Search Results (44)

Respiratory syncytial virus (RSV), a member of the genus Orthopneumovirus, is an etiological agent in infant lower respiratory tract infections (LRTIs) producing substantial global morbidity. Here, secretoglobin (Scgb1a1)-derived progenitors play a primary role in triggering innate, inflammatory, and cell state transitions in response to RSV LRTIs. Whether RSV activation of innate signaling in this epithelial sentinel population leads to chronic airway disease is unknown. To understand the role of innate signaling in Scgb1a1-derived progenitors, a model of RSV post-viral disease (PVLD) was developed and studied in the presence or absence of RelA conditional knockout (CKO). Single-cell RNA sequencing (scRNA-seq) studies showed that RSV-PVLD induced a transition of atypical, differentiation-intermediate, alveolar type 2 (aAT2) cells characterized by tumor protein 63 (TRP63), aquaporin 3 (AQP3), and Itgβ4 expression, as well as changes in PDGFRβ mesenchyme. A single-cell trajectory analysis and lineage-tracing experiments using Scgb1a1 CreER^TM X mTmG mice demonstrated that the Scgb1a1+ populations were precursors to the aAT2 population. Mechanistically, we found that the formation of the aAT2 population was prevented by RelA CKO. A differential gene expression analysis revealed that RSV-PVLD coordinately upregulates nuclear receptor subfamily 1 group D (Nr1d1/2), clock and basic helix-loop-helix ARNT-like 1 (Bmal) genes both in the aAT2 cell and in its Pdgfrα+ mesenchymal niche in a RelA-dependent manner. A systematic analysis of intercellular epithelial–mesenchymal communication in the scRNA-seq data showed that the clock-dysregulated epithelial–mesenchymal niche produces aberrant ANGPTL4 expression. ANGPTL4 upregulation was confirmed by the measurement of both its mRNA and protein. Moreover, ANGPTL4 is biologically active in the BALF of RSV-PVLD mice, inhibiting lipoprotein lipase activity. We conclude that RSV-PVLD is mediated, at least in part, by RelA signaling in Scgb1a1-derived epithelial progenitors, dysregulating ANGPTL4 signaling in an epithelial–mesenchymal niche, resulting in persistence of atypical alveolar epithelial cells with dysregulated of clock gene expression. Full article

Background: Deprivation of sleep (DS) might affect mood and cognitive abilities, including psychomotor functions (PF). Molecular mechanisms underlying these effects remain unclear, though studies suggest that the circadian rhythm plays a role. Methods: Seventy participants underwent polysomnography (PSG) and DS. PF was evaluated using Bimanual Eye–Hand Coordination Test (BEHCT). Mood, PF, and clock gene expression (Circadian Locomotor Output Cycles Kaput (CLOCK), Brain and Muscle ARNT-Like 1 (BMAL1), Period Circadian Regulator 1 (PER1), Cryptochrome Circadian Regulator 1 (CRY1), Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1), and Neuronal PAS Domain Protein 2 (NPAS2)) were analyzed post-PSG and post-DS. Mood changes after DS classified participants as responders (RE) or non-responders (NR). Results: In NRs, but not REs, the BEHCT error count positively correlated with the expression of BMAL1, CRY1, PER1, NR1D1 (R = 0.60, p = 0.002; R = 0.49, p = 0.018; R = 0.57, p = 0.023; and R = 0.53, p = 0.011, respectively), with PER1 explaining its variability in 57.8% (b = 0.174, R² = 0.578, F = 20.144, and p < 0.001). Conclusions: Obtained results suggest that altered clock gene expression may contribute to individual differences in mood and PF following DS. Full article

Widespread in coastal environments, artificial light at night (ALAN) is suspected to disrupt organisms’ biological rhythms by altering natural light cycles and thus constitutes a growing threat to these ecosystems. This study evaluates the effects of ALAN exposure at low and realistic intensity (~1 lx) on a coastal keystone species, the oyster Crassostrea gigas. The results reveal that ALAN significantly impairs the expression of core circadian clock genes (CgClock and CgBmal1) as well as the valve opening behavior, affecting rhythmic characteristics such as its robustness and daily profile. At the same time, ALAN leads to a decrease in daily shell growth and to a disruption of the gill microbiota, associated with an obliterated day/night difference in microbial alpha diversity. A direct correlation between a decrease in daily rhythm robustness, limitation of shell growth, and some microbial strands is shown, suggesting that biological rhythm disruption caused by ALAN might have harmful physiological consequences in oysters. Full article

The brain and muscle ARNT-like 1 protein, also known as BMAL1 or ARNTL1, is one of the key transcriptional regulators of circadian rhythms that controls the diurnal dynamics of a wide range of behavioral, hormonal, and biochemical factors in most living creatures around the Earth. This protein also regulates many physiological processes, and its disruption leads to pathological conditions in organisms, including nervous system disorders. The high evolutionary conservativity of BMAL1 allows for the construction of in vitro and in vivo models using experimental animals and the investigation of BMAL1-dependent molecular mechanisms of these diseases. In this review, we have collected data from human and animal studies concerning the roles of BMAL1 in processes such as neuroinflammation, trauma and neurodegeneration, neurodevelopment and myelinization, mood disorders, addictions, cognitive functions, and neurosignaling. Additionally, we provide information about the biochemical regulation of BMAL1 and pharmacological approaches to change its activity. Here, we conclude that BMAL1 functions in the nervous system go far beyond circadian rhythm regulation in most cell types, including neurons, glial cells, and microglial cells. Under pathological conditions, lack or overexpression of this protein can exert both protective and destructive effects. Thus, proper therapeutic modulation of BMAL1 activity is a promising approach for improving nervous system disorders. Full article

Vitamin B12 (B12) is a strong antioxidant and a cofactor for methionine synthase supporting DNA/RNA/protein methylation. We previously demonstrated that oral high-dose B12 supplement mitigates diabetic cardiomyopathy in Akita diabetic mice expressing twice the normal levels of Elmo1 (Engulfment and cell motility 1). To assess how B12 prevents early kidney damage, we treated Elmo1^HH mice and diabetic Elmo1^HH Ins2^Akita/+ mice with or without B12 in drinking water starting at 8 weeks of age. At 16 weeks, markedly reduced mesangial expansion was detected in the B12-treated diabetic kidneys (22% of glomeruli affected vs. 70% in the untreated diabetic kidneys). RNAseq analysis of the kidneys revealed that B12 suppressed expression of genes for adaptive immune response, while it upregulated those for solute carrier transporters and antioxidant genes. Strikingly, B12 treatment suppressed activators of circadian rhythm, Clock and Bmal1, and upregulated repressors like Cry1/2, Per1-3 and Dbp, suggesting a shift in their rhythmicity. B12 also upregulated linker histone H1 variants, and enhanced chromatin stability and cell cycle regulation. In BU.MPT proximal tubular cells in culture, B12 shifted forward the circadian expression phase of Bmal1 and Per1. Taken together, B12 supplement effectively mitigates early development of diabetic nephropathy in diabetic mice, potentially involving regulation of circadian rhythm. Full article

Preeclampsia (PE), a major cause of maternal and perinatal morbidity, is a hypertensive pregnancy disorder with poorly defined pathogenesis. While dysregulation of core circadian genes including brain and muscle ARNT-like 1 (BMAL1; also termed ARNTL) and circadian locomotor output cycles kaput (CLOCK) has been implicated in PE, the contribution of their genetic polymorphisms to PE remains unclear. In this case–control study, polymorphisms in BMAL1 and CLOCK were genotyped using MassARRAY in 202 PE patients (97 early-onset [eoPE], 105 late-onset [loPE]) and 400 controls. Following genotyping and linkage disequilibrium-pruning (r² > 0.8) to retain representative tag SNPs, the final set for association analysis comprised three non-redundant BMAL1 SNPs (rs4757144, rs11022780, rs969485) and one CLOCK SNP (rs1048004). After confounder adjustment, no significant associations were detected for CLOCK variants, whereas the BMAL1 rs11022780 variant demonstrated a significant protective effect against PE (TT vs. CC: OR = 0.26 [95% CI 0.09–0.78]; recessive model: OR = 0.25 [95% CI 0.09–0.74]), particularly in the eoPE subgroup. Expression quantitative trait locus (eQTL) analysis confirmed that this SNP correlated with BMAL1 mRNA expression in whole blood, and protein–protein interaction analysis highlighted BMAL1′s central role in circadian networks, implying a genetically influenced regulatory mechanism of PE through BMAL1 expression. Full article

Mammalian circadian rhythms, governing ~24 h oscillations in behavior, physiology, and hormone levels, are orchestrated by transcriptional–translational feedback loops centered around the core clock protein cryptochrome 1 (CRY1). While CRY1 ubiquitination is known to regulate clock function, the roles of specific ubiquitination sites remain unclear. Here, we identify lysine 151 (K151) as a critical residue modulating the circadian period through non-canonical mechanisms. Using site-directed mutagenesis, we generated CRY1-K151Q/R mutants mimicking constitutive deubiquitination. Circadian rescue assays in Cry1/2-deficient cells revealed period shortening (K151Q: −2.25 h; K151R: −1.4 h; n = 3, p < 0.01, Student’s t-test), demonstrating K151’s functional importance. Despite normal nuclear localization kinetics, K151Q/R mutants exhibited reduced transcriptional repression in luciferase assays, a weakened interaction with BMAL1 by the luciferase complementation assay, and enhanced binding to E3 ligase FBXL12 (but not FBXL3) while showing more stability than wild-type CRY1. Notably, the absence of ubiquitination-linked degradation or altered FBXL3 engagement suggests a ubiquitination-independent mechanism. We propose that CRY1-K151 serves as a structural hub fine-tuning circadian periodicity by modulating core clock protein interactions rather than through traditional ubiquitin-mediated turnover. These findings redefine the mechanistic landscape of post-translational clock regulation and offer new therapeutic avenues for circadian disorders. Full article

Humans are continuously exposed to blue light from sunlight, computers, and smartphones. While blue light has been reported to affect living organisms, its role in fat synthesis and weight changes remains unclear. In this study, we investigated the effects of prolonged blue light exposure on weight changes in mice and the protective role of tranexamic acid (TA). Mice were exposed daily to blue light from a light-emitting diode for five months. Blue light exposure led to increased fat mass and body weight. The expression of the clock genes arnt-like 1 (Bmal1) and Clock was reduced in the brain and muscle of exposed mice. In addition, reduced Sirt1 and increased mammalian target of rapamycin complex 1 (mTORC1)/sterol regulatory element-binding protein 1 (SREBP1) were observed. The levels of liver X receptor a and liver kinase B1/5′AMP-activated protein kinase a1, both involved in SREBP1-mediated lipogenesis, were also elevated. TA treatment prevented the blue light-induced suppression of Bmal1/Clock and modulated the subsequent series of signal transduction. These findings suggest that prolonged blue light exposure suppresses the clock gene Bmal1/Clock, reduces Sirt1, and activates lipogenic pathways, contributing to weight gain. TA appears to regulate clock gene expression and mitigate blue light-induced weight gain. Full article

The biological clock is crucial for controlling the circadian rhythm of the human body and maintaining the stable cyclic changes of various human life activities. Cardiovascular disease has become one of the primary problems affecting human life and health in today’s society. Cardiovascular disease exhibits distinct circadian rhythms, with the core clock gene protein Brain and muscle ARNT-like protein 1 (BMAL1) playing critical roles in both physiological cardiac function and pathological processes. BMAL1 regulates myocardial gene expression, maintains normal structures, and stabilizes circadian rhythms to preserve cardiac homeostasis. In the pathological state of myocardial ischemia, BMAL1 ameliorates myocardial ischemic injury by regulating intrinsic mechanisms such as oxidative stress response, energy metabolism, immune-inflammatory response, and apoptosis and autophagy in cardiomyocytes. This review systematically examines BMAL1’s involvement in myocardial ischemic injury through the circadian regulation of cardiac function. We analyze its multidimensional impacts on oxidative stress, energy metabolism, immune-inflammatory responses, apoptosis, and autophagy, highlighting the biological significance of this clock gene in ischemic pathophysiology. Full article

Circadian rhythms are molecular oscillations governed by transcriptional–translational feedback loops (TTFLs) operating in nearly all cell types and are fundamental to physiological homeostasis. Key circadian regulators, such as circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period (PER), and cryptochrome (CRY) gene families, regulate intracellular metabolism, oxidative balance, mitochondrial function, and synaptic plasticity. Circadian disruption is known as a central contributor to the molecular pathophysiology of neurodegenerative disorders. Disease-specific disruptions in clock gene expression and melatoninergic signaling are known as potential early-stage molecular biomarkers. Melatonin, a neurohormone secreted by the pineal gland, modulates clock gene expression, mitochondrial stability, and inflammatory responses. It also regulates epigenetic and metabolic processes through nuclear receptors and metabolic regulators involved in circadian and cellular stress pathways, thereby exerting neuroprotective effects and maintaining neuronal integrity. This review provides recent findings from the past five years, highlighting how circadian dysregulation mediates key molecular and cellular disturbances and the translational potential of circadian-based therapies in neurodegenerative diseases. Full article

Background: Hypoxia-inducible factor 1 (HIF-1) affects the circadian clock in obstructive sleep apnea (OSA) and may have a bidirectional relationship with circadian mechanisms. This study examined the link between circadian clock and HIF-1 in OSA patients versus controls. Methods: 70 participants underwent polysomnography (PSG), and were assigned into OSA (apnea–hypopnea index (AHI) ≥ 5, n = 54) or control (AHI < 5, n = 16) groups. BMAL1 (brain and muscle ARNT like 1), CLOCK (circadian locomotor output cycles kaput), PER1 (period 1), CRY1 (cryptochrome 1), HIF-1α, and HIF-1β gene expressions and protein levels were measured in evening and morning samples, collected before and after PSG. Results: The OSA group was characterized by increased CLOCK, CRY1, PER1 and HIF-1a protein levels, both in the morning and evening (all p < 0.05), and decreased morning expression of BMAL1 (p = 0.02). Associations between almost all circadian clock gene expressions and both HIF-1 subunits were observed in the OSA group at both time points (all p < 0.05), apart from association between PER1 and HIF-1α in the morning (R = 0.050, p = 0.73). In controls, only a correlation between HIF-1α levels and CRY1 expression in the morning (R = 0.588, p = 0.02) was found. Conclusions: OSA affects the circadian clock and HIF-1 pathway, with increased CLOCK, CRY1, PER1, and HIF-1α protein levels observed in OSA patients. The interplay between these systems may involve complex posttranscriptional and posttranslational mechanisms. Full article

Circadian rhythms are important for maintaining homeostasis, from regulating physiological activities (e.g., sleep–wake cycle and cognitive performance) to cellular processes (e.g., cell cycle and DNA damage repair). Melatonin is a key regulator of circadian rhythms and exerts control by binding to melatonin receptor 1 (MT1), decreasing neuronal firing in the suprachiasmatic nucleus (SCN). Previous work studying effects of melatonin on circadian rhythms utilized in vivo models. Since MT1 is also expressed outside of the brain, it is important to study impacts of melatonin on circadian gene oscillations in vitro. We evaluated the effects of melatonin and an MT1 inverse agonist, UCSF7447, in U2OS circadian reporter cell lines, which facilitate detailed assessments of oscillatory changes. We report that cellular circadian rhythms are responsive to treatment with MT1-targeting molecules; their activities are not dependent upon the SCN. Corroborating in vivo data, both melatonin and UCSF7447 lengthened the periods of BMAL1 and PER2, and while melatonin delayed circadian phases, UCSF7447 advanced them. Compounds were also dosed at two different times, however this did not yield changes. Our findings indicate the importance of utilizing in vitro models and that the direct effects of melatonin likely go beyond the SCN and should be explored further. Full article

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. Full article

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. Full article

The promising possibility of an organic photodetector (OPD) is emerging in the field of sensing applications for its tunable absorption range, flexibility, and large-scale fabrication abilities. In this work, we fabricated a bulk heterojunction OPD with a device structure of glass/ITO/PEDOT:PSS/P3HT:PC₆₁BM/Al using the spin-coating process and characterized the dark and photocurrent densities at different applied bias conditions for red, green, and blue incident LEDs. The OPD photocurrent density exhibited a magnitude up to 2.5–3 orders higher compared to the dark current density at a −1 V bias while it increased by up to 3–4 orders at zero bias conditions for red, green, and blue lights, showing an increasing trend when a higher voltage is applied in the negative direction. Different OPD inner periphery shapes, the OPD to LED distance, and OPD area were also considered to bring the variation in the OPD dark and photocurrent densities, which can affect the on/off ratio of the OPD–LED hybrid system and is a critical phenomenon for any sensing application. Full article