Circadian Rhythm Misalignment Research Articles

Piperine regulates the circadian rhythms of hepatic clock gene expressions and gut microbiota in high-fat diet-induced obese rats

The interplay between the host circadian clock and microbiota has significant influences on host metabolism processes, and circadian desynchrony triggered by high-fat diet (HFD) is closely related to metabolic disorders. In this study, the modulatory effects of piperine (PIP) on lipid metabolism homeostasis, gut microbiota community and circadian rhythm of hepatic clock gene expressions in obese rats were investigated. The Sprague-Dawley (SD) rats were fed with normal diet (ND), HFD and HFD supplemented with PIP, respectively. After 9 weeks, rats were sacrificed with tissue and fecal samples collected for circadian analysis. Results showed that chronic PIP administration ameliorated the obesity-induced alterations in lipid metabolism and dysregulation of hepatic clock gene expressions in obese rats. The gut microbial communities studied through 16S rRNA sequencing showed that PIP ameliorated the imbalanced microbiota and recovered the circadian rhythm of Lactobacillaceae, Desulfovibrionaceae, Paraprevotellaceae, and Lachnospiraceae. The fecal metabolic profiles indicated that 3-dehydroshikimate, cytidine and lithocholyltaurine were altered, which were involved in the amino acid and fatty acid metabolism process. These findings could provide theoretical basis for PIP to work as functional food to alleviate the lipid metabolism disorder, circadian rhythm misalignment, and gut microbiota dysbiosis with wide applications in the food and pharmaceutic industries.

Intertwined relationship of dynamin-related protein 1, mitochondrial metabolism and circadian rhythm.

In recent years, mitochondria have gained significant interest in the field of biomedical research due to their impact on human health and ageing. As mitochondrial dynamics are strongly controlled by clock genes, misalignment of the circadian rhythm leads to adverse metabolic health effects. In this review, by exploring various aspects of research and potential links, we hope to update the current understanding of the intricate relationship between DRP1-mediated mitochondrial dynamics and changes in circadian rhythmicity leading to health issues. Thus, this review addresses the potential bidirectional relationships between DRP1-linked mitochondrial function and circadian rhythm misalignment, their impact on different metabolic pathways, and the potential therapeutics for metabolic and systemic disorders.

549 A Nationwide Pilot Study Testing a Remotely-Delivered Prolonged Nightly Fasting Intervention in Stressed Midlife Adults Living with Obesity and Memory Decline

OBJECTIVES/GOALS: Cognitive decline is associated with obesity, stress, poor sleep, and circadian rhythm misalignment, which are themselves functionally intertwined. Irregular food intake timing exacerbates these all. Prolonged nightly fasting (PNF) aligns food intake with innate circadian rhythms. METHODS/STUDY POPULATION: A nationwide, remotely-delivered, 2-arm randomized controlled trial was conducted to assess feasibility and 8-week outcomes of cognition, stress, sleep, eating behaviors, and general eating habits, after a PNF intervention (14-hr nightly fast, 6 nights/week, no calories after 8pm) compared to a health education control (HEC) condition. Eligible participants were living with obesity, stress (Perceived stress scale-4 (PSS-4) total score ≥5), and memory “not as good as it used to be.” Data were collected via Zoom meetings with participants and trained staff and entered into REDCap. All participants had weekly staff check-in calls to report fasting times (PNF group only) and feedback. RESULTS/ANTICIPATED RESULTS: Eligible participants were enrolled from 37 of 50 US states; N=58, 86% women, 71% white, 93% non-Latinx, mean (SD) 50.1 (5.1) years of age, BMI 35.6 (3.6) kg/m^2. No group differences existed at baseline. Linear mixed-effects models were used to compare group differences across all outcome changes. Compared to the HEC condition, the PNF intervention was associated with improved sleep quality (Pittsburgh Sleep Quality Index; B = -2.52; SE = 0.90; 95% CI-4.30 to -0.74; p=0.006). Stress, everyday cognition, and emotional eating behavior significantly changed over time (p<0.02), but there were no group differences. Analysis of feasibility outcomes are on-going. DISCUSSION/SIGNIFICANCE: Changing food intake timing 6 days per week, to exclude nighttime eating without mandating food quality/quantity change, may benefit many individuals living with obesity, stress and memory decline to improve their sleep. Improved sleep quality may lead to more health benefits over time.

Chrononutrition in the Prevention and Management of Metabolic Disorders: A Literature Review.

The concept of time-restricted eating (TRE) or time-restricted feeding (TRF) promotes daily periods of feeding and fasting to determine whole-body physiology. Chronic misalignment of circadian rhythms or chrono-disruption is related to an increased risk of diverse metabolic disorders. The progression of non-communicable diseases seems to be affected by the timing of meals. As a result, intermittent fasting is a promising approach for their management. The aim of the present literature review is to examine and scrutinize the TRE protocols in the fields of prevention and management of metabolic disorders. This is a thorough literature review of the reported associations among circadian rhythm, metabolic disorders, diabetes mellitus, obesity, TRE, TRF, dietary habits, circadian disruption, cardiovascular diseases, atherosclerosis, and non-alcoholic fatty liver to find the already existing clinical studies from the last decade (2014-2024) in the most precise scientific online databases, using relevant specific keywords. Several inclusion and exclusion criteria were applied to scrutinize only longitudinal, cross-sectional, descriptive, and prospective clinical human studies. The currently available clinical findings remain scarce and suggest that chrononutrition behaviors such as TRE or TRF may promote several metabolic benefits, mainly in body weight control and fat loss. Improvements in glucose levels and lipid profiles are currently quite controversial since some clinical studies show little or no effect. As far as liver diseases are concerned, the efficacy of intermittent fasting seems to be stronger in the management of non-alcoholic fatty liver disease due to body weight decline and fat loss. Even if there has been a gradual increase in clinical studies in the last few years, providing promising perspectives, currently, there is no conclusive evidence for the role of chrononutrition in metabolic disorders. Future studies should be well-designed with longer duration and larger sample sizes. Moreover, it is important to examine the best timing of the eating window and its feasibility.

Wake up to gastro-oesophageal reflux disease: The interplay between arousal and night-time reflux.

This review examines the temporal association between nocturnal gastro-oesophageal reflux and sleep-arousal cycles. Most nocturnal gastro-oesophageal reflux events occur during the awake cycle, and arousals precede most nocturnal gastro-oesophageal reflux events, indicating that arousal from sleep predisposes to nocturnal gastro-oesophageal reflux. This sheds light on the complex relationship between nocturnal gastro-oesophageal reflux and sleep, and has implications for managing nocturnal gastro-oesophageal reflux symptoms. The appearance of symptoms and the pathophysiology of nocturnal gastro-oesophageal reflux are influenced by sleep hygiene, sleep disturbances and the misalignment of circadian rhythms. Nocturnal gastro-oesophageal reflux and its related sleep disorders are prevalent and negatively impact the quality of life. There is conflicting evidence on whether nocturnal gastro-oesophageal reflux and sleep disturbances are causally linked, and whether sleep disturbances drive nocturnal gastro-oesophageal reflux. Poor sleep quality increases oesophageal hypersensitivity and overall acid exposure. The nocturnal gastro-oesophageal reflux is linked to the more severe forms of gastro-oesophageal reflux disease, especially with atypical/extra-oesophageal manifestations and complications of mucosal damage such as oesophagitis and stricture, Barret's oesophagus, and oesophageal adenocarcinoma. This review highlights the role of sleep problems in presenting nocturnal gastro-oesophageal reflux, and the potential benefits of treating sleep disturbances in enhancing patient care and quality of life.

Maternal Circadian Disruption from Shift Work and the Impact on the Concentration of Melatonin in Breast Milk.

Background and Objective: Melatonin in breast milk exhibits a 24-hour circadian rhythm, present in nighttime breast milk but nearly undetectable in daytime breast milk. Shift work can disrupt the circadian timing of individuals, evident in changes in melatonin in saliva and urine samples. However, it is unknown whether these changes are also reflected in breast milk from a shift working mother. The aim of this study was to investigate whether maternal circadian rhythm disturbance from shift work impacts the melatonin concentration in breast milk. Materials and Methods: Breast milk and saliva samples were collected from 11 shift working mothers at four timepoints across five consecutive days. This included during their day shift or nonworkdays to act as a control, night shift, subsequent night shifts and postnight shift. Where possible, pre- and postfeed collections were also undertaken. Samples were grouped into four-time intervals: 12-6:30 am, 7-11:30 am, 12-6:30 pm, 7-11:30 pm, and melatonin levels (picogram per milliliter) in the breast milk and saliva samples were analyzed. Results: There was a significant decrease in breast milk melatonin (p = 0.026) at the 12-6:30 am time interval on subsequent night shifts, compared with control days. However, there was no overall time and shift type interaction effect (p = 0.70). In addition, no observed difference in melatonin levels was found in saliva samples, or when comparing pre- and postfeed breast milk. Breast milk melatonin however was found to be significantly higher compared with saliva (p > 0.001), at all but one time interval. Conclusion: The findings suggest that there is a potential effect of maternal circadian rhythm disruption from shift work on breast milk melatonin levels. This is an important step in exploring the role of maternal circadian timing and the effect on breast milk composition. Expansion of this research and exploration of other circadian rhythm misalignment sleep disorders on breast milk is highly recommended.

Circadian Rhythm Misalignment Induced Differential Expression of Mineralocorticoid Receptor Type I and Aldosterone in Kidneys and Urine of Male Rats

Circadian Rhythm Misalignment Induced Differential Expression of Mineralocorticoid Receptor Type I and Aldosterone in Kidneys and Urine of Male Rats

Circadian Adaptation of Melatonin and Cortisol in Police Officers Working Rotating Shifts.

Misalignment of behavior and circadian rhythms due to night work can impair sleep and waking function. While both simulated and field-based studies suggest that circadian adaptation to a nocturnal schedule is slow, the rates of adaptation in real-world shift-work conditions are still largely unknown. The aim of this study was to evaluate the extent of adaptation of 24-h rhythms with 6-sulfatoxymelatonin (aMT6s) and cortisol in police officers working rotating shifts, with a special attention to night shifts. A total of 76 police officers (20 women; aged 32 ± 5.4 years, mean ± SD) from the province of Quebec, Canada, participated in a field study during their 28- or 35-day work cycle. Urine samples were collected for ~32 h before a series of day, evening, and night shifts to assess circadian phase. Before day, evening, and night shifts, 60%-89% of officers were adapted to a day schedule based on aMT6 rhythms, and 71%-78% were adapted based on cortisol rhythms. To further quantify the rate of circadian adaptation to night shifts, initial and final phases were determined in a subset of 37 officers with suitable rhythms for both hormones before and after 3-8 consecutive shifts (median = 7). Data were analyzed with circular and linear mixed-effects models. After night shifts, 30% and 24% of officers were adapted to a night-oriented schedule for aMT6s and cortisol, respectively. Significantly larger phase-delay shifts (aMT6s: -7.3 ± 0.9 h; cortisol: -6.3 ± 0.8 h) were observed in police officers who adapted to night shifts than in non-adapted officers (aMT6s: 0.8 ± 0.9 h; cortisol: 0.2 ± 1.1 h). Consistent with prior research, our results from both urinary aMT6s and cortisol midpoints indicate that a large proportion of police officers remained in a state of circadian misalignment following a series of night shifts in dim-light working environments.

The Role of Circadian Rhythms in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), as a most common metabolic disrupted disease, has several main symptoms, including ovarian insufficiency, hyperandrogenism, insulin resistance, etc., which may lead to female infertility. Many studies on the processes of PCOS have been done throughout the years, but unfortunately, the pathophysiology of PCOS is still not fully figured out. The circadian rhythm is the metronomic adjustment of the organisms to the external environment at all levels, from the molecular to the individual. It is revealed in multiple studies that there is a clear association between the progression of PCOS and the disturbance of circadian rhythms. Numerous studies have demonstrated that circadian rhythms can influence the development of PCOS by altering the Wnt/β-catenin, GPCR/cAMP/PKA, PI3K/AKT, and MAPK signaling pathways of the hypothalamic-pituitary-ovarian/hypothalamic-pituitary-adrenal axis, which result in abnormal hormone expression, receptor resistance, and metabolic disorders. The circadian rhythm misalignment may contribute to the formation and development of PCOS through the expression of certain genes that control the canonical signaling pathway. It is foreseeable that more preventive and targeted treatment for PCOS is the hot zone of clinical research in the future. This article aimed to review the state regarding the link between circadian rhythm disorder and PCOS, focus on the pathophysiology of PCOS, explore the pathways of circadian rhythm in the process of PCOS, and seek to offer a clear direction and practical approach for the prevention and treatment of PCOS.

The Associations of Chronotype and Shift Work With Rheumatoid Arthritis.

The circadian clock regulates multiple aspects of human physiology including immunity. People have a circadian preference termed chronotype. Those with an evening preference may be better suited to shift work, but also carry higher risk of adverse health. Shift work leads to misalignment of circadian rhythms and is associated with increased risk of inflammatory disease such as asthma and cancer. Here, we investigate the association between chronotype, shift work, and rheumatoid arthritis (RA). The associations between exposures of shift work and chronotype on risk of RA were studied in up to 444,210 U.K. Biobank participants. Multivariable logistic regression models were adjusted for covariates: age, sex, ethnicity, alcohol intake, smoking history, Townsend Deprivation Index (TDI), sleep duration, length of working week, and body mass index (BMI). After adjusting for covariates, individuals with a morning chronotype had lower odds of having rheumatoid arthritis (RA; odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88-0.99) when compared to intermediate chronotypes. The association between morning chronotype and RA persisted with a more stringent RA case definition (covariate-adjusted OR: 0.89, 95% CI: 0.81-0.97). When adjusted for age, sex, ethnicity, and TDI, shift workers had higher odds of RA (OR: 1.22, 95% CI: 1.1-1.36) compared to day workers that attenuated to the null after further covariate adjustment (OR: 1.1, 95% CI: 0.98-1.22). Morning chronotypes working permanent night shifts had significantly higher odds of RA compared to day workers (OR: 1.89, 95% CI: 1.19-2.99). These data point to a role for circadian rhythms in RA pathogenesis. Further studies are required to determine the mechanisms underlying this association and understand the potential impact of shift work on chronic inflammatory disease and its mediating factors.

0099 Circadian Rest-Activity Rhythm Development is associated with Weight Gain in Early Infancy

Abstract Introduction In early childhood, irregular sleep schedules that may promote circadian rhythm misalignment predict greater weight gain. However, circadian rest-activity (CRA) rhythmicity in infancy in relation to growth is understudied. The aim of the present study was to investigate the association between newborn circadian rest-activity rhythmicity and change in weight-for-age from birth to three months. Methods Data were captured as a secondary data analysis from the Snuggle Bug / Acurrucadito Study (see Support). English or Spanish speaking mothers (n=41, age M±SD=33.1±4.6y, 31.7% Hispanic/Latina) and their full-term (≥37wk) infants of normal weight (2.5-4kg; 58.5% female; 25.6% WIC enrolled) were recruited from Phoenix, Arizona. CRA rhythmicity was measured at eight weeks with ankle-worn Micro Motionloggers (Ambulatory Monitoring Inc.) for five 24hr periods at one-minute epochs. CRA metrics assessed included 24hr autocorrelation, mesor, magnitude, acrophase, goodness-of-fit R2, interdaily stability, intradaily variability, and relative amplitude. Birthweight was mother-reported and 3mon infant weight was measured with a Seca scale. Weight-for-age Z-scores (WAZ) by infant sex were computed based upon World Health Organization growth charts and the change difference between timepoints was the primary outcome. Regression models adjusting for birth WAZ examined the relationships between CRA metrics at eight weeks with change in WAZ from birth to 3mo. Results At eight weeks, mean±SD CRA metrics were as follows: 24hr autocorrelation of 0.25±0.03, mesor of 115.6±14.7, amplitude of 68.1±18.3, goodness-of-fit R2 of 0.42±0.10, acrophase of 14:12±1:42, interdaily stability of 0.57±0.12, intradaily variability of 0.93±0.19, and relative amplitude of 0.61±0.11. Mean birth WAZ and change in WAZ from birth to 3mon were 0.39±0.73 and -0.57±0.77, respectively. After adjusting for birth WAZ, in separate models, greater mesor (R2 Change=0.10, β=-0.32, p=0.03), amplitude (R2 Change=0.11, β=-0.34, p=0.03), and goodness-of-fit R2 (R2 Change=0.10, β=-0.32, p=0.04) were significantly associated with less change in WAZ from birth to 3mon. Conclusion Among relatively healthy, full-term infants born of normal weight, greater 24hr circadian rest-activity rhythmicity achieved by 8 weeks was associated with slower rate of weight gain across the newborn stage. Promoting behaviors and environmental cues from parents that strengthen early circadian rhythmicity in their infants may promote healthy weight trajectories. Support (if any) NIH/NHLBI R01HL147931

Preliminary Study on the Effect of a Night Shift on Blood Pressure and Clock Gene Expression.

Night shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease. One of the underlying mechanisms seems to be that shift work promotes hypertension, but results have been variable. This cross-sectional study was carried out in a group of internists with the aim of performing a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift, and a paired analysis of clock gene expression after a night of rest and a night of work. Each participant wore an ambulatory blood pressure monitor (ABPM) twice. The first time was for a 24 h period that included a 12 h day shift (08.00-20.00) and a night of rest. The second time was for a 30 h period that included a day of rest, a night shift (20.00-08.00), and a subsequent period of rest (08.00-14.00). Subjects underwent fasting blood sampling twice: after the night of rest and after the night shift. Night shift work significantly increased night systolic blood pressure (SBP), night diastolic blood pressure (DBP), and heart rate (HR) and decreased their respective nocturnal decline. Clock gene expression increased after the night shift. There was a direct association between night blood pressure and clock gene expression. Night shifts lead to an increase in blood pressure, non-dipping status, and circadian rhythm misalignment. Blood pressure is associated with clock genes and circadian rhythm misalignement.

Circadian rhythm of carbohydrate metabolism in health and disease

The article presents a review of the main circadian mechanisms regulating carbohydrate metabolism and their role in maintenance of energy homeostasis; the molecular genetic structure of the circadian system is also discussed. The role of adipose tissue and other organs and systems in the maintenance of circadian rhythm of carbohydrate metabolism, both in health and in obesity and diabetes, is highlighted. Particular attention is paid to diurnal rhythms of endocrine factors responsible for metabolic patterns of hormones such as cortisol, growth hormone and melatonin. Gender differences in the circadian regulation of energy and carbohydrate metabolism are also discussed, as well as their changes in different age periods. Article provides detailed review of the mechanisms of glucose utilization, reactivity of the pancreatic islets and peripheral insulin sensitivity shifts at different time periods of the day in people with normal body weight, android and gynoid types of obesity, both in women and men. Protective factors of energy metabolism circadian regulation structure preventing the development of diabetes mellitus and cardiovascular disease in individuals with so-called “metabolically healthy” obesity type are discussed. Article provides a review of various pathways of circadian rhythm disturbances, mechanisms of their development, as well as exogenous and endogenous factors leading to carbohydrate metabolic circadian rhythm misalignment, such as shift work, untiming of natural and artificial lighting, jet lags, sleep disorders. Represented data contribute to a new look at the pathogenesis of obesity and carbohydrate metabolism disorders in various types of obesity in men and women, that provides basis for searching for new effective methods of prevention and treatment of these conditions, elaboration of evidence-based diets and physical activity recommendations, as well as approaches to their medical treatment.

Is obstructive sleep apnea a circadian rhythm disorder?

Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.

Circadian Timing, Information processing and Metabolism (TIME) study: protocol of a longitudinal study of sleep duration, circadian alignment and cardiometabolic health among overweight adults

BackgroundBoth short sleep duration and circadian rhythm misalignment are risk factors for metabolic dysfunction, but the underlying mechanisms are unknown. The goal of this study is to examine how sleep duration and circadian alignment predict changes in cardiometabolic risk factors over a 12-month period, and test cognitive function and hedonic eating tendencies as potential mechanisms.MethodsWe will recruit a sample of 120 working aged adults with BMI 25–35 kg/m2 (overweight to class I obesity). The protocol includes 5 visits over a 12-month period. Study visits include wrist actigraphy to measure sleep behaviors, 24-h diet recalls, dim light melatonin collection, a computerized neurobehavioral assessment, eating in the absence of hunger task, and frequently sampled IV glucose tolerance test.DiscussionThe results of the TIME study will advance the understanding of how both short sleep duration and circadian misalignment contribute to behavioral aspects of obesity and metabolic dysfunction.Trial registrationClinicalTrials.Gov, NCT04759755, registered retrospectively February 13, 2021.

The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis

Misalignment of physiological circadian rhythms promotes obesity which is characterized by white adipose tissue (WAT) expansion. Differentiation of Adipose stem/progenitor cells (ASCs) contributes to WAT increase but the importance of the cellular clock in this process is incompletely understood. In the present study, we reveal the role of the circadian transcription factor Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) in human ASCs, isolated from subcutaneous (s)WAT samples of patients undergoing routine elective plastic abdominal surgery. We show that circadian synchronization by serum-shock or stimulation with adipogenic stimuli leads to a different expression pattern of ARNTL2 relative to its well-studied paralogue ARNTL1. We demonstrate that ARNTL2 mRNA is downregulated in ASCs upon weight-loss (WL) whereas ARNTL2 protein is rapidly induced in the course of adipogenic differentiation and highly abundant in adipocytes. ARNTL2 protein is maintained in ASCs cooperatively by mechanistic Target of Rapamycin (mTOR) and Mitogen-activated Protein Kinase (MAPK) signalling pathways while ARNTL2 functions as an inhibitor on both circuits, leading to a feedback mechanism. Consistently, ectopic overexpression of ARNTL2 repressed adipogenesis by facilitating the degradation of ARNTL1, inhibition of Kruppel-Like Factor 15 (KLF15) gene expression and down-regulation of the MAPK-CCAAT/enhancer-binding protein β (C/EBPβ) axis. Western blot analysis of sWAT samples from normal-weight, obese and WL donors revealed that ARNTL2 protein was solely elevated by WL compared to ARNTL1 which underscores unique functions of both transcription factors. In conclusion, our study reveals ARNTL2 to be a WL-regulated inhibitor of adipogenesis which might provide opportunities to develop strategies to ameliorate obesity.

Long-term environmental exposure of darkness induces hyperandrogenism in PCOS via melatonin receptor 1A and aromatase reduction.

Polycystic ovary syndrome (PCOS) is a common and complex disorder impairing female fertility, yet its etiology remains elusive. It is reported that circadian rhythm disruption might play a crucial role in PCOS pathologic progression. Here, in this research, we investigated the effect of environmental long-term circadian rhythm dysfunction and clarified its pathogenic mechanism in the development of PCOS, which might provide the targeted clinical strategies to patients with PCOS. Female SD rats were used to construct a circadian rhythm misalignment model with constant darkness (12/12-h dark/dark cycle), and the control group was kept under normal circadian rhythm exposure (12/12-h light/dark cycle) for 8 weeks. We measured their reproductive, endocrinal, and metabolic profiles at different zeitgeber times (ZTs). Different rescue methods, including melatonin receptor agonist and normal circadian rhythm restoration, and in vitro experiments on the KGN cell line were performed. We found that long-term darkness caused PCOS-like reproductive abnormalities, including estrous cycle disorder, polycystic ovaries, LH elevation, hyperandrogenism, and glucose intolerance. In addition, the expression of melatonin receptor 1A (Mtnr1a) in ovarian granulosa cells significantly decreased in the darkness group. Normal light/dark cycle and melatonin receptor agonist application relieved hyperandrogenism of darkness-treated rats. In vitro experiments demonstrated that decreased MTNR1A inhibited androgen receptor (AR) and CYP19A1 expression, and AR acted as an essential downstream factor of MTNR1A in modulating aromatase abundance. Overall, our finding demonstrates the significant influence of circadian rhythms on PCOS occurrence, suggests that MTNR1A and AR play vital roles in pathological progression of hyperandrogenism, and broadens current treatment strategies for PCOS in clinical practice.

Impact of circadian clock dysfunction on human health

All living organisms exhibit circadian rhythms. Humans show circadian rhythm of the different physiological functions such as sleep-wake cycle, core body temperature, feeding behavior, metabolic activity, heart rate variability, hormone secretion, and others. The hypothalamic suprachiasmatic nucleus (SCN) acts as a primary circadian pacemaker. Peripheral tissues have an endogenous circadian clock; however, SCN synchronizes the circadian activity of the peripheral clocks. The retinohypothalamic tract (RHT) from retinal ganglionic cells carries the photic signal into the SCN that regulates the rhythmic expression of the core clock genes through the feedback loop. At the output level, the SCN connects with the pineal gland and the peripheral tissues with the help of neuroendocrine mediators. Disruption of circadian clock functions is detrimental to health. Shift work, night work, chronic or acute jet lag, and light-at-night have adverse effects on circadian functions. Misalignment of circadian rhythm alters the expression of core clock genes, leading to deregulation of cellular activity and metabolic functions. Circadian rhythm dysfunction causes many pathologic conditions, including sleep disorders, cardiovascular problems, metabolic dysfunction, infertility, poor physical performance, as well as cancer. The present work has reviewed the relationship between circadian clock dysfunction and impaired physiological activities.

Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers.

The circadian system is an innate clock mechanism that governs biological processes on a near 24-hour cycle. Circadian rhythm disruption (i.e., misalignment of circadian rhythms), which results from the lack of synchrony between the master circadian clock located in the suprachiasmatic nuclei (SCN) and the environment (i.e., exposure to day light) or the master clock and the peripheral clocks, has been associated with increased risk of and unfavorable cancer outcomes. Growing evidence supports the link between circadian disruption and increased prevalence and mortality of genitourinary cancers (GU) including prostate, bladder, and renal cancer. The circadian system also plays an essential role on the timely implementation of chronopharmacological treatments, such as melatonin and chronotherapy, to reduce tumor progression, improve therapeutic response and reduce negative therapy side effects. The potential benefits of the manipulating circadian rhythms in the clinical setting of GU cancer detection and treatment remain to be exploited. In this review, we discuss the current evidence on the influence of circadian rhythms on (disease) cancer development and hope to elucidate the unmet clinical need of defining the extensive involvement of the circadian system in predicting risk for GU cancer development and alleviating the burden of implementing anti-cancer therapies.

Circadian Oscillation of Natural Antisense Transcripts Related to Human Core Clock Genes

Circadian clocks are autonomous intracellular oscillators that synchronize metabolic and physiological processes with the external signals. So, misalignment of environmental and endogenous circadian rhythms leads to disruption of biological activities in living organisms. Noncoding transcripts including antisense RNAs are an important component of the molecular clocks. Commonly, the antisense transcripts are involved in the regulation of gene expression. PER2AS and CRY1AS are the only known Natural Antisense Transcripts (NAT) among the core clock genes, which overlap with the PER2 and CRY1 genes, respectively. In this study, we hypothesized that PER2AS and CRY1AS like the other clock genes, exhibit the oscillatory behavior in a 24-hour period and affect the expression of PER2 and CRY1. First, the A549 cell line was cultured under standard conditions. After horse serum shock, RNA extraction and cDNA synthesis was performed; then the expression fluctuations of PER2AS, CRY1AS, PER2, and CRY1 were measured with Real-time PCR. Our result showed that PER2AS and CRY1AS had similar oscillation patterns with their sense strand during 24-hour period. Therefore, we suggested that PER2AS and CRY1AS transcripts probably by preventing the interaction of miRNAs with PER2 and CRY1 mRNAs, influence the expression of them, positively.