Review

Authors: Wei Ruan, Xiaoyi Yuan, Holger K Eltzschig...

The circadian clock evolved in diverse organisms to integrate external environmental changes and internal physiology. The clock endows the host with temporal precision and robust adaptation to the surrounding environment. When circadian rhythms are perturbed or misaligned, as a result of jet lag, shiftwork or other lifestyle factors, adverse health consequences arise, and the risks of diseases such as cancer, cardiovascular diseases or metabolic disorders increase. Although the negative impact of circadian rhythm disruption is now well established, it remains underappreciated how to take advantage of biological timing, or correct it, for health benefits. In this Review, we provide an updated account of the circadian system and highlight several key disease areas with altered circadian signalling. We discuss environmental and lifestyle modifications of circadian rhythm and clock-based therapeutic strategies, including chronotherapy, in which dosing time is deliberately optimized for maximum therapeutic index, and pharmacological agents that target core clock components and proximal regulators. Promising progress in research, disease models and clinical applications should encourage a concerted effort towards a new era of circadian medicine.

Topics: Animals; Cardiovascular Diseases; Circadian Clocks; Circadian Rhythm; Drug Administration Schedule; Drug Chronotherapy; Humans; Metabolic Diseases; Neoplasms; Time Factors

PubMed: 33589815
DOI: 10.1038/s41573-020-00109-w

Review

Authors: Yool Lee, Jeffrey M Field, Amita Sehgal...

Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. virus and parasite infections), and medical interventions (e.g. medication). With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease.

Topics: Animals; Chronotherapy; Circadian Clocks; Circadian Rhythm; Humans; Sleep

PubMed: 34547953
DOI: 10.1177/07487304211044301

Review

Authors: Ravi Allada, Joseph Bass

Topics: Cardiovascular Diseases; Chronobiology Disorders; Chronotherapy; Circadian Clocks; Circadian Rhythm; Humans; Infections; Neoplasms; Sleep Wake Disorders

PubMed: 33567194
DOI: 10.1056/NEJMra1802337

Review

Authors: Christoph Scheiermann, Yuya Kunisaki, Paul S Frenette...

Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.

Topics: Adaptive Immunity; Animals; Blood Cell Count; Chronobiology Disorders; Circadian Rhythm; Circadian Rhythm Signaling Peptides and Proteins; Disease Susceptibility; Drug Chronotherapy; Feedback, Physiological; Gene Expression Regulation; Hormones; Humans; Immune System; Immunity, Humoral; Inflammation; Mammals; Mice; Models, Immunological; Transcription, Genetic

PubMed: 23391992
DOI: 10.1038/nri3386

Review

Authors: Anand R Saran, Shravan Dave, Amir Zarrinpar...

Circadian clock proteins are endogenous timing mechanisms that control the transcription of hundreds of genes. Their integral role in coordinating metabolism has led to their scrutiny in a number of diseases, including nonalcoholic fatty liver disease (NAFLD). Discoordination between central and peripheral circadian rhythms is a core feature of nearly every genetic, dietary, or environmental model of metabolic syndrome and NAFLD. Restricting feeding to a defined daily interval (time-restricted feeding) can synchronize the central and peripheral circadian rhythms, which in turn can prevent or even treat the metabolic syndrome and hepatic steatosis. Importantly, a number of proteins currently under study as drug targets in NAFLD (sterol regulatory element-binding protein [SREBP], acetyl-CoA carboxylase [ACC], peroxisome proliferator-activator receptors [PPARs], and incretins) are modulated by circadian proteins. Thus, the clock can be used to maximize the benefits and minimize the adverse effects of pharmaceutical agents for NAFLD. The circadian clock itself has the potential for use as a target for the treatment of NAFLD.

Topics: Animals; Caloric Restriction; Circadian Rhythm; Circadian Rhythm Signaling Peptides and Proteins; Drug Chronotherapy; Energy Metabolism; Fasting; Humans; Liver; Non-alcoholic Fatty Liver Disease; Signal Transduction; Time Factors

PubMed: 32061597
DOI: 10.1053/j.gastro.2020.01.050

Review

Authors: Tobias Eckle, Júlia Bertazzo, Tarak Nath Khatua...

The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing the circadian molecular clock's significance in the pathogenesis and pathophysiology of myocardial ischemia and heart failure progression. However, translational preclinical studies targeting the heart's circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine. In this review, we explore circadian molecular mechanisms and novel therapies, including (1) intense light, (2) small molecules modulating the circadian mechanism, and (3) chronotherapies such as cardiovascular drugs and meal timings. These promise significant clinical translation in circadian medicine for cardiovascular disease. (4) Additionally, we address the differential functioning of the circadian mechanism in males versus females, emphasizing the consideration of biological sex, gender, and aging in circadian therapies for cardiovascular disease.

Topics: Male; Animals; Myocardial Reperfusion Injury; Circadian Rhythm; Chronotherapy; Heart Failure; Myocardial Ischemia; Circadian Clocks

PubMed: 38484024
DOI: 10.1161/CIRCRESAHA.123.323522

Review

Authors: Tyler A Steele, Erik K St Louis, Aleksandar Videnovic...

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.

Topics: Benzofurans; Chronobiology Disorders; Circadian Rhythm; Cyclopropanes; Humans; Neurodegenerative Diseases

PubMed: 33844152
DOI: 10.1007/s13311-021-01031-8

Authors: Ray Zhang, Nicholas F Lahens, Heather I Ballance...

To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.

Topics: Animals; Chronotherapy; Circadian Rhythm; Databases, Nucleic Acid; Gene Expression Profiling; Gene Expression Regulation; Humans; Mice; Transcriptome

PubMed: 25349387
DOI: 10.1073/pnas.1408886111

Review

Authors: Annabelle Ballesta, Pasquale F Innominato, Robert Dallmann...

Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes.

Topics: Animals; Cardiovascular Diseases; Circadian Rhythm; Drug Chronotherapy; Humans; Immune System Diseases; Metabolic Diseases; Neoplasms; Precision Medicine; Systems Biology

PubMed: 28351863
DOI: 10.1124/pr.116.013441

Authors: Jiao Wang, Qiong Huang, Xingbin Hu...

UNLABELLED

Trastuzumab is the only approved targeted drug for first-line treatment of HER2-positive advanced gastric cancer, but the high rate of primary resistance and rapid emergence of secondary resistance limit its clinical benefits. We found that trastuzumab-resistant (TR) gastric cancer cells exhibited high glycolytic activity, which was controlled by hexokinase 2 (HK2)-dependent glycolysis with a circadian pattern [higher at zeitgeber time (ZT) 6, lower at ZT18]. Mechanistically, HK2 circadian oscillation was regulated by a transcriptional complex composed of PPARγ and the core clock gene PER1. In vivo and in vitro experiments demonstrated that silencing PER1 disrupted the circadian rhythm of PER1-HK2 and reversed trastuzumab resistance. Moreover, metformin, which inhibits glycolysis and PER1, combined with trastuzumab at ZT6, significantly improved trastuzumab efficacy in gastric cancer. Collectively, these data introduce the circadian clock into trastuzumab therapy and propose a potentially effective chronotherapy strategy to reverse trastuzumab resistance in gastric cancer.

SIGNIFICANCE

In trastuzumab-resistant HER2-positive gastric cancer, glycolysis fluctuates with a circadian oscillation regulated by the BMAL1-CLOCK-PER1-HK2 axis, which can be disrupted with a metformin-based chronotherapy to overcome trastuzumab resistance.

Topics: Circadian Rhythm; Hexokinase; Humans; Metformin; Period Circadian Proteins; Stomach Neoplasms; Trastuzumab

PubMed: 35255118
DOI: 10.1158/0008-5472.CAN-21-1820