Search Results (286)

The circadian clock, an intrinsic 24 h cellular timekeeping system, regulates fundamental biological processes, including tumor physiology and metabolism. Cancer stem cells (CSCs), a subpopulation of cancer cells with self-renewal and tumorigenic capacities, are implicated in tumor initiation, recurrence, and metastasis. Despite growing evidence for the circadian clock’s involvement in regulating CSC functions, its precise regulatory mechanisms remain largely unknown. Here, using a human osteosarcoma (OS) model (143B), we have shown that core molecular clock factors are critical for OS stem cell survival and behavior via direct modulation of CSC and lipid metabolic pathways. In single-cell-derived spheroid formation assays, 143B OS cells exhibited robust spheroid-forming capacity under 3D culture conditions. Furthermore, siRNA-mediated depletion of core clock components (i.e., BMAL1, CLOCK, CRY1/2, PER1/2)—essential positive and negative elements of the circadian clock feedback loop—significantly reduced spheroid formation in 143B CSCs isolated from in vivo OS xenografts. In contrast, knockdown of the secondary clock-stabilizing factor genes NR1D1 and NR1D2 had little effect. We also found that knockdown of BMAL1, CLOCK, or CRY1/2 markedly impaired the migration and invasion capacities of 143B CSCs. At the molecular level, silencing of BMAL1, CLOCK, or CRY1/2 distinctly altered the expression of genes associated with stem cell properties and the epithelial–mesenchymal transition (EMT) in 143B CSCs. In addition, disruption of BMAL1, CLOCK, or CRY1/2 expression significantly reduced lipid droplet formation by downregulating the expression of genes involved in lipogenesis (e.g., DGAT1, FASN, ACSL4, PKM2, CHKA, SREBP1), which are closely linked to CSC/EMT processes. Furthermore, transcriptomic analysis of human OS patient samples revealed that compared with other core clock genes, CRY1 was highly expressed in OS tumors relative to controls, and its expression exhibited strong positive correlations with patient prognosis, survival, and LD biogenesis gene expression. These findings highlight the critical role of the molecular circadian clock in regulating CSC properties and metabolism, underscoring the therapeutic potential of targeting the core clock machinery to enhance OS treatment outcomes. Full article

Background/Objectives: Epigenetic clocks have emerged as a tool to quantify biological age, providing a more accurate estimate of an individual’s health status than chronological age, helping to identify risk factors for accelerated aging and evaluating the reversibility of therapeutic strategies. This study aimed to evaluate the potential association between epigenetic acceleration of biological age and obesity, as well as to determine whether nutritional interventions for body weight loss could slow down this acceleration. Methods: Biological age was estimated using three epigenetic clocks (Horvath (Hv), Hannum (Hn), and Levine (Lv)) based on the leukocyte methylome analysis of individuals with normal weight (n = 20), obesity (n = 24), and patients with obesity following a VLCKD (n = 10). We analyzed differences in biological age estimates, the relationship between age acceleration and obesity, and the impact of VLCKD. Correlations were assessed between age acceleration, BMI, and various metabolic parameters. Results: Analysis of the epigenetic clocks revealed an acceleration of biological age in individuals with obesity (Hv = +3.4(2.5), Hn = +5.7(3.2), Lv = +3.9(2.7)) compared to a slight deceleration in individuals with normal weight. This epigenetic acceleration correlated with BMI (p < 0.0001). Interestingly, patients with obesity following a VLCKD showed a deceleration in estimated biological age, both in nutritional ketosis (Hv = −3.3(4.0), Hn = −6.3(5.3), Lv = −8.8(4.5)) and at endpoint (Hv = −1.1(4.3), Hn = −7.4(5.6), Lv = −8.2(5.3)). Relevantly, this slowdown in age is associated with BMI (p < 0.0001), ketonemia (p ≤ 0.001), and metabolic parameters (p < 0.05). Conclusions: Our findings highlight the applicability of epigenetic clocks to monitor obesity-related biological aging in precision medicine and show the potential efficacy of the VLCKD in slowing obesity-related epigenetic aging. Full article

Background/Objectives: Glaucoma, a leading cause of irreversible blindness, has been associated with systemic and ocular aging processes. This study aimed to investigate the relationship between glaucoma and accelerated biological aging using fundus-derived age prediction. Additionally, the role of systemic factors and retinal vascular changes in this association was explored. Methods: A total of 6023 participants, including 547 glaucoma patients and 547 matched controls, were analyzed. Fundus-derived predicted age was assessed using a deep learning model (EfficientNet). Systemic factors such as BMI, blood pressure, lipid profiles, liver function markers, glucose levels, and retinal vascular changes (Scheie classifications) were analyzed. Statistical comparisons and multivariate regression analyses were performed to evaluate the impact of glaucoma on predicted age acceleration, adjusting for age, gender, and systemic factors. Results: Glaucoma was significantly associated with higher predicted age acceleration (prediction difference: −1.5 ± 4.5 vs. −2.1 ± 4.5 years; p = 0.040). Multivariate regression confirmed that glaucoma independently influenced predicted age (p = 0.021) and prediction difference (p = 0.021). Among systemic factors, γ-GTP was positively associated with prediction difference (p = 0.036), while other factors, such as BMI, blood pressure, and glucose levels, showed no significant association. Retinal vascular changes, including hypertensive and sclerotic changes (Scheie classifications), were significantly more prevalent in glaucoma patients and correlated with predicted age acceleration. Conclusions: Glaucoma is associated with accelerated biological aging, as indicated by fundus-derived predicted age. Systemic factors such as γ-GTP and retinal vascular changes may play contributory roles. Fundus-derived predicted age holds promise as a non-invasive biomarker for monitoring systemic aging. Further longitudinal studies are warranted to establish causal relationships and enhance clinical applications. Full article

The circadian clock is a fundamental timekeeping system that regulates rhythmic biological processes in response to environmental light–dark cycles. In mammals, core clock genes (CLOCK, BMAL1, PER, and CRY) orchestrate these rhythms through transcriptional–translational feedback loops, influencing various physiological functions, including bone remodeling. Bone homeostasis relies on the coordinated activities of osteoblasts, osteoclasts, and osteocytes, with increasing evidence highlighting the role of circadian regulation in maintaining skeletal integrity. Disruptions in circadian rhythms are linked to bone disorders such as osteoporosis. Posttranslational modifications (PTMs), including phosphorylation, acetylation, and ubiquitination, serve as crucial regulators of both circadian mechanisms and bone metabolism. However, the specific role of PTMs in integrating circadian timing with bone remodeling remains underexplored. This review examines the intersection of circadian regulation and PTMs in bone biology, elucidating their impact on bone cell function and homeostasis. Understanding these interactions may uncover novel therapeutic targets for skeletal diseases associated with circadian disruptions. Full article

Breast cancer therapies have dramatically improved survival rates, but their long-term effects, especially on aging survivors, need careful consideration. This review delves into how breast cancer treatments and aging intersect, focusing on the epigenetic changes triggered by chemotherapy, radiation, hormonal treatments, and targeted therapies. Treatments can speed up biological aging by altering DNA methylation, histone modifications, and chromatin remodeling, affecting gene expression without changing the DNA sequence itself. The review explains the double-edged sword effect of therapy-induced epigenetic modifications, which help fight cancer but also accelerate aging. Chemotherapy and targeted therapies, in particular, impact DNA methylation and histone modifications, promoting chronic inflammation and shortening telomeres. These changes increase biological age, as seen in epigenetic clocks and biomarkers like p21, which also play roles in drug resistance and therapeutic decisions. Chronic inflammation, driven by higher levels of inflammatory cytokines such as TNF-α and IL-6 as well as telomere shortening, significantly contributes to the aging characteristics of breast cancer survivors. Non-coding RNAs, including microRNAs and long non-coding RNAs, are crucial in regulating gene expression and aging pathways altered by these treatments. This review explores new therapies targeting these epigenetic changes, like DNA methylation inhibitors, histone deacetylase inhibitors, and microRNA-based treatments, to reduce the aging effects of cancer therapy. Non-drug approaches, such as dietary changes and lifestyle modifications, also show promise in combating therapy-induced aging. It also highlights the clinical signs of aging-related side effects, such as heart and lung problems, endocrine and reproductive issues, and reduced quality of life. The development of comprehensive methods like the CHEMO-RADIAT score to predict major cardiovascular events after therapy is discussed. Understanding the epigenetic changes caused by breast cancer therapies offers valuable insights for creating interventions to enhance the health span and quality of life for survivors. Continued research is crucial to fully understand these epigenetic alterations and their long-term health impacts. Full article

Prenatal exposure to metals can influence fetal programming via DNA methylation and has been linked to adverse birth outcomes and long-term consequences. Epigenetic clocks estimate the biological age of a given tissue based on DNA methylation and are potential health biomarkers. This study leveraged the Extremely Low Gestational Age Newborn (ELGAN) study (n = 265) to evaluate associations between umbilical cord tissue concentrations of 11 metals as single exposures as well as mixtures in relation to (1) placental epigenetic gestational age acceleration (eGAA) and the (2) methylation status of the Robust Placental Clock (RPC) CpGs. Linear mixed effect regression models were stratified by infant sex. Both copper (Cu) and manganese (Mn) were significantly associated with a decelerated placental eGA of −0.98 (95% confidence interval (CI): −1.89, −0.07) and −0.90 weeks (95% CI: −1.78, −0.01), respectively, in male infants. Cu and Mn levels were also associated with methylation at RPC CpGs within genes related to processes including energy homeostasis and inflammatory response in placenta. Overall, these findings suggest that prenatal exposures to Cu and Mn impact placental eGAA in a sex-dependent manner in ELGANs, and future work could examine eGAA as a potential mechanism mediating in utero metal exposures and later life consequences. Full article

We investigated the transcription of circadian clock genes in publicly available datasets of gene expression in medulloblastoma (MB) tissues using the R2 Genomics Analysis and Visualization Platform. Differential expression of the core clock genes among the four consensus subgroups of MB (defined in 2012 as Group 3, Group 4, the SHH group, and the WNT group) included the core clock genes (CLOCK, NPAS2, PER1, PER2, CRY1, CRY2, BMAL1, BMAL2, NR1D1, and TIMELESS) and genes which encode proteins that regulate the transcription of clock genes (CIPC, FBXL21, and USP2). The over-expression of several clock genes, including CIPC, was found in individuals with the isochromosome 17q chromosomal aberration in MB Group 3 and Group 4. The most significant biological pathways associated with clock gene expression were ribosome subunits, phototransduction, GABAergic synapse, WNT signaling pathway, and the Fanconi anemia pathway. Survival analysis of clock genes was examined using the Kaplan–Meier method and the Cox proportional hazards regression model through the R2 Genomics Platform. Two clock genes most significantly related to survival were CRY1 and USP2. The data suggest that several clock proteins, including CRY1 and USP2, be investigated as potential therapeutic targets in MB. Full article

This study aimed to determine the dynamics of dormancy using triphenyl tetrazolium chloride (TTC) and asymbiotic germination in Laelia speciosa (Kunth) Schltr. seeds stored for three years and one year at different temperatures. This is the first report of a circannual rhythm in L. speciosa seeds under controlled storage conditions. Two experiments were carried out: (a) with seeds from wild populations of L. speciosa collected at two different times and dehydrated to 4% relative humidity (RH) and stored for three years at 25 °C, 6 °C, −20 °C, and −80 °C, and (b) with seeds from six fruits stored in liquid nitrogen (LN2; −196 °C) at 25 °C for 12 months. The germination conditions were 25 ± 1 °C with 16 h of light (23 μmol m⁻² s⁻¹) and 8 h of darkness for both trials. Because they have a rudimentary embryo, orchids are attributed a morphological latency; however, the staining of the embryo with TTC (>92%) in all the evaluations carried out throughout a year and the decrease in asymbiotic germination in the intermediate evaluations record a circannual biological cycle or clock, under temperature and humidity control (4% RH). Full article

Organisms have the capacity to detect day–night fluctuations through oscillators regulated by circadian clock genes, which are crucial for regulating various biological processes. Numerous studies have demonstrated a marked association between these genes and various growth traits of sheep. This study identified polymorphisms at 23 potential loci within five clock genes in four Chinese sheep breeds. Only two polymorphic insertion/deletions (InDels) were detected in CLOCK and PER3 genes, respectively. The distribution of these two loci in four Chinese sheep breeds and their association with growth traits were further explored. A 12 bp deletion was found in the intron of the CLOCK gene (rs604230640), which was significantly associated with body height (p < 0.05), body oblique length (p < 0.05) and cannon girth (p < 0.05) in Hu sheep (HS). A 22 bp insertion in the intron of the PER3 gene (rs600537720) with a dominant genotype of insertion/insertion (II) was found to have a significant association with chest depth (p < 0.05) in Small-Tail Han sheep (STHS), tail width (p < 0.05) in Tong Sheep (TS), and in Lanzhou fat-tailed sheep (LFTS). In conclusion, this study has elucidated the polymorphisms of CLOCK and PER3 genes and has examined the influence of these two genes on the growth traits of sheep. Concurrently, the two molecular markers identified in CLOCK and PER3 could potentially serve in the marker-assisted selection of growing-related traits in local Chinese sheep breeds. Full article

Dex is a drug commonly used as an immunosuppressive and anti-inflammatory agent in humans and animals. GCs have a profound impact on melatonin expression and biological rhythm. However, the effect of chronic exposure to Dex on melatonin secretion and biological clock gene expression in ruminants is still unclear. Ten goats were randomly divided into two groups: the control group was injected with saline, and the Dex-treated group was intramuscularly injected daily for 21 d with 0.2 mg/kg Dex. The rhythm of melatonin secretion in the plasma was disturbed in the Dex group, and the plasma and colon levels of melatonin were lower in the Dex group compared to the control group (p < 0.05). Dex leads to a significant decrease in the expression of Arylalkylamine N-acetyltransferase (AANAT), a key melatonin synthase, in the pineal gland and colon. Detecting intestinal leakage-related indices showed that diamine oxidase (DAO) and lipopolysaccharide (LPS) content increased significantly in the Dex group (p < 0.05). We also detected genes associated with biological rhythms in the plasma. In the control group, the five tested genes showed circadian rhythms, but the circadian rhythms of Clock, Cry1, Cry2, and Per2 were abolished or blunted by the Dex (p < 0.05). Protein levels of CLOCK and BMAL1 in the colon changed significantly (p < 0.05). In conclusion, the above experimental results show that chronic exposure to Dex leads to the disorder of the circadian rhythms of melatonin secretion and clock genes. Full article

In this work, we study the magnetocaloric effect (MCE) in a working substance corresponding to a square lattice of spins with Q possible orientations, known as the “Q-state clock model”. When the Q-state clock model has $Q\ge 5$ possible configurations, it presents the famous Berezinskii–Kosterlitz–Thouless (BKT) phase associated with vortex states. We calculate the thermodynamic quantities using Monte Carlo simulations for even Q numbers, ranging from $Q=2$ to $Q=8$ spin orientations per site in a lattice. We use lattices of different sizes with $N=L\times L=8^2,{16}^2,{32}^2,{64}^2,\mathrm{and}{128}^2$ sites, considering free boundary conditions and an external magnetic field varying between $B=0$ and $B=1.0$ in natural units of the system. By obtaining the entropy, it is possible to quantify the MCE through an isothermal process in which the external magnetic field on the spin system is varied. In particular, we find the values of Q that maximize the MCE depending on the lattice size and the magnetic phase transitions linked with the process. Given the broader relevance of the Q-state clock model in areas such as percolation theory, neural networks, and biological systems, where multi-state interactions are essential, our study provides a robust framework in applied quantum mechanics, statistical physics, and related fields. Full article

Background/Objectives: Circadian clocks are endogenous systems that regulate numerous biological, physiological, and behavioral events in living organisms. Aging attenuates the precision and robustness of circadian clocks, leading to prolonged and dampened circadian gene oscillation rhythms and amplitudes. This study investigated the effects of food-derived polyphenols such as ellagic acid and its metabolites (urolithin A, B, and C) on the aging clock at the cellular level using senescent human fibroblast cells, TIG-3 cells. Methods: Lentivirus-infected TIG-3 cells expressing Bmal1-luciferase were used for real-time luciferase monitoring assays. Results: We revealed that urolithins boosted the amplitude of circadian gene oscillations at different potentials; urolithin A (UA) amplified the best. Furthermore, we discovered that UA unstabilizes PER2 protein while stabilizing SIRT1 protein, which provably enhances BMAL1 oscillation. Conclusions: The findings suggest that urolithins, particularly UA, have the potential to modulate the aging clock and may serve as therapeutic nutraceuticals for age-related disorders associated with circadian dysfunction. Full article

Yakutia is one of the coldest permanently inhabited regions in the world, characterized by a subarctic climate with average January temperatures near −40 °C and the minimum below −60 °C. Recently, we demonstrated accelerated epigenetic aging of the Yakutian population in comparison to their Central Russian counterparts, residing in a considerably milder climate. In this paper, we analyzed these cohorts from the inflammaging perspective and addressed two hypotheses: a mismatch in the immunological profiles and accelerated inflammatory aging in Yakuts. We found that the levels of 17 cytokines displayed statistically significant differences in the mean values between the groups (with minimal p-value = 2.06 × 10⁻¹⁹), and 6 of them are among 10 SImAge markers. We demonstrated that five out of these six markers (PDGFB, CD40LG, VEGFA, PDGFA, and CXCL10) had higher mean levels in the Yakutian cohort, and therefore, due to their positive chronological age correlation, might indicate a trend toward accelerated inflammatory aging. At the same time, a statistically significant biological age acceleration difference between the two cohorts according to the inflammatory SImAge clock was not detected because they had similar levels of CXCL9, CCL22, and IL6, the top contributing biomarkers to SImAge. We introduced an explainable deep neural network to separate individual inflammatory profiles between the two groups, resulting in over 95% accuracy. The obtained results allow for hypothesizing the specificity of cytokine and chemokine profiles among people living in extremely cold climates, possibly reflecting the effects of long-term human (dis)adaptation to cold conditions related to inflammaging and the risk of developing a number of pathologies. Full article

Background: Chronobiology has gained attention in the context of paediatric neurological and neuropsychiatric disorders, including migraine, epilepsy, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD). Disruptions in circadian rhythms are associated with key symptoms such as sleep disturbances, mood dysregulation, and cognitive impairments, suggesting a potential for chronobiology-based therapeutic approaches. Methods: This narrative review employs a systematic approach to identify relevant studies through searches of three major scientific databases, NCBI/PubMed, ScienceDirect, and Scopus, up to July 2024. We used a combination of broad and condition-specific keywords, such as “chronobiology”, “biorhythm”, “pediatric”, “epilepsy”, “ADHD”, and “ASD”, among others. Articles in English that focused on clinical features, treatments, or outcomes related to circadian rhythms in paediatric populations were included, while non-peer-reviewed articles and studies lacking original data were excluded. Rayyan software was used for article screening, removing duplicates, and facilitating consensus among independent reviewers. Results: A total of 87 studies were included in the analysis. Findings reveal a consistent pattern of circadian rhythm disruptions across the disorders examined. Specifically, dysregulation of melatonin and cortisol secretion is observed in children with ASD, ADHD, and PTSD, with altered circadian timing contributing to sleep disturbances and mood swings. Alterations in core clock genes (CLOCK, BMAL1, PER, and CRY) were also noted in children with epilepsy, which was linked to seizure frequency and timing. Chronotherapy approaches showed promise in managing these disruptions: melatonin supplementation improved sleep quality and reduced ADHD symptoms in some children, while light therapy proved effective in stabilizing sleep–wake cycles in ASD and ADHD patients. Additionally, behaviour-based interventions, such as the Early Start Denver Model, showed success in improving circadian alignment in children with ASD. Conclusions: This review highlights the significant role of circadian rhythm disruptions in paediatric neurological and neuropsychiatric disorders, with direct implications for treatment. Chronobiology-based interventions, such as melatonin therapy, light exposure, and individualized behavioural therapies, offer potential for improving symptomatology and overall functioning. The integration of chronotherapy into clinical practice could provide a paradigm shift from symptom management to more targeted, rhythm-based treatments. Future research should focus on understanding the molecular mechanisms behind circadian disruptions in these disorders and exploring personalized chronotherapeutic approaches tailored to individual circadian patterns. Full article

Long noncoding RNAs (LncRNAs) play essential roles in numerous biological processes in mammals, such as reproductive physiology and endocrinology. Cryptorchidism is a common male reproductive disease. Circadian rhythms are actively expressed in the reproductive system. In this study, a total of 191 LncRNAs were obtained from yak testes and cryptorchids. Then, we identified NTRK2’s relationship to circadian rhythm and behavioral processes. Meanwhile, the ceRNA (LncRNA-MSTRG.19083.1/miR-429-y/NTRK2) network was constructed, and its influence on circadian rhythm was revealed. The results showed that NTRK2 and LncRNA-MSTRG.19083.1 were significantly upregulated, and miR-429-y was obviously decreased in cryptorchid tissue; NTRK2 protein was mainly distributed in the Leydig cells of the testis. In addition, the upregulation of the expression level of miR-429-y resulted in the significant downregulation of LncRNA and NTRK2 levels, while the mRNA and protein levels of CREB, CLOCK, and BMAL1 were significantly upregulated; the knockdown of miR-429-y resulted in the opposite changes. Our findings suggested that LncRNA-MSTRG.19083.1 competitively binds to miR-429-y to target NTRK2 to regulate circadian rhythm through the cAMP pathway. Taken together, the results of our study provide a comprehensive understanding of how the LncRNA-miRNA-mRNA networks operate when yak cryptorchidism occurs. Knowledge of circadian-rhythm-associated mRNAs and LncRNAs could be useful for better understanding the relationship between circadian rhythm and reproduction. Full article