Circadian Rhythm Genes and Their Association with Sleep and Sleep Restriction.

Deprivation of sleep (DS) and its effects on circadian rhythm gene expression are not well understood despite their influence on various physiological and psychological processes. This study aimed to elucidate the changes in the expression of circadian rhythm genes following a night of sleep and DS. Their correlation with sleep architecture and physical activity was also examined. The study included 81 participants who underwent polysomnography (PSG) and DS with actigraphy. Blood samples were collected after PSG and DS. Expression levels of brain and muscle ARNT-like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain protein 2 (NPAS2), period 1 (PER1), cryptochrome 1 (CRY1) and nuclear receptor subfamily 1 group D member 1 (NR1D1) were analyzed using qRT-PCR. DS decreased the expression of CLOCK and BMAL1 while increasing PER1. PER1 expression correlated positively with total sleep time and non-rapid-eye-movement (NREM) sleep duration and negatively with sleep latency, alpha, beta and delta waves in the O1A2 lead. Physical activity during DS showed positive correlations with CLOCK, BMAL1, and CRY1. The findings highlight the role of PER1 in modulating sleep patterns, suggesting potential targets for managing sleep-related disorders. Further research is essential to deepen the understanding of these relationships and their implications.

Circadian clock dysregulation: a potential mechanism of depression in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is characterized by co-occurrence with affective disorders. Our study aims to investigate the association of circadian clock gene expressions, and the presence and severity of depressive symptoms in OSA patients. The study included 184 individuals, who underwent polysomnography (PSG) and had their peripheral blood collected in the evening before and the morning after the PSG. Patients were divided into two groups: the OSA (apnea-hypopnea index (AHI) > 5) and the control group (AHI < 5). RNA was extracted from peripheral blood leukocytes. Expression levels of the selected genes (BMAL1, CLOCK, PER1, CRY1, NPAS2, and NR1D1) were assessed by qRT-PCR. Questionnaire data was collected in the morning (including the Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Chronotype Questionnaire (CQ), and Montgomery-Åsberg Depression Rating Scale (MADRS)). The expression of all examined circadian clock genes in OSA patients was upregulated in the morning compared to the evening (except NPAS2). No differences were observed between OSA and control groups at either time point. Additionally, there was a positive correlation between the severity of depressive symptoms (assessed with MADRS) and morning expression of circadian genes in the group of OSA patients. Finally, in multivariable linear regression, ISI score (B = 0.750, p < 0.001), AM score of CQ (B = 0.416, p = 0.007), and morning PER1 gene expression (B = 4.310, p = 0.042) were found to be predictive factors for greater severity of depression symptoms in OSA patients. Dysregulated circadian clock gene expression in OSA patients is linked to depressive symptom severity, suggesting circadian disruption may underlie affective symptoms in OSA.

Investigating the Link between Circadian Clock Gene Expressions, Chronotype, Insomnia, and Daytime Sleepiness in Patients with Obstructive Sleep Apnea.

INTRODUCTION: This study aimed to investigate the relationship between obstructive sleep apnea (OSA), circadian rhythms, and individual sleep-wake preferences, as measured by chronotype, and to assess the association between circadian clock gene expression and subjective sleep-related variables. METHODS: A total of 184 individuals were recruited, underwent polysomnography (PSG), and completed questionnaires including a chronotype questionnaire (CQ), insomnia severity index (ISI), and Epworth sleepiness scale (ESS). Blood samples were collected in the evening before and morning after PSG. Gene expression analysis included BMAL1, CLOCK, PER1, CRY1, NPAS2, and NR1D1. RESULTS: In the OSA group, the subjective amplitude (AM score of CQ) positively correlated with all circadian clock genes in the morning (R ≥ 0.230 and p < 0.05 for each one), while the morningness-eveningness (ME score of CQ) was only associated with the evening BMAL1 level (R = 0.192; p = 0.044). In healthy controls, insomnia severity correlated with evening expression of BMAL1, PER1, and CRY1. CONCLUSIONS: The findings highlight the complex interplay between OSA, circadian rhythms, and sleep-related variables, suggesting potential determinants of morning chronotype in OSA and implicating disrupted circadian clock function in subjective feelings of energy throughout the day. Further research is warranted to elucidate underlying mechanisms and guide personalized management strategies.

The Complex Relationship between Neuromodulators, Circadian Rhythms, and Insomnia in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) has been linked to disruptions in circadian rhythm and neurotrophin (NFT) signaling. This study explored the link between neuromodulators, chronotype, and insomnia in OSA. The participants (n = 166) underwent polysomnography (PSG) before being categorized into either the control or the OSA group. The following questionnaires were completed: Insomnia Severity Index (ISI), Epworth Sleepiness Scale, Chronotype Questionnaire (morningness-eveningness (ME), and subjective amplitude (AM). Blood samples were collected post-PSG for protein level assessment using ELISA kits for brain-derived neurotrophic factor (BDNF), proBDNF, glial-cell-line-derived neurotrophic factor, NFT3, and NFT4. Gene expression was analyzed utilizing qRT-PCR. No significant differences were found in neuromodulator levels between OSA patients and controls. The controls with insomnia exhibited elevated neuromodulator gene expression (p < 0.05). In the non-insomnia individuals, BDNF and NTF3 expression was increased in the OSA group compared to controls (p = 0.007 for both); there were no significant differences between the insomnia groups. The ISI scores positively correlated with all gene expressions in both groups, except for NTF4 in OSA (R = 0.127, p = 0.172). AM and ME were predicting factors for the ISI score and clinically significant insomnia (p < 0.05 for both groups). Compromised compensatory mechanisms in OSA may exacerbate insomnia. The correlation between chronotype and NFT expression highlights the role of circadian misalignments in sleep disruptions.

The effect of sleep and its restriction on selected inflammatory parameters.

Insufficient sleep duration may lead to a series of immune dysfunctions. One of the factors influencing this effect could be physical activity (PA). The study aimed to assess the impact of deprivation of sleep (DS) on selected inflammatory parameters. Seventy-seven participants completed the protocol consisting of polysomnography (PSG) conducted in a sleep laboratory and DS, monitored with an actigraph. PA was assessed with actigraphy, which categorized participants as active or inactive. White blood cells (WBC) values negatively correlated with sleep efficiency based on sleep diaries and PSG parameters (total sleep time, sleep efficiency, and REM duration), but regression analysis showed that WBC depends only on the sleep diary parameter. Granulocytes (GRA) positively correlated with REM latency, and negatively with sleep efficiency. After DS, all participants exhibited an elevated GRA count. The number of WBC and GRA increased also in the active group; inactive participants showed no changes in inflammatory parameters. The overall number of WBC depends primarily on the quality of sleep over a period of several days. Under the influence of sleep deprivation, the number of GRA increases, but the number of leukocytes depends on the level of physical activity during DS.

Association between glucose metabolism, the circadian cycle and hypoxia: Evaluation of the NPAS2 and Rev-Erb-α protein serum levels in obstructive sleep apnea patients - a pilot study.

BACKGROUND: Obstructive sleep apnea (OSA) is one of the risk factors for diabetes mellitus type 2 (DM2). As OSA is associated with the disruption of the circadian rhythm, it affects circadian clock proteins, including neuronal PAS domain protein 2 (NPAS2) and nuclear receptor subfamily 1 group D member 1 (Rev-Erb-α). These proteins have been shown to be related to metabolic abnormalities, i.a., insulin resistance. OBJECTIVES: The present pilot study aimed to investigate the NPAS2 and Rev-Erb-α protein serum levels in the groups of patients with severe OSA and severe OSA+DM2 in comparison with healthy controls, taking into account correlations with polysomnography (PSG) parameters (e.g., oxygen saturation (SpO2) variables). MATERIAL AND METHODS: A total of 40 participants were included in the study. They were split into 3 groups as follows: the OSA group (n = 17; apnea-hypopnea index (AHI) >30, no DM2); the OSA+DM2 group (n = 7; AHI > 30 and DM2); and the control group (n = 16; AHI < 5, no DM2). All participants underwent a nocturnal PSG examination and had their blood collected the following morning. The serum levels of NPAS2 and Rev-Erb-α proteins were assessed using the enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean NPAS2 protein level was significantly lower in the OSA group as compared to healthy individuals (p = 0.017). Additionally, the OSA group presented with lower NPAS2 protein levels as compared to the OSA+DM2 group, but only a tendency was observed (p = 0.094). No differences in the Rev-Erb-α protein concentration were noticed. Furthermore, a negative correlation between AHI during rapid eye movement (REM) sleep and the NPAS2 protein serum level was observed (r = -0.478; p = 0.002). CONCLUSIONS: Serum NPAS2 protein might be involved in metabolic dysregulation present among OSA patients, while the mechanism itself may be associated with REM sleep.

D-Loop Mutations as Prognostic Markers in Glioblastoma-A Pilot Study.

Glioblastoma, a highly aggressive brain tumor, poses significant treatment challenges. A deeper investigation into its molecular complexity is essential for the identification of novel prognostic biomarkers and therapeutic strategies, potentially improving patient outcomes in terms of survival and quality of life. While nuclear DNA mutations have been extensively studied, the role of mitochondrial DNA (mtDNA) mutations, specifically in the D-loop region, remains poorly understood. This prospective case-control study aimed to assess the prognostic significance of the mtDNA D-loop m.16126T>C variant in glioblastoma patients. Immunohistochemistry and droplet digital PCR (ddPCR) were employed for mutation analysis, complemented by statistical analyses and a literature review. The study cohort comprised 22 glioblastoma patients (mean age 59.36 ± 14.17, 12 (54.55%) females), and 25 controls (59.48 ± 13.22, 12 (80%) females). The D-loop m.16126T>C variant was observed in four (18%) of the glioblastoma samples and was associated with shorter median survival (9.5 vs. 18 months; p = 0.016, log-rank test). This study underscores the importance of investigating mtDNA, especially D-loop variants, in glioblastoma, suggesting its potential as a prognostic biomarker and, therefore, its possible therapeutic targets, warranting further exploration.

Evaluation of daytime sleepiness and insomnia symptoms in OSA patients with a characterization of symptom-defined phenotypes and their involvement in depression comorbidity-a cross-sectional clinical study.

Introduction: Recent research highlights the significance of insomnia and sleepiness, shifting from obstructive sleep apnea (OSA) severity and sleep structure, in defining OSA phenotypes. Objectives: This study aimed to characterize insomnia and sleepiness associated with OSA phenotypes and assess their involvement in depression symptoms (DS) in OSA. Materials and methods: This cross-sectional, clinical study included 181 participants who underwent polysomnography (PSG) and filled out questionnaires, including the Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), and Beck Depression Index (BDI). They were categorized into phenotypes: insomnia-sleepiness (I + S; ESS ≥ 11; ISI ≥ 15; n = 20), sleepiness (S; ESS ≥ 11; ISI < 15; n = 22), insomnia (I; ESS < 11; ISI ≥ 15), and asymptomatic (A; ESS < 11; ISI<15; n=55). Results: A linear regression model for the BDI score (R2 = 0.357, p < 0.001) included ISI score and subjective-to-objective sleep latency ratio. The ISI score was a predictive factor for mild and moderate DS [OR = 1.23 (95% CI: 1.09-1.38), p < 0.001 and OR = 1.39 (95% CI: 1.13-1.72), p = 0.002]. The I and I + S phenotypes are characterized by higher BDI scores (p < 0.001 and p = 0.02), longer subjective sleep latency (p = 0.008 and p = 0.04), and shorter subjective total sleep time (TST; p = 0.049 and p = 0.006) compared to A. Furthermore, the I and I + S groups had shorter subjective TST than S (p = 0.03 and p = 0.047). The I and I + S had higher BDI scores than A (p < 0.001 and p = 0.02, respectively) and S (p < 0.001 and p = 0.02, respectively). The I phenotype was associated with the risk of mild and moderate DS (OR = 5.61 (95% CI: 1.91-16.53), p < 0.001 and OR = 9.55 (95% CI: 1.81-50.48), p = 0.008 respectively). Moreover, the I + S phenotype presented an even greater risk for mild DS (OR = 10.29 (95% CI: 2.95-35.85), p < 0.001). Conclusion: Using clinical features for OSA phenotyping holds promise for finding OSA individuals with increased risk for DS occurrence.

Interactions between neurotrophins, mood, and physical activity under the conditions of sleep deprivation.

Sleep deprivation (DS) is the forced elimination of sleep. While brain-derived neurotrophic factor (BDNF) has been extensively studied in the context of in mood changes following DS, the role of other neurotrophins remains elusive. This study explores the impact of DS on BDNF, glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) at mRNA and protein level, considering their potential links to mood disturbances. The study involved 81 participants subjected to polysomnography (PSG) and DS. Blood samples, mood assessments, and actigraphy data were collected twice, after PSG and DS. NT mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured. Participants were divided into Responders and Non-Responders based on mood improvement after DS. DS reduced BDNF mRNA expression in all participants, with no change in serum BDNF protein. GDNF protein decreased in Non-Responders, while Responders exhibited reduced GDNF mRNA. NT3 protein increased in both groups, while NT3 mRNA decreased in Respondents. NT4 protein rose universally post-DS, but NT4 mRNA remained unchanged. Physical activity (PA) negatively correlated with mRNA expression of BDNF, GDNF, and NT3 post-DS. The study's short DS duration and exclusion of immature NT forms limit comprehensive insights. GDNF, together with NT3, might play an important role in mood response to DS. PA during DS seems to impair the mRNA expression of NTs in leukocytes. Future studies on the subject of sleep deprivation might consider investigating the relationship between BDNF and NT4 in the context of their apparent redundancy.

The Relationship between Sleep Parameters Measured by Polysomnography and Selected Neurotrophic Factors.

BACKGROUND: The molecular underpinnings of insufficient sleep remain underexplored, with disruptions in the neurotrophic signaling pathway emerging as a potential explanation. Neurotrophins (NTs), including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4 (NT4), and glial-cell-line-derived growth factor (GDNF), play crucial roles in nerve cell growth and repair. However, their associations with sleep patterns are poorly understood. This study aimed to investigate the relationship between the chosen neurotrophins and objective sleep parameters. METHODS: The study involved 81 participants subjected to polysomnography (PSG). Blood samples were collected after PSG. The mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured using real-time quantitative reverse-transcription PCR (qRT-PCR) or enzyme-linked immunosorbent assay (ELISA) methods, respectively. RESULTS: BDNF and NT3 proteins were negatively correlated with NREM events, while NT4 protein positively correlated with REM events. Electroencephalography power analysis revealed BDNF protein's negative correlation with delta waves during rapid eye movement and non-rapid eye movement sleep. CONCLUSION: The study highlights associations between neurotrophins and sleep, emphasizing BDNF's role in regulating NREM and REM sleep. The EEG power analysis implicated BDNF in delta wave modulation, shedding light on potential neurotrophic mechanisms underlying sleep effects on cognitive and mood processes.

Evaluation of the Continuous Positive Airway Pressure Effect on Neurotrophins' Gene Expression and Protein Levels.

Neurotrophins (NT) might be associated with the pathophysiology of obstructive sleep apnea (OSA) due to concurrent intermittent hypoxia and sleep fragmentation. Such a relationship could have implications for the health and overall well-being of patients; however, the literature on this subject is sparse. This study investigated the alterations in the serum protein concentration and the mRNA expression of the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NTF3), and neurotrophin-4 (NTF4) proteins following a single night of continuous positive airway pressure (CPAP) therapy. This study group consisted of 30 patients with OSA. Venous blood was collected twice after a diagnostic polysomnography (PSG) and PSG with CPAP treatment. Gene expression was assessed with a quantitative real-time polymerase chain reaction. An enzyme-linked immunosorbent assay was used to determine the protein concentrations. After CPAP treatment, BDNF, proBDNF, GDNF, and NTF4 protein levels decreased (p = 0.002, p = 0.003, p = 0.047, and p = 0.009, respectively), while NTF3 increased (p = 0.001). Sleep latency was correlated with ΔPSG + CPAP/PSG gene expression for BDNF (R = 0.387, p = 0.038), NTF3 (R = 0.440, p = 0.019), and NTF4 (R = 0.424, p = 0.025). OSA severity parameters were not associated with protein levels or gene expressions. CPAP therapy could have an impact on the posttranscriptional stages of NT synthesis. The expression of different NTs appears to be connected with sleep architecture but not with OSA severity.

Shedding light on neurofilament involvement in cognitive decline in obstructive sleep apnea and its possible role as a biomarker.

Obstructive sleep apnea is one of the most common sleep disorders with a high estimated global prevalence and a large number of associated comorbidities in general as well as specific neuropsychiatric complications such as cognitive impairment. The complex pathogenesis and effects of the disorder including chronic intermittent hypoxia and sleep fragmentation may lead to enhanced neuronal damage, thereby contributing to neuropsychiatric pathologies. Obstructive sleep apnea has been described as an independent risk factor for several neurodegenerative diseases, including Alzheimer's disease and all-cause dementia. The influence of obstructive sleep apnea on cognitive deficits is still a topic of recent debate, and several mechanisms, including neurodegeneration and depression-related cognitive dysfunction, underlying this correlation are taken into consideration. The differentiation between both pathomechanisms of cognitive impairment in obstructive sleep apnea is a complex clinical issue, requiring the use of multiple and costly diagnostic methods. The studies conducted on neuroprotection biomarkers, such as brain-derived neurotrophic factors and neurofilaments, are recently gaining ground in the topic of cognition assessment in obstructive sleep apnea patients. Neurofilaments as neuron-specific cytoskeletal proteins could be useful non-invasive indicators of brain conditions and neurodegeneration, which already are observed in many neurological diseases leading to cognitive deficits. Additionally, neurofilaments play an important role as a biomarker in other sleep disorders such as insomnia. Thus, this review summarizes the current knowledge on the involvement of neurofilaments in cognitive decline and neurodegeneration in obstructive sleep apnea patients as well as discusses its possible role as a biomarker of these changes.

The Effect of Serotonin Transmission on Depressive and Insomnia Symptoms in Inflammatory Bowel Diseases.

The serotonergic pathway may impact the pathogenesis and the course of inflammatory bowel diseases (IBDs). The aim of this study was to investigate the relationship between 5-HT, the serotonin transporter (SERT), and the clinical course of the disease with the occurrence of sleep and mood disorders. Participants completed sleep questionnaires and the Beck Depression Inventory (BDI). Serum 5-HT, SERT protein expression, and mRNA levels were quantified. Additionally, patients treated with anti-TNF therapy were examined before and after treatment. In this study, 77 patients with IBD and 41 healthy controls (HCs) were enrolled and 24 of them were treated with anti-TNF therapy. Patients with IBD had higher 5-HT levels and SERT protein expression than the HCs, but not mRNA SERT levels (p = 0.015, p = 0.001, p = 0.069, respectively). Similar results were obtained for patients in the active state of the disease compared to the non-active state. There was a positive relationship between insomnia severity and SERT protein expression. BDI did not correlate with serotonin or SERT. After anti-TNF therapy, only 5-HT levels were decreased. 5-HT and SERT protein are overexpressed in active IBD and may represent a candidate for novel disease activity biomarkers. The correlation between the SERT protein level and the severity of insomnia symptoms might be among the underlying biochemical factors of sleep disturbances. Anti-TNF treatment might contribute to the reduction in 5-HT levels.

REM-OSA as a Tool to Understand Both the Architecture of Sleep and Pathogenesis of Sleep Apnea-Literature Review.

Sleep is a complex physiological state, which can be divided into the non-rapid eye movement (NREM) phase and the REM phase. Both have some unique features and functions. This difference is best visible in electroencephalography recordings, respiratory system activity, arousals, autonomic nervous system activity, or metabolism. Obstructive sleep apnea (OSA) is a common condition characterized by recurrent episodes of pauses in breathing during sleep caused by blockage of the upper airways. This common condition has multifactorial ethiopathogenesis (e.g., anatomical predisposition, sex, obesity, and age). Within this heterogenous syndrome, some distinctive phenotypes sharing similar clinical features can be recognized, one of them being REM sleep predominant OSA (REM-OSA). The aim of this review was to describe the pathomechanism of REM-OSA phenotype, its specific clinical presentation, and its consequences. Available data suggest that in this group of patients, the severity of specific cardiovascular and metabolic complications is increased. Due to the impact of apneas and hypopneas predominance during REM sleep, patients are more prone to develop hypertension or glucose metabolism impairment. Additionally, due to the specific function of REM sleep, which is predominantly fragmented in the REM-OSA, this group presents with decreased neurocognitive performance, reflected in memory deterioration, and mood changes including depression. REM-OSA clinical diagnosis and treatment can alleviate these outcomes, surpassing the traditional treatment and focusing on a more personalized approach, such as using longer therapy of continuous positive airway pressure or oral appliance use.

The role of microRNAs in pathophysiology and diagnostics of metabolic complications in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is one of the most common sleep disorders, which is characterized by recurrent apneas and/or hypopneas occurring during sleep due to upper airway obstruction. Among a variety of health consequences, OSA patients are particularly susceptible to developing metabolic complications, such as metabolic syndrome and diabetes mellitus type 2. MicroRNAs (miRNAs) as epigenetic modulators are promising particles in both understanding the pathophysiology of OSA and the prediction of OSA complications. This review describes the role of miRNAs in the development of OSA-associated metabolic complications. Moreover, it summarizes the usefulness of miRNAs as biomarkers in predicting the aforementioned OSA complications.

Influence of glutamatergic and GABAergic neurotransmission on obstructive sleep apnea.

Glutamate and γ-aminobutyric acid (GABA) are the two main neurotransmitters in the human brain. The balance between their excitatory and inhibitory functions is crucial for maintaining the brain's physiological functions. Disturbance of glutamatergic or GABAergic neurotransmission leads to serious health problems including neurodegeneration, affective and sleep disorders. Both GABA and glutamate are involved in the control of the sleep-wake cycle. The disturbances in their function may cause sleep and sleep-related disorders. Obstructive sleep apnea (OSA) is the most common sleep respiratory disorder and is characterized by repetitive collapse of the upper airway resulting in intermittent hypoxia and sleep fragmentation. The complex pathophysiology of OSA is the basis of the development of numerous comorbid diseases. There is emerging evidence that GABA and glutamate disturbances may be involved in the pathogenesis of OSA, as well as its comorbidities. Additionally, the GABA/glutamate targeted pharmacotherapy may also influence the course of OSA, which is important in the implementation of wildly used drugs including benzodiazepines, anesthetics, and gabapentinoids. In this review, we summarize current knowledge on the influence of disturbances in glutamatergic and GABAergic neurotransmission on obstructive sleep apnea.

Correlations between the symptoms of insomnia, depression, sleep quality, antitumor necrosis factor therapy, and disrupted circadian clock gene expression in inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) might be accompanied by emotional disturbances. Circadian rhythm genes, such as brain and muscle ARNT­Like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain protein 2 (NPAS2), or nuclear receptor subfamily 1 group D member 1 (NR1D1) are related to inflammation and psychiatric symptoms that might modulate their expression. OBJECTIVES: The study aimed to compare the expression of the BMAL1, CLOCK, NPAS2, NR1D1 mRNA in IBD patients and healthy controls (HCs). We evaluated the association between the gene expression and the disease severity, antitumor necrosis factor (TNF) therapy, sleep quality, insomnia, and depression. PATIENTS AND METHODS: A total of 81 IBD patients and 44 HCs were recruited and classified according to the disease activity and IBD type (ulcerative colitis [UC] or Crohn disease [CD]). The participants filled out questionnaires assessing their sleep quality, daytime sleepiness, insomnia, and depression. Venous blood samples were collected, and the IBD patients on the anti­TNF therapy had their blood drawn before and after 14 weeks of the treatment. RESULTS: In comparison with HCs, the IBD group had decreased expression of all studied genes apart from the BMAL1 gene. UC individuals with exacerbation had decreased expression of the CLOCK and the NPAS2 genes, as compared with the remission group. UC severity negatively correlated with the CLOCK, NPAS2, and NR1D1 mRNA levels. The IBD participants with depression symptoms had a decreased expression of the CLOCK and the NR1D1 genes, as compared with those without mood disturbances. Poor sleep quality was associated with a decreased expression of the NR1D1 gene. Biologic treatment decreased the expression of the BMAL1 gene. CONCLUSIONS: Disruption of the clock gene expression might constitute a molecular background of sleep disorders and depression in IBD and might contribute to UC exacerbation.

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain-gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn's disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications.