Circadian Rhythm Disruption Research Articles

Environmental study and stress-related biomarkers modifications in a crew during analog astronaut mission EMMPOL 6.

Human presence in space is increasingly frequent, but we must not forget that it is a hostile environment. We aimed to study the characteristics of experimental scenarios, to obtain data on human response to isolation, disruption of circadian rhythm and high levels of psychophysical stress. In these experiments, we evaluated stress response in five young healthy subjects inside an earth-based moon-settlement-like habitat during a 1-week long analog astronaut mission. Wearable devices were used to monitor daily step count of the subjects, physical activity, heart rate during physical exercise and at rest, and sleep parameters. From saliva and urine samples collected every day at awakening, we studied oxy-inflammation biomarkers and hormones (stress and appetite) were studied too. At the end of the week, all subjects revealed an increase in oxidative stress and cortisol levels but no inflammation biomarkers variations, in conjunction with increasing time/daily exercise. Furthermore, a significant decrease in hours of sleep/day, sleep quality, and REM phase of sleep was recorded and correlated with the increase of reactive oxygen species. Oxidative stress increased in a short period of time and may be attributed to the influence of psychological stress during confinement, as well as increased exercise and decreased amount of sleep. On a long-term basis, this could impact performance.

Circadian rhythm in neurodegenerative disease: the role of RNA modifications and potential application of RNA-based therapeutics

Neurodegenerative diseases usually present as progressive impairment of the motor or mental functions of the central or peripheral nervous system, which is often linked to genetic and biochemical factors. The main features include synaptic and neuronal deficits, abnormal protein homeostasis, DNA and RNA defects, inflammation, and pathological protein aggregation. Clinical evidence suggests that circadian rhythms affect different neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, through oxidative stress, neuroinflammation, and other mechanisms. Disruptions in circadian rhythms, which are often linked to alterations in RNA modifications, contribute to disease progression. This review provides an overview of current research progress on neurodegenerative diseases and outlines their relationship in terms of aberrant circadian rhythm, highlights the role of RNA modifications in circadian rhythm-regulated neurodegenerative diseases, and presents the potential applications of RNA-based drugs for treating neurodegenerative diseases.

Association between rest-activity rhythm and diabetic retinopathy among US middle-age and older diabetic adults.

The disruption of circadian rhythm has been reported to aggravate the progression of diabetic retinopathy (DR). Rest-activity rhythm (RAR) is a widely used method for measuring individual circadian time influencing behavior. In this study, we sought to explore the potential association between RAR and the risk of DR. Diabetic participants aged over 40 from 2011-2014 National Health and Nutrition Examination Survey (NHANES) were enrolled. Data from the wearable device ActiGraph GT3X was used to generate RAR metrics, including interdaily stability (IS), intradaily variability (IV), most active 10-hour period (M10), least active 5-hour period (L5), and Relative amplitude (RA). Weighted multivariable logistic regression analysis and restricted cubic spline analysis were conducted to examine the association between RAR metrics and DR risk. Sensitivity analysis was also conducted to examine the robustness of the findings. An unsupervised K-means clustering analysis was conducted to identify patterns in IV and M10. A total of 1,096 diabetic participants were enrolled, with a DR prevalence of 20.53%. The mean age of participants was 62.3 years, with 49.57% being male. After adjusting covariates, IV was positively associated with DR (β: 3.527, 95%CI: 1.371-9.073). Compared with the lowest quintile of IV, the highest quintile of IV had 136% higher odds of DR. In contrast, M10 was negatively associated with DR (β: 0.902, 95%CI: 0.828-0.982), with participants in the highest M10 quintile showing 48.8% lower odds of DR. Restricted cubic spline analysis confirmed that these associations were linear. Meanwhile, sensitivity analysis confirmed the robustness. K-means clustering identified three distinct clusters, with participants in Cluster C (high-IV, low-M10) had a significantly higher risk of DR comparing with Cluster A (low-IV, high-M10). A more fragmented rhythm and lower peak activity level might be associated with an increased risk of DR. These findings indicate that maintaining a more rhythmic sleep-activity behavior might mitigate the development of DR. Further research is necessary to establish causality and understand the underlying mechanisms, and focus on whether interventions designed to enhance daily rhythm stability and increase diurnal activity level can effectively mitigate the risk of progression of DR.

Capsaicin‐mediated repair of circadian disruption‐induced Intestinal barrier damage via the gut microbiota

AbstractCircadian clock serves as a regulator of gastrointestinal health, and the disruption of circadian rhythm may trigger the dysregulation of the intestinal barrier functions. This study investigated the effectiveness of capsaicin (CAP) in mitigating intestinal barrier dysfunction induced by circadian disruption in male SPF C57BL/6J mice. Our findings indicated that CAP supplementation attenuated abnormal weight gain, alterations in serum lipid levels, and misalignment in hepatic and colonic circadian clock gene expressions in mice caused by constant darkness (CD) treatment. The restoration of the intestinal barrier integrity was also observed through the increase in mucosal thickness and goblet cell numbers. Both the diversity and the circadian rhythm of gut microbiota were improved in CAP‐treated group. Correlation analysis indicated that CAP could modulate the gut microbiota by affecting intestinal barrier function and systemic metabolism in CD‐treated mice. These results highlight the potential of CAP as a functional food component in maintaining the intestinal barrier homeostasis through regulating gut microbiota.

Daytime Dysfunction: Symptoms Associated with Nervous System Disorders Mediated by SIRT1.

Daytime dysfunction, including symptoms like sleepiness, poor memory, and reduced responsiveness, is not well researched. It is crucial to develop animal models and study the biological mechanisms involved. We simulated sleep disorders through sleep deprivation, and stressful stimuli were used to establish daytime functional animal models. We used tests like the sodium pentobarbital sleep synergy test and the DSI telemetry system to measure sleep duration and structure. We also used tests like the Morris water maze, open field test, grip test, and baton twirling test to assess mental and physical fatigue. To assess the intrinsic biological mechanisms, we measured sleep-wake-related neurotransmitters and related receptor proteins, circadian rhythm-related proteins and cognition-related proteins in hypothalamus tissue, and oxidative stress, inflammatory factors, S100β, and HPA axis-related indexes in serum. Multi-factor sleep deprivation resulted in the disruption of sleep-wakefulness structure, memory-cognitive function degradation, decreased grip coordination, and other manifestations of decreased energetic and physical strength. The intrinsic biological mechanisms were related to the disturbed expression of sleep-wake, circadian rhythm, memory-cognition-related proteins, as well as the significant elevation of inflammatory factors, oxidative stress, the HPA axis, and other related indicators. Intrinsically related biological mechanisms and reduced sirt1 expression can lead to disruption of circadian rhythms; resulting in disruption of their sleep-wake-related neurotransmitter content and receptor expression. Meanwhile, the reduced expression of sirt1 also resulted in reduced expression of synapse-associated proteins. This study prepared an animal model of daytime dysfunction by means of multi-factor sleep deprivation. With sirt1 as a core target, the relevant biological mechanisms of neurological disorders were modulated.

REV-ERBα Mitigates Astrocyte Activation and Protects Dopaminergic Neurons from Damage.

Parkinson's disease (PD) is characterized by astrocyte activation and disruptions in circadian rhythm. Within the astrocyte population, two distinct reactive states exist: A1 and A2. A1 astrocytes are associated with neurotoxicity and inflammation, while A2 astrocytes exhibit neuroprotective functions. Our investigation focused on the role of REV-ERBα, a member of the nuclear receptor superfamily and a key regulator of the circadian clock, in astrocyte activation. We observed that REV-ERBα expression in A1 astrocytes was reduced to one-third of its normal level. Notably, activation of REV-ERBα prompted a transformation of astrocytes from A1 to A2. Mechanistically, REV-ERBα inhibition was linked to the classical NF-κB pathway, while it concurrently suppressed the STAT3 pathway. Furthermore, astrocytes with low REV-ERBα expression were associated with dopaminergic neurons apoptosis. Intriguingly, the opposite effect was observed when using a REV-ERBα agonist, which mitigated astrocyte activation and reduced dopaminergic neuron damage by 50%. In summary, our study elucidates the pivotal role of REV-ERBα in modulating astrocyte function and its potential implications in PD pathogenesis.

The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans.

The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10μM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100μM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10μM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100μM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.

Comparative Analysis of Taste Perception Among Airline Pilots, Construction Workers, and Office Employees.

Objective Occupational exposures may influence gustatory sensations through mechanisms such as fatigue, acute or chronic stress, circadian rhythm disruptions, and exposure to various chemicals. In this cross-sectional study, we sought to compare taste perception across three professional groups, namely airline pilots, construction workers, and office employees, by assessing taste identification times for sweet, salty, sour, and bitter flavors, alongside salivary pH levels. Methods The study cohort consisted of 90 healthy male participants, with 30 individuals in each occupational group, matched for age and professional experience. Salivary pH was measured using pH meter paper, whereas taste identification times were assessed using aqueous solutions applied to dissolvable strips for each taste. Results There were no significant differences in salivary pH among the study groups. However, airline pilots exhibited a significantly longer identification time for sweet taste (9.8 ± 3.9 seconds) compared to construction workers (7.0 ± 3.1 seconds, P < 0.05) and office employees (7.1 ± 3.3 seconds, P < 0.05). Conversely, construction workers demonstrated a significantly prolonged identification time for sour taste (6.1 ± 2.9 seconds) compared to pilots (4.2 ± 2.6 seconds, P < 0.05) and office employees (4.6 ± 2.5 seconds, P < 0.05). No significant differences were observed in the identification times for salty and bitter tastes across the groups. Conclusion We found significant differences in taste perception among airline pilots, construction workers, and office employees, particularly concerning sweet and sour tastes. These findings suggest that occupational factors may influence gustatory function in a complex manner. Further research is warranted to explore the underlying mechanisms and potential implications for dietary habits and health within specific occupational groups.

Circadian control of polycyclic aromatic hydrocarbon-induced dysregulation of endothelial tight junctions and mitochondrial bioenergetics

The study evaluates the impact of environmental toxicants, such as polycyclic aromatic hydrocarbons (PAHs), on circadian regulations and functions of brain endothelial cells, which form the main structural element of the blood-brain barrier (BBB). PAH are lipophilic and highly toxic environmental pollutants that accumulate in human and animal tissues. Environmental factors related to climate change, such as an increase in frequency and intensity of wildfires or enhanced strength of hurricanes or tropical cyclones, may lead to redistribution of these toxicants and enhanced human exposure. These natural disasters are also associated with disruption of circadian rhythms in affected populations, linking increased exposure to environmental toxicants to alterations of circadian rhythm pathways. Several vital physiological processes are coordinated by circadian rhythms, and disruption of the circadian clock can contribute to the development of several diseases. The blood-brain barrier (BBB) is crucial for protecting the brain from blood-borne harmful substances, and its integrity is influenced by circadian rhythms. Exposure of brain endothelial cells to a human and environmentally-relevant PAH mixture resulted in dose-dependent alterations of expression of critical circadian modulators, such as Clock, Bmal1, Cry1/2, and Per1/2. Moreover, silencing of the circadian Clock gene potentiated the impact of PAHs on the expression of the main tight junction genes and proteins (namely, claudin-5, occludin, JAM-2, and ZO-2), as well as mitochondrial bioenergetics. Findings from this study contribute to a better understanding of pathological influence of PAH-induced health effects, especially those related to circadian rhythm disruption.

Shift Work Increases the Risk of Circadian Syndrome Rather than Metabolic Syndrome: A Cross-Sectional Study of NHANES 2005-2010.

Introduction: Shift work disrupts sleep-wake cycles and may lead to adverse health outcomes, including cardiovascular disease and metabolic disorders. This study examines the association between shift work and the risks of metabolic syndrome (MetS) and circadian syndrome (CircS) in U.S. workers. Methods: We analyzed data from 4173 participants aged 18 and above from the National Health and Nutrition Examination Survey (NHANES) spanning 2005-2010. Shift work status was determined based on work hours, and MetS and CircS were defined using established criteria. Statistical analyses included weighted multivariate logistic regression models, weighted multivariate linear regression models, and inverse probability weighted propensity score matching to ensure accurate comparison between shift and nonshift workers. Results: The study found no significant association between shift work and the prevalence of MetS. However, shift workers exhibited a higher prevalence of CircS compared with nonshift workers. This association was more pronounced in specific subgroups, including those under 60 years of age and various ethnicities. The study highlights the heightened risk of CircS among shift workers, underscoring the potential impact of shift work on circadian rhythm disruptions. Conclusion: Shift work is associated with an increased risk of CircS but not MetS, according to NHANES 2005-2010 data.

Identification of a circadian-based prognostic signature predicting cancer-associated fibroblasts infiltration and immunotherapy response in bladder cancer.

Circadian rhythm disruption impacts the efficiency of both chemotherapy and immunotherapy, yet identifying the key factors involved remains challenging. Circadian rhythm disruption can trigger aberrant fibroblasts activation, suggesting potential roles of cancer-associated fibroblasts (CAFs) in addressing this issue. In this paper, TCGA-BLCA patients were classified into two subgroups based on the expression of core circadian rhythm genes (CCRGs). The CCRG-based subgroups showed distinct fibroblast-related signals, from which a risk model composed of five fibroblast-related genes was finally established with excellent survival prognostic value in both TCGA and GEO datasets. The risk model was positively associated with the infiltration of CAFs and can efficiently predict the immunotherapy response in BLCA. Besides, high-risk score was associated with reduced sensitivity to a majority of traditional chemotherapeutic drugs such as oxaliplatin and gemcitabine. Further, the correlation between CCRGs and the risk genes was analyzed. Among the five risk genes, FAM20C displayed the most extensive correlation with the CCRGs and exhibited the strongest connection with CAFs infiltration. Moreover, FAM20C independently served as a predictor for the response to immunotherapy in BLCA. In conclusion, this study has identified a circadian-based signature for evaluating CAFs infiltration and predicting the efficacy of chemotherapy and immunotherapy. The central gene FAM20C has emerged as a promising candidate which merits further investigations.

GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.

Disruptions in circadian rhythms are associated with an increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24-h feeding-fasting cycle. To address our objective, wild-type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a control or leucine-devoid diet (LeuD) for 8 days in total darkness. On the last day, blood and livers were collected at CT3 (CT = circadian time) and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched-chain amino acid concentrations (r2 = 0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillations in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Furthermore, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio, and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole body metabolism.NEW & NOTEWORTHY This work reveals that the eIF2 kinase GCN2 functions to support diurnal patterns in the hepatic integrated stress response during natural feeding and is necessary to maintain circadian rhythms in energy expenditure, respiratory exchange ratio, and physical activity during amino acid stress.

Altered circadian expression of clock genes and clock-regulatory epigenetic modifiers in saliva of children with fetal alcohol spectrum disorders

Prenatal alcohol-exposed (AE) infants and children often demonstrate disrupted sleep patterns, including more frequent awakenings, reduced total sleep time, and more night-to-night sleep variability. Despite the strong connection between sleep patterns and circadian rhythmicity, relatively little is known about circadian rhythm disruptions in individuals with AE. Recently, several reports demonstrated that evaluating the expression patterns of human clock genes in biological fluids could reveal an individual’s circadian phenotype. Human saliva offers an emerging and easily available physiological sample that can be collected non-invasively for core-clock gene transcript analyses. We compared the expression patterns of core-clock genes and their regulatory genes in salivary samples of children aged 6–10 years-old with and without AE during the light cycle between ZT0-ZT11. We isolated the RNA from the samples and measured the expression patterns of core clock genes and clock regulating genes using the human specific primers with quantitative real-time PCR. Analysis of core clock genes expression levels in saliva samples from AE children indicates significantly altered levels in expression of core-clock BMAL1, CLOCK, PER1-3 and CRY1,2, as compared to those in age-matched control children. We did not find any sex difference in levels of clock genes in AE and control groups. Cosinor analysis was used to evaluate the rhythmic pattern of these clock genes, which identified circadian patterns in the levels of core clock genes in the control group but absent in the AE group. The gene expression profile of a salivary circadian biomarker ARRB1 was rhythmic in saliva of control children but was arhythmic in AE children. Altered expression patterns were also observed in clock regulatory genes: NPAS2, NFL3, NR1D1, DEC1, DEC2, and DBP, as well as chromatin modifiers: MLL1, P300, SIRT1, EZH2, HDAC3, and ZR1D1, known to maintain rhythmic expression of core-clock genes. Overall, these findings provide the first evidence that AE disturbs the circadian patten expression of core clock genes and clock-regulatory chromatin modifiers in saliva.

Shift Work and Associated Health Consequences: A Review

This literature review aims to examine the complex relationship between engaging in shift work and its subsequent health sequelae, while also shedding light on fields of research that require further investigation. Indexing services (i.e., Scopus and PubMed) were used to identify pertinent studies, prioritizing original research, review articles, and meta-analyses from 2018 to 2023. Papers not published in English or where full-text translation was not available, research conducted solely on non-human populations, as well as proposal and opinion papers, were excluded. Papers published before 2018 and those with a sample size of 50 participants or fewer were also omitted. The author conducted a thorough evaluation of each study to ensure its relevance and significance. After deduplication of the search results and implementation of the exclusion criteria, 51 papers were shortlisted for this review. The keywords used for the literature search were “shift work”, “health”, “night shift”, “cardiovascular”, “circadian, cancer”, “disease”, “dose-response relationship”, and “long working hours”. The results showed that shift work significantly impacts various aspects of health, presenting risks in the areas of cardiovascular health, cancer susceptibility, circadian rhythm, immunity, metabolism, reproductive health, and mental well-being. Shift workers have increased risks for diabetes, hypertension, adverse cardiac events, circadian dysrhythmia, metabolic syndrome, mental health disorders, and even certain types of cancer. Shift work exhibits significant associations with sexual and reproductive dysfunction in both sexes, including elevated risks for miscarriages and preterm birth. In conclusion, the findings underscore the need for comprehensive health interventions and further research to understand the intricate relationships between shift work and long-term health consequences. Highlights: Disruption of circadian rhythm due to shift work contributes to various health issues, including altered melatonin levels, immune dysfunction, and metabolic disturbances. There is a critical need for longitudinal studies to explore interventions and workplace policies that can mitigate the adverse health effects of shift work. Addressing the multifaceted impact of shift work on health requires a holistic approach that considers factors like circadian rhythm optimization, workplace support, and tailored interventions.

Resilience to Chronic Stress is Characterized by Circadian Brain-Liver Coordination

BackgroundChronic stress has a profound impact on circadian regulation of physiology. In turn, disruption of circadian rhythms increases the risk of developing both psychiatric and metabolic disorders. To explore the role of chronic stress in modulating the links between neural and metabolic rhythms, we characterized the circadian transcriptional regulation across different brain regions and the liver as well as serum metabolomics in mice exposed to chronic social defeat stress, a validated model for studying depressive-like behaviors. MethodsMale C57BL/6J mice underwent chronic social defeat stress, and subsequent social interaction screening identified distinct behavioral phenotypes associated with stress resilience and susceptibility. Stressed mice and their control littermates were sacrificed every 4 hours over the circadian cycle for comprehensive analyses of the circadian transcriptome in the hypothalamus, hippocampus, prefrontal cortex, and liver together with assessments of the circadian circulatory metabolome. ResultsOur data demonstrate that stress adaptation was characterized by reprogramming of the brain as well as the hepatic circadian transcriptome. Stress resiliency was associated with an increase in cyclic transcription in the hypothalamus, hippocampus, and liver. Furthermore, cross-tissue analyses revealed that resilient mice had enhanced transcriptional coordination of circadian pathways between the brain and liver. Conversely, susceptibility to social stress resulted in a loss of cross-tissue coordination. Circadian serum metabolomic profiles corroborated the transcriptome data, highlighting that stress-resilient mice gained circadian rhythmicity of circulating metabolites, including bile acids and sphingomyelins. ConclusionsThis study reveals that resilience to stress is characterized by enhanced metabolic rhythms and circadian brain-liver transcriptional coordination.

Bipolar Disorder: A Comprehensive Analysis of its Etiology, Impact, and Treatment Options

Bipolar disorder (BD) is a disorder significantly impacts individuals worldwide, marked by alternating episodes of mania and depression. The onset and progression of the disease are impact by a interplay of genetic factors, neurobiological differences, environmental stressors, hormonal imbalances, and circadian rhythm disruptions. These factors collectively contribute to the manifestation and exacerbation of the disorder. The disorder profoundly affect both mental and physical health. The pervasive impact on daily life can be overwhelming, resulting in severe emotional distress. This distress is compounded by the high risk of suicide associated with the disorder, underscoring the critical need for vigilant care and comprehensive support to ensure the well-being of affected individuals. Effective treatment requires a holistic approach combining pharmacological interventions, psychotherapy, and lifestyle adjustments. Mood stabilizers, antipsychotics, and antidepressants, alongside Cognitive Behavioral Therapy (CBT), psychoeducation, and family therapy, form the cornerstone of treatment. Lifestyle modifications, including regular exercise, adequate sleep, and balanced nutrition, are crucial for symptom management. Electroconvulsive Therapy (ECT) is considered for severe cases. This review underscores the need for continuous research and innovation in therapeutic strategies and emphasizes bridging global disparities in mental health services to ensure equitable care and improve the well-being of people with bipolar disorder.

Chinese formula Guben-Jiannao Ye alleviates the dysfunction of circadian and sleep rhythms in APP/PS1 mice implicated in activation of the PI3K/AKT/mTOR signaling pathway

Ethnopharmacological relevanceThe Chinese formula Guben-Jiannao Ye (GBJNY) formula has a long history of usage in traditional Chinese medicine (TCM) for the treatment of learning and memory disorders as well as senile insomnia. This formulation is derived from Sun Simiao's five tonic pills. Furthermore, modern pharmacological investigations have revealed its ability to improve cognitive impairment and ameliorate sleep-wake circadian rhythm disorders. However, the precise mechanism underlying its efficacy remains elusive. Aim of the studyThe current research explored the modulatory effects and possible mechanisms of GBJNY in circadian rhythm sleep-wake disorders and cognitive dysfunction in Alzheimer's disease using transcriptome sequencing and experimental validation. Materials and methodsThe LC-MS/MS tandem technology was utilized to qualitatively discern the active components present in GBJNY. The APP/PS1 mice received continuous treatment with GBJNY or Melatonin for 3 months. The learning and memory abilities of mice were assessed utilizing the Morris water maze (MWM) test, while sleep changes were studied utilizing the electroencephalogram (EEG) and electromyogram (EMG). Concurrently, mice's hippocampus clock gene rhythmicity was investigated. Subsequently, we employed HE staining, Golgi staining, and immunofluorescence to observe GBJNY's impact on synaptic damage and neuronal loss. We performed high-throughput sequencing to analyze the mRNA expression profiles of mice, aiming to identify differentially expressed genes (DEGs). Subsequently, we conducted GO and KEGG enrichment analyses to explore associated signaling pathways. Furthermore, we evaluated the expression levels of proteins involved in the PI3K/AKT/mTOR pathway and Aβ deposition in the hippocampus of mice. Through this comprehensive approach, we sought to elucidate and validate the potential mechanisms of action of GBJNY in APP/PS1 mice. ResultsResults showed 216 DEGs. Following this, we conducted GO enrichment and KEGG pathway analyses to delve deeper into the distinctions and fundamental functions of the mRNA target genes. The enrichment analysis underscored the prominence of the PI3K/Akt/mTOR signaling pathway as the most pivotal among them. Through in vivo experiments, it was further demonstrated that the administration of GBJNY enhanced memory and learning capacities in APP/PS1 mice. Additionally, GBJNY treatment resulted in alterations in the sleep-wake circadian rhythm, characterized by reduced wakefulness and an increase in non-rapid eye movement (NREM) sleep. Moreover, alterations in the peak expression of Per1, Per2, Clock, Cry1, Cry2, and Bmal1 mRNA were noted in the hippocampus of treated mice. Particularly noteworthy were the observed reductions in amyloid-beta (Aβ) deposition within the hippocampus, improvements in neuronal synaptic integrity, and upregulation of mTOR, Akt, and PI3K protein expression in the hippocampal region. These findings underscore the critical involvement of the PI3K/Akt/mTOR signaling pathway in mitigating disturbances in sleep-wake circadian rhythms. ConclusionsGBJNY enhanced the cognitive performance of APP/PS1 mice and altered clock gene expression patterns, alleviating sleep-wake circadian rhythm disruptions. The fundamental mechanism appears to be linked to the PI3K/Akt/mTOR pathway regulation, offering a foundation for potential clinical applications.

The circadian rhythm as therapeutic target in inflammatory bowel disease

Abstract The primary objectives of the management of patients with inflammatory bowel disease (IBD) are to prevent IBD flares, prevent/delay disease progression and improve patients’ quality of life. To this end, one needs to identify risk factor(s) associated with flare-ups and disease progression. We posit that disruption of circadian rhythms is one of the key factors that is associated with risk of flare-up and disease progression. This hypothesis is based on published studies that show: (1) The circadian rhythm regulates many biological processes including multiple IBD-relevant biological processes that are critical in inflammatory/immune processes such as environment/microbe interaction, microbe/host interaction, intestinal barrier integrity and mucosal immunity—all central in the pathogenesis of IBD, and (2) Circadian machinery is the primary tool for the host to interact with the environment. Circadian misalignment results in a loss of preparedness of the host to respond and adjust to the environmental changes that could make the host more vulnerable to IBD flare-ups. In this review, we first provide an overview of circadian rhythms and its role in healthy and disease states. Then we present data to support our hypothesis that: (1) IBD patients have disrupted circadian rhythms (“social jet lag”) and (2) circadian misalignment and associated disrupted sleep decreases the resiliency of IBD patients resulting in microbiota dysbiosis, more disrupted intestinal barrier integrity and a more aggressive disease phenotype. We also show that circadian-directed interventions have a potential to mitigate the deleterious impact of disrupted circadian and improve IBD disease course.

Disruption of Circadian Clock Induces Abnormal Mammary Morphology and Aggressive Basal Tumorigenesis by Enhancing LILRB4 Signaling.

Epidemiological studies have shown that circadian rhythm disruption (CRD) is associated with the risk of breast cancer. However, the role of CRD in mammary gland morphology and aggressive basal mammary tumorigenesis and the molecular mechanisms underlying CRD and cancer risk remain unknown. To investigate the effect of CRD on aggressive tumorigenesis, a genetically engineered mouse model that recapitulates the human basal type of breast cancer was used for this study. The effect of CRD on mammary gland morphology was investigated using wild-type mice model. The impact of CRD on the tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA seq. ScRNA seq was substantiated by multiplexing immunostaining, flow cytometry, and realtime PCR. The effect of LILRB4 immunotherapy on CRD-induced tumorigenesis was also investigated. Here we identified the impact of CRD on basal tumorigenesis and mammary gland morphology and identified the role of LILRB4 on CRD-induced lung metastasis. We found that chronic CRD disrupted mouse mammary gland morphology and increased tumor burden, and lung metastasis and induced an immunosuppressive tumor microenvironment by enhancing LILRB4a expression. Moreover, CRD increased the M2-macrophage and regulatory T-cell populations but decreased the M1-macrophage, and dendritic cell populations. Furthermore, targeted immunotherapy against LILRB4 reduced CRD-induced immunosuppressive microenvironment and lung metastasis. These findings identify and implicate LILRB4a as a link between CRD and aggressive mammary tumorigenesis. This study also establishes the potential role of the targeted LILRB4a immunotherapy as an inhibitor of CRD-induced lung metastasis.

Computational Analyses Reveal Deregulated Clock Genes Associated with Breast Cancer Development in Night Shift Workers.

Breast cancer (BC) is the leading cause of cancer death among women worldwide. Women employed in shift jobs face heightened BC risk due to prolonged exposure to night shift work (NSW), classified as potentially carcinogenic by the International Agency for Research on Cancer (IARC). This risk is linked to disruptions in circadian rhythms governed by clock genes at the cellular level. However, the molecular mechanisms are unclear. This study aimed to assess clock genes as potential BC biomarkers among women exposed to long-term NSW. Clock gene expression was analysed in paired BC and normal breast tissues within Nurses' Health Studies I and II GEO datasets. Validation was performed on additional gene expression datasets from healthy night shift workers and women with varying BC susceptibility, as well as single-cell sequencing datasets. Post-transcriptional regulators of clock genes were identified through miRNA analyses. Significant alterations in clock gene expression in BC compared to normal tissues were found. BHLHE40, CIART, CLOCK, PDPK1, and TIMELESS were over-expressed, while HLF, NFIL3, NPAS3, PER1, PER3, SIM1, and TEF were under-expressed. The downregulation of PER1 and TEF and upregulation of CLOCK correlated with increased BC risk in healthy women. Also, twenty-six miRNAs, including miR-10a, miR-21, miR-107, and miR-34, were identified as potential post-transcriptional regulators influenced by NSW. In conclusion, a panel of clock genes and circadian miRNAs are suggested as BC susceptibility biomarkers among night shift workers, supporting implications for risk stratification and early detection strategies.