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Nature Reviews. Drug Discovery Apr 2021The circadian clock evolved in diverse organisms to integrate external environmental changes and internal physiology. The clock endows the host with temporal precision... (Review)
Review
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 -
Journal of Biological Rhythms Dec 2021Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and... (Review)
Review
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 -
The New England Journal of Medicine Feb 2021
Review
Topics: Cardiovascular Diseases; Chronobiology Disorders; Chronotherapy; Circadian Clocks; Circadian Rhythm; Humans; Infections; Neoplasms; Sleep Wake Disorders
PubMed: 33567194
DOI: 10.1056/NEJMra1802337 -
Nature Reviews. Immunology Mar 2013Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian... (Review)
Review
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 -
Gastroenterology May 2020Circadian clock proteins are endogenous timing mechanisms that control the transcription of hundreds of genes. Their integral role in coordinating metabolism has led to... (Review)
Review
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 -
Hypertension (Dallas, Tex. : 1979) Mar 2023Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or... (Review)
Review
Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.
Topics: United States; Humans; Blood Pressure; National Heart, Lung, and Blood Institute (U.S.); Precision Medicine; Hypertension; Chronotherapy; Circadian Rhythm; Antihypertensive Agents
PubMed: 36448463
DOI: 10.1161/HYPERTENSIONAHA.122.19372 -
Neurotherapeutics : the Journal of the... Jan 2021Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the... (Review)
Review
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 -
JBMR Plus Oct 2021Physiological circadian (ie, 24-hour) rhythms are critical for bone health. Animal studies have shown that genes involved in the intrinsic molecular clock demonstrate... (Review)
Review
Physiological circadian (ie, 24-hour) rhythms are critical for bone health. Animal studies have shown that genes involved in the intrinsic molecular clock demonstrate potent circadian expression patterns in bone and that genetic disruption of these clock genes results in a disturbed bone structure and quality. More importantly, circulating markers of bone remodeling show diurnal variation in mice as well as humans, and circadian disruption by, eg, working night shifts is associated with the bone remodeling disorder osteoporosis. In this review, we provide an overview of the current literature on rhythmic bone remodeling and its underlying mechanisms and identify critical knowledge gaps. In addition, we discuss novel (chrono)therapeutic strategies to reduce osteoporosis by utilizing our knowledge on circadian regulation of bone. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 34693186
DOI: 10.1002/jbm4.10504 -
Disrupting Circadian Rhythm via the PER1-HK2 Axis Reverses Trastuzumab Resistance in Gastric Cancer.Cancer Research Apr 2022Trastuzumab 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...
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 -
Pharmaceutics Jul 2023Circadian rhythms are internal manifestations of the 24-h solar day that allow for synchronization of biological and behavioral processes to the external solar day. This... (Review)
Review
Circadian rhythms are internal manifestations of the 24-h solar day that allow for synchronization of biological and behavioral processes to the external solar day. This precise regulation of physiology and behavior improves adaptive function and survival. Chronotherapy takes advantage of circadian rhythms in physiological processes to optimize the timing of drug administration to achieve maximal therapeutic efficacy and minimize negative side effects. Chronotherapy for cancer treatment was first demonstrated to be beneficial more than five decades ago and has favorable effects across diverse cancer types. However, implementation of chronotherapy in clinic remains limited. The present review examines the evidence for chronotherapeutic treatment for solid tumors. Specifically, studies examining chrono-chemotherapy, chrono-radiotherapy, and alternative chronotherapeutics (e.g., hormone therapy, TKIs, antiangiogenic therapy, immunotherapy) are discussed. In addition, we propose areas of needed research and identify challenges in the field that remain to be addressed.
PubMed: 37631237
DOI: 10.3390/pharmaceutics15082023