The impact of stress and stress hormones on endogenous clocks and circadian rhythms

In mammals, daily rhythms in physiology and behavior are under control of a circadian pacemaker situated in the suprachiasmatic nucleus (SCN). This master clock receives photic input from the retina and coordinates peripheral oscillators present in other tissues, maintaining all rhythms in the body synchronized to the environmental light-dark cycle. In line with its function as a master clock, the SCN appears to be well protected against unpredictable stressful stimuli. However, available data indicate that stress and stress hormones at certain times of day are capable of shifting peripheral oscillators in, e.g., liver, kidney and heart, which are normally under control of the SCN. Such shifts of peripheral oscillators may represent a temporary change in circadian organization that facilitates adaptation to repeated stress. Alternatively, these shifts of internal rhythms may represent an imbalance between precisely orchestrated physiological and behavioral processes that may have severe consequences for health and well-being

Chronic social defeat stress shifts peripheral circadian clocks in male mice in a tissue-specific and time-of-day dependent fashion

Uncontrollable stress is linked to the development of many diseases, some of which are associated with disrupted daily rhythms in physiology and behavior. While available data indicate that the master circadian pacemaker in the suprachiasmatic nucleus (SCN) is unaffected by stress, accumulating evidence suggest that circadian oscillators in peripheral tissues and organs can be shifted by a variety of stressors and stress hormones. In the present study, we examined effects of acute and chronic social defeat stress in mice and addressed the question of whether effects of uncontrollable stress on peripheral clocks are tissue specific and depend on time of day of stress exposure. We used mice that carry a luciferase reporter gene fused to the circadian clock gene Period2 (PER2::LUC) to examine daily rhythms of PER2 expression in various peripheral tissues. Mice were exposed to social defeat stress in the early (ZT13-14) or late (ZT21-22) dark phase, either once (acute stress) or repeatedly on 10 consecutive days (chronic stress). One hour after the last stressor, tissue samples from liver, lung, kidney, and white adipose tissue (WAT) were collected. Social defeat stress caused a phase delay of several hours in the rhythm of PER2 expression in lung and kidney, but this delay was stronger after chronic than after acute stress. Moreover, shifts only occurred after stress in the late dark phase, not in the early dark phase. PER2 rhythms in liver and WAT were not significantly shifted by social defeat, suggesting a different response of various peripheral clocks to stress. This study indicates that uncontrollable social defeat stress is capable of shifting peripheral clocks in a time of day dependent and tissue specific manner. These shifts in peripheral clocks were smaller or absent after a single stress exposure and may therefore be the consequence of a cumulative chronic stress effect

Hypoxia associated multi-omics molecular landscape of tumor tissue in patients with hepatocellular carcinoma

The present study was designed to update the knowledge about hypoxia-related multi-omic molecular landscape in hepatocellular carcinoma (HCC) tissues. Large-size HCC datasets from multiple centers were collected. The hypoxia exposure of tumor tissue from patients in 10 HCC cohorts was estimated using a novel HCC-specific hypoxia score system constructed in our previous study. A comprehensive bioinformatical analysis was conducted to compare hypoxia-associated multi-omic molecular features in patients with a high hypoxia score to a low hypoxia score. We found that patients with different exposure to hypoxia differed significantly in transcriptomic, genomic, epigenomic, and proteomic alterations, including differences in mRNA, microRNA (miR), and long non-coding RNA (lncRNA) expression, differences in copy number alterations (CNAs), differences in DNA methylation levels, differences in RNA alternative splicing events, and differences in protein levels. HCC survival-associated molecular events were identified. The potential correlation between molecular features related to hypoxia has also been explored, and various networks have been constructed. We revealed a particularly comprehensive hypoxia-related molecular landscape in tumor tissues that provided novel evidence and perspectives to explain the role of hypoxia in HCC. Clinically, the data obtained from the present study may enable the development of individualized treatment or management strategies for HCC patients with different levels of hypoxia exposure.</p

Effects of stress on circadian organization: how social defeat stress changes the alignment of peripheral circadian clocks

All organs in our body display 24-hour rhythms, regulated by interacting clock genes and proteins in the cells. All these organs and their rhythms are precisely tuned to each other to provide optimal support for our behaviour and performance. The brain contains a small group of nerve cells, called the suprachiasmatic nucleus (SCN), which coordinates the rhythms elsewhere in the body and also assures these rhythms are synchronized to the day-night cycle in the world around us. A disturbance in this system of clocks and rhythms can have a major impact on our well-being and health. One factor that may cause such disturbance in this so-called circadian system is stress. While the master clock in the SCN appears to be well protected against effects of stress, previous research showed that uncontrollable stress may shift the rhythms in peripheral organs. This new research in mice shows that effects of social stress on peripheral rhythms are tissue-specific and time-of-day dependent. It also shows that effects of stress accumulated with repeated or chronic stress. The shifts in peripheral rhythms could at least partly be explained by glucocorticoid stress hormones, which are released by the adrenal glands during stress. Although the hormone melatonin is generally seen as an important signal that is used by the SCN to coordinate peripheral rhythms, in the present studies it could not prevent the effects of stress

Clinical Features and Management of Urethral Foreign Bodies in Children: A 10-Year Retrospective Study

(1) Background: Urethral foreign bodies (UFBs) are very rare in children, and their treatment remains challenging. (2) Methods: A retrospective analysis was performed on 40 patients who were admitted to our hospital due to UFBs from June 2011 to June 2021. The clinical features and treatment experiences of these children are summarized. (3) Results: A total of 40 children were enrolled in the study, 17 boys and 23 girls. A majority of the boys (median age: 11.8 years) were of puberal age, and the main cause of the UFBs was sexual gratification (94.1%). Girls were almost always in early childhood (median age: 1.8 years), and most of the UFBs were related to specific clothing in specific regions and seasons. Ultrasound had a high accuracy in the diagnosis of female UFBs; the sensitivity and specificity were 88.9% and 85.7%, respectively. Most UFBs could be removed using a cystoscope (82.4% in boys, 100% in girls). All the children had a good prognosis and no complications occurred during follow-up. (4) Conclusions: Ultrasound is a reliable and sensitive method for the diagnosis of UFBs in girls. Cystoscopy is a reliable surgical method for UFBs

Melatonin does not affect the stress-induced phase shifts of peripheral clocks in male mice

Repeated or chronic stress can change the phase of peripheral circadian rhythms. Melatonin (Mel) is thought to be a circadian clock-controlled signal that might play a role in synchronizing peripheral rhythms, in addition to its direct suppressing effects on the stress axis. In this study we test whether Mel can reduce the social-defeat stress–induced phase shifts in peripheral rhythms, either by modulating circadian phase or by modulating the stress axis. Two experiments were performed with male Mel-deficient C57BL/6J mice carrying the circadian reporter gene construct (PER2::LUC). In the first experiment, mice received night-restricted (ZT11-21) Mel in their drinking water, resulting in physiological levels of plasma Mel peaking in the early dark phase. This treatment facilitated re-entrainment of the activity rhythm to a shifted light-dark cycle, but did not prevent the stress-induced (ZT21-22) reduction of activity during stress days. Also, this treatment did not attenuate the phase-delaying effects of stress in peripheral clocks in the pituitary, lung, and kidney. In a second experiment, pituitary, lung, and kidney collected from naive mice (ZT22-23), were treated with Mel, dexamethasone (Dex), or a combination of the two. Dex application affected PER2 rhythms in the pituitary, kidney, and lung by changing period, phase, or both. Administering Mel did not influence PER2 rhythms nor did it alleviate Dex-induced delays in PER2 rhythms in those tissues. We conclude that exogenous Mel is insufficient to affect peripheral PER2 rhythms and reduce stress effects on locomotor activity and phase changes in peripheral tissues.</p

Melatonin Does Not Affect the Stress-Induced Phase Shifts of Peripheral Clocks in Male Mice

Repeated or chronic stress can change the phase of peripheral circadian rhythms. Melatonin (Mel) is thought to be a circadian clock-controlled signal that might play a role in synchronizing peripheral rhythms, in addition to its direct suppressing effects on the stress axis. In this study we test whether Mel can reduce the social-defeat stress–induced phase shifts in peripheral rhythms, either by modulating circadian phase or by modulating the stress axis. Two experiments were performed with male Mel-deficient C57BL/6J mice carrying the circadian reporter gene construct (PER2::LUC). In the first experiment, mice received night-restricted (ZT11-21) Mel in their drinking water, resulting in physiological levels of plasma Mel peaking in the early dark phase. This treatment facilitated re-entrainment of the activity rhythm to a shifted light-dark cycle, but did not prevent the stress-induced (ZT21-22) reduction of activity during stress days. Also, this treatment did not attenuate the phase-delaying effects of stress in peripheral clocks in the pituitary, lung, and kidney. In a second experiment, pituitary, lung, and kidney collected from naive mice (ZT22-23), were treated with Mel, dexamethasone (Dex), or a combination of the two. Dex application affected PER2 rhythms in the pituitary, kidney, and lung by changing period, phase, or both. Administering Mel did not influence PER2 rhythms nor did it alleviate Dex-induced delays in PER2 rhythms in those tissues. We conclude that exogenous Mel is insufficient to affect peripheral PER2 rhythms and reduce stress effects on locomotor activity and phase changes in peripheral tissues.</p

Data files supporting the figures and analyses in Kong et al. - Melatonin Does Not Affect the Stress-Induced Phase Shifts of Peripheral Clocks in Male Mice

AbstractRepeated or chronic stress can change the phase of peripheral circadian rhythms. Melatonin is thought to be a circadian clock-controlled signal that might play a role in synchronizing peripheral rhythms, in addition to its direct suppressing effects on the stress axis. In this study we test whether melatonin can reduce the social-defeat stress induced phase shifts in peripheral rhythms, either by modulating circadian phase or by modulating the stress axis. Two experiments were performed with male melatonin deficient C57BL/6J mice carrying the circadian reporter gene construct (PER2::LUC). In the first experiment, mice received night-restricted (ZT11-21) melatonin in their drinking water, resulting in physiological levels of plasma melatonin peaking in the early dark phase. This treatment facilitated re-entrainment of the activity rhythm to a shifted light-dark cycle, but did not prevent the stress-induced (ZT21-22) reduction of activity during stress days. Also, this treatment did not attenuate the phase delaying effects of stress in peripheral clocks in the pituitary, lung and kidney. In a second experiment, pituitary, lung and kidney collected from naïve mice (ZT22-23), were treated with melatonin (Mel), dexamethasone (Dex), or a combination of the two. Dex application affected PER2 rhythms in the pituitary, kidney and lung, by changing period, phase or both. Administering Mel did not influence PER2 rhythms nor did it alleviate Dex-induced delays in PER2 rhythms in those tissues. We conclude that exogenous melatonin is insufficient to affect peripheral PER2 rhythms and reduce stress effects on locomotor activity and phase changes in peripheral tissues.</p

Adrenalectomy prevents the effects of social defeat stress on PER2 rhythms in some peripheral tissues in male mice

While stress does not affect the phase or period of the central pacemaker in the suprachiasmatic nucleus, it can shift clocks in peripheral tissues. Our previous studies showed significant delays of the PER2 rhythms in lung and kidney following social defeat stress. The mechanism underlying these effects is not fully understood, but might involve glucocorticoids (GC) released during the stressor. In the present study, we performed social defeat stress in adrenalectomized (ADX) mice to see if the induction of endogenous GC is necessary for the stress-induced phase shifts of peripheral clocks. We used mice that carry a luciferase reporter gene fused to the circadian clock gene Period2 (PER2::LUC) to examine daily rhythms of PER2 expression in various peripheral tissues. Mice were exposed to 5 consecutive daily social defeat stress in the late dark phase (ZT21-22). Running wheel rotations were recorded during 7 baseline and 5 social defeat days, which showed that social defeat stress suppressed locomotor activity without affecting the phase of the rhythm. This suppression of activity was not prevented by ADX. One hour after the last stressor, tissue samples from the liver, kidney and lung were collected and cultured for ex vivo bioluminescence recordings. In the liver, PER2 rhythms were not affected by social defeat stress or ADX. In the kidney, social defeat stress caused a > 4 h phase delay of the PER2 rhythm, which was prevented by ADX, supporting the hypothesis of a crucial role of GC in this stress effect. In the lung, social defeat stress caused an 8 h phase delay, but, surprisingly, a similar phase delay was seen in ADX animals independent of defeat. The latter indicates complex effects of stress and stress hormones on the lung clock. In conclusion, the findings show that repeated social defeat stress in the dark phase can shift PER2 rhythms in some tissues (lung, kidney) and not others (liver). Moreover, the social defeat stress effect in some tissues appears to be mediated by glucocorticoids (kidney) whereas the mechanism in other tissues is more complex (lung)