Circadian Rhythm Disruption Research Articles

Pharmacological investigation of vitamin E with combined oral contraceptives on INHBA gene against PCOS that intricate through melatonin PKC pathway

The most prevalent endocrine and metabolic condition in women of reproductive age are polycystic ovary syndrome (PCOS) with significant risk factors such as circadian rhythm and melatonin disruption. The aim of this study is to assess the effect of vitamin E in combination with a combined oral contraceptive (COC) on continuous light-induced PCOS using hormonal measures, oxidative stress (OS) indicators, and the inhibin beta-A (INHBA) gene, which targets the melatonin protein kinase C (PKC) pathway. An in silico technique anticipated INHBA's binding affinity for vitamin E and COC. For the in vivo investigation (IAEC/240/2021), female SD rats were divided into six groups and subjected to a 16-week induction period, followed by a 2-month test drug treatment with drospirenone (DRSP) as a standard. Serum testosterone, FSH, melatonin, and OS were calculated as hormonal markers. The expression of the INHBA gene was studied to see if it could be linked to the circadian rhythm and OS via the melatonin PKC pathway. According to the in silico study, vitamin E and DRSP had higher binding energy for the INHBA (–8.6 kcal/mol and –8.4 kcal/mol, respectively). When compared to the control group, in vivo results showed a substantial decrease in testosterone levels (p = .05), as well as changes in FSH (p = .78) and melatonin (p = .13). IHNBA gene expression has also dramatically increased, stimulating FSH production in the pituitary gland. Vitamin E and COC concomitantly are beneficial against PCOS because it modulates OS, which in turn influences circadian rhythm and the melatonin PKC pathway.

Advanced glycation and glycoxidation end products in bone.

Hyperglycemia and oxidative stress, enhanced in diabetes and aging, result in excessive accumulation of advanced glycation and glycoxidation end products (AGEs/AGOEs) in bone. AGEs/AGOES are considered to be "the missing link" in explaining increased skeletal fragility with diabetes, aging, and osteoporosis where increased fracture risk cannot be solely explained by bone mass and/or fall incidences. AGEs/AGOEs disrupt bone turnover and deteriorate bone quality through alterations of organic matrix (collagen and non-collagenous proteins), mineral, and water content. AGEs and AGOEs are also associated with bone fragility in other conditions such as Alzheimer's disease, circadian rhythm disruption, and cancer. This review explains how AGEs and AGOEs accumulate in bone and impact bone quality and bone fracture, and how AGES/AGOEs are being targeted in preclinical and clinical investigations for inhibition or removal, and for prediction and management of diabetic, osteoporotic and insufficiency fractures.

The Antihypertensive Guanabenz Exacerbates Integrated Stress Response and Disrupts the Brain Circadian Clock.

The circadian clock regulates a variety of biological processes that are normally synchronized with the solar day. Disruption of circadian rhythms is associated with health problems. Understanding the signaling mechanisms that couple cell physiology and metabolism to circadian timekeeping will help to develop novel therapeutic strategies. The integrated stress response (ISR) is activated by the cellular stressors to maintain physiological homeostasis by orchestrating mRNA translation. Aberrant ISR has been found in a number of neurological diseases that exhibit disrupted circadian rhythms and sleep. Recent work has started to uncover a critical role for the ISR in regulating the physiology of the circadian clock. Guanabenz (2,6-dichlorobenzylidene aminoguanidine acetate) is an orally bioavailable α2-adrenergic receptor agonist that has been used as an antihypertensive for decades. Recent studies demonstrated that guanabenz can regulate the ISR. Here, we assessed the effects of guanabenz on cellular and behavioral circadian rhythms using a multidisciplinary approach. We found that guanabenz can induce the ISR by increasing eIF2α phosphorylation in cultured fibroblasts as well as in the mouse brain. The hyperphosphorylation of eIF2α by guanabenz is associated with the shortened circadian period in cells and animals and the disruption of behavioral circadian rhythms in mice. Guanabenz administration disrupted circadian oscillations of the clock protein Per1 and Per2 in the mouse suprachiasmatic nucleus, the master pacemaker. These results uncover a significant yet previously unidentified role of guanabenz in regulating circadian rhythms and indicate that exacerbated ISR activation can impair the functions of the brain's circadian clock by disrupting clock gene expression.

Octopamine Rescues Endurance and Climbing Speed in Drosophila Clkout Mutants with Circadian Rhythm Disruption.

Circadian rhythm disturbances are associated with various negative health outcomes, including an increasing incidence of chronic diseases with high societal costs. While exercise can protect against the negative effects of rhythm disruption, it is not available to all those impacted by sleep disruptions, in part because sleep disruption itself reduces exercise capacity. Thus, there is a need for therapeutics that bring the benefits of exercise to this population. Here, we investigate the relationship between exercise and circadian disturbances using a well-established Drosophila model of circadian rhythm loss, the Clkout mutant. We find that Clkout causes reduced exercise capacity, measured as post-training endurance, flight performance, and climbing speed, and these phenotypes are not rescued by chronic exercise training. However, exogenous administration of a molecule known to mediate the effects of chronic exercise, octopamine (OA), was able to effectively rescue mutant exercise performance, including the upregulation of other known exercise-mediating transcripts, without restoring the circadian rhythms of mutants. This work points the way toward the discovery of novel therapeutics that can restore exercise capacity in patients with rhythm disruption.

The Molecular Circadian Clock Is a Target of Anti-cancer Translation Inhibitors.

Circadian-paced biological processes are key to physiology and required for metabolic, immunologic, and cardiovascular homeostasis. Core circadian clock components are transcription factors whose half-life is precisely regulated, thereby controlling the intrinsic cellular circadian clock. Genetic disruption of molecular clock components generally leads to marked pathological events phenotypically affecting behavior and multiple aspects of physiology. Using a transcriptional signature similarity approach, we identified anti-cancer protein synthesis inhibitors as potent modulators of the cardiomyocyte molecular clock. Eukaryotic protein translation inhibitors, ranging from translation initiation (rocaglates, 4-EGI1, etc.) to ribosomal elongation inhibitors (homoharringtonine, puromycin, etc.), were found to potently ablate protein abundance of REV-ERBα, a repressive nuclear receptor and component of the molecular clock. These inhibitory effects were observed both in vitro and in vivo and could be extended to PER2, another component of the molecular clock. Taken together, our observations suggest that the activity spectrum of protein synthesis inhibitors, whose clinical use is contemplated not only in cancers but also in viral infections, must be extended to circadian rhythm disruption, with potential beneficial or iatrogenic effects upon acute or prolonged administration.

Associations between sleep and circadian disruption in shift work and perpetration of interpersonal violence

Research has uncovered substantial consequences of shift work on health outcomes through disruption of sleep and circadian rhythms. Less explored is how the effects of shift work on sleep and circadian rhythms can facilitate interpersonal aggression and violence within the home (i.e., intimate partner violence, child abuse). Given challenges in direct studies on this topic, integration across related literature is critical. In this narrative review, we identify compounding variables centered around sleep and circadian rhythms that place shift workers at an increased risk of perpetrating interpersonal violence. Shift workers have impaired sleep and altered circadian rhythms. Associated alternations in executive functioning, stress, and alcohol use provide pathways to increase risk for interpersonal violence. A model of interactions facilitating the relationship between shift work and interpersonal violence is proposed to promote prevention efforts and motivate policy change.

Long-term spaceflight composite stress induces depressive behaviors in model rats through disrupting hippocampus synaptic plasticity.

Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, including the central nervous system, which could trigger anxiety and depression. This study aimed to identify changes in hippocampus synaptic plasticity under LSCS. The present study simulated the real long-term space station environment by conducting a 42-day experiment that involved simulating microgravity, isolation, noise, circadian rhythm disruptions, and low pressure. The mood and behavior of the rats were assessed by behavior test. Transmission electron microscopy and patch-clamp were used to detect the changes in synapse morphology and electrophysiology, and finally, the expression of NMDA receptor channel proteins was detected by western blotting. The results showed that significant weight loss, anxiety, and depressive behaviors in rats were observed after being exposed to LSCS environment for 42 days. The synaptic structure was severely damaged, manifested as an obvious decrease in postsynaptic density thickness and synaptic interface curvature (p < 0.05; p < 0.05, respectively). Meanwhile, LTP was significantly impaired (p < 0.0001), and currents in the NMDAR channel were also significantly reduced (p < 0.0001). Further analysis found that LSCS decreased the expression of two key subtype proteins on this channel. These results suggested that LSCS-induced depressive behaviors by impairing synaptic plasticity in rat hippocampus.

Reward sensitivity and social rhythms during goal-striving: An ecological momentary assessment investigation of bipolar spectrum disorders

BackgroundThe reward/circadian rhythm model of bipolar spectrum disorders (BSDs) posits that when individuals with hypersensitive reward systems encounter reward-relevant events, they experience social and circadian rhythm disruption, leading to mood symptoms. The aim of the current study is to test an element of this theoretical model by investigating changes in social rhythms during and after an ecologically-valid reward-relevant event and evaluating whether the strength of these associations differ by trait reward sensitivity and BSD diagnostic group. MethodsYoung adults from three groups (low BSD risk with moderate reward sensitivity [MRew], high BSD risk with high reward sensitivity [HRew], and high reward sensitivity with BSD [HRew+BSD]) completed a reward responsiveness task and 20-day ecological momentary assessment study structured around a participant-specific goal occurring on day 15. Social rhythm disruption (SRD) and social rhythm regularity (SRR) were assessed daily. Multilevel models examined whether reward sensitivity and group moderated associations between study phase (baseline [days 1–5], goal-striving [days 16–20], or outcome [days 16–20]) and social rhythms. ResultsParticipants experienced greater SRD after the goal-striving event during the outcome phase, compared to the baseline phase. The HRew+BSD group had significant decreases in SRR during the outcome phase, and this pattern differed significantly from the low-risk and high-risk groups. Greater task reward responsiveness also was associated with significant decreases in SRR during the outcome phase. LimitationsThis study did not test whether social rhythm irregularity was associated with subsequent mood change. ConclusionsParticipants exhibited social rhythm changes over the course of this ecologically valid goal-striving period, providing evidence for the interplay between reward-activating events and social rhythms. The HRew+BSD group showed a distinct pattern in which their social rhythms were more irregular after completing reward-relevant goal-striving that was not observed for the low-BSD risk or high-BSD risk groups. These findings provide additional support for Interpersonal and Social Rhythms Therapy.

Targeting Cartilage miR-195/497 Cluster for Osteoarthritis Treatment Regulates the Circadian Clock

Introduction: Osteoarthritis (OA) is the most prevalent and debilitating joint disease without an effective therapeutic option. Multiple risk factors for OA have been identified, including abnormal chondrocyte miRNA secretion and circadian rhythms disruption, both of which have been found to cause progressive damage and loss of articular cartilage. Environmental disruption of circadian rhythms in mice predisposes animals to cartilage injury and OA. Methods: The role of miR-195/497 cluster during OA progression was verified by mouse OA model with intra-articular injection of Agomir and Antagomir. We performed micro-CT analysis, Osteoarthritis Research Society International scores, and histological analysis in mouse knee joints. RNA sequencing was performed on the mouse cartilage cell line to explore the molecular mechanism of the miR-195/497 cluster and proteins in signaling pathway were evaluated using Western blot. Senescence-associated phenotypes were detected by Western blot, senescence β-galactosidase staining, and immunofluorescence. Results: This study demonstrated that miR-195/497-5p expression is disrupted in OA with senescent chondrocytes. In addition, miR-195/497-5p influenced the circadian rhythm of mice chondrocytes by modulating the expression of the Per2 protein, resulting in the gradual degradation of articular cartilage. We found that the miR-195/497 cluster targets DUSP3 expression. The deletion of the miR-195/497 cluster increased the level of DUSP3 expression and decreased the levels of phosphorylated ERK 1/2 and CREB. Per2 transcription is upregulated by stimulating CREB and ERK 1/2 phosphorylation. Conclusion: Our findings identify a regulatory mechanism connecting chondrocyte miR-195/497-5p to cartilage maintenance and repair and imply that circadian rhythm disturbances affected by miR-195/497-5p are risk factors for age-related joint diseases such as OA.

Circadian clock crosstalks with autism.

The mechanism underlying autism spectrum disorder (ASD) remains incompletely understood, but researchers have identified over a thousand genes involved in complex interactions within the brain, nervous, and immune systems, particularly during the mechanism of brain development. Various contributory environmental effectsincluding circadian rhythm have also been studied in ASD. Thus, capturing the global picture of the ASD-clock network in combined form is critical. We reconstructed the protein-protein interaction network of ASD and circadian rhythm to understand the connection between autism and the circadian clock. A graph theoretical study is undertaken to evaluate whether the network attributes are biologically realistic. The gene ontology enrichment analyses provide information about the most important biological processes. This study takes a fresh look at metabolic mechanisms and the identification of potential key proteins/pathways (ribosome biogenesis, oxidative stress, insulin/IGF pathway, Wnt pathway, and mTOR pathway), as well as the effects of specific conditions (such as maternal stress or disruption of circadian rhythm) on the development of ASD due to environmental factors. Understanding the relationship between circadian rhythm and ASD provides insight into the involvement of these essential pathways in the pathogenesis/etiology of ASD, as well as potential early intervention options and chronotherapeutic strategies for treating or preventing the neurodevelopmental disorder.

FRI375 Validation Of A Novel Mouse Placenta Explant Protocol For Screening Of Drugs Modulating Circadian Rhythms

Abstract Disclosure: J.S. Lee: None. H.M. Hoffmann: None. Introduction Pre-eclampsia is one of the leading causes of maternal, fetal, and neonatal morbidity and mortality, complicating about 4% of pregnancies. Recent work has identified PERIOD3 (PER3), a gene regulating 24-hour circadian rhythms, to be downregulated in the preeclamptic placenta. The role of circadian rhythms in the placenta largely remains unknown. Our goal is to establish an organotypic placental preparation to allow screening of drugs that regulate circadian rhythms. These studies are a first step towards understanding how circadian rhythm changes are caused in the placenta and will be the basis for future studies to understand how circadian rhythm disruption in the placenta cause pregnancy complications, such as preeclampsia. Methods We established a novel organotypic placenta preparation allowing to study circadian rhythms in a LumiCycle using gestation day (GD) 14 and GD18 placental explants from the validated circadian reporter mouse Per2::Luciferase. Using H&amp;E we validated the explants to be &amp;gt;80% enriched in either decidua (DC) which is strictly of maternal origin, labyrinth (LB) which is strictly of fetal origin, and the junctional zone (JZ) which consists of binucleated cells fused of maternal and fetal cells. Results Through H&amp;E staining, we validated by distinct morphology that the DC is enriched with neutrophils; the JZ contains spongiotrophoblasts and glycogen trophoblasts; whereas the LB has anucleated red blood cells. We next established a protocol to record Per2::Luciferase circadian rhythms for &amp;lt;6 days. We found that the Per2::Luciferase circadian rhythm shortens with increased gestational age, where the period in DC, LZ and LB in the GD14 placenta is ∼4h longer than in the GD18 placenta, showing an unexpected plasticity in circadian timekeeping in the placenta. Because PER3 is downregulated in the pre-eclamptic placenta, we asked if the explants would be useful for pharmacologically screenings. We applied PF670462 (1μM), which stabilizes PER1/2/3, or epidermal growth factor (EGF, 30ng/mL), a growth factor important in placental function and a PER2 enhancer. PF670462 lengthened Per2::Luciferase period in the DC and JZ, confirming the expected circadian rhythm stabilizing effect of PF670462. Surprisingly, EGF only modulated circadian rhythms in the GD14 placental, where EGF shortened Per2::Luciferase period in DC, and lengthen the period in the JZ and LB zones in the GD14 placenta. This data suggests EGF has gestational age and placenta zone specific effects. Conclusion We validated a novel ex vivo placental preparation to study circadian rhythms at GD14 and GD18. We identified a placenta zone and gestation age specific effect of EGF, an effect future studies will further expand on. This model will be useful to complete pharmacological screenings of drugs that can restore circadian rhythms in the preeclamptic placenta. Presentation: Friday, June 16, 2023

Restricting mealtime ameliorates neurodegeneration

Alzheimer's disease is often accompanied by disruptions in circadian rhythms, which may exacerbate the disease's progression. In this issue, Whittaker and colleagues demonstrate that the modulation of circadian rhythms by time-restricted feeding can alter the disease trajectory in Alzheimer's mouse models.

Bioinformatics Integrative Analysis of Circadian Rhythms Effects on Atopic Dermatitis and Dendritic Cells.

Atopic dermatitis (AD) is an allergic inflammatory skin disease caused by aberrant and over-reactive immune response. Although circadian rhythm disruption is implicated in multiple immunoinflammatory conditions, including AD, the mechanisms at the molecular level underlying AD and circadian rhythms remain elusive. Bulk and single-cell RNA-sequencing data of AD patients were acquired from the Gene Expression Omnibus, including GSE121212, GSE120721, and GSE153760 datasets. A single-sample gene set enrichment analysis was performed to estimate circadian rhythm gene expression levels. A differential expression analysis was utilized to identify the key candidate genes in AD. CIBERSORT was used to quantify the proportions of immune cells, and the R package "Seurat" was utilized to investigate single-cell RNA-sequencing data. Circadian rhythm gene expression levels were lower in AD skin samples than in normal skin samples. Dendritic cells were significantly upregulated and negatively correlated with circadian rhythm gene expression levels in AD patients. Compared with circadian rhythm-related genes in the control samples, ARNTL2, NOCT, and RORC were differentially expressed in AD; ARNTL2 and NOCT were significantly upregulated, whereas RORC was significantly downregulated in AD. ARNTL2, NOCT, and RORC also showed robust abilities to diagnose AD. We validated that the abundance of the dendritic cell was positively correlated with the ARNTL2 and NOCT expression levels using bulk RNA-sequencing data of the GSE121212 and single-cell RNA-sequencing data of the GSE153760. Moreover, the functional enrichment analysis showed that the IL-17 and NF-κB signaling pathways, Th1 and Th2 cell differentiations, and primary immunodeficiency, were enriched in AD patients. The findings of this study suggested that the circadian rhythm is involved in the progression of AD, and RNTL2, NOCT, and RORC as well as dendritic cells are differentially expressed in AD. These findings could be used to introduce diagnostic and chronotherapeutic modalities for AD.

Gut microbiota-bile acid-vitamin D axis plays an important role in determining oocyte quality and embryonic development.

To reveal whether gut microbiota and their metabolites are correlated with oocyte quality decline caused by circadian rhythm disruption, and to search possible approaches for improving oocyte quality. A mouse model exposed to continuous light was established. The oocyte quality, embryonic development, microbial metabolites and gut microbiota were analyzed. Intragastric administration of microbial metabolites was conducted to confirm the relationship between gut microbiota and oocyte quality and embryonic development. Firstly, we found that oocyte quality and embryonic development decreased in mice exposed to continuous light. Through metabolomics profiling and 16S rDNA-seq, we found that the intestinal absorption capacity of vitamin D was decreased due to significant decrease of bile acids such as lithocholic acid (LCA), which was significantly associated with increased abundance of Turicibacter. Subsequently, the concentrations of anti-Mullerian hormone (AMH) hormone in blood and melatonin in follicular fluid were reduced, which is the main reason for the decline of oocyte quality and early embryonic development, and this was rescued by injection of vitamin D3 (VD3). Secondly, melatonin rescued oocyte quality and embryonic development by increasing the concentration of lithocholic acid and reducing the concentration of oxidative stress metabolites in the intestine. Thirdly, we found six metabolites that could rescue oocyte quality and early embryonic development, among which LCA of 30mg/kg and NorDCA of 15mg/kg had the best rescue effect. These findings confirm the link between ovarian function and gut microbiota regulation by microbial metabolites and have potential value for improving ovary function.

The effect of circadian preference and sleep disturbances on depression in children 6 to 12 years of age

ABSTRACT Circadian rhythm and sleep disruption have been associated with depressive symptoms in children. This study was conducted to determine sleep disturbances and circadian preferences and their possible associations with depression in healthy children 6 to 12 years of age. A total of 111 healthy children (mean age 7.5 years; 62.2% male) were included. Sleep disturbances and depression were determined by the Sleep Disturbance Scale for Children (SDSC) and the Children’s Depression Inventory (CDI), respectively. Circadian preference was evaluated by the Morningness – Eveningness Stability Scale improved (MESSi). SDSC was correlated with CDI (r = 0.396, p < 0.001). Morning affect was inversely correlated with CDI (r = −0.405, p < 0.001), SDSC (r = −0.348, p < 0.001), and three subdimensions of SDSC, i.e. disorders of initiating and maintaining sleep (DIMS, r = −0.317, p = 0.001), disorders of arousal (DA, r = −0.375, p < 0.001) and disorders of excessive somnolence (DOES, r = −0.303, p = 0.001). Distinctness was inversely correlated with CDI (r = −0.402, p < 0.001) and SDSC (r = −0.274, p < 0.001). Increased use of electronic devices was associated with higher CDI (p = 0.003), while decreased duration of physical activity with higher SDSC (p = 0.017). Our findings support the recommendations addressing sleep and circadian preferences as lifestyle modifications in reducing depression in children.

INFLUENCE OF COMBINED EFFECT OF CONSTANT ILLUMINATION AND CHRONIC ALCOHOL INTOXICATION ON HEPATOCYTE ULTRASTRUCTURE IN MALE AND FEMALE WISTAR RATS

Light pollution causes melatonin deficiency and circadian rhythm disruption. Thus, it is associated with hepatopathy. Circadian rhythm disruption increases liver damage from alcohol and the severity of alcoholism.&#x0D; The aim of the study was to examine the combined effect of constant illumination and chronic alcohol intoxication (CAI) on hepatocyte ultrastructure in male and female rats.&#x0D; Materials and Methods. The study was carried out on 120 male and 80 female Wistar outbred rats aged 6 months. The experiment lasted 3 weeks. Differences in morphological patterns of hepatocyte ultrastructure were visually assessed. The percentage of hepatocytes containing lipid vacuoles was calculated.&#x0D; Results. Constant illumination and chronic alcohol intoxication caused allostasis. Hepatocyte edema, mitochondria swelling, karyopyknosis, fatty degeneration, and hepatocyte death were detected in the liver cells of male and female rats. The above-mentioned pathological changes were less severe in females. Moreover, collagen layers did not proliferate into the liver tissues in female rats. So, we can conclude that the combined effect of constant illumination and CAI do not lead to inflammatory changes and architectural distortion in the liver of female rats. Taking into account the morphological picture of the liver of male and female rats and a number of biochemical parameters that describe its functional state, the obtained data on gender differences in the hepatocyte ultrastructure in rats exposed to CAI and constant illumination allow us to report that hepatocyte adaptation to stress is more successful in female rats than in male ones.

Review article circadian disruption in pathophysiology of diabetes mellitus

Diabetes mellitus is a leading endocrine disease with a steadily increasing incidence, and its complications impose a heavy burden on the healthcare. Although pathophysiology of diabetes mellitus has been extensively investigated through the recent decades, the role of circadian rhythms in this regard was vaguely described. Circadian rhythms comprise an autonomous system of neuroendocrine signals and transcription factors that enfold key physiological processes into a daily cycle. Circadian clocks are subdivided into central (located in the suprachiasmatic nuclei of the hypothalamus) and peripheral oscillators (located in organs and cells) which produce circadian variations in the activity of virtually all cells within the human body, including the β cells of the pancreas. Circadian rhythm disruption causes circadian desynchronization which is associated with impaired glucose metabolism and insulin secretion, thereby being considered as one of the triggers of diabetes mellitus. Production of melatonin, a master regulator of circadian rhythms and a potent antioxidant, is significantly reduced in patients with diabetes mellitus. Circadian desynchronization may be triggered by a jetlag or an eating disorder. At present, circadian disruption is viewed as an important cause for the development of diabetes mellitus, although the mechanisms of such link have not been fully elucidated hitherto and might include genetic predisposition and increased oxidative stress. Timely diagnosis and appropriate treatment of circadian disruption in patients with diabetes mellitus may ameliorate the severity or prevent diabetes complications.

Research Progress on the Relationship between Mental Health and Sleep Disorders

The relationship between mental status and sleep disorders has gained significant attention in recent years. Extensive research has elucidated a bidirectional association between these two domains, highlighting the impact of mental health on sleep and the influence of sleep disturbances on mental well-being. This review provides an overview of the current progress in understanding this complex relationship.In exploring the impact of mental health on sleep disorders, the effects of anxiety, stress, depression, and bipolar disorder on sleep quality and patterns are discussed. Conversely, the influence of sleep disorders, such as insomnia, sleep apnea, and narcolepsy, on mental health outcomes is examined. Neurobiological mechanisms, including shared neural pathways and neurotransmitter dysregulation, as well as the disruption of circadian rhythms, are explored as underlying factors linking mental health and sleep disorders.Moreover, the review discusses various treatment approaches and interventions for individuals with comorbid mental health and sleep disorders. Psychological interventions, pharmacological options, and lifestyle modifications are highlighted as strategies to improve both mental health and sleep outcomes.The review concludes by identifying research gaps, calling for continued interdisciplinary collaboration, and emphasizing the importance of public awareness and education. Future directions and implications for addressing this intricate relationship are discussed to enhance our understanding and develop effective interventions.Overall, the review underscores the significance of recognizing and addressing the bidirectional relationship between mental status and sleep disorders, with the ultimate goal of improving the well-being of individuals affected by these conditions.

Metabolic Basis of Circadian Dysfunction in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The management of PD is a challenging aspect for general physicians and neurologists. It is characterized by the progressive loss of dopaminergic neurons. Impaired α-synuclein secretion and dopamine release may cause mitochondrial dysfunction and perturb energy metabolism, subsequently altering the activity and survival of dopaminergic neurons, thus perpetuating the neurodegenerative process in PD. While the etiology of PD remains multifactorial, emerging research indicates a crucial role of circadian dysfunction in its pathogenesis. Researchers have revealed that circadian dysfunction and sleep disorders are common among PD subjects and disruption of circadian rhythms can increase the risk of PD. Hence, understanding the findings of circadian biology from translational research in PD is important for reducing the risk of neurodegeneration and for improving the quality of life. In this review, we discuss the intricate relationship between circadian dysfunction in cellular metabolism and PD by summarizing the evidence from animal models and human studies. Understanding the metabolic basis of circadian dysfunction in PD may shed light on novel therapeutic approaches to restore circadian rhythm, preserve dopaminergic function, and ameliorate disease progression. Further investigation into the complex interplay between circadian rhythm and PD pathogenesis is essential for the development of targeted therapies and interventions to alleviate the burden of this debilitating neurodegenerative disorder.

Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.

Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eμ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.