Understanding Of Circadian Rhythms Research Articles

Circadian Rhythm Sleep-Wake Disorders.

This article provides an overview of advances in the understanding of circadian rhythms and the health implications of circadian disruption. Circadian medicine is a relatively new concept, with widespread overlap with many other areas of medicine. Circadian clocks rely on feedback loops that control the expression of many genes. Functional circadian oscillators exist at multiple physiologic levels and facilitate a multimodal clock mechanism. The suprachiasmatic nucleus is the central circadian pacemaker. Peripheral tissues can be entrained by other stimuli (such as food intake) and can uncouple from the suprachiasmatic nucleus pacemaker; this discovery may provide new therapeutic options for circadian rhythm disorders. Numerous modern developments have altered our circadian clocks and these changes are associated with poor health outcomes. Circadian clocks are ubiquitous throughout our body and regulate multiple body functions. Several studies have highlighted that circadian disruption can result in significant negative mental and physical health consequences. A deeper understanding of the effects of misalignment between our circadian clocks and the external environment may ultimately have therapeutic implications for our health.

Identification of key genes modules linking diabetic retinopathy and circadian rhythm.

Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Recent studies highlighted the crucial impact of circadian rhythms (CR) on normal retinopathy in response to the external light cues. However, the role of circadian rhythms in DR pathogenesis and potential investigational drugs remains unclear. To investigate the weather CR affects DR, differential expression analysis was employed to identify differentially expressed genes (DEGs) from the GEO database (GSE160306). Functional enrichment analysis was conducted to identify relevant signaling pathways. LASSO regression was utilized to screen pivotal genes. Weighted gene co-expression network anlaysis (WGCNA) was applied to identify different modules. Additionally, we use the Comparative Toxicogenomics Database (CTD) database to search key genes related to drugs or molecular compounds. The diabetic mouse model received three consecutive intraperitoneal injections of streptozotocin (STZ) during 3 successive days. We initially identified six key genes associated with circadian rhythm in DR, including COL6A3, IGFBP2, IGHG4, KLHDC7A, RPL26P30, and MYL6P4. Compared to normal tissue, the expression levels of COL6A3 and IGFB2 were significantly increased in DR model. Furthermore, we identified several signaling pathways, including death domain binding, insulin-like growth factor I binding, and proteasome binding. We also observed that COL6A3 was positively correlated with macrophages (cor=0.628296895, p=9.96E-08) and Th17 cells (cor=0.665120835, p=9.14E-09), while IGFBP2 showed a negatively correlated with Tgd (cor=-0.459953045, p=0.000247284) and Th2 cells (cor=-0.442269719, p=0.000452875). Finally, we identified four drugs associated with key genes: Resveratrol, Vitamin E, Streptozocin, and Sulindac. Our findings revealed several key genes related to circadian rhythms and several relevant drugs in DR, providing a novel insight into the mechanism of DR and potential implications for future DR treatment. This study contributes to a better understanding of CR in DR and its implications for future therapeutic interventions.

A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.

Circadian dysregulation involves malignant tumor initiation and progression, but the understanding of circadian rhythm’s roles in bladder cancer (BCa) remains insufficient. The circadian rhythm-related genes were collected and clustered based on the Cancer Genome Atlas (TCGA), and the clustering was significantly associated with the prognosis and risk clinicopathological features. Through genomic difference analysis and gene pairing, a circadian rhythm-related signature was successfully established. Kaplan-Meier survival analysis and time-dependent receiver operating curves displayed that the prognosis model was a reliable prognosis biomarker both in the training cohort (n = 396, P = 2.687e-10) and external validation cohort (n = 224, P = 1.45e-02). The patients with high risk have high immune infiltration and high expression of immune checkpoint genes, which partly account for the poor prognosis. TIDE algorithm and the validation in IMvigor210 cohort indicated that the risk signature was a promising marker for the immunotherapeutic response. The risk model could also predict the therapeutic response of cisplatin, which was validated in the Genomics of Drug Sensitivity in Cancer database (P = 0.0049), TCGA (P = 0.038), and T24 BCa cells treated with cisplatin. The functional enrichment showed the risk model was significantly correlated with some malignant phenotypes, such as angiogenesis, epithelial-mesenchymal transition, and KRAS signaling pathway. Totally, we proposed a novel circadian rhythm-related signature for prognosis evaluation, which also helped to predict the immune infiltration and cisplatin sensitivity in BCa.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Updates on Pediatric Sleep Disorders

Pediatric sleep medicine is a developing field with recent advances in pathophysiology, diagnosis, and/or management of circadian rhythm disorders, obstructive sleep apnea, narcolepsy, and parasomnias. This article aims to provide a review and highlight recent updates in these specific sleep disorders. Our understanding of circadian rhythms and melatonin profiling is becoming clearer, which opens up new diagnostic possibilities and treatment refinement. In obstructive sleep apnea, symptoms do not clearly correlate with the apnea-hypopnea index, and other sleep measures need to be studied in order to understand how treatments may provide benefit to patients. There has been the first clinical treatment trial in pediatric narcolepsy and promising drugs are on the horizon. While parasomnia treatment has not advanced much, our understanding of its pathophysiology and associated diagnostic features is growing. Advancements across a number of areas of pediatric sleep medicine offers exciting avenues for more accurate and timely diagnoses and evidence-based management to improve patient care.

Sleep and Circadian Rhythm Disorder in Bipolar Affective Disorder.

Symptoms of affective disorders encompass a range of changes to biological processes such as sleep and appetite. These processes are regulated over a 24-h cycle known as the circadian rhythm. Sleep is a particularly useful marker of this rhythm as it is readily measurable and functionally significant. Sleep disturbance is common in bipolar affective disorder and may act as a marker, and precipitant, of relapse. Circadian rhythms are modulated by environmental and social cues and have been shown to be influenced by treatment in BPAD. As such understanding of circadian rhythms may lead to a better understanding of the pathophysiology of BPAD and its treatment. This chapter will explore the neurobiology of the circadian clock and the putative role of circadian rhythm dysregulation in the pathophysiology and treatment of bipolar affective disorder (BPAD).

William Timberlake: An Ethologist’s Psychologist

William Timberlake was one of several psychologists who, in the wake of traditional learning theory, aimed to develop an improved theoretical basis for the study of learning via greater incorporation of ecology and evolution. In this short biography, I place Timberlake’s varied work in historical context. Originally trained as a neoHullian behaviorist, Timberlake sought to integrate the laboratory approach and methodological rigor of behaviorism, with the ethologist’s interest in the animal as such. Starting at Indiana University in 1969, he stayed there his entire professional career, where he was one of the founders of the university’s internationally recognized Center for the Integrative Study of Animal Behavior. He is best known for his behavior systems theory, which characterizes animal behavior as an evolved complex hierarchically organized system. Timberlake has also made diverse contributions to the study of reinforcement, explanations of superstitious behavior and misbehavior, and the understanding of circadian rhythms and their modification, among other areas.

Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer.

Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption.

On the Adaptive Significance of Circadian Clocks for Their Owners

Circadian rhythms are believed to be an evolutionary adaptation to daily environmental cycles resulting from Earth's rotation about its axis. A trait evolved through a process of natural selection is considered as adaptation; therefore, rigorous demonstration of adaptation requires evidence suggesting evolution of a trait by natural selection. Like any other adaptive trait, circadian rhythms are believed to be advantageous to living beings through some perceived function. Circadian rhythms are thought to confer advantage to their owners through scheduling of biological functions at appropriate time of daily environmental cycle (extrinsic advantage), coordination of internal physiology (intrinsic advantage), and through their role in responses to seasonal changes. So far, the adaptive value of circadian rhythms has been tested in several studies and evidence indeed suggests that they confer advantage to their owners. In this review, we have discussed the background for development of the framework currently used to test the hypothesis of adaptive significance of circadian rhythms. Critical examination of evidence reveals that there are several lacunae in our understanding of circadian rhythms as adaptation. Although it is well known that demonstrating a given trait as adaptation (or setting the necessary criteria) is not a trivial task, here we recommend some of the basic criteria and suggest the nature of evidence required to comprehensively understand circadian rhythms as adaptation. Thus, we hope to create some awareness that may benefit future studies in this direction. (Author correspondence: vsharma@jncasr.ac.in or vksharmas@gmail.com)

Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

Heart attacks and circadian rhythms

Aims: This study has two main aims. First, to confirm a peak incidence of heart attacks (acute myocardial infarction or AMI) occurring in the early hours of the morning and second, to explore the links between acute myocardial infarction and circadian rhythms. Circadian rhythms control a host of biochemical, biological and behavioural patterns in humans. There is an internal mechanism for circadian rhythms known as the biological clock and external factors such as the light/dark cycle that ensures that our internal clock is synchronized with the environment. Methods: This is a quantitative study collating data from patients attending a district general hospital with a diagnosis of ST-segment elevation MI as part of the Myocardial Ischaemia (formerly Infarction) National Audit Database (MINAP). Results: The results of the study show that there is a significant peak in incidence of AMI in the morning hours between 6 am and 12 noon. This peak accounts for 34% of all patients presenting with AMI which is statistically significant (P<0.001). The review of the literature suggests a link between the peak in incidence of AMI and circadian rhythms. Conclusions: An understanding of circadian rhythms is important to understand how patients with AMI and other acute coronary syndromes can be treated but also how to prevent their occurrence.