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.

Sleep and circadian rhythm disturbances as risk and progression factors for multiple chronic overlapping pain conditions: a protocol for a longitudinal study.

Introduction: Chronic overlapping pain conditions (COPCs), such as chronic low back pain (cLBP) and fibromyalgia, frequently cooccur and incur substantial healthcare costs. However, to date, much focus has been placed on individual anatomically based chronic pain conditions, whereas little is known about the mechanisms underlying progression to multiple (more than 1) COPCs. This study aims to address the gap by investigating the role of common and modifiable risk factors, specifically sleep and circadian rhythm disturbances, in the development of multiple COPCs. Methods: The study will enroll 300 participants with cLBP, including 200 with cLBP only and 100 with cLBP plus other COPCs (ie, fibromyalgia, temporomandibular disorders, irritable bowel syndrome, and chronic headaches) and follow them up for 12 months. Sleep and circadian rhythms will be assessed using wireless sleep electroencephalography, 24-hour evaluation of the rhythm of urinary 6-sulfatoxymelatonin, actigraphy, and sleep diaries. Pain amplification using quantitative sensory testing, psychological distress using validated self-report measures, and the number of pain sites using a pain body map will also be assessed. Perspectives: This research aims to (1) comprehensively characterize sleep/circadian disturbances in individuals with single and multiple COPCs using multimodal in-home assessments; (2) examine the associations between sleep/circadian disturbances, changes in pain amplification, and psychological distress; and (3) investigate the relationship among these factors and the progression in the number of pain sites, a proxy for multiple COPCs. The findings will provide insights into the mechanisms leading to multiple COPCs, potentially informing treatment and prevention strategies for these complex conditions.

The Influence of Circadian Rhythms on DNA Damage Repair in Skin Photoaging.

Circadian rhythms, the internal timekeeping systems governing physiological processes, significantly influence skin health, particularly in response to ultraviolet radiation (UVR). Disruptions in circadian rhythms can exacerbate UVR-induced skin damage and increase the risk of skin aging and cancer. This review explores how circadian rhythms affect various aspects of skin physiology and pathology, with a special focus on DNA repair. Circadian regulation ensures optimal DNA repair following UVR-induced damage, reducing mutation accumulation, and enhancing genomic stability. The circadian control over cell proliferation and apoptosis further contributes to skin regeneration and response to UVR. Oxidative stress management is another critical area where circadian rhythms exert influence. Key circadian genes like brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) modulate the activity of antioxidant enzymes and signaling pathways to protect cells from oxidative stress. Circadian rhythms also affect inflammatory and immune responses by modulating the inflammatory response and the activity of Langerhans cells and other immune cells in the skin. In summary, circadian rhythms form a complex defense network that manages UVR-induced damage through the precise regulation of DNA damage repair, cell proliferation, apoptosis, inflammatory response, oxidative stress, and hormonal signaling. Understanding these mechanisms provides insights into developing targeted skin protection and improving skin cancer prevention.

Circadian Rhythm Disruption in Cancer Survivors: From Oncogenesis to Quality of Life.

BACKGROUND: Circadian rhythms are approximately 24-hour cycles in physiological and behavioral processes. They are entrained to the external solar day via blue wavelength light. Disruptions in these intrinsic rhythms can lead to circadian dysfunction, which has several negative implications on human health, including cancer development and progression. AIMS: Here we review the molecular mechanisms of circadian disruption and their impact on tumor development and progression, discuss the interplay between circadian dysfunction and cancer in basic scientific studies and clinical data, and propose the potential clinical implications of these data that may be used to improve patient outcomes and reduce cost of treatment. MATERIALS & METHODS: Using scientific literature databases, relevant studies were analyzed to draw overarching conclusions of the relationship between circadian rhythm dysruption and cancer. CONCLUSIONS: Circadian disruption can be mediated by a number of environmental factors such as exposure to light at night, shift work, jetlag, and social jetlag which drive oncogenesis. Tumor growth and progression, as well as treatment, can lead to long-term alterations in circadian rhythms that negatively affect quality of life in cancer survivors.

Biobehavioral predictors of mood, pain, fatigue, and insomnia in endometrial cancer survivors.

OBJECTIVE: Endometrial cancer survivors experience persistent health-related quality of life concerns, including pain, fatigue, and disrupted emotional and social functioning. The purpose of this longitudinal study was to evaluate associations between biobehavioral factors, including daytime physical activity, nighttime sleep, and 24-h circadian rest-activity rhythms, with psychological and physical symptoms following endometrial cancer surgery. METHODS: This study included 69 adult female patients undergoing surgery for endometrial cancer. At each of three assessment points (1, 4, and 16 weeks post-surgery), participants wore a wrist actigraph for 3 days and completed a sleep log and self-report measures of depression and anxiety (Inventory of Depression and Anxiety Symptoms), pain (Brief Pain Inventory), fatigue (Fatigue Symptom Inventory), and insomnia (Insomnia Severity Index). Physical activity, sleep, and 24-h rest-activity indices were derived from actigraphy. Mixed- and fixed-effects linear regression models were utilized to evaluate relationships between actigraphy indices and patient-reported outcomes. RESULTS: Clinically elevated fatigue persisted for a majority of participants (64 %), while a sizeable minority continued to report clinically elevated insomnia (41 %) and pain (19 %) at 16-weeks post-surgery. Participants who recorded less daytime activity, more disrupted sleep, and less consistent 24-h rest-activity rhythms by actigraphy reported more depression and anxiety symptoms and greater pain and fatigue. Within individual participants, at time points when activity was lowest, sleep most disrupted, and 24-h rest-activity rhythms least consistent, participants experienced more psychological and physical symptoms. CONCLUSIONS: Findings suggest that disruptions in daytime physical activity, nighttime sleep, and 24-h rest-activity patterns contribute to patient-reported outcomes in the weeks and months after endometrial cancer treatment. Findings support modifiable intervention targets to address co-occurring physical and psychological symptoms and optimize health and recovery after endometrial cancer surgery.

Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

The impact of diurnal variations on emergence delirium following general anesthesia and surgery in children.

Background: Emergence delirium (ED) is a widely recognized issue that prolongs mechanical ventilation and post-anesthesia care unit (PACU) resuscitation time, consequently increasing hospital costs and mortality. Postoperative disturbance in circadian rhythms, commonly leading to sleep disorders, has been identified as a significant risk factor for ED. However, the influence of surgery timing (morning vs. afternoon) on the incidence of ED in pediatric patients undergoing general anesthesia remains unknown. Methods: Patients aged 2-6 years who were operated on under general anesthesia with a bispectral index value between 50 and 60 were categorized based on anesthesia start time into either the morning surgery group (Group M, 8:00-12:00) or the afternoon surgery group (Group A, 13:00-17:00). The primary outcome was the post-extubation incidence of ED assessed by the Cornell Assessment of Pediatric Delirium (CAPD) score. Secondary outcomes included extubation time, duration of PACU stay, and adverse postoperative events and complications. Results: We recruited a total of 560 patients, 280 in group M and 280 in group A. Compared to Group M, Group A exhibited a significantly higher incidence of ED (p < 0.001), elevated CAPD scores (p < 0.001), and prolonged PACU stays (p < 0.001). Notably, there was no significant difference in extubation time and anesthesia-related adverse events or other postoperative complications between the groups. Conclusion: Our study highlights that the time of surgery significantly affects the incidence of ED, CAPD scores, and PACU stay duration in children. Further validation of these findings may guide future strategies to reduce ED.

Integration of circadian rhythms and immunotherapy for enhanced precision in brain cancer treatment.

Circadian rhythms significantly impact (patho)physiological processes, with disruptions linked to neurodegenerative diseases and heightened cancer vulnerability. While immunotherapy has shown promise in treating various cancers, its efficacy in brain malignancies remains limited. This review explores the nexus of circadian rhythms and immunotherapy in brain cancer treatment, emphasising precision through alignment with the body's internal clock. We evaluate circadian regulation of immune responses, including cell localisation and functional phenotype, and discuss how circadian dysregulation affects anti-cancer immunity. Additionally, we analyse and assess the effectiveness of current immunotherapeutic approaches for brain cancer including immune checkpoint blockades, adoptive cellular therapies, and other novel strategies. Future directions, such as chronotherapy and personalised treatment schedules, are proposed to optimise immunotherapy precision against brain cancers. Overall, this review provides an understanding of the often-overlooked role of circadian rhythms in brain cancer and suggests avenues for improving immunotherapeutic outcomes.

Protective role of melatonin against radiation-induced disruptions in behavior rhythm of zebrafish (danio rerio).

Ionizing radiation, as an increasingly serious environmental pollutant, has aroused widespread public concern. Melatonin, as an indole heterocyclic compound, is known to have anti-inflammatory and antioxidant effects. However, few studies have considered the comprehensive impact of melatonin on radiation damage. In this study, we used zebrafish as experimental materials and employed methods such as acridine orange staining, enzyme-linked immunosorbent assay (ELISA), video tracking for automated behavior analysis, microscope imaging, and real-time fluorescence quantitative analysis. Zebrafish embryos at 2 h post-fertilization (hpf) were treated under four different experimental conditions to assess their growth, development, and metabolic consequences. Our findings indicate that 0.10 Gy gamma radiation significantly augments body length, eye area, spine width, and tail fin length in zebrafish, along with a marked increase in oxidative stress (P < 0.05). Moreover, it enhances cumulative swimming distance, time, and average speed, suggesting elevated activity levels. We observed circadian rhythm phase shifts, peak increases, and cycle shortening, accompanied by abnormal expression of genes pivotal to biological rhythms, exercise, melatonin synthesis, apoptosis/anti-apoptosis, and oxidation/antioxidant balance. The inclusion of melatonin (1 × 10-5 mol/L MLT) ameliorated these radiation-induced anomalies, while its independent effect on zebrafish was negligible. Melatonin can regulate oxidative stress responses, hinders apoptosis responses, and reprogramming the expression of rhythm-related genes in zebrafish embryos after reprogramming radiation stimulation. Overall, our research highlights melatonin's critical role in countering the biological damage inflicted by gamma radiation, proposing its potential as a therapeutic agent in radiation protection.

A New Frontier in Cystic Fibrosis Pathophysiology: How and When Clock Genes Can Affect the Inflammatory/Immune Response in a Genetic Disease Model.

Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes' involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD.

Circadian rhythms and breast cancer: from molecular level to therapeutic advancements.

BACKGROUND AND OBJECTIVES: Circadian rhythms, the endogenous biological clocks that govern physiological processes, have emerged as pivotal regulators in the development and progression of breast cancer. This comprehensive review delves into the intricate interplay between circadian disruption and breast tumorigenesis from multifaceted perspectives, encompassing biological rhythms, circadian gene regulation, tumor microenvironment dynamics, and genetic polymorphisms. METHODS AND RESULTS: Epidemiological evidence underscores the profound impact of external factors, such as night shift work, jet lag, dietary patterns, and exercise routines, on breast cancer risk and progression through the perturbation of circadian homeostasis. The review elucidates the distinct roles of key circadian genes, including CLOCK, BMAL1, PER, and CRY, in breast cancer biology, highlighting their therapeutic potential as molecular targets. Additionally, it investigates how circadian rhythm dysregulation shapes the tumor microenvironment, fostering epithelial-mesenchymal transition, chronic inflammation, and immunosuppression, thereby promoting tumor progression and metastasis. Furthermore, the review sheds light on the association between circadian gene polymorphisms and breast cancer susceptibility, paving the way for personalized risk assessment and tailored treatment strategies. CONCLUSIONS: Importantly, it explores innovative therapeutic modalities that harness circadian rhythms, including chronotherapy, melatonin administration, and traditional Chinese medicine interventions. Overall, this comprehensive review emphasizes the critical role of circadian rhythms in the pathogenesis of breast cancer and highlights the promising prospects for the development of circadian rhythm-based interventions to enhance treatment efficacy and improve patient outcomes.

Chronobiology of Cancers in the Liver and Gut.

Circadian rhythms dictate the timing of cellular and organismal physiology to maintain homeostasis. Within the liver and gut, circadian rhythms influence lipid and glucose homeostasis, xenobiotic metabolism, and nutrient absorption. Disruption of this orchestrated timing is known to negatively impact human health and contribute to disease progression, including carcinogenesis. Dysfunctional core clock timing has been identified in malignant growths and may be used as a molecular signature of disease progression. Likewise, the circadian clock and its downstream effectors also represent potential for novel therapeutic targets. Here, the role of circadian rhythms in the pathogenesis of cancers of the liver and gut will be reviewed, and chronotherapy and chronopharmacology will be explored as potential treatment options.

Assessing sleep in primary brain tumor patients using smart wearables and patient-reported data: Feasibility and interim analysis of an observational study.

Background: Sleep-wake disturbances are common and disabling in primary brain tumor (PBT) patients but studies exploring longitudinal data are limited. This study investigates the feasibility and relationship between longitudinal patient-reported outcomes (PROs) and physiologic data collected via smart wearables. Methods: Fifty-four PBT patients ≥ 18 years wore Fitbit smart-wearable devices for 4 weeks, which captured physiologic sleep measures (eg, total sleep time, wake after sleep onset [WASO]). They completed PROs (sleep hygiene index, PROMIS sleep-related impairment [SRI] and Sleep Disturbance [SD], Morningness-Eveningness Questionnaire [MEQ]) at baseline and 4 weeks. Smart wearable use feasibility (enrollment/attrition, data missingness), clinical characteristics, test consistency, PROs severity, and relationships between PROs and physiologic sleep measures were assessed. Results: The majority (72%) wore their Fitbit for the entire study duration with 89% missing < 3 days, no participant withdrawals, and 100% PRO completion. PROMIS SRI/SD and MEQ were all consistent/reliable (Cronbach's alpha 0.74-0.92). Chronotype breakdown showed 39% morning, 56% intermediate, and only 6% evening types. Moderate-severe SD and SRI were reported in 13% and 17% at baseline, and with significant improvement in SD at 4 weeks (P = .014). Fitbit-recorded measures showed a correlation at week 4 between WASO and SD (r = 0.35, P = .009) but not with SRI (r = 0.24, P = .08). Conclusions: Collecting sleep data with Fitbits is feasible, PROs are consistent/reliable, > 10% of participants had SD and SRI that improved with smart wearable use, and SD was associated with WASO. The skewed chronotype distribution, risk and impact of sleep fragmentation mechanisms warrant further investigation. Trial Registration: NCT04 669 574.

Multi-omics correlates of insulin resistance and circadian parameters mapped directly from human serum.

While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome-wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi-omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells.

Melanopsin in the human and chicken choroid.

The choroid embedded in between retina and sclera is essential for retinal photoreceptor nourishment, but is also a source of growth factors in the process of emmetropization that converts retinal visual signals into scleral growth signals. Still, the exact control mechanisms behind those functions are enigmatic while circadian rhythms are involved. These rhythms are attributed to daylight influences that are melanopsin (OPN4) driven. Recently, OPN4-mRNA has been detected in the choroid, and while its origin is unknown we here seek to identify the underlying structures using morphological methods. Human and chicken choroids were prepared for single- and double-immunohistochemistry of OPN4, vasoactive intestinal peptide (VIP), substance P (SP), CD68, and α-smooth muscle actin (ASMA). For documentation, light-, fluorescence-, and confocal laser scanning microscopy was applied. Retinal controls proved the reliability of the OPN4 antibody in both species. In humans, OPN4 immunoreactivity (OPN4-IR) was detected in nerve fibers of the choroid and adjacent ciliary nerve fibers. OPN4+ choroidal nerve fibers lacked VIP, but were co-localized with SP. OPN4-immunoreactivity was further detected in VIP+/SP + intrinsic choroidal neurons, in a hitherto unclassified CD68-negative choroidal cell population thus not representing macrophages, as well as in a subset of choroidal melanocytes. In chicken, choroidal nerve fibers were OPN4+, and further OPN4-IR was detected in clustered suprachoroidal structures that were not co-localized with ASMA and therefore do not represent non-vascular smooth-muscle cells. In the choroidal stroma, numerous cells displayed OPN4-IR, the majority of which was VIP-, while a few of those co-localized with VIP and were therefore classified as avian intrinsic choroidal neurons. OPN4-immunoreactivity was absent in choroidal blood vessels of both species. In summary, OPN4-IR was detected in both species in nerve fibers and cells, some of which could be identified (ICN, melanocytes in human), while others could not be classified yet. Nevertheless, the OPN4+ structures described here might be involved in developmental, light-, thermally-driven or nociceptive mechanisms, as known from other systems, but with respect to choroidal control this needs to be proven in upcoming studies.

Exploring the association between melatonin and nicotine dependence (Review).

Due to the addictive qualities of tobacco products and the compulsive craving and dependence associated with their use, nicotine dependence continues to be a serious public health concern on a global scale. Despite awareness of the associated health risks, nicotine addiction contributes to numerous acute and chronic medical conditions, including cardiovascular disease, respiratory disorders and cancer. The nocturnal secretion of pineal melatonin, known as the 'hormone of darkness', influences circadian rhythms and is implicated in addiction­related behaviors. Melatonin receptors are found throughout the brain, influencing dopaminergic neurotransmission and potentially attenuating nicotine­seeking behavior. Additionally, the antioxidant properties of melatonin may mitigate oxidative stress from chronic nicotine exposure, reducing cellular damage and lowering the risk of nicotine­related health issues. In addition to its effects on circadian rhythmicity, melatonin acting via specific neural receptors influences sleep and mood, and provides neuroprotection. Disruptions in melatonin signaling may contribute to sleep disturbances and mood disorders, highlighting the potential therapeutic role of melatonin in addiction and psychiatric conditions. Melatonin may influence neurotransmitter systems involved in addiction, such as the dopaminergic, glutamatergic, serotonergic and endogenous opioid systems. Preclinical studies suggest the potential of melatonin in modulating reward processing, attenuating drug­induced hyperactivity and reducing opioid withdrawal symptoms. Chronotherapeutic approaches targeting circadian rhythms and melatonin signaling show promise in smoking cessation interventions. Melatonin supplementation during periods of heightened nicotine cravings may alleviate withdrawal symptoms and reduce the reinforcing effects of nicotine. Further research is required however, to examine the molecular mechanisms underlying the melatonin­nicotine association and the optimization of therapeutic interventions. Challenges include variability in individual responses to melatonin, optimal dosing regimens and identifying biomarkers of treatment response. Understanding these complexities could lead to personalized treatment strategies and improve smoking cessation outcomes.

Polygenic risk scores for mood disorders and actigraphy estimates of sleep and circadian rhythms: A preliminary study in bipolar disorders.

In bipolar disorders, abnormalities of sleep patterns and of circadian rhythms of activity are observed during mood episodes, but also persist during euthymia. Shared vulnerabilities between mood disorders and abnormalities of sleep patterns and circadian rhythms of activity have been suggested. This exploratory study investigated the association between polygenic risk scores for bipolar disorder and major depressive disorder, actigraphy estimates of sleep patterns, and circadian rhythms of activity in a sample of 62 euthymic individuals with bipolar disorder. The polygenic risk score - bipolar disorder and polygenic risk score - major depressive disorder were calculated for three stringent thresholds of significance. Data reduction was applied to aggregate actigraphy measures into dimensions using principal component analysis. A higher polygenic risk score - major depressive disorder was associated with more fragmented sleep, while a higher polygenic risk score - bipolar disorder was associated with a later peak of circadian rhythms of activity. These results remained significant after adjustment for age, sex, bipolar disorder subtype, body mass index, current depressive symptoms, current tobacco use, and medications prescribed at inclusion, but not after correction for multiple testing. In conclusion, the genetic vulnerabilities to major depression and to bipolar disorder might be associated with different abnormalities of sleep patterns and circadian rhythms of activity. The results should be replicated in larger and independent samples.

Arsenic-induced disruption of circadian rhythms and glutamine anaplerosis in human urothelial carcinoma.

Inorganic arsenic (iAs)-induced urothelial carcinoma (UC) develops into a poor-prognosis malignancy. Arsenic-induced oxidative stress contributes to circadian rhythm disruption altered metabolism. Glutamine anaplerosis is a common metabolic feature of rapidly proliferating malignant cells, in which glutaminase (GLS) is a key enzyme in this process. Therefore, this study intends to determine if arsenic-induced oxidative stress can alter circadian rhythms and promote glutamine anaplerosis. Exonic expression of core circadian molecules (CLOCK, ARNTL, and NR1D1) and GLS in varying grades of UC were assessed using 423 bladder cancer samples from the TCGA Urothelial Bladder Cancer (BLCA) dataset. The levels of circadian proteins and metabolic markers in 44 UC patients from non-black foot disease (BFD) and BFD areas were detected by immunohistochemistry. In vitro and in vivo experiments elucidated the regulatory mechanisms of arsenic-mediated circadian disturbance and metabolic alteration. Public database analysis showed that ARNTL, NR1D1, and GLS exhibited greater expression in more high-grade UC. Strong immunoreactivity for BMAL1, GLS, and low levels of NR1D1 were found in malignant urothelial lesions, especially in arsenic-exposed UC. Arsenic-induced overexpression of BMAL1 and GLS involves activation of NADH: quinone oxidoreductase 1 (NQO1), continuously altering the NADH oscillations to promote glutamate metabolism in SV-HUC-1, T24 and BFTC-905 cells. These phenomenon were also demonstrated in the urothelium of arsenic-exposed animals. The present findings highlight the potential clinical significance of BMAL1 and GLS in UC in the BFD region. Furthermore, these results suggest that arsenic interferes with circadian rhythm and glutamine anaplerosis by NADH oscillatory imbalance in urothelial cells and urothelial cancer cells, predisposing them to malignant development.

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.

Natural Compounds for Preventing Age-Related Diseases and Cancers.

Aging is a multifaceted process influenced by hereditary factors, lifestyle, and environmental elements. As time progresses, the human body experiences degenerative changes in major functions. The external and internal signs of aging manifest in various ways, including skin dryness, wrinkles, musculoskeletal disorders, cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. Additionally, cancer, like aging, is a complex disease that arises from the accumulation of various genetic and epigenetic alterations. Circadian clock dysregulation has recently been identified as an important risk factor for aging and cancer development. Natural compounds and herbal medicines have gained significant attention for their potential in preventing age-related diseases and inhibiting cancer progression. These compounds demonstrate antioxidant, anti-inflammatory, anti-proliferative, pro-apoptotic, anti-metastatic, and anti-angiogenic effects as well as circadian clock regulation. This review explores age-related diseases, cancers, and the potential of specific natural compounds in targeting the key features of these conditions.