BACKGROUND: The Chinese formula Guben-Jiannao Ye (GBJNY) formula has a long history of usage in traditional Chinese medicine (TCM) for the treatment of learning and memory disorders as well as senile insomnia. This formulation is derived from Sun Simiao\'s five tonic pills. Furthermore, modern pharmacological investigations have revealed its ability to improve cognitive impairment and ameliorate sleep-wake circadian rhythm disorders. However, the precise mechanism underlying its efficacy remains elusive.
OBJECTIVE: The current research explored the modulatory effects and possible mechanisms of GBJNY in circadian rhythm sleep-wake disorders and cognitive dysfunction in Alzheimer\'s disease using transcriptome sequencing and experimental validation.
METHODS: The LC-MS/MS tandem technology was utilized to qualitatively discern the active components present in GBJNY. The APP/PS1 mice received continuous treatment with GBJNY or Melatonin for 3 months. The learning and memory abilities of mice were assessed utilizing the Morris water maze (MWM) test, while sleep changes were studied utilizing the electroencephalogram (EEG) and electromyogram (EMG). Concurrently, mice\'s hippocampus clock gene rhythmicity was investigated. Subsequently, we employed HE staining, Golgi staining, and immunofluorescence to observe GBJNY\'s impact on synaptic damage and neuronal loss. We performed high-throughput sequencing to analyze the mRNA expression profiles of mice, aiming to identify differentially expressed genes (DEGs). Subsequently, we conducted GO and KEGG enrichment analyses to explore associated signaling pathways. Furthermore, we evaluated the expression levels of proteins involved in the PI3K/AKT/mTOR pathway and Aβ deposition in the hippocampus of mice. Through this comprehensive approach, we sought to elucidate and validate the potential mechanisms of action of GBJNY in APP/PS1 mice.
RESULTS: Results showed 216 DEGs. Following this, we conducted GO enrichment and KEGG pathway analyses to delve deeper into the distinctions and fundamental functions of the mRNA target genes. The enrichment analysis underscored the prominence of the PI3K/Akt/mTOR signaling pathway as the most pivotal among them. Through in vivo experiments, it was further demonstrated that the administration of GBJNY enhanced memory and learning capacities in APP/PS1 mice. Additionally, GBJNY treatment resulted in alterations in the sleep-wake circadian rhythm, characterized by reduced wakefulness and an increase in non-rapid eye movement (NREM) sleep. Moreover, alterations in the peak expression of Per1, Per2, Clock, Cry1, Cry2, and Bmal1 mRNA were noted in the hippocampus of treated mice. Particularly noteworthy were the observed reductions in amyloid-beta (Aβ) deposition within the hippocampus, improvements in neuronal synaptic integrity, and upregulation of mTOR, Akt, and PI3K protein expression in the hippocampal region. These findings underscore the critical involvement of the PI3K/Akt/mTOR signaling pathway in mitigating disturbances in sleep-wake circadian rhythms.
CONCLUSIONS: GBJNY enhanced the cognitive performance of APP/PS1 mice and altered clock gene expression patterns, alleviating sleep-wake circadian rhythm disruptions. The fundamental mechanism appears to be linked to the PI3K/Akt/mTOR pathway regulation, offering a foundation for potential clinical applications.

Affective disorders are frequently associated with disrupted circadian rhythms. The existence of rhythmic secretion of central serotonin (5-hydroxytryptamine, 5-HT) pattern has been reported; however, the functional mechanism underlying the circadian control of 5-HTergic mood regulation remains largely unknown. Here, we investigate the role of the circadian nuclear receptor REV-ERBα in regulating tryptophan hydroxylase 2 (Tph2), the rate-limiting enzyme of 5-HT synthesis. We demonstrate that the REV-ERBα expressed in dorsal raphe (DR) 5-HTergic neurons functionally competes with PET-1-a nuclear activator crucial for 5-HTergic neuron development. In mice, genetic ablation of DR 5-HTergic REV-ERBα increases Tph2 expression, leading to elevated DR 5-HT levels and reduced depression-like behaviors at dusk. Further, pharmacological manipulation of the mice DR REV-ERBα activity increases DR 5-HT levels and affects despair-related behaviors. Our findings provide valuable insights into the molecular and cellular link between the circadian rhythm and the mood-controlling DR 5-HTergic systems.

Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the retina are known to express the circadian clock in rodents, however, retinal clock expression in the human has not previously been localized. Moreover, the effect of local circadian clock dysfunction on retinal homeostasis is incompletely understood. We demonstrate an age-dependent decline in circadian clock gene and protein expression in the human retina. Using an animal model of targeted Bmal1 deficiency, we identify the circadian clock of the retinal Müller glia as essential for neuronal survival, vascular integrity, and retinal function. These results suggest a potential role for the local retinal circadian clock within the Müller glia in age-related retinal disease and retinal degeneration.

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UNASSIGNED: Time-restricted eating (TRE), a dietary pattern reducing the duration of daily food consumption, has recently gained popularity. Existing studies show the potential benefits of TRE for cardiometabolic health. Uncertainty remains about whether these benefits are solely from altered meal timing or influences on other health behaviors, including sleep. Despite growing scientific interest in the effects of TRE on sleep parameters, the topic has not been systematically explored.
UNASSIGNED: This review examined the effects of TRE interventions (daily fasting duration ≥14 h) lasting at least 8 weeks on objective and subjective sleep parameters. Six randomized control trials were identified through Pubmed, Embase, Google Scholar, and Scopus through September 2023.
UNASSIGNED: Of the included studies, three employed objective sleep measures using wearables and five studies assessed sleep subjectively through self-report questionnaires. Only one study reported significant improvements in subjective sleep quality following a TRE intervention. Additionally, one study found significant decreases in sleep duration, two studies found significant decreases in sleep efficiency, and one found significant increases in sleep onset latency.
UNASSIGNED: Current evidence indicates that short to mid-term TRE does not typically worsen sleep parameters. However, some populations may experience reduced sleep disturbances, while others may experience reductions in sleep efficiency. Longer duration studies with objective sleep assessments are needed to better understand the effects of TRE on sleep parameters.

Most mammalian cells have molecular circadian clocks that generate widespread rhythms in transcript and protein abundance. While circadian clocks are robust to fluctuations in the cellular environment, little is known about the mechanisms by which the circadian period compensates for fluctuating metabolic states. Here, we exploit the heterogeneity of single cells both in circadian period and a metabolic parameter-protein stability-to study their interdependence without the need for genetic manipulation. We generated cells expressing key circadian proteins (CRYPTOCHROME1/2 (CRY1/2) and PERIOD1/2 (PER1/2)) as endogenous fusions with fluorescent proteins and simultaneously monitored circadian rhythms and degradation in thousands of single cells. We found that the circadian period compensates for fluctuations in the turnover rates of circadian repressor proteins and uncovered possible mechanisms using a mathematical model. In addition, the stabilities of the repressor proteins are circadian phase dependent and correlate with the circadian period in a phase-dependent manner, in contrast to the prevailing model.

Social jetlag (SJL), resulting from misalignment between biological rhythms and social schedules, has emerged as a prevalent phenomenon in modern society, particularly among young athletes. However, the effect of SJL on performance is poorly studied. Jump and dynamic balance are two key skills in volleyball, as the first allows the player to perform better both during the offense and defense phase, and the second is fundamental in landing and in injury prevention. Therefore, our aim was to investigate the effect of SJL on jump skill performance and balance in female volleyball players. Thirty female volleyball players (mean age: 17.3 ± 0.88 years) participated in the study. SJL was assessed using the Munich ChronoType Questionnaire (MCTQ), integrated with Jankowsky\'s sleep-corrected formula. Jump skill performance was evaluated using a standardized jump test, the Vertec Jump Test, while balance was assessed with the Y Balance Test. The tests were performed at 09:00 a.m. and at 06:00 p.m. The results revealed that players with greater SJL exhibited decreased jump performance, characterized by lower vertical jump height (p = 0.02). Furthermore, players with lower SJL showed the typical difference between morning and afternoon performance (p = 0.001), demonstrating their synchronization between biological rhythms and social commitments, while no statistically significant difference between the two sessions was shown in players with higher SJL. Regarding balance, no significant association with SJL was found, but the morning session yielded lower results than the afternoon one (p = 0.01). These findings highlight the detrimental impact of SJL on jump skill performance, underscoring the importance of optimizing sleep-wake schedules and circadian alignment to enhance athletic performance. Future research should explore targeted interventions, such as sleep hygiene education, to minimize social jetlag and promote optimal performance in adolescent athletes.

Breast cancer (BC) is one of the most common and fatal malignancies among women worldwide. Circadian rhythms have emerged in recent studies as being involved in the pathogenesis of breast cancer. In this paper, we reviewed the molecular mechanisms by which the dysregulation of the circadian genes impacts the development of BC, focusing on the critical clock genes, brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK). We discussed how the circadian rhythm disruption (CRD) changes the tumor microenvironment (TME), immune responses, inflammation, and angiogenesis. The CRD compromises immune surveillance and features and activities of immune effectors, including CD8+ T cells and tumor-associated macrophages, that are important in an effective anti-tumor response. Meanwhile, in this review, we discuss bidirectional interactions: age and circadian rhythms, aging further increases the risk of breast cancer through reduced vasoactive intestinal polypeptide (VIP), affecting suprachiasmatic nucleus (SCN) synchronization, reduced ability to repair damaged DNA, and weakened immunity. These complex interplays open new avenues toward targeted therapies by the combination of clock drugs with chronotherapy to potentiate the immune response while reducing tumor progression for better breast cancer outcomes. This review tries to cover the broad area of emerging knowledge on the tumor-immune nexus affected by the circadian rhythm in breast cancer.

UNASSIGNED: A circadian rhythm of myocardial infarction has been described but there is little data on its relation with seasons and months.
UNASSIGNED: From June 2013 to June 2018, we analyzed the alerts for acute ST-segment elevation myocardial infarction (STEMI) in a Spanish region with 6.64 million inhabitants, universal health coverage, and an organized STEMI reperfusion network. We selected those patients which an identifiable culprit plaque.
UNASSIGNED: We recruited 6765 cases of STEMI due to type I acute myocardial infarction (type-I AMI), with mean age of 63.2 years (range 17-101, standard deviation [SD] 13.7), 5238 were males (77.4%) and 2801 (41.9%) were 65 years or older. The hourly distribution followed a fixed pattern in all months, with most of the events occurring between 6:00 AM and 4:00 PM, a peak at approximately 01:00 PM and a valley between 10:00 PM and 06:00 AM. No significant difference was found when comparing the mean time to first medical contact between July (the month with more daylight hours) and December (the month with shortest days). No significant differences were found between male and female patients, or between patients aged 65 years or older and younger patients. There was a close correlation between the number of events per month and the number of events occurring during the day (6 AM to 6 PM, r = 0.988, p = 0.001) and during the night (6 PM to 6 AM, r = 0.944, p < 0.001), with different slopes of the regression lines (t-test, p < 0.001), so that the difference between day-night occurrences increased with the total incidence.
UNASSIGNED: There is a circadian pattern in the presentation of STEMI that is not influenced by sex and age. The different incidence of STEMI at different times of the year does not affect the circadian pattern in terms of the shape of the curve or the mean time of presentation, although diurnal events increase more than nocturnal events, suggesting that triggers are most likely to act during vulnerable periods as determined by a circadian-based rhythm.

Disrupted sleep due to nighttime eating can raise various concerns, impacting both physical health and overall well-being. Nevertheless, there is a lack of direct evidence linking nighttime eating with the female reproduction system, possibly due to the absence of suitable models. Here, we use the laying hen, a diurnal animal maintained under ad libitum feeding, as a vertebrate model to quantify the impact of nighttime eating on reproduction and aging. To do this, we have built an Arduino-based setup that regulates food availability and exclusively tracks the eating events of individuals. Our data indicate that synchronizing food availability with the natural sleep-wake rhythm substantially improves reproduction and extends healthspan in hens. With reproductive aging becoming progressively more prevalent in contemporary society due to the trend of delayed childbearing, synchronizing eating with the natural rhythm could help mitigate reproductive aging in vertebrates and potentially in humans as well.