Circadian Rhythm Disruption Research Articles

Cross-Sex Hormone Therapy Is Associated With Loss of Circadian Rhythm in the Male Rat.

Transgender women are individuals born male but identify as female. Many transgender women undergo gender-affirming hormone therapy to alleviate the distress that can occur due to gender incongruence. For transgender women, gender-affirming hormone therapy includes 17β-estradiol (E2) combined with an antiandrogen therapy (AA) or surgical intervention. Numerous studies suggest that the risk of cardiovascular disease is elevated in transgender women; yet, the biological effects of gender-affirming hormone therapy on cardiovascular health are unknown. We hypothesize that a shift in the hormonal milieu versus natal sex in the male rat is associated with an increase in blood pressure at baseline and an enhanced responsiveness to a hypertensive challenge. We developed clinically relevant models that mimic gender-affirming hormone therapy combination therapies utilized for the endocrine treatment of gender dysphoria in transgender women. Chronic E2 plus castration or the E2+antiandrogen spironolactone was associated with a significant reduction in lean mass and testosterone. At baseline, 24-hour mean arterial pressure did not differ in E2+castration or E2+antiandrogen therapy versus control, but circadian rhythm was disrupted. In response to chronic Ang II (angiotensin II; 200 ng/kg per minute), the Ang II-induced increase in blood pressure was attenuated in E2+castration compared with control, but the blood pressure response to Ang II was similar in E2+antiandrogen therapy versus control. Thus, these data indicate that the type of combination therapy utilized may exert differential effects on blood pressure and that disruption of circadian rhythm may be a contributory factor to the increased risk of adverse cardiovascular outcomes in transgender women exposed to high 17β-estradiol coupled to androgen suppression.

REV-ERBα Inhibits Osteoclastogenesis and Protects against Alveolar Bone Loss.

Circadian rhythm disruption is thought to be associated with periodontitis, and molecular clock genes play critical roles in regulating bone homeostasis. However, the specific contribution of molecular clock genes to alveolar bone resorption caused by periodontitis is poorly understood. In this study, we introduced a novel Periodontitis Circadian Rhythm Score (PeriCRS) model that was established through machine learning using periodontal transcriptomic data from periodontitis clinical cohorts in the Gene Expression Omnibus (GEO) database. This approach revealed the potential regulatory role of circadian rhythm disruption in periodontitis and identified key molecular clock genes associated with alveolar bone destruction. Moreover, we established an experimental periodontitis model with circadian rhythm disturbance via periodontal ligation in mice exposed to a 6-h advanced LD12:12 cycle every 2 d. Our bioinformatics analysis revealed that NR1D1, which encodes REV-ERBα, is a pivotal factor in the impact of circadian rhythm disruption on periodontitis in periodontal tissues. Next, we confirmed the abnormal expression of the molecular clock gene Rev-erbα in inflammatory periodontal tissue in mice and confirmed that circadian rhythm disruption altered REV-ERBα expression. Furthermore, the activation of REV-ERBα with the agonist SR9009 notably decreased RANKL-induced osteoclast differentiation and suppressed the expression of osteoclast-related factors. Subsequent in vivo experiments demonstrated that SR9009 mitigated alveolar bone loss caused by periodontitis. Mechanistically, we found that the IL-22-STAT3 pathway inhibited REV-ERBα expression and modulated RANKL-induced osteoclast differentiation in vitro. Our results elucidate the role of REV-ERBα in osteoclastogenesis and suggest a potential new therapeutic avenue for addressing alveolar bone resorption associated with periodontitis.

Steroid hormones, vitamin D and melatonin in rapidly rotating shift female hospital workers

Disruption of circadian rhythm caused by night-shift work has been associated with several disorders, including cancer. Health care personnel often works at night to insure the continuity of care. Aim of this study was to evaluate the influence of night-shift work on serum and saliva levels of steroid hormones, vitamin D, and melatonin in hospital female workers. Ninety-seven female hospital workers were recruited: 46 nurses performing clockwise rapid rotating shift schedule on a 5-day cycle, including one night, and 51 day workers. Thirteen steroid hormones and vitamin D were assessed in morning serum samples; cortisol, cortisone and melatonin were assessed in morning and evening saliva samples. We fitted multiple regression models adjusted for age, BMI, sampling month, ovarian cycle phase, and use of oral contraceptives (OC). Rapidly rotating clockwise shift work was associated with increased levels of serum corticosterone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), and androstenedione, and decreased levels of estradiol and vitamin D. OC modulated the association between serum cortisol, corticosterone and 11-deoxycortisol and work shift. The normal circadian phase of salivary melatonin, cortisol and cortisone was not affected by shift work. In female hospital nurses, the clockwise rapid rotating shift schedule increases the level of some hormones, likely associated with stress. No increase of estradiol, nor modification of salivary hormones was observed.

Multi-omics analysis of the toxic effects on gill tissues of crucian carp (Carassius auratus) from chronic exposure to environmentally relevant concentrations of Di(2-ethylhexyl) phthalate (DEHP)

The pervasive use of the plasticizer di(2-ethylhexyl) phthalate (DEHP) poses potential risks to global aquatic ecosystems. This study systematically evaluated the adverse effects of chronic exposure to environmentally relevant concentrations of DEHP on gill tissues of crucian carp, utilizing histological examination, metabolomic, and transcriptomic analysis. The results demonstrated that DEHP induced significant histopathological alterations in gill tissues, with significant enrichment observed in multiple pathways associated with amino acid, hormone, lipid, and xenobiotic metabolism. Metabonomics-transcriptomics analyses indicated that DEHP-induced significantly over-activation of cytochrome P450 1B1-like (p < 0.001) and cytochrome P450 3A30-like (p < 0.05) via the nuclear xenobiotic receptors pathway was a key factor contributing to the disruption of tryptophan metabolism and steroid hormone biosynthesis, as well as inducing circadian rhythm disruption. Moreover, circadian rhythm disruption further exacerbated the imbalance of cytochrome P450 (CYP450) enzyme system as well as linoleic acid, arachidonic acid, sphingolipid, and glycerophospholipid metabolism. Overall, the feedback regulation between the CYP450 enzyme system and circadian rhythms emerged as the primary mechanism underlying DEHP-induced metabolic and transcriptional disruptions, ultimately resulting in gill toxicity. This study not only enriched the toxic effects on aquatic organisms of chronic exposure to DEHP, but provided potential biomarkers for the environmental risk assessment of DEHP.

An integrated multi-omics analysis identifies novel regulators of circadian rhythm and sleep disruptions under unique light environment in Antarctica.

Light is the dominant zeitgeber for biological clocks, and its regulatory mechanism for sleep-wake activity has been extensively studied. However, the molecular pathways through which the unique Antarctic light environment, with polar days in summer and polar nights in winter, affects human sleep and circadian rhythm remain largely unidentified, although previous studies have observed delayed circadian rhythm and sleep disruptions among expeditioners during polar nights. In this study, we conducted comprehensive dynamic research on the expeditioners residing in Antarctica for over one year. By integrating the phenotypic changes with multi-omics data, we tried to identify the novel candidate regulators and their correlation networks involved in circadian and sleep disorders under abnormal light exposure. We found that during the austral winter, expeditioners exhibited delayed bedtime and getting up time, reduced sleep efficiency, and increased sleep fragmentation. Meanwhile, serum dopamine metabolite levels significantly increased, while serotonin metabolites and antioxidants decreased. These changes were accompanied by altered expression of genes and proteins associated with neural functions, cellular activities, transcriptional regulation, and so on. Through the correlation and causal mediation analysis, we identified several potential pathways modulating human sleep-wake activity, involving genes and proteins related to neural function, glucose metabolism, extracellular matrix homeostasis, and some uncharacterized lncRNAs. Based on the identified causal mediators, LASSO regression analysis further revealed a novel candidate gene, Shisa Family Member 8 (SHISA8), as a potential key regulatory hub in this process. These findings shed light on the probable molecular mechanisms of sleep disorders in Antarctica and suggest SHISA8 as a novel candidate target for medical intervention in sleep disorders under unique light environments.

Liver-gut axis signaling regulates circadian energy metabolism in shift workers.

Circadian rhythm is critical to maintaining the whole-body metabolic homeostasis of an organism. Chronic disruption of circadian rhythm by shift work is an important risk factor for metabolic diseases. Fibroblast growth factor 15/19 (FGF15/19), a key component in the liver-gut axis, potently suppresses bile acid (BA) synthesis and improves insulin sensitivity. FGF15/19 emerges as a novel pharmaceutical target for prevention and treatment of metabolic diseases. The nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) deacetylase plays an important role in the maintenance of hepatic homeostasis by linking hepatic metabolism to circadian rhythm. Here, our clinical study identified that circadian rhythmicity and levels of plasma FGF19 and BA profiling, and cellular NAD+-dependent SIRT1 signaling were disturbed in night shift (NS, n = 10) compared to day shift (DS, n = 12) nurses. Our invitro data showed that recombinant FGF19 protein rescued cellular circadian rhythm disrupted by SIRT1 inhibitors. Furthermore, we determined the effect of FGF15 on circadian rhythm and hepatic metabolism in wild-type (WT), Fgf15 knockout (KO), and Fgf15 transgenic (TG) mice. The expressions of circadian-controlled genes (CCGs) involved in SIRT1 signaling, BA and lipid metabolism, and inflammation were disrupted in Fgf15 KO compared to WT and/or Fgf15 TG mice. Moreover, systemic FGF15 deficiency led to the circadian disturbance of NAD+-dependent SIRT1 signaling and significant reduction during nighttime in mice. These findings suggest that FGF15/19 regulates the circadian energy metabolism, which warrants further studies as a putative prognostic biomarker and pharmaceutical target for preventing against metabolic diseases associated with chronic shift work.

Effects of chronodisruption and alcohol consumption on gene expression in reward-related brain areas in female rats.

Circadian dysfunction caused by exposure to aberrant light-dark conditions is associated with abnormal alcohol consumption in humans and animal models. Changes in drinking behavior have been linked to alterations in clock gene expression in reward-related brain areas, which could be attributed to either the effect of chronodisruption or alcohol. To date, however, the combinatory effect of circadian disruption and alcohol on brain functions is less understood. Moreover, despite known sex differences in alcohol drinking behavior, most research has been carried out on male subjects only, and therefore implications for females remain unclear. To address this gap, adult female rats housed under an 11 h/11 h light-dark cycle (LD22) or standard light conditions (LD24, 12 h/12 h light-dark) were given access to an intermittent alcohol drinking protocol (IA20%) to assess the impact on gene expression in brain areas implicated in alcohol consumption and reward: the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS). mRNA expression of core clock genes (Bmal1, Clock, Per2), sex hormone receptors (ERβ, PR), glutamate receptors (mGluR5, GluN2B), a calcium-activated channel (Kcnn2), and an inflammatory cytokine (TNF-α) were measured at two-time points relative to the locomotor activity cycle. Housing under LD22 did not affect alcohol intake but significantly disrupted circadian activity rhythms and reduced locomotion. Significant changes in the expression of Bmal1, ERβ, and TNF-α were primarily related to the aberrant light conditions, whereas changes in Per2 and PR expression were associated with the effect of alcohol. Collectively, these results indicate that disruption of circadian rhythms and/or intermittent alcohol exposure have distinct effects on gene expression in the female brain, which may have implications for the regulation of alcohol drinking, addiction, and, ultimately, brain health.

Association of evening chronotype, sleep quality and cognitive impairment in patients with major depressive disorder.

This study aimed to investigate the independent or synergistic effects of evening chronotype and poor sleep quality on cognitive impairment in patients with major depressive disorder (MDD). A cross-sectional study was conducted on 249 individuals diagnosed with MDD, recruited from the Mental Health Center of Renmin Hospital of Wuhan University. Chronotype preference was assessed using the reduced Horne and Ostberg Morningness - Eveningness Questionnaire (rMEQ), while sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Cognitive function was evaluated through the Digit Symbol Substitution Test (DSST), defining impairment as a DSST score ≤ 56 (the lowest quartile of the cohort). Univariate analysis and logistic regression models were employed to explore the factors associated with cognitive impairment, focusing on the potential interactive effects of evening chronotype and poor sleep quality. Of the 249 subjects recruited, about 41% were classified as evening chronotype. These individuals exhibited poorer sleep quality and more severe depressive symptoms compared to non-evening chronotype (p < 0.01). Univariate analysis revealed that first episode status, Hamilton Depression Rating Scale (HAMD-17) scores, evening chronotype, and poor sleep quality were significantly associated with cognitive impairment (p < 0.05). Multivariate logistic regression analysis further demonstrated that the co-existence of evening chronotype and poor sleep quality significantly increased the likelihood of cognitive impairment (adjusted odds ratio [AdjOR] = 2.65, 95% confidence interval [CI] = 1.09-6.45, p < 0.05). Our findings suggest that evening chronotype, poor sleep quality, and their interaction are important contributors to cognitive impairment in patients with MDD, alongside the severity of depression and first episode status. These results emphasize the need for integrated approaches targeting circadian rhythm disruptions and sleep disturbances in the treatment of cognitive dysfunction in MDD.

Disruption of circadian rhythm as a potential pathogenesis of nocturia.

Increasing evidence suggested the multifactorial nature of nocturia, but the true pathogenesis of this condition still remains to be elucidated. Contemporary clinical medications are mostly symptom based, aimed at either reducing nocturnal urine volume or targeting autonomic receptors within the bladder to facilitate urine storage. The day-night switch of the micturition pattern is controlled by circadian clocks located both in the central nervous system and in the peripheral organs. Arousal threshold and secretion of melatonin and vasopressin increase at night-time to achieve high-quality sleep and minimize nocturnal urine production. In response to the increased vasopressin, the kidney reduces the glomerular filtration rate and facilitates the reabsorption of water. Synchronously, in the bladder, circadian oscillation of crucial molecules occurs to reduce afferent sensory input and maintain sufficient bladder capacity during the night sleep period. Thus, nocturia might occur as a result of desynchronization in one or more of these circadian regulatory mechanisms. Disrupted rhythmicity of the central nervous system, kidney and bladder (known as the brain-kidney-bladder circadian axis) contributes to the pathogenesis of nocturia. Novel insights into the chronobiological nature of nocturia will be crucial to promote a revolutionary shift towards effective therapeutics targeting the realignment of the circadian rhythm.

Effect of Standard versus Advanced Dimmable Lighting Systems on the Circadian Rhythms of Hospital Personnel

ABSTRACT The health of shift workers is seriously compromised due to circadian rhythm disruption. Not only do these shift workers lack sufficient exposure to natural light, the main circadian rhythm synchronizer, but they are also exposed to static electric lighting environments with the same luminous flux intensity throughout the entire night. Advances in lighting design make the accurate control of flux and spectra of electric lighting possible, allowing settings to be optimized for the appropriate regulation of circadian rhythms while also ensuring task performance. This research aims to quantify the effect of advanced lighting systems on the biological clock of nurses working night shifts in intensive care units, by replacing the fluorescent fixtures with dimmable luminaires. Diurnal and nocturnal levels of the main urine metabolite of melatonin, 6-sulfatoximelatonin, were assayed and a perception test of sleep quality and work performance was also carried out. The results show that the use of LED dimmable lighting results in an improvement in melatonin and cortisol levels of night shift workers, as well as improved concentration and sleep quality.

HPB SO76 - Is there a difference in liver transplant outcomes between daytime vs nighttime transplants?

Abstract Background Liver transplantation (LT) is the most effective treatment for end-stage liver disease. Night-time transplantations are often scheduled to minimize cold ischemia time (CIT), but they may pose challenges due to potential fatigue and circadian rhythm disruptions among surgical teams. This study aims to investigate the effect of transplant timing on the outcomes of liver transplant patients. Method A preliminary retrospective analysis was conducted on liver transplants performed between January and May 2018. Surgeries were categorized into daytime (8:00 am–8:00 pm) and nighttime (8:00 pm–8.00 am) groups. Outcomes examined included operative time, early mortality, complications (wound, vascular, biliary, and other) occurring within 30 days post-surgery, CIT, re-transplantation, length of ITU stay and length of hospital stay. Results The nighttime group, the mean recipient age was 50.17 years (SD 10.86). Surgery duration averaged 5.67 hours (SD 1.57) with a mean CIT of 8.08 hours (SD 2.41). The average hospital stay was 14days, with 1-year and 3-year survival rates of 100% and 95.68%. Acute rejection occurred in 8.7% of patients. The daytime group, the mean recipient age was 51.83 years (SD 10.86). Surgery duration averaged 5.05 hours (SD 1.20) with a mean CIT of 7.31 hours (SD 1.97). Hospital stays averaged 12.88days, with 1-year and 3-year survival rates of 97.2% and 91.67%. Acute rejection occurred in 13.9% of patients. Conclusion The preliminary results suggest slight differences in outcomes between the two groups, but a larger cohort of patients needs to be analyzed to determine statistical significance. This study will be expanded to include 400 transplant patients for a more comprehensive analysis.

Abstract 4115634: Potential Role for Circadian Disruption in Acute Kidney Injury-driven Cardiovascular Disease

Background/Hypothesis: Circadian disruption and AKI, even if kidney function recovers, are linked to an increased risk of CVD and death. We explored the hypothesis that AKI was associated with CVD through circadian disruption. Approach: Sixteen ~25-week-old PER2::Luciferase (a real-time reporter of circadian rhythm) C57BL/6J male mice had micro-clamps applied to both renal pedicles for ~26 minutes to produce a recoverable AKI. Three animals underwent a sham procedure. Three animals had to be euthanized all others had serum creatinine (Scr) measured on day 2. Twelve weeks after surgery, all animals (n=13) were euthanized. Results: The sham group's day 2 Scr (n=3; mean 0.10 [range 0.08 - 0.15]) was unchanged from baseline (0.11 [0.07 - 0.18]). Based on the day 2 Scr, 3 mice were classified as having mild/moderate AKI (Scr increased ≤ 3-fold) (0.16 [0.08 - 0.20]) and 7 as having severe AKI (Scr increased &gt; 3-fold) (0.98 [0.26 - 1.93]). By 12 weeks post-AKI, the Scr (0.16 [0.1 - 0.2 mg/dl]) of all animals returned to a level statistically similar to baseline. Immunohistochemistry demonstrated that 6 of 7 mice with severe AKI had atherosclerotic-like lesions in the aortic root (A), sinus, or coronaries (B): 4 mice had lesions averaging 9,754.7 µm 2 and 2 mice had coronary artery lumen narrowing averaging 56.2%. Similar lesions were found in 1 of 3 mice with mild/moderate AKI, but no lesions were found in the sham animals (C). The lesions had CD45+ cells on their surface and in the adventitia (A inset), but were devoid of CD68+ and SMC alpha-actin+ cells. In the neointima, SMC alpha-actin+ cells predominated (B inset). Mouse liver, lung, adrenal gland, renal cortex, outer and inner medulla were collected at 15:00 and analyzed for 5 days by Lumicycle. Circadian rhythms were evaluated with JTK_CYCLE. No apparent AKI-dependent differences were observed in the liver, lung, adrenal, or renal outer medulla. However, the amplitude of renal inner medulla rhythms decreased with AKI (P = 0.008), while the amplitude of renal cortex increased with AKI (P = 0.01, E&amp;F). Conclusions: This is the first report of an AKI model resulting in atherosclerosis-like lesions in wild-type mice without the need for a high-fat diet, genetic manipulation, or further provocation. The lesions were associated with a disruption of the intrarenal circadian rhythms. We will discuss the implications of this research as well as the metabolic consequences of the circadian disruption.

Investigating the Resilience of Kidneys in Rats Exposed to Chronic Partial Sleep Deprivation and Circadian Rhythm Disruption as Disruptive Interventions

Sleep is a vital biological function that significantly influences overall health. While sleep deprivation (SD) and circadian rhythm disruption are known to negatively impact various organs, their specific effects on kidney function remain understudied. This study aimed to investigate the impact of chronic partial sleep deprivation and circadian rhythm disruption on renal function in rats, providing insights into the relationship between sleep disturbances and kidney health. A total of 40 male Wistar rats were divided into five groups: a control group, a group with circadian rhythm disruption (CIR), a group with sleep deprivation during the light phase (SD-AM), a group with sleep deprivation during the dark phase (SD-PM), and a group with combined sleep deprivation and circadian rhythm disruption (SD-CIR). Sleep deprivation was induced using a specialized machine, depriving rats of sleep for four hours daily, while circadian rhythm disruption was achieved through a 3.5-hour light/dark cycle. After four weeks, kidney tissues and blood samples were collected for histological and biochemical analyses. The results showed that all experimental groups exhibited reduced water intake, with the CIR and SD-CIR groups also showing significantly lower food intake and reduced weight gain compared to controls. Oxidative stress markers revealed increased serum malondialdehyde (MDA) levels in the SD-PM and SD-CIR groups. Despite these metabolic and oxidative changes, histological examination of the kidneys revealed no significant alterations in renal structure or function across the groups. This study highlights the negative effects of chronic partial sleep deprivation and circadian rhythm disruption on feeding behavior, weight gain, and oxidative stress in rats. However, these interventions did not significantly alter renal structure or function. Further research is needed to explore the physiological mechanisms underlying these findings and the potential long-term effects of sleep disturbances on kidney health.

Influence of melatonin on the development of obesity

In recent years, increasing attention of researchers has been paid to the role of melatonin in the regulation of body weight. When analyzing literature data, the problem of the mechanism of action of melatonin on the body and its use in the correction of metabolic disorders is considered. Disruption of circadian rhythms caused by the use of artificial light at night leads to decreased melatonin secretion. This helps increase appetite and reduce energy costs. In addition, melatonin plays a major role in modulating the secretion of adipokines by influencing lipid metabolism. Decreased melatonin production causes insulin resistance and metabolic circadian disorganization, leading to obesity. Assessing the role of melatonin in the development of obesity and its accompanying pathologies is a promising area of scientific research in the field of diagnosis, prevention and treatment of endocrine and cardiovascular pathologies.

Potential circadian rhythms impacts on amblyopia treatment outcomes

Traditional treatments for amblyopia, such as patching and atropine penalization, often yield variable outcomes, underscoring the need for alternative or supplementary strategies. Circadian rhythms, which regulate various physiological processes including those associated with ocular health, may significantly influence the success of these treatments. The report proposes three hypotheses: (1) aligning amblyopia treatments with circadian rhythms through the modulation of melatonin and dopamine levels may enhance treatment responsiveness, (2) synchronizing treatment schedules with the patient’s diurnal rhythms could improve effectiveness, and (3) disruptions in circadian rhythms might negatively affect treatment outcomes. The expected implications of these hypotheses suggest a need for further research into the interplay between circadian rhythms and amblyopia therapy to optimize outcomes.

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.

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA generates transcript isoforms by utilizing various polyadenylation sites (PASs) from the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.

Circadian rhythm disruption: a potential trigger in Parkinson's disease pathogenesis.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), abnormal accumulation of α-synuclein (α-syn), and activation of microglia leading to neuroinflammation. Disturbances in circadian rhythm play a significant role in PD, with most non-motor symptoms associated with disruptions in circadian rhythm. These disturbances can be observed years before motor symptoms appear and are marked by the emergence of non-motor symptoms related to PD, such as rapid eye movement sleep behavior disorder (RBD), restless leg syndrome (RLS), excessive daytime sleepiness (EDS), depression and anxiety, changes in blood pressure, gastrointestinal dysfunction, and urinary problems. Circadian rhythm disruption precedes the onset of motor symptoms and contributes to the progression of PD. In brief, this article outlines the role of circadian rhythm disruption in triggering PD at cellular and molecular levels, as well as its clinical manifestations. It also explores how circadian rhythm research can contribute to preventing the onset and progression of PD from current and future perspectives.

Circadian rhythm disruption modulates enteric neural precursor cells differentiation leading to gastrointestinal motility dysfunction via the NR1D1/NF-κB axis

ObjectivesCircadian rhythm disruption (CRD) is implicated with numerous gastrointestinal motility diseases, with the enteric nervous system (ENS) taking main responsibility for the coordination of gastrointestinal motility. The purpose of this study is to explore the role of circadian rhythms in ENS remodeling and to further elucidate the underlying mechanisms.MethodsFirst, we established a jet-lagged mice model by advancing the light/dark phase shift by six hours every three days for eight weeks. Subsequent changes in gastrointestinal motility and the ENS were then assessed. Additionally, a triple-transgenic mouse strain (Nestin-creERT2 × Ngfr-DreERT2: DTRGFP) was utilized to track the effects of CRD on the differentiation of enteric neural precursor cells (ENPCs). RNA sequencing was also performed to elucidate the underlying mechanism.ResultsCompared to the control group, CRD significantly accelerated gastrointestinal motility, evidenced by faster intestinal peristalsis (P < 0.01), increased fecal output (P < 0.01), and elevated fecal water content (P < 0.05), as well as enhanced electrical field stimulation induced contractions (P < 0.05). These effects were associated with an increase in the number of glial cells and nitrergic neurons in the colonic myenteric plexus. Additionally, ENPCs in the colon showed a heightened differentiation into glial cells and nitrergic neurons. Notably, the NR1D1/nuclear factor-kappaB (NF-κB) axis played a crucial role in the CRD-mediated changes in ENPCs differentiation. Supplementation with NR1D1 agonist or NF-κB antagonist was able to restore gastrointestinal motility and normalize the ENS in jet-lagged mice.ConclusionsCRD regulates the differentiation of ENPCs through the NR1D1/NF-κB axis, resulting in dysfunction of the ENS and impaired gastrointestinal motility in mice.

Meal timing and risk of metabolic syndrome in the prospective French NutriNet-Santé biobank

Abstract Background Circadian rhythm disruption has been associated with higher risks of cardiometabolic diseases and several cancers. Mistimed eating patterns can desynchronize circadian rhythms, and could therefore influence metabolic health. However, long-term associations between meal timing and the metabolic syndrome remain unclear. The aim of this study was to evaluate the prospective associations between meal timing and the risk of developing metabolic syndrome. Methods We used measured biological and clinical data from 16 353 adults (51 years ± 13.72) in the NutriNet-Santé biobank (2011-2014), and examined the associations between meal timing, assessed with repeated 24-hour dietary records during the first two years of follow-up (starting 2009), and the risk of metabolic syndrome, using modified Poisson regression models, adjusted for main confounders. Results At the end of follow-up (mean 2.1 years (SD = 1.2)), a later timing of the first meal of the day was associated with a moderately higher risk of metabolic syndrome (1,788 cases; RR per 1-hour delay = 1.05; 95% CI: 1.00-1.10). However, after adjusting for overall diet quality, this association was attenuated (RR: 1.04; 95% CI: 0.99-1.09). Overall, we found no evidence of an association between the occurrence of metabolic syndrome and the time of the last meal (RR: 0.99; 95% CI: 0.95-1.05), the number of eating occasions (RR: 1.00; 95% CI: 0.98 - 1.03), or night-time fasting duration (RR: 1.03; 95% CI: 0.99 1.07). Conclusions In this large prospective study, timing of the first meal showed modest associations with metabolic syndrome. Further investigations using a longer follow-up are needed to elucidate how meal timing influences metabolic health. Key messages • Beyond the nutritional quality of meals, meal timing, particularly time of first meal, may be an accessible prevention strategy for metabolic health. • More largescale prospective and intervention studies are needed to better understand the links between meal timing and metabolic health.