The Impact of Time-Restricted Meal Intake on Glycemic Control and Weight Management in Type 2 Diabetes Mellitus Patients: An 18-Month Longitudinal Study.

AIMS: This study aimed to investigate the impact of time-restricted meal intake (TRM) on anthropometric and biochemical parameters in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 400 patients diagnosed with T2DM were selected from the Endocrinology Department at King George's Medical University (KGMU), Lucknow, based on the American Diabetes Association (ADA) guidelines and specific criteria. A total of 127 patients were lost to follow-up, resulting in 273 patients who completed the study. The patients were randomly assigned to two groups: the TRM group (consenting to have an early dinner at 7 pm) and the control group (non-TRM/late-night eater group). Baseline data were recorded, and follow-up assessments were conducted at six months, 12 months, and 18 months. Informed consent was obtained, and a diet chart was regularly maintained and updated. RESULTS:  The TRM group experienced a significant weight loss of 3.88 kg (5.45%) and a substantial reduction in BMI by 1.5 units (5.26%). In contrast, the non-TRM/control group had smaller reductions in weight (1.36 kg, 1.77%) and BMI (0.5 units, 1.65%). TRM group showed significant reductions in fasting blood sugar levels by 33.9 mg/dl (21.17%), postprandial blood sugar levels by 94.6 mg/dl (38.88%), and glycosylated hemoglobin (HbA1c) levels by 1.37 (15.87%). These improvements were significantly greater than the reductions observed in the control group, which had decreases of 29.3 mg/dl (17.85%) in fasting blood sugar levels, 41.6 mg/dl (16.84%) in postprandial blood sugar levels, and 0.59 (6.89%) in HbA1c levels. CONCLUSION: Our findings underscore the potential of TRM as an effective strategy for weight management and glycemic control in patients with T2DM, even in a long-term context. These results support time-restricted eating as a sustainable lifestyle modification for managing chronic metabolic diseases.

Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with type 2 diabetes: a randomized crossover trial.

Exercise is recommended in the treatment of type 2 diabetes and can improve insulin sensitivity. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia. Metformin is the most commonly prescribed initial pharmacological intervention in type 2 diabetes, and may alter adaptions to exercise. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to investigate glycaemic outcomes of moderate intensity morning vs. evening exercise in people with type 2 diabetes being prescribed metformin monotherapy. In this study, nine males and nine females with type 2 diabetes undergoing metformin monotherapy (age 61 ± 8.2 years, mean ± SD) completed a 16-week crossover trial including 2-week baseline recording, 6 weeks randomly assigned to a morning exercise (07.00-10.00 h) or evening exercise (16.00-19.00 h) and a 2-week wash-out period. Exercise arms consisted of 30 min of walking at 70% of estimated max heart rate every other day. Glucose levels were measured with continuous glucose monitors and activity measured by wrist-worn monitors. Food-intake was recorded by 4-day food diaries during baseline, first and last 2 weeks of each exercise arm. There was no difference in exercise intensity, total caloric intake or total physical activity between morning and evening arms. As primary outcomes, acute (24 h) glucose area under the curve (AUC), was lower (P = 0.02) after acute morning exercise (180.6 ± 68.4 mmol/l) compared to baseline (210.3 ± 76.7 mmol/l); and there were no differences identified for glucose (mmol/l) between baseline, morning and evening exercise at any specific time point when data were analysed with two-way ANOVA. As secondary outcomes, acute glucose AUC was significantly lower (P = 0.01) in participants taking metformin before breakfast (152.5 ± 29.95 mmol/l) compared with participants taking metformin after breakfast (227.2 ± 61.51 mmol/l) only during the morning exercise arm; and during weeks 5-6 of the exercise protocol, glucose AUC was significantly lower (P = 0.04) for participants taking metformin before breakfast (168.8 ± 15.8 mmol/l), rather than after breakfast (224.5 ± 52.0 mmol/l), only during morning exercise. Our data reveal morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. This beneficial effect upon glucose levels of combined morning exercise and pre-breakfast metformin persisted through the final 2 weeks of the trial. Our findings suggest that morning moderate intensity exercise combined with pre-breakfast metformin intake may benefit the management of glycaemia in people with type 2 diabetes. KEY POINTS: Morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. Morning exercise combined with pre-breakfast metformin persistently reduced glucose compared to morning exercise combined with post-breakfast metformin through the final week (week 6) of the intervention. Our study suggests it may be possible to make simple changes to the time that people with type 2 diabetes take metformin and perform exercise to improve their blood glucose.

Circadian neurogenetics and its implications in neurophysiology, behavior, and chronomedicine.

The circadian rhythm affects multiple physiological processes, and disruption of the circadian system can be involved in a range of disease-related pathways. The genetic underpinnings of the circadian rhythm have been well-studied in model organisms. Significant progress has been made in understanding how clock genes affect the physiological functions of the nervous system. In addition, circadian timing is becoming a key factor in improving drug efficacy and reducing drug toxicity. The circadian biology of the target cell determines how the organ responds to the drug at a specific time of day, thus regulating pharmacodynamics. The current review brings together recent advances that have begun to unravel the molecular mechanisms of how the circadian clock affects neurophysiological and behavioral processes associated with human brain diseases. We start with a brief description of how the ubiquitous circadian rhythms are regulated at the genetic, cellular, and neural circuit levels, based on knowledge derived from extensive research on model organisms. We then summarize the latest findings from genetic studies of human brain disorders, focusing on the role of human clock gene variants in these diseases. Lastly, we discuss the impact of common dietary factors and medications on human circadian rhythms and advocate for a broader application of the concept of chronomedicine.

[Circadian rhythm and health: dialogue between traditional Chinese medicine and modern medicine].

Circadian rhythm refers to the daily rhythmic variations in an organism. The irregular lifestyles of modern humans have led to a high incidence of chronic diseases, highlighting an inseparable relationship between disrupted circadian rhythm and disease development. TCM has long discussed rhythmic variations, with records dating back to the Yellow Emperor's Inner Canon(Huang Di Nei Jing), which laid a rich theoretical foundation for the research on circadian rhythm. Modern medical research has provided a more comprehensive explanation of its molecular mechanisms. This article integrated the current understanding of circadian rhythm in both Chinese and western medicine, emphasizing the crucial relationship between rhythm regulation and disease treatment. By highlighting the interdisciplinary nature of the two fields, it offers new directions for exploring the field of chronomedicine.

Advances in circadian clock regulation of reproduction.

The mammalian circadian clock is an endogenously regulated oscillator that is synchronized with solar time and cycle within a 24-h period. The circadian clock exists not only in the suprachiasmatic nucleus (SCN) of the hypothalamus, a central pacemaker of the circadian clock system, but also in numerous peripheral tissues known as peripheral circadian oscillators. The SCN and peripheral circadian oscillators mutually orchestrate the diurnal rhythms of various physiological and behavioral processes in a hierarchical manner. In the past two decades, peripheral circadian oscillators have been identified and their function has been determined in the mammalian reproductive system and its related endocrine glands, including the hypothalamus, pituitary gland, ovaries, testes, uterus, mammary glands, and prostate gland. Increasing evidence indicates that both the SCN and peripheral circadian oscillators play discrete roles in coordinating reproductive processes and optimizing fertility in mammals. The present study reviews recent evidence on circadian clock regulation of reproductive function in the hypothalamic-pituitary-gonadal axis and reproductive system. Additionally, we elucidate the effects of chronodisruption (as a result of, for example, shift work, jet lag, disrupted eating patterns, and sleep disorders) on mammalian reproductive performance from multiple aspects. Finally, we propose potential behavioral changes or pharmaceutical strategies for the prevention and treatment of reproductive disorders from the perspective of chronomedicine. Conclusively, this review will outline recent evidence on circadian clock regulation of reproduction, providing novel perspectives on the role of the circadian clock in maintaining normal reproductive functions and in diseases that negatively affect fertility.

Circadian biology to advance therapeutics for mood disorders.

Mood disorders account for a significant global disease burden, and pharmacological innovation is needed as existing medications are suboptimal. A wide range of evidence implicates circadian and sleep dysfunction in the pathogenesis of mood disorders, and there is growing interest in these chronobiological pathways as a focus for treatment innovation. We review contemporary evidence in three promising areas in circadian-clock-based therapeutics in mood disorders: targeting the circadian system informed by mechanistic molecular advances; time-tailoring of medications; and personalizing treatment using circadian parameters. We also consider the limitations and challenges in accelerating the development of new circadian-informed pharmacotherapies for mood disorders.

Watching the clock in glioblastoma.

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 14.2% of all diagnosed tumors and 50.1% of all malignant tumors, and the median survival time is approximately 8 months irrespective of whether a patient receives treatment without significant improvement despite expansive research (Ostrom QT, Price M, Neff C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neurooncology. 2022; 24(suppl 5):v1-v95.). Recently, important roles for the circadian clock in GBM tumorigenesis have been reported. Positive regulators of circadian-controlled transcription, brain and muscle ARNT-like 1 (BMAL1), and circadian locomotor output cycles kaput (CLOCK), are highly expressed also in GBM and correlated with poor patient prognosis. BMAL1 and CLOCK promote the maintenance of GBM stem cells (GSCs) and the establishment of a pro-tumorigenic tumor microenvironment (TME), suggesting that targeting the core clock proteins may augment GBM treatment. Here, we review findings that highlight the critical role the circadian clock plays in GBM biology and the strategies by which the circadian clock can be leveraged for GBM treatment in the clinic moving forward.

Molecular crosstalk between circadian clock and cancer and therapeutic implications.

The circadian clock governs activity of many physiological processes, thereby playing a pivotal role in human health. Circadian disruption is closely associated with cancer development; in particular, recent discoveries have provided strong evidence supporting specific functions of different molecular clock components in either promoting or inhibiting tumorigenesis. This narrative review aims to summarize the existing data on molecular connections between the clock and cancer. These results along with future efforts pave the road to targeting the circadian clock as a novel pathway for therapeutic intervention. Given the implications of chrono-nutrition interventions such as time-restricted feeding in extending lifespan, chrono-nutrition may have preventive and therapeutic applications for individuals with and at-risk of age-related diseases including cancer.

The Promises of Proteomics and Metabolomics for Unravelling the Mechanism and Side Effect Landscape of Beta-Adrenoceptor Antagonists in Cardiovascular Therapeutics.

Cardiovascular medicine witnessed notable advances for the past decade. Multiomics research offers a new lens for precision/personalized medicine for existing and emerging drugs used in the cardiovascular clinic. Beta-blockers are vital in treating hypertension and chronic heart failure. However, clinical use of beta-blockers is also associated with side effects and person-to-person variations in their pharmacokinetics and pharmacodynamics. A comprehensive understanding of the mechanisms that underpin the side effect landscape of beta-blockers is imperative to optimize their therapeutic value. In addition, current research emphasizes the circadian clock's vital roles in regulating pharmacological parameters. Administration of the beta-blockers at specific dosing times could potentially improve their effectiveness and reduce their toxic effects. The rapid development of mass spectrometry technologies with chemical proteomics and thermal proteome profiling methods has also substantially advanced our understanding of underlying side effects mechanisms by unbiased deconvolution of drug targets and off-targets. Metabolomics is steadily demonstrating its utility for conducting mechanistic and toxicological analyses of pharmacological compounds. This article discusses the promises of cutting-edge proteomics and metabolomics approaches to investigate the molecular targets, mechanism of action, adverse effects, and dosing time dependency of beta-blockers.

Data integration and analysis for circadian medicine.

Data integration, data sharing, and standardized analyses are important enablers for data-driven medical research. Circadian medicine is an emerging field with a particularly high need for coordinated and systematic collaboration between researchers from different disciplines. Datasets in circadian medicine are multimodal, ranging from molecular circadian profiles and clinical parameters to physiological measurements and data obtained from (wearable) sensors or reported by patients. Uniquely, data spanning both the time dimension and the spatial dimension (across tissues) are needed to obtain a holistic view of the circadian system. The study of human rhythms in the context of circadian medicine has to confront the heterogeneity of clock properties within and across subjects and our inability to repeatedly obtain relevant biosamples from one subject. This requires informatics solutions for integrating and visualizing relevant data types at various temporal resolutions ranging from milliseconds and seconds to minutes and several hours. Associated challenges range from a lack of standards that can be used to represent all required data in a common interoperable form, to challenges related to data storage, to the need to perform transformations for integrated visualizations, and to privacy issues. The downstream analysis of circadian rhythms requires specialized approaches for the identification, characterization, and discrimination of rhythms. We conclude that circadian medicine research provides an ideal environment for developing innovative methods to address challenges related to the collection, integration, visualization, and analysis of multimodal multidimensional biomedical data.

The circadian neurobiology of reward.

Circadian clocks are important regulators of physiology and behavior. In the brain, circadian clocks have been described in many centers of the central reward system. They affect neurotransmitter signaling, neuroendocrine circuits, and the sensitivity to external stimulation. Circadian disruption affects reward signaling, promoting the development of behavioral and substance use disorders. In this review, we summarize our current knowledge of circadian clock-reward crosstalk. We show how chronodisruption affects reward signaling in different animal models. We then translate these findings to circadian aspects of human reward (dys-) function and its clinical implications. Finally, we devise approaches to and challenges in implementing the concepts of circadian medicine in the therapy of substance use disorders.

Chronobiological parameters as predictors of early treatment response in major depression.

BACKGROUND: Alterations in circadian system organization have been related to major depressive disorder manifestations. This study aimed to evaluate chronobiological parameters, such as sleep, levels of 6-sulfatoxymelatonin, and others derived from actimetry as potential predictors of adequate treatment response in MDD. METHODS: 98 adult women with confirmed diagnosis of MDD were included. Participants completed standard questionnaires (Hamilton Depression Rating Scale - HAM-D; Munich Chronotype Questionnaire - MCTQ) at baseline and after 4 weeks of treatment. Urinary samples for assessing 6-sulfatoxymelatonin were collected on the day before and immediately after pharmacological treatment administration, and 28 continuous days of actigraphy data were collected during the protocol. Participants were classified into Responder (R) or Non-responder (NR) to antidepressant treatment in 4 weeks (early responder), which was characterized by a ≥50 % decrease in the HAM-D score. RESULTS: The following biological rhythms variables significantly predicted a better treatment response in a model controlling for age, sex, and previous treatments: higher levels of activity (M10 - average activity in the 10 most active hours within the 24 h-day) and an earlier center of the 10 most active hours (M10c), as well as lower intradaily variability (IV) of light exposure. Sleep parameters and 6-sulfatoxymelatonin levels did not associate with treatment response prediction. LIMITATION: Actimetry data were not assessed before changing in the treatment plan. CONCLUSION: Different patterns in activity and light exposure might be linked to early antidepressant response.

Circadian medicine for aging attenuation and sleep disorders: Prospects and challenges.

Aging causes progressive deterioration of daily rhythms in behavioral and metabolic processes and disruption in the regular sleep-wake cycle. Circadian disruption is directly related to diverse age-induced health abnormalities. Rising evidence from various organisms shows that core clock gene mutations cause premature aging, reduced lifespan, and sleeping irregularities. Improving the clock functions and correcting its disruption by pharmacological interventions or time-regulated feeding patterns could be a novel avenue for effective clinical management of aging and sleep disorders. To this end, many drugs for sleep disorders and anti-aging compounds interact with the core clock machinery and alter the circadian output. Evaluation of dosing time-dependency and circadian regulation of drug metabolism for therapeutic improvement of the existing drugs is another fundamental facet of chronomedicine. Multiple studies have demonstrated dose-dependent manipulation of the circadian period and phase-shifting by pharmacologically active compounds. The chronobiology research field is gradually moving towards the development of novel therapeutic strategies based on targeting the molecular clock or dosing time-oriented medications. However, such translational research ventures would require more experimental evidence from studies on humans. This review discusses the impact of circadian rhythms on aging and sleep, emphasizing the potentiality of circadian medicine in aging attenuation and sleep disorders.

Circadian clocks in health and disease: Dissecting the roles of the biological pacemaker in cancer.

In modern society, there is a growing population affected by circadian clock disruption through night shift work, artificial light-at-night exposure, and erratic eating patterns. Concurrently, the rate of cancer incidence in individuals under the age of 50 is increasing at an alarming rate, and though the precise risk factors remain undefined, the potential links between circadian clock deregulation and young-onset cancers is compelling. To explore the complex biological functions of the clock, this review will first provide a framework for the mammalian circadian clock in regulating critical cellular processes including cell cycle control, DNA damage response, DNA repair, and immunity under conditions of physiological homeostasis. Additionally, this review will deconvolute the role of the circadian clock in cancer, citing divergent evidence suggesting tissue-specific roles of the biological pacemaker in cancer types such as breast, lung, colorectal, and hepatocellular carcinoma. Recent evidence has emerged regarding the role of the clock in the intestinal epithelium, as well as new insights into how genetic and environmental disruption of the clock is linked with colorectal cancer, and the molecular underpinnings of these findings will be discussed. To place these findings within a context and framework that can be applied towards human health, a focus on how the circadian clock can be leveraged for cancer prevention and chronomedicine-based therapies will be outlined.

Keeping an eye on circadian time in clinical research and medicine.

BACKGROUND: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. CONTENT: The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. CONCLUSION: Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

Planetary sleep medicine: Studying sleep at the individual, population, and planetary level.

Circadian rhythms are a series of endogenous autonomous oscillators that are generated by the molecular circadian clock which coordinates and synchronizes internal time with the external environment in a 24-h daily cycle (that can also be shorter or longer than 24 h). Besides daily rhythms, there exist as well other biological rhythms that have different time scales, including seasonal and annual rhythms. Circadian and other biological rhythms deeply permeate human life, at any level, spanning from the molecular, subcellular, cellular, tissue, and organismal level to environmental exposures, and behavioral lifestyles. Humans are immersed in what has been called the "circadian landscape," with circadian rhythms being highly pervasive and ubiquitous, and affecting every ecosystem on the planet, from plants to insects, fishes, birds, mammals, and other animals. Anthropogenic behaviors have been producing a cascading and compounding series of effects, including detrimental impacts on human health. However, the effects of climate change on sleep have been relatively overlooked. In the present narrative review paper, we wanted to offer a way to re-read/re-think sleep medicine from a planetary health perspective. Climate change, through a complex series of either direct or indirect mechanisms, including (i) pollution- and poor air quality-induced oxygen saturation variability/hypoxia, (ii) changes in light conditions and increases in the nighttime, (iii) fluctuating temperatures, warmer values, and heat due to extreme weather, and (iv) psychological distress imposed by disasters (like floods, wildfires, droughts, hurricanes, and infectious outbreaks by emerging and reemerging pathogens) may contribute to inducing mismatches between internal time and external environment, and disrupting sleep, causing poor sleep quantity and quality and sleep disorders, such as insomnia, and sleep-related breathing issues, among others. Climate change will generate relevant costs and impact more vulnerable populations in underserved areas, thus widening already existing global geographic, age-, sex-, and gender-related inequalities.

Diurnal and circadian rhythmicity of the human blood transcriptome overlaps with organ- and tissue-specific expression of a non-human primate.

BACKGROUND: Twenty-four-hour rhythmicity in mammalian tissues and organs is driven by local circadian oscillators, systemic factors, the central circadian pacemaker and light-dark cycles. At the physiological level, the neural and endocrine systems synchronise gene expression in peripheral tissues and organs to the 24-h-day cycle, and disruption of such regulation has been shown to lead to pathological conditions. Thus, monitoring rhythmicity in tissues/organs holds promise for circadian medicine; however, most tissues and organs are not easily accessible in humans and alternative approaches to quantify circadian rhythmicity are needed. We investigated the overlap between rhythmic transcripts in human blood and transcripts shown to be rhythmic in 64 tissues/organs of the baboon, how these rhythms are aligned with light-dark cycles and each other, and whether timing of tissue-specific rhythmicity can be predicted from a blood sample. RESULTS: We compared rhythmicity in transcriptomic time series collected from humans and baboons using set logic, circular cross-correlation, circular clustering, functional enrichment analyses, and least squares regression. Of the 759 orthologous genes that were rhythmic in human blood, 652 (86%) were also rhythmic in at least one baboon tissue and most of these genes were associated with basic processes such as transcription and protein homeostasis. In total, 109 (17%) of the 652 overlapping rhythmic genes were reported as rhythmic in only one baboon tissue or organ and several of these genes have tissue/organ-specific functions. The timing of human and baboon rhythmic transcripts displayed prominent 'night' and 'day' clusters, with genes in the dark cluster associated with translation. Alignment between baboon rhythmic transcriptomes and the overlapping human blood transcriptome was significantly closer when light onset, rather than midpoint of light, or end of light period, was used as phase reference point. The timing of overlapping human and baboon rhythmic transcriptomes was significantly correlated in 25 tissue/organs with an average earlier timing of 3.21 h (SD 2.47 h) in human blood. CONCLUSIONS: The human blood transcriptome contains sets of rhythmic genes that overlap with rhythmic genes of tissues/organs in baboon. The rhythmic sets vary across tissues/organs, but the timing of most rhythmic genes is similar in human blood and baboon tissues/organs. These results have implications for development of blood transcriptome-based biomarkers for circadian rhythmicity in tissues and organs.

Circadian clock synchrony and chronotherapy opportunities in cancer treatment.

Cell-autonomous, tissue-specific circadian rhythms in gene expression and cellular processes have been observed throughout the human body. Disruption of daily rhythms by mistimed exposure to light, food intake, or genetic mutation has been linked to cancer development. Some medications are also more effective at certain times of day. However, a limited number of clinical studies have examined daily rhythms in the patient or drug timing as treatment strategies. This review highlights advances and challenges in cancer biology as a function of time of day. Recent evidence for daily rhythms and their entrainment in tumors indicate that personalized medicine should include understanding and accounting for daily rhythms in cancer patients.

Circadian Timekeeping in Anticancer Therapeutics: An Emerging Vista of Chronopharmacology Research.

BACKGROUND: Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Circadian medicine in cancer is principally reliant on the control of growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. In recent years, based on extensive high-throughput studies, we witnessed the arrival of several drugs and drug-like compounds that can modulate circadian timekeeping for therapeutic gain in cancer management. OBJECTIVE: This perspective article intends to illustrate the current trends in circadian medicine in cancer, focusing on clock-modulating pharmacological compounds and circadian regulation of anticancer drug metabolism and efficacy. Scope and Approach: Considering the critical roles of the circadian clock in metabolism, cell signaling, and apoptosis, chronopharmacology research is exceedingly enlightening for understanding cancer biology and improving anticancer therapeutics. In addition to reviewing the relevant literature, we investigated the rhythmic expression of molecular targets for many anticancer drugs frequently used to treat different cancer types. Key Findings and Conclusion: There are adequate empirical pieces of evidence supporting circadian regulation of drug metabolism, transport, and detoxification. Administration of anticancer drugs at specific dosing times can improve their effectiveness and reduce the toxic effects. Moreover, pharmacological modulators of the circadian clock could be used for targeted anticancer therapeutics such as boosting circadian rhythms in the host can markedly reduce the growth and viability of tumors. All in all, precision chronomedicine can offer multiple advantages over conventional anticancer therapy.

Clocks, Rhythms, Sex, and Hearts: How Disrupted Circadian Rhythms, Time-of-Day, and Sex Influence Cardiovascular Health.

Cardiovascular diseases are the top cause of mortality in the United States, and ischemic heart disease accounts for 16% of all deaths around the world. Modifiable risk factors such as diet and exercise have often been primary targets in addressing these conditions. However, mounting evidence suggests that environmental factors that disrupt physiological rhythms might contribute to the development of these diseases, as well as contribute to increasing other risk factors that are typically associated with cardiovascular disease. Exposure to light at night, transmeridian travel, and social jetlag disrupt endogenous circadian rhythms, which, in turn, alter carefully orchestrated bodily functioning, and elevate the risk of disease and injury. Research into how disrupted circadian rhythms affect physiology and behavior has begun to reveal the intricacies of how seemingly innocuous environmental and social factors have dramatic consequences on mammalian physiology and behavior. Despite the new focus on the importance of circadian rhythms, and how disrupted circadian rhythms contribute to cardiovascular diseases, many questions in this field remain unanswered. Further, neither time-of-day nor sex as a biological variable have been consistently and thoroughly taken into account in previous studies of circadian rhythm disruption and cardiovascular disease. In this review, we will first discuss biological rhythms and the master temporal regulator that controls these rhythms, focusing on the cardiovascular system, its rhythms, and the pathology associated with its disruption, while emphasizing the importance of the time-of-day as a variable that directly affects outcomes in controlled studies, and how temporal data will inform clinical practice and influence personalized medicine. Finally, we will discuss evidence supporting the existence of sex differences in cardiovascular function and outcomes following an injury, and highlight the need for consistent inclusion of both sexes in studies that aim to understand cardiovascular function and improve cardiovascular health.