be tested in different circadian times. However, in our previous study we demonstrated that rats exposed to 8-h phase delay shifts every second day substantially lengthened their period of activity rhythm by about 4 h [25,35], which is out of the range of free-running periods in rats [36] Moreover, clock gene expression in peripheral organs exhibited robust rhythmicity [25,37] indicating that rats were synchronised among each other. Since all behavioural tests were performed during the second half of the light phase on the second day after prolonged dark phase, it is likely that both SHIFT and CTRL rats were tested during their subjective passive phase (Fig. 1, 2). ...
... Recent studies have shown that rapid shifts of LD cycle may prevent entrainment to such light schedules and induce a free-running like pattern of activity rhythm in animals [18] suggesting that SHIFT rats could be tested in different circadian times. However, in our previous study we demonstrated that rats exposed to 8-h phase delay shifts every second day substantially lengthened their period of activity rhythm by about 4 h [25,35], which is out of the range of free-running periods in rats [36] Moreover, clock gene expression in peripheral organs exhibited robust rhythmicity [25,37] indicating that rats were synchronised among each other. Since all behavioural tests were performed during the second half of the light phase on the second day after prolonged dark phase, it is likely that both SHIFT and CTRL rats were tested during their subjective passive phase (Fig. 1, 2). ...
... Therefore, access to food at equal intervals throughout the light/ dark cycle, which abolishes the daily feeding rhythm, does not reset peripheral clock rhythms. It is well known that information about light (and darkness) is very important to set the circadian clocks in the SCN and periphery (Yamazaki et al. 2000;Wu et al. 2008;Herichova et al. 2014;Herrero et al. 2015). Recently, Ikeda et al. (2015) showed that the length of the light period during the light/dark cycle affects the acrophase of Per2 in kidney, liver, and salivary gland under the 6-meals-a-day feeding schedule. ...
The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to synchronize the tissue-specific rhythms of the peripheral clocks with the environmental day/night changes via neural, humoral and/or behavioral connections. The feeding rhythm is considered an important Zeitgeber for peripheral clocks, as daytime feeding reverses (clock) gene rhythms in the periphery, but not in the SCN. In this study, we investigated the necessity of a daily feeding rhythm for maintaining gene expression rhythms in epididymal white adipose tissue (eWAT). We showed that 7 of 9 rhythmic metabolic/adipokine genes, but not clock genes, lost their rhythmicity upon exposure to 6-meals-a-day feeding. Previously, we showed comparable effects of adrenalectomy on eWAT; therefore, subsequently we investigated the effect of simultaneous disruption of these humoral and behavioral signaling pathways, by exposing adrenalectomized animals to 6-meals-a-day feeding. Interestingly, under these conditions, all the clock genes and 10 of 11 rhythmic metabolic/adipokine genes lost their rhythmicity. These data indicate that adrenal hormones and feeding rhythm are indispensable for maintaining daily rhythms in metabolic/adipokine gene, but not clock gene, expression in eWAT. In contrast, at least one of these two signals should be present in order for eWAT clock gene rhythms to be maintained.
... Such situation may occur in shift workers who are exposed to two independent time cues, the photic and food. It is well known that light act via the retina and entrains the master circadian oscillator in the SCN (Warren et al. 2006), while food acts mainly through the liver and synchronises peripheral oscillators (Escobar et al. 2009), which have been found also in the heart (Herichová et al. 2014) and vessels (Xie et al. 2015). Such dual synchronising effects can lead to internal desynchronisation and splitting of circadian rhythms in LA which is governed predominantly by the SCN and cardiovascular rhythm, which are controlled in a more complex way than the physical activity. ...
Effects of phase delay shifts (PDS) of light in combination with moderately increased salt intake (SL) (2%) or time restriction of food (FR) during the light-time (passive phase) on heart rate (HR), blood pressure (BP) and locomotor activity (LA) in radiotelemetry-measured rats were evaluated. PDS decreased amplitude and spectral power of circadian oscillations of HR, BP and LA. Moderately increased SL did not interfere with the circadian rhythmicity of HR, BP or LA. A prominent decrease in amplitude and spectral power of circadian oscillations was observed if food was available during the lighttime. Combination of PDS with FR split cardiovascular and behavioural parameters. In conclusion, food availability during the light-time in combination with PDS decreased amplitude and spectral power of circadian oscillations of BP, HR and LA more than PDS only. Different response of cardiovascular and behavioural parameters to photic and non-photic stimuli can have consequences for shift workers.
Cardiovascular (CV) health is often expressed by changes in heart rate and blood pressure, the physiological record of which may be affected by moving, anaesthesia, handling, time of day and many other factors in rodents. Telemetry measurement minimises these modulations and enables more accurate physiological recording of heart rate and blood pressure than non-invasive methods. Measurement of arterial blood pressure by telemetry requires implanting a catheter tip into the artery. Telemetry enables us to sample physiological parameters with a high frequency continuously for several months. By measuring the pressure in the artery using telemetry, we can visualize pressure changes over a heart cycle as the pressure wave. From the pressure wave, we can subtract systolic, diastolic, mean and pulse pressure. From the beat-to-beat interval (pressure wave) and the RR' interval (electrocardiogram), we can derive the heart rate. From beat-to-beat variability, we can evaluate the autonomic nervous system's activity and spontaneous baroreflex sensitivity and their impact on CV activity. On a long-term scale, circadian variability of CV parameters is evident. Circadian variability is the result of the circadian system's activity, which synchronises and organises many activities in the body, such as autonomic and reflex modulation of the CV system and its response to load over the day. In the presented review, we aimed to discuss telemetry devices, their types, implantation, set-up, limitations, short-term and long-term variability of heart rate and blood pressure in CV research. Data collection by telemetry should be, despite some limitations, standard in modern experimental CV research.
Social jetlag (SJL) is defined as the discrepancy between social and biological rhythms and calculated by the difference between the midpoint of sleep time on working-days and free-days. Previous human and mouse studies showed SJL is positively related to evening chronotype and significantly related to smoking habit, cardiovascular risk, cognitive ability, and that SJL-mimicking conditions, simulating the real lifestyle situation of SJL in many humans, disrupt the regularity of estrous cycles of female animals. The effects of SJL-mimicking conditions on circadian rhythms and cognitive function and the reasons why the discrepancy between social and biological rhythms is involved in SJL have not yet been investigated. Therefore, in this study, we utilized a mouse model of SJL-mimicking conditions – 6-hour delayed-light/dark (LD) conditions for 2 days and normal-LD conditions for the following 5 days – applied for several weeks during which biological rhythms were monitored. Circadian rhythms of central and peripheral clocks and metabolism of the mice under the SJL-mimicking condition were always delayed for 2–3 hours compared with those under the normal-LD condition. Moreover, SJL-mimicking conditions impaired their cognitive function using a novel object recognition test. Only the delayed timing of either the light phase of the LD or of feeding for 2 days, comparable to the free-days situation of humans, delayed the circadian staging of rhythms the following 5 days. Furthermore, sleep deprivation during the early mornings for 5 days, which is comparable to early rise times experienced by humans on working-days and does affect the staging of circadian rhythms (circadian misalignment schedule), delayed the locomotor activity rhythms the next 2 days, comparable to free-days in humans, which is similar to the lifestyle rhythm of the evening chronotype. Our results demonstrated that the circadian misalignment schedule for 5 days changed the locomotor activity rhythms the following 2 days to the evening chronotype, that light- and/or feeding-shift conditions for 2 days exacerbate SJL, and that SJL-mimicking conditions delay the metabolic rhythm and cause cognitive impairment.
The incidence of colorectal cancer (CRC) shows a sex-dependent difference in humans. The aim of this study was to analyze estrogen receptor beta mRNA (ERbeta) expression in patients with CRC with respect to their gender and clinicopathological features. Since cancer progression is accompanied by tumor vascularization, VEGF-A (vascular endothelial growth factor A) transcription was analyzed along with ERbeta mRNA. ERbeta mRNA was also correlated with the expression of clock genes, which are known to influence the cell cycle. ERbeta mRNA expression in females with CRC showed an inverse association with increasing tumor staging that was not observed in males. Lower levels of ERbeta mRNA were observed in females with a higher clinical stage compared with those with earlier-stage tumors. ERbeta mRNA expression showed a significant positive correlation with mRNA of clock genes period 2 and cryptochrome 2 in healthy but not in cancerous tissue in males. Expression of VEGF-A mRNA showed a negative correlation with ERbeta mRNA after splitting of the cohort according to gender and nodus involvement. We propose that gender differences in ERbeta mRNA expression in tumors during the early stages of CRC can partially explain the lower occurrence of CRC in females compared with males.
Exercise intolerance is the first symptom of heart disease. Yet an objective and standardised method in canine cardiology to assess exercise capacity in a clinical setting is lacking. In contrast, exercise testing is a powerful diagnostic tool in humans, providing valuable information on prognosis and impact of therapeutic intervention. To investigate whether an exercise test reveals differences between dogs with early stage mitral regurgitation (MR) and dogs without cardiac disease, 12 healthy beagles (healthy group, HG) and 12 dogs with presymptomatic MR (CHIEF B1 / B2, patient group, PG) underwent a six-stage submaximal exercise test (ET) on a motorised treadmill. They trotted in their individual comfort speed for three minutes per stage, first without incline, afterwards increasing it by 4% for every subsequent stage. Blood samples were taken at rest and during two 3-minute breaks in the course of the test. Further samples were taken after the completion of the exercise test and again after a 3-hour recovery period. Measured parameters included heart rate, lactate and the cardiac biomarkers N-terminal pro-B-Type natriuretic peptide and cardiac Troponin I. The test was performed again under the same conditions in the same dogs three weeks after the first trial to evaluate individual repeatability. Cardiac biomarkers increased significantly in both HG and PG in the course of the test. The increase was more pronounced in CHIEF B1 / B2 dogs than in the HG. N-terminal pro-B-Type natriuretic peptide increased from 435 ± 195 to 523 ± 239 pmol/L (HG) and from 690 to 815 pmol/L (PG). cTnI increased from 0.020 to 0.024 ng/mL (HG) and from 0.06 to 0.08 ng/ml (PG). The present study provides a method to assess exercise-induced changes in cardiac biomarkers under clinical conditions. The increase of NT-proBNP and cTnI is more pronounced in dogs with early-stage MR than in healthy dogs. Results indicate that measuring the parameters before and after exercise is adequate and taking blood samples between the different stages of the ET does not provide additional information. Also, stress echocardiography was inconclusive. It can be concluded that exercise testing, especially in combination with measuring cardiac biomarkers, could be a helpful diagnostic tool in canine cardiology.
