Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or ...silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
The circadian clock regulates multiple aspects of human physiology including immunity. People have a circadian preference termed chronotype. Those with an evening preference may be better suited to ...shift work, but also carry higher risk of adverse health. Shift work leads to misalignment of circadian rhythms and is associated with increased risk of inflammatory disease such as asthma and cancer. Here, we investigate the association between chronotype, shift work, and rheumatoid arthritis (RA). The associations between exposures of shift work and chronotype on risk of RA were studied in up to 444,210 U.K. Biobank participants. Multivariable logistic regression models were adjusted for covariates: age, sex, ethnicity, alcohol intake, smoking history, Townsend Deprivation Index (TDI), sleep duration, length of working week, and body mass index (BMI). After adjusting for covariates, individuals with a morning chronotype had lower odds of having rheumatoid arthritis (RA; odds ratio OR: 0.93, 95% confidence interval CI: 0.88-0.99) when compared to intermediate chronotypes. The association between morning chronotype and RA persisted with a more stringent RA case definition (covariate-adjusted OR: 0.89, 95% CI: 0.81-0.97). When adjusted for age, sex, ethnicity, and TDI, shift workers had higher odds of RA (OR: 1.22, 95% CI: 1.1-1.36) compared to day workers that attenuated to the null after further covariate adjustment (OR: 1.1, 95% CI: 0.98-1.22). Morning chronotypes working permanent night shifts had significantly higher odds of RA compared to day workers (OR: 1.89, 95% CI: 1.19-2.99). These data point to a role for circadian rhythms in RA pathogenesis. Further studies are required to determine the mechanisms underlying this association and understand the potential impact of shift work on chronic inflammatory disease and its mediating factors.
Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in ...industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma.
We describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype.
Compared with day workers, 'permanent' night shift workers had a higher likelihood of moderate-severe asthma (OR 1.36 (95% CI 1.03 to 1.8)) and all asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV
<80% predicted). We found an increase in the risk of moderate-severe asthma in morning chronotypes working irregular shifts, including nights (OR 1.55 (95% CI 1.06 to 2.27)).
The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.
The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, ...adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.
The gut microbiota is important for host health and immune system function. Moreover autoimmune diseases, such as rheumatoid arthritis, are associated with significant gut microbiota dysbiosis, ...although the causes and consequences of this are not fully understood. It has become clear that the composition and metabolic outputs of the microbiome exhibit robust 24 h oscillations, a result of daily variation in timing of food intake as well as rhythmic circadian clock function in the gut. Here, we report that experimental inflammatory arthritis leads to a re‐organization of circadian rhythmicity in both the gut and associated microbiome. Mice with collagen induced arthritis exhibited extensive changes in rhythmic gene expression in the colon, and reduced barrier integrity. Re‐modeling of the host gut circadian transcriptome was accompanied by significant alteration of the microbiota, including widespread loss of rhythmicity in symbiont species of Lactobacillus, and alteration in circulating microbial derived factors, such as tryptophan metabolites, which are associated with maintenance of barrier function and immune cell populations within the gut. These findings highlight that altered circadian rhythmicity during inflammatory disease contributes to dysregulation of gut integrity and microbiome function.
Allergic diseases impose a significant global disease burden, however, the influence of light at night exposure on these diseases in humans has not been comprehensively assessed. We aimed to ...summarize available evidence considering the association between light at night exposure and major allergic diseases through a systematic review and meta-analysis.
We completed a search of six databases, two registries, and Google Scholar from inception until December 15, 2023, and included studies that investigated the influence of artificial light at night (ALAN, high vs. low exposure), chronotype (evening vs. morning chronotype), or shift work (night vs. day shift work) on allergic disease outcomes (asthma, allergic rhinitis, and skin allergies). We performed inverse-variance random-effects meta-analyses to examine the association between the exposures (ALAN exposure, chronotype, or shiftwork) and these allergic outcomes. Stratification analyses were conducted by exposure type, disease type, participant age, and geographical location along with sensitivity analyses to assess publication bias.
We included 12 publications in our review. We found that exposure to light at night was associated with higher odds of allergic diseases, with the strongest association observed for ALAN exposure (OR: 1.88; 95% CI: 1.04 to 3.39), followed by evening chronotype (OR: 1.35; 95% CI: 0.98 to 1.87) and exposure to night shift work (OR: 1.33; 95% CI: 1.06 to 1.67). When analyses were stratified by disease types, light at night exposure was significantly associated with asthma (OR: 1.62; 95% CI: 1.19 to 2.20), allergic rhinitis (OR: 1.89; 95% CI: 1.60 to 2.24), and skin allergies (OR: 1.11; 95% CI: 1.09 to 1.91). We also found that the association between light at night exposure and allergic diseases was more profound in youth (OR: 1.63; 95% CI: 1.07 to 2.48) than adults (OR: 1.30; 95% CI: 1.03 to 1.63). Additionally, we observed significant geographical variations in the association between light at night exposure and allergic diseases.
Light at night exposure was associated with a higher prevalence of allergic diseases, both in youth and adults. More long-term epidemiological and mechanistic research is required to understand the possible interactions between light at night and allergic diseases.
We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).
We recruited adults (age 16-80 years old) with a clinical diagnosis of RA (active disease ...DAS28 > 3.2). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA.
RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases.
RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.
Asthma is a rhythmic inflammatory disease of the airway, regulated by the circadian clock. "Spill-over" of airway inflammation into the systemic circulation occurs in asthma and is reflected in ...circulating immune cell repertoire. The objective of the present study was to determine how asthma impacts peripheral blood diurnal rhythmicity.
10 healthy and 10 mild/moderate asthma participants were recruited to an overnight study. Blood was drawn every 6 h for 24 h.
The molecular clock in blood cells in asthma is altered;
is significantly more rhythmic in asthma compared to healthy controls. Blood immune cell numbers oscillate throughout the day, in health and asthma. Peripheral blood mononucleocytes from asthma patients show significantly enhanced responses to immune stimulation and steroid suppression at 16:00 h, compared to at 04:00 h. Serum ceramides show complex changes in asthma: some losing and others gaining rhythmicity.
This is the first report showing that asthma is associated with a gain in peripheral blood molecular clock rhythmicity. Whether the blood clock is responding to rhythmic signals received from the lung or driving rhythmic pathology within the lung itself is not clear. Dynamic changes occur in serum ceramides in asthma, probably reflecting systemic inflammatory action. The enhanced responses of asthma blood immune cells to glucocorticoid at 16:00 h may explain why steroid administration is more effective at this time.
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