Dysregulation Of Circadian Rhythms Research Articles

Impact of Modern Lifestyle on Circadian Health and Its Contribution to Adipogenesis and Cancer Risk.

Recent research underscores a crucial connection between circadian rhythm disruption and cancer promotion, highlighting an urgent need for attention. Explore the molecular mechanisms by which modern lifestyle factors-such as artificial light exposure, shift work, and dietary patterns-affect cortisol/melatonin regulation and cancer risk. Employing a narrative review approach, we synthesized findings from Scopus, Google Scholar, and PubMed to analyze lifestyle impacts on circadian health, focusing on cortisol and melatonin chronobiology as molecular markers. We included studies that documented quantitative changes in these markers due to modern lifestyle habits, excluding those lacking quantitative data or presenting inconclusive results. Subsequent sections focused solely on articles that quantified the effects of circadian disruption on adipogenesis and tumor microenvironment modifications. This review shows how modern habits lead to molecular changes in cortisol and melatonin, creating adipose microenvironments that support cancer development. These disruptions facilitate immune evasion, chemotherapy resistance, and tumor growth, highlighting the critical roles of cortisol dysregulation and melatonin imbalance. Through the presented findings, we establish a causal link between circadian rhythm dysregulation and the promotion of certain cancer types. By elucidating this relationship, the study emphasizes the importance of addressing lifestyle factors that contribute to circadian misalignment, suggesting that targeted interventions could play a crucial role in mitigating cancer risk and improving overall health outcomes.

Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming

Profound functional switch of key regulatory factors may play a major role in homeostasis and disease. Dysregulation of circadian rhythm (CR) is strongly implicated in cancer with mechanisms poorly understood. We report here that the function of REV-ERBα, a major CR regulator of the orphan nuclear receptor subfamily, is dramatically altered in tumors in both its genome binding and functional mode. Loss of CR is linked to a functional inversion of REV-ERBα from a repressor in control of CR and metabolic gene programs in normal tissues to a strong activator in different cancers. Through changing its association from NCoR/HDAC3 corepressor complex to BRD4/p300 coactivators, REV-ERBα directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERBα partners with pioneer factor FOXA1 and directly stimulates a large number of signaling genes, including multiple growth factors, receptor tyrosine kinases, RASs, AKTs, and MAPKs. Moreover, elevated REV-ERBα reprograms FOXA1 to bind new targets through a BRD4-mediated increase in local chromatin accessibility. Pharmacological targeting with SR8278 diminishes the function of both REV-ERBα and FOXA1 and synergizes with BRD4 inhibitor in effective suppression of tumorigenic programs and tumor growth. Thus, our study revealed a functional inversion by a CR regulator in driving gene reprogramming as an unexpected paradigm of tumorigenesis mechanism and demonstrated a high effectiveness of therapeutic targeting such switch.

Overexpression of NR1D1 portends disease recurrence in thyroid cancer.

Dysregulation of circadian rhythms has been linked to cancer susceptibility. Thyroid cancer cells demonstrate altered circadian oscillations in endogenous clock transcripts. Our previous research identified NR1D1, a component of the circadian clock, as one of the recurrence-associated genes in papillary thyroid cancer. The objective of this study was to investigate the expression pattern of NR1D1 in thyroid cancer and explore its prognostic and translational implications. We assessed NR1D1 expression using immunohistochemical analysis and examined its correlation with clinicopathological parameters. In vitro and in vivo experiments were performed to elucidate the oncogenic roles of NR1D1 and potential mechanisms. Nuclear NR1D1 expression was present in thyroid follicular epithelial-derived cancers, whereas normal thyroid tissue and benign nodular goiter showed no detectable NR1D1 immunoreactivity. Patients with high expression of NR1D1 had more advanced disease stages, extrathyroidal extension, lymphovascular invasion, and shorter recurrence-free survival compared to those with low levels of NR1D1. Through gain- and loss-of-function studies, we demonstrated that NR1D1 modulation affected the growth of organoids, resistance to anoikis, and the invasive and migratory capacity of thyroid cancer cells. The invasion-promoting effect of NR1D1 was regulated by the β-catenin/ZEB1 axis. Moreover, the overexpression of NR1D1 accelerated xenograft growth and lung metastasis in vivo. NR1D1 is overexpressed in malignant thyroid tumors and has prognostic significance. Our findings suggest therapeutic potential in targeting NR1D1 for thyroid cancer.

Insomnia and circadian rhythms dysregulation in people who have attempted suicide: correlations with markers of inflammation and suicidal lethality

Introduction Suicide is a widespread problem, with risk factors still a challenge. The aim was to assess correlations among insomnia, circadian rhythm, and inflammatory markers in individuals who attempted suicide. Materials and Methods Consecutive patients hospitalised following an attempted suicide, were assessed. Psychiatric diagnosis (DSM-5-TR Criteria), lethality of the suicide attempt (Suicide Intent Scale-SIS), and inflammatory parameters NLR (neutrophil-lymphocyte ratio) PLR (platelet-lymphocyte ratio), and SII (systemic inflammation index/neutrophil-to-platelet ratio on lymphocytes), were computed. Depressive and manic symptoms (Beck Depression Inventory-BDI-II, Young Mania Rating Scale- YMRS), circadian rhythms disturbances (Biological Rhythms Interview of Assessment in Neuropsychiatry-BRIAN), insomnia symptoms (Insomnia Severity Index-ISI) were assessed together with socio-demographic, clinical and pharmacological data. Results The final sample included 52 individuals. Patients who experienced insomnia during the preceding two weeks utilised high lethality methods, reported heightened dysregulation of chronobiological rhythms, heightened severity of depression, and elevated levels of inflammatory markers. High lethality was best predicted by insomnia symptoms (OR = 20.1, CI-95% 4.66-87.25, p = 0.001), by disturbances of circadian rhythms (OR = 6.97, CI-95% 1.82-26.66, p = 0.005), and by NLR indices (OR 4.00, CI-95% 1.14-13.99, p = 0.030). Conclusions Sleep disturbances may be a risk factor for suicidal lethality, along with markers of inflammation. It is plausible that insomnia and circadian sleep dysregulation may contribute to inflammation, thereby promoting suicidal risk.

Circadian disruptions and their role in the development of hypertension.

Circadian fluctuations in physiological setpoints are determined by the suprachiasmatic nucleus (SCN) which exerts control over many target structures within and beyond the hypothalamus via projections. The SCN, or central pacemaker, orchestrates synchrony between the external environment and the internal circadian mechanism. The resulting cycles in hormone levels and autonomic nervous system (ANS) activity provide precise messages to specific organs, adjusting, for example, their sensitivity to approaching hormones or metabolites. The SCN responds to both photic (light) and non-photic input. Circadian patterns are found in both heart rate and blood pressure, which are linked to daily variations in activity and autonomic nervous system activity. Variations in blood pressure are of great interest as several cardiovascular diseases such as stroke, arrhythmias, and hypertension are linked to circadian rhythm dysregulation. The disruption of normal day-night cycles, such as in shift work, social jetlag, or eating outside of normal hours leads to desynchronization of the central and peripheral clocks. This desynchronization leads to disorganization of the cellular processes that are normally driven by the interactions of the SCN and photic input. Here, we review autonomic system function and dysfunction due to regulation and interaction between different cardiorespiratory brain centers and the SCN, as well as social, lifestyle, and external factors that may impact the circadian control of blood pressure.

Effect of Urolithin A on the Improvement of Circadian Rhythm Dysregulation in Intestinal Barrier Induced by Inflammation.

Circadian rhythm plays an important role in intestinal homeostasis and intestinal immune function. Circadian rhythm dysregulation was reported to induce intestinal microbiota dysbiosis, intestinal barrier disruption, and trigger intestinal inflammation. However, the relationship between intestinal microbiota metabolites and the circadian rhythm of the intestinal barrier was still unclear. Urolithin A (UA), a kind of intestinal microbial metabolite, was selected in this study. Results showed UA influenced on the expression rhythm of the clock genes BMAL1 and PER2 in intestinal epithelial cells. Furthermore, the study investigated the effects of UA on the expression rhythms of clock genes (BMAL1 and PER2) and tight junctions (OCLN, TJP1, and CLND1), all of which were dysregulated by inflammation. In addition, UA pre-treatment by oral administration to female C57BL/6 mice showed the improvement in the fecal IgA concentrations, tight junction expression (Clnd1 and Clnd4), and clock gene expression (Bmal1 and Per2) in a DSS-induced colitis model induced using DSS treatment. Finally, the Nrf2-SIRT1 signaling pathway was confirmed to be involved in UA's effect on the circadian rhythm of intestinal epithelial cells by antagonist treatment. This study also showed evidence that UA feeding showed an impact on the central clock, which are circadian rhythms in SCN. Therefore, this study highlighted the potential of UA in treating diseases like IBD with sleeping disorders by improving the dysregulated circadian rhythms in both the intestinal barrier and the SCN.

Excessive daytime sleepiness in myotonic dystrophy: a narrative review.

Excessive daytime sleepiness (EDS) is a common and debilitating symptom in both forms of myotonic dystrophy (DM), significantly impacting patients' quality of life. The review focuses on the purpose of examining the current understanding of EDS in these conditions, the difficulty in correctly accessing it, the recent findings related to its etiology and prevalence, and a summary of potential therapeutic implications. We conducted a comprehensive search through PubMed, selecting studies that provided significant insights into the mechanisms, prevalence, and management of EDS in DM1 and DM2. EDS is highly prevalent in both DM1 and DM2. Polysomnographic studies have revealed prominent dysregulation of REM sleep in DM1, suggesting a possible narcoleptic-like phenotype and alterations in NREM sleep that contributes to daytime sleepiness. Other factors have been proposed to explain EDS in DM1, including dysregulation of the sleep-wake circadian rhythm through nocturnal actigraphy analysis. The central origin of EDS is increasingly delineated supported by serotonin and orexin pathways dysfunction, and recent neuroradiological findings showing that in DM1 hippocampus volume was positively correlated with self-reported fatigue and somnolence. Sleep-disordered breathing and respiratory dysfunctions are prevalent in DM, their direct correlation with EDS remains complex and inconclusive, but respiratory evaluation should be recommended if obstructive sleep apneas or respiratory muscle dysfunctions are suspected. Drug interventions, such as modafinil and mexiletine, have shown promise in managing excessive daytime sleepiness and reducing myotonia without significant cardiac conduction effects. Enhancing EDS management in myotonic dystrophy is key to improving overall patient well-being.

Intermittent fasting as a promising method of treatment of metabolically associated steatotic liver disease. Review

Metabolic‑associated steatotic liver disease (MASLD) is one of the most common diseases of the century. According to a recent meta‑analysis, its prevalence in the Western world is estimated at approximately 25% of the entire adult population. Currently, there is no single pharmacological treatment of MASLD approved by international guidelines. Therefore, changes in the lifestyle, diet and eating behavior remain the cornerstone of the treatment of MASLD. Recently, a lot of attention in the treatment of obesity and MASLD is paid to the so‑called intermittent fasting (IF) — a food regimen, the essence of which is to divide the day into periods of eating (food window) and complete refusal of food. Because chronic dysregulation of circadian rhythms may increase the risk of metabolic disease, time‑restricted diets, or dietary interventions, including IF, may maintain circadian rhythms and ameliorate metabolic disease. Acting on the main metabolic pathways, IF in patients with MASLD is able to restore metabolic flexibility, which is understood as the ability of the body to coordinate the sensation, exchange, storage and utilization of nutrients, as well as to choose adequate metabolic pathways to maintain energy homeostasis in accordance with the availability and demand for energy substrates. Several possible mechanisms of the influence of intermittent fasting on the pathogenesis of MASLD are known, in particular, energy switching to ATP generation processes, such as β‑oxidation; reduction of inflammation and oxidative stress; improvement of autophagy, sensitivity to insulin and composition of gut microbiota. Randomized controlled clinical trials demonstrated that depending on the type and duration of the diets, IF can lead to significant weight loss compared to hypocaloric or other diets, it affects almost all of the major metabolic drivers of MASLD, thus slowing the progression of liver disease and serving as an additional tool in the treatment of this pathology. Thus, intermittent fasting can become a promising, effective, and cheap treatment method with low side effects for a wide range of patients.

Impact of food additives on neurodevelopmental processes in zebrafish (Danio rerio): Exploring circadian clock genes and dopamine system.

Assessing the impact of food additives on neurodevelopmental processes extends beyond traditional acute toxicity evaluations to address subtler, long-term effects. This study investigates the impact of common food additives (tartrazine, sunset yellow, sodium benzoate, and aspartame) on neurodevelopment in zebrafish embryos, observed from 18hours postfertilization (hpf) to 91 days postfertilization (dpf). Results show reduced 96hpf locomotor activity after aspartame exposure, with elevated additives correlating with decreased heart rates and induced neurodegenerative phenotypes, including bent tails and abnormal pigmentation. Although locomotor activity decreases at 7 days postexposure, a gradual recovery is observed. Transcriptome analysis indicates alterations in clock genes (Cry2 and Per2) and dopamine-related genes (NURR1 and tyrosine hydroxylase) in zebrafish larvae. Dietary additive exposure during embryonic development impacts clock genes, influencing dopamine activity and resulting in neurobehavioral changes. This study underscores potential risks associated with dietary additive exposure during critical developmental stages, warranting reconsideration of consumption guidelines, especially for expectant mothers. Observed neurodevelopmental toxicity, even below recommended levels, emphasizes the importance of safeguarding neurodevelopmental health in early life. Our findings contribute to understanding the neurotoxic effects of dietary additives, emphasizing the necessity of protecting neurodevelopment during vulnerable periods. This study is the first to demonstrate a direct correlation between food additives and the dysregulation of key circadian rhythm and dopaminergic genes in zebrafish, providing new insights into the neurodevelopmental impacts of dietary additives. These findings pave the way for further research into the molecular mechanisms and potential implications for human health.

Alteration of circadian sleep-wake rhythm and salivary melatonin secretion in idiopathic/isolated REM sleep behavior disorder: Preliminary evidence

Objective/BackgroundIdiopathic/isolated REM sleep behavior disorder (iRBD) is widely regarded as an early sign of neurodegeneration leading to synucleinopathies. While circadian rhythm alterations in iRBD have been preliminarily demonstrated, evidence on melatonin secretion patterns in this clinical condition is limited. To address this knowledge gap, this exploratory study aimed to integrate salivary melatonin measurement with actigraphic monitoring in individuals with iRBD and age-matched healthy controls (HC) under real-life conditions. MethodsParticipants diagnosed with iRBD and HC underwent clinical evaluation and wore an actigraph for seven days and nights. Salivary melatonin concentrations were measured at five time points during the last night of recording. Comparative analyses were conducted on clinical data, actigraphic parameters, and melatonin levels between the two groups. ResultsiRBD participants (n = 18) showed greater motor (p < 0.01) and non-motor symptoms (p < 0.001), alongside disruptions in circadian sleep-wake rhythm compared to HC (n = 10). Specifically, actigraphy revealed a delayed central phase measurement (p < 0.05), reduced activity during the most active hours (p < 0.001), and decreased relative amplitude (p < 0.05). Total salivary melatonin concentration was significantly lower in iRBD (p < 0.05), with a slight but non-significant phase delay in dim light melatonin onset. ConclusionsThis exploratory study highlights a dysregulation of circadian sleep-wake rhythm coupled with reduced melatonin secretion in iRBD. Future research could add to these preliminary findings to evaluate novel treatment approaches to regulate the sleep-wake cycle and elucidate the implications of circadian dysregulation in the conversion from iRBD to neurodegeneration.

Using single-sample networks to identify the contrasting patterns of gene interactions and reveal the radiation dose-dependent effects in multiple tissues of spaceflight mice

Transcriptome profiles are sensitive to space stressors and serve as valuable indicators of the biological effects during spaceflight. Herein, we transformed the expression profiles into gene interaction patterns by single-sample networks (SSNs) and performed the integrated analysis on the 301 spaceflight and 290 ground control samples, which were obtained from the GeneLab platform. Specifically, an individual SSN was established for each sample. Based on the topological structures of 591 SSNs, the differentially interacted genes (DIGs) were identified between spaceflights and ground controls. The results showed that spaceflight disrupted the gene interaction patterns in mice and resulted in significant enrichment of biological processes such as protein/amino acid metabolism and nucleic acid (DNA/RNA) metabolism (P-value < 0.05). We observed that the mice exposed to radiation doses within the three intervals (4.66–7.14, 7.592–8.295, 8.49–22.099 mGy) exhibited similar gene interaction patterns. Low and medium doses resulted in changes to the circadian rhythm, while the damaging effects on genetic material became more pronounced in higher doses. The gene interaction patterns in response to space stressors varied among different tissues, with the spleen, lung, and skin being the most responsive to space radiation (P-value < 0.01). The changes observed in gene networks during spaceflight conditions might contribute to the development of various diseases, such as mental disorders, depression, and metabolic disorders, among others. Additionally, organisms activated specific gene networks in response to virus reactivation. We identified several hub genes that were associated with circadian rhythms, suggesting that spaceflight could lead to substantial circadian rhythm dysregulation.

Abstract 3436: Circadian rhythm dysregulation with risk of gastrointestinal cancers: A large-scale prospective analysis

Abstract Introduction: The incidence of multiple gastrointestinal (GI) cancers has been rising among younger adults with unknown etiology. Circadian rhythm dysregulation due to increasing exposures to artificial lighting, irregular work hours, and frequent travel, has been recently linked with multiple diseases. Disruption of the circadian clock drives Apc LOH to hyperactivate Wnt signaling and enhances MYC-dependent glycolytic metabolism to accelerate colorectal cancer progression. However, the association between circadian rhythm dysregulation, quantified by relative amplitude (RA)–a parameter derived from rest-activity patterns, and risk of colorectal and other GI cancers has not been evaluated in epidemiologic studies. Methods: We prospectively examined the associations between RA and risk of incident GI cancers among 87,653 UK Biobank participants who wore an Axivity AX3 triaxial accelerometer over 7 days (2013-15) with follow-up to 2021. RA was derived and averaged across all valid days, using the difference between the mean activity levels during the most active 10-hour period and the least active 5-hour period. Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: During 512,074 person-years, 1,079 incident GI cancer cases occurred. After multivariable adjustment, lower RA was associated with an increased risk of overall GI cancer (RR per SD [standard deviation] = 1.12, 95% CI 1.04-1.21, P for trend = 0.01). Compared to individuals in the highest tertile (T1), those with RA in the lowest tertile (T3) had a 25% increased risk of overall GI cancer (RR = 1.25, 95% CI 1.05-1.50). The positive associations with GI cancers were mainly driven by gastric cancer (RR per SD = 1.33, 95% CI 1.02-1.74, P for trend= 0.04) and colon cancer (RR per SD = 1.13, 95% CI 1.00-1.28, P for trend = 0.03). Conclusion: In this large-scale, prospective analysis of accelerometer data, circadian rhythm dysregulation was associated with subsequent risk of GI cancers, primarily gastric and colon cancer. To our knowledge, this is among the first population-based studies reporting the positive link between circadian rhythm dysregulation with cancer risk. Citation Format: Yi Kang, Shinghei Mok, Xiaoyu Zong, Yin Cao. Circadian rhythm dysregulation with risk of gastrointestinal cancers: A large-scale prospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3436.

Network dynamics investigation of omics-data-driven circadian-hypoxia crosstalk logical model in gallbladder cancer reveals key therapeutic target combinations.

Recent findings in cancer research have pointed towards the bidirectional interaction between circadian and hypoxia pathways. However, little is known about their crosstalk mechanism. In this work, we aimed to investigate this crosstalk at a network level utilizing the omics information of gallbladder cancer. Differential gene expression and pathway enrichment analysis were used for selecting the crucial genes from both the pathways, followed by the construction of a logical crosstalk model using GINsim. Functional circuit identification and node perturbations were then performed. Significant node combinations were used to investigate the temporal behavior of the network through MaBoSS. Lastly, the model was validated using published in vitro experimentations. Four new positive circuits and a new axis viz. BMAL1/ HIF1αβ/ NANOG, responsible for stemness were identified. Through triple node perturbations viz.a. BMAL:CLOCK (KO or E1) + P53 (E1) + HIF1α (KO); b. P53 (E1) + HIF1α (KO) + MYC (E1); and c. HIF1α (KO) + MYC (E1) + EGFR (KO), the model was able to inhibit cancer growth and maintain a homeostatic condition. This work provides an architecture for drug simulation analysis to entrainment circadian rhythm and in vitro experiments for chronotherapy-related studies. Insight Box. Circadian rhythm and hypoxia are the key dysregulated processes which fuels-up the cancer growth. In the present work we have developed a gallbladder cancer (GBC) specific Boolean model, utilizing the RNASeq data from GBC dataset and tissue specific interactions. This work adequately models the bidirectional nature of interactions previously illustrated in experimental papers showing the effect of hypoxia on dysregulation of circadian rhythm and the influence of this disruption on progression towards metastasis. Through the dynamical study of the model and its response to different perturbations, we report novel triple node combinations that can be targeted to efficiently reduce GBC growth. This network can be used as a generalized framework to investigate different crosstalk pathways linked with cancer progression.

Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.

Circadian rhythm is a self-regulating 24-hour system that synchronizes with the day and night cycle in organisms. The regulation of this system is controlled by clock genes, which function to harmoniously express molecular levels that facilitate the orderly coordination of various cellular processes, such as sleep, metabolism, endocrine function, cell proliferation and immunity. The root cause of tumorigenesis is that the body loses its normal regulation of cell growth at the genetic level. Long-term disruptions in circadian rhythms caused by factors such as shift work, jet lag, and unstable sleep patterns can impact cellular health, leading to various health problems, including cancer. Circadian rhythm controls most cellular functions related to cancer progression, which has a significant impact on the ability of immune cells to detect cancer cells and promote their clearance and has crucial implication for future tumor immunotherapy. This article aims to review the crosstalk between dysregulation of circadian rhythm and tumorigenesis, tumor metabolism, and immune response. Additionally, we discuss the role of circadian rhythm disruption in tumor therapy, highlighting its potential to optimize treatment timing and improve therapeutic outcomes.

Evaluation of Rhodanine Indolinones as AANAT Inhibitors.

Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N-acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X-ray crystal-based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine-indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5-carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency.

Renal tubular SGK1 is required to achieve blood pressure surge and circadian rhythm.

Blood pressure (BP) follows a circadian pattern that rises during the active phase of the day (morning surge) and decreases during the inactive (night dipping) phase of the day. The morning surge coincides with increased circulating glucocorticoids and aldosterone, ligands for glucocorticoid receptors and mineralocorticoid receptors, respectively. Serum- and glucocorticoid-induced kinase 1 (SGK1), a clock-controlled and glucocorticoid receptor- and mineralocorticoid receptor-induced gene, plays a role in BP regulation in human and animal models. However, the role of SGK1 in BP circadian regulation has not yet been demonstrated. Using telemetry, we analyzed BP in the inducible renal tubule-specific Sgk1Pax8/LC1 model under basal K+ diet (1% K+) and high-K+ diet (HKD; 5% K+). Our data revealed that, under basal conditions, renal SGK1 plays a minor role in BP regulation; however, after 1 wk of HKD, Sgk1Pax8/LC1 mice exhibited significant defects in diastolic BP (DBP), including a blunted surge, a decreased amplitude, and reduced day/night differences. After prolonged HKD (7 wk), Sgk1Pax8/LC1 mice had lower BP than control mice and exhibited reduced DBP amplitude, together with decreased DBP day/night differences and midline estimating statistic of rhythm (MESOR). Interestingly, renal SGK1 deletion increased pulse pressure, likely secondary to an increase in circulating aldosterone. Taken together, our data suggest that 1) the kidney plays a significant role in setting the BP circadian rhythm; 2) renal tubule SGK1 mediates the BP surge and, thus, the day/night BP difference; 3) long-term renal SGK1 deletion results in lower BP in mutant compared with control mice; and 4) renal SGK1 indirectly regulates pulse pressure due to compensatory alterations in aldosterone levels.NEW & NOTEWORTHY Dysregulation of blood pressure (BP) circadian rhythm is associated with metabolic, cardiovascular, and kidney diseases. Our study provides experimental evidence demonstrating, for the first time, that renal tubule serum- and glucocorticoid-induced kinase 1 (SGK1) plays an essential role in inducing the BP surge. Inhibitors and activators of SGK1 signaling are parts of several therapeutic strategies. Our findings highlight the importance of the drug intake timing to be in phase with SGK1 function to avoid dysregulation of BP circadian rhythm.

Incidence of type 2 diabetes mellitus among shift workers: a scoping review.

Objectives The purpose of this scoping review was to map the relationship between the increase in the incidence of T2DM among people who work in shifts and what are the possible shift work-related factors associated with this increase. Methods A scoping review was conducted, following the proposal of the Joanna Briggs Institute. The Population, Concept, and Context strategy was used to formulate the guiding question. The proposed question was: “What is the incidence of type 2 diabetes mellitus among shift workers?” Results After excluding duplicate articles, analyzing titles and abstracts, and excluding articles that did not answer the guiding question, 8 articles remained and were included in this review. Shift work schedules increase the incidence of T2DM, which was associated with the period the shift work was performed, circadian rhythm dysregulation, the length of exposure, ethnicity, occupation, and socioeconomic status. This increase is also associated with decreased frequency of physical activity, increased smoking rates and excessive calorie consumption with subsequent higher rates of overweight and obesity. Conclusions Therefore, continuous education and health policy programs for shift workers at the workplace and outside of it, are necessary to avoid or at least postpone the incidence of T2DM among these professionals. Future studies are warranted to fulfill the knowledge gaps involving shift work schedules and the incidence of T2DM.

Shift Work as a Cardiovascular Disease Risk Factor: A Narrative Review.

Shift work has emerged as a significant health concern in recent years, and research has revealed a link to circadian rhythm dysregulation and atherosclerosis, both of which can increase the risk of cardiovascular disease (CVD). Currently, there is a lack of updated reviews regarding the impact of shiftwork on CVD. Thus, the present narrative review aims to provide a comprehensive summary of the latest research on the relationship between shift work and CVD, identify potential gaps in the current knowledge, and highlight areas for future research. Database searches for peer-reviewed articles published between January 2013 to January 2023 on shift work associated CVD revealed many studies that found shift work is linked with increased prevalence of carotid artery plaque, increased arterial stiffness, and carotid artery intima-media thickness (IMT) all suggestive of a progression of atherosclerosis attributable to shift work. Hypertension, diabetes, and a sedentary lifestyle are known risks for CVD, and the results of the present study suggest that shift work should be added to that list. The elevation of inflammatory markers and DNA damage in shift workers may be linked to their increased progression of atherosclerosis and the positive association of shift work with coronary artery disease. There are minimal studies on mitigating approaches for shift work-related CVD, such as diet modification or exercise, emphasizing the need for further directed research in this area.

Emotionally clocked out: cell-type specific regulation of mood and anxiety by the circadian clock system in the brain.

Circadian rhythms are self-sustained oscillations of biological systems that allow an organism to anticipate periodic changes in the environment and optimally align feeding, sleep, wakefulness, and the physiological and biochemical processes that support them within the 24 h cycle. These rhythms are generated at a cellular level by a set of genes, known as clock genes, which code for proteins that inhibit their own transcription in a negative feedback loop and can be perturbed by stress, a risk factor for the development of mood and anxiety disorders. A role for circadian clocks in mood and anxiety has been suggested for decades on the basis of clinical observations, and the dysregulation of circadian rhythms is a prominent clinical feature of stress-related disorders. Despite our understanding of central clock structure and function, the effect of circadian dysregulation in different neuronal subtypes in the suprachiasmatic nucleus (SCN), the master pacemaker region, as well as other brain systems regulating mood, including mesolimbic and limbic circuits, is just beginning to be elucidated. In the brain, circadian clocks regulate neuronal physiological functions, including neuronal activity, synaptic plasticity, protein expression, and neurotransmitter release which in turn affect mood-related behaviors via cell-type specific mechanisms. Both animal and human studies have revealed an association between circadian misalignment and mood disorders and suggest that internal temporal desynchrony might be part of the etiology of psychiatric disorders. To date, little work has been conducted associating mood-related phenotypes to cell-specific effects of the circadian clock disruptions. In this review, we discuss existing literature on how clock-driven changes in specific neuronal cell types might disrupt phase relationships among cellular communication, leading to neuronal circuit dysfunction and changes in mood-related behavior. In addition, we examine cell-type specific circuitry underlying mood dysfunction and discuss how this circuitry could affect circadian clock. We provide a focus for future research in this area and a perspective on chronotherapies for mood and anxiety disorders.

0906 Feasibility of measures of sleep, circadian timing and lipid profiles for identifying mild cognitive impairment

Abstract Introduction Sleep disruption and circadian misalignment has been evident in patients with mild cognitive impairment (MCI). Together, sleep and circadian rhythm dysregulation can contribute to dyslipidemia, which has been proposed to play crucial roles in neurodegenerative process according to its known neurotoxicity. We aimed to compare parameters regarding lipid, nocturnal sleep and circadian timing between amnestic MCI (aMCI) and normal controls (NC), and to determine whether those parameters can be associated with the presence of aMCI in the elderly. Methods Participants above 50 years old were recruited from the Dementia Clinic at Kangwon National University Hospital, and two Public Care Centers for dementia patients. Neurocognitive tests were administered to each participant. The diagnosis of aMCI was made according to Petersen’s criteria. Eighteen aMCI patients (76.6 ±6.1 years) and 21 NC (70.4±6.7years) were finally selected. Actigraphy monitoring (Actiwatch 2; Respironics, USA) was conducted for 5 days. The dim light melatonin onset (DLMO) as an indicator of circadian timing was determined from five hourly saliva samples obtained before sleep onset. Fasting plasma total cholesterol, triglycerides, high density lipoprotein cholesterol, and low density lipoprotein cholesterol were assayed. The sleep parameters, DLMO and lipid profiles were compared between the two groups. For these measures, receiver operating characteristic (ROC) analysis was performed to assess the usefulness of discriminating between the aMCI and NC. Results There were no significant differences in sleep parameters, DLMO and lipid profiles between the aMCI and NC groups. The bedtime and sleep onset were derived as indicators for discriminating aMCI (p=0.003 and p=0.054, respectively). The area under the ROC for bedtime was 0.861(cut-off scores ≥ 22:02, sensitivity= 0.76, specificity=0.75). Conclusion We did not reveal the usefulness of the DLMO and lipid profiles for identifying aMCI. However, we found that the bedtime had good discrimination power between aMCI and cognitively normal elderly, suggesting later sleep habits would be associated with the presence of aMCI in the elderly. Support (if any) Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science and ICT (2020R1F1A1050416); Research Funds from the Institute of Medical Science, Chosun University, Republic of Korea, 2022.