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Although dysfunctional circadian clock has emerged as a hallmark of cancer, fundamental gaps remain in our understanding of the underlying mechanisms involved. Here, we systematically analyze the core genes of the circadian clock (CLOCK, ARNTL, ARNTL2, NPAS2, NR1D1, NR1D2, CRY1, CRY2, RORA, RORB, RORC, PER1, PER2, and PER3) across a broad range of cancers. To our surprise, core negative regulators (PER1, PER2, PER3, CRY1, and CRY2) are consistently downregulated, while core positive regulators show minimal alterations, indicating disrupted circadian clock in cancers. Such downregulation originates from copy number variations where heterozygous deletion predominates. The disrupted circadian clock is significantly associated with patient outcome. Further pathway enrichment analysis suggests that the circadian clock widely impacts 45 pathways such as the Ras signaling pathway and T cell receptor signaling pathway. By using state-of-the-art immune cell deconvolution and pathway quantification, we demonstrate that abnormal circadian clock contributes to T cell exhaustion and global upregulation of immune inhibitory molecules such as PD-L1 and CTLA-4. In summary, the rhythm of the circadian clock is disrupted in cancers. Abnormal circadian clock linked with immune evasion may serve as a potential hallmark of cancer.

Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is essential to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock disturbances may offer new insights. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-shift schedule, compared with a simulated day-shift schedule, were analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhythmicity under constant routine following either or both simulated shift schedules. However, while traditional markers of the circadian clock in the SCN—melatonin, cortisol, and PER3 expression—maintained a stable phase alignment after both schedules, only a few metabolites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine following the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavioral time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circadian clock. Characterization of these metabolite rhythms will provide insight into the underlying mechanisms linking shift work and metabolic disorders.

Metabolism is one of the most complex cellular biochemical reactions, providing energy and substances for basic activities such as cell growth and proliferation. Early studies have shown that glucose is an important nutrient in osteoblasts. In addition, amino acid metabolism and fat metabolism also play important roles in bone reconstruction. Mammalian circadian clocks regulate the circadian cycles of various physiological functions. In vertebrates, circadian rhythms are mediated by a set of central clock genes: muscle and brain ARNT like-1 ( Bmal1), muscle and brain ARNT like-2 (Bmal2), circadian rhythmic motion output cycle stagnates (Clock), cryptochrome 1 (Cry1), cryptochrome2 (Cry2), period 1 (Per1), period 2 (Per2), period 3 (Per3) and neuronal PAS domain protein 2 ( Npas2) . Negative feedback loops, controlled at both the transcriptional and posttranslational levels, adjust these clock genes in a diurnal manner. According to the results of studies on circadian transcriptomic studies in several tissues, most rhythmic genes are expressed in a tissue-specific manner and are affected by tissue-specific circadian rhythms. The circadian rhythm regulates several activities, including energy metabolism, feeding time, sleeping, and endocrine and immune functions. It has been reported that the circadian rhythms of mammals are closely related to bone metabolism. In this review, we discuss the regulation of the circadian rhythm/circadian clock gene in osteoblasts/osteoclasts and the energy metabolism of bone, and the relationship between circadian rhythm, bone remodeling, and energy metabolism. We also discuss the therapeutic potential of regulating circadian rhythms or changing energy metabolism on bone development/bone regeneration.

Breast cancer has a multifactorial etiology. One of the supposed and novel mechanisms is an alteration of circadian gene expression. Circadian genes play a crucial role in many physiological processes. These processes, such as genomic stability, DNA repair mechanism and apoptosis, are frequently disrupted in breast tumors. To assess the significance of circadian gene expression in breast cancer, we carried out an analysis of CLOCK, BMAL1, NPAS2, PER1, PER2, PER3 and CRY1, CRY2, TIMELESS, CSNK1E expression by the use of the quantitative Real-Time PCR technique in tumor tissue and non-tumor adjacent normal tissue sampled from 107 women with a newly diagnosed disease. The obtained data were compared to the clinical and histopathological features. PER1, PER2, PER3, CRY2 were found to be significantly down-expressed, while CLOCK, TIMELESS were over-expressed in the studied tumor samples compared to the non-tumor samples. Only gene expression of CRY1 was significantly down-regulated with progression according to the TNM classification. We found significantly decreased expression of CRY2, PER1, PER2 genes in the ER/PR negative breast tumors compared to the ER/PR positive tumors. Additionally, expression of CRY2, NPAS2 genes had a decreased level in the poorly differentiated tumors in comparison with the well and moderately differentiated ones. Our results indicate that circadian gene expression is altered in breast cancer tissue, which confirms previous observations from various animal and in vitro studies.

BackgroundThere is a significant association between Inflammatory Bowel Disease (IBD) and sleep disorders. Disruption of the circadian rhythm is associated with IBD, and genes regulating the circadian rhythm may play a crucial role in the inflammatory process of IBD.MethodsThis study included 25 healthy controls (HCs) and 32 IBD patients from March 1, 2024, to February 1, 2025. Peripheral blood mononuclear cells from venous blood samples were collected from participants to measure circadian gene mRNA expression levels (BMAL1, CLOCK, PER1, PER2, PER3, CRY1, CRY2) and to assess the correlation between gene expression levels and clinical inflammatory indicators. Additionally, a subset of IBD patients and all HCs completed sleep questionnaires such as the Insomnia Severity Index (ISI) to evaluate their sleep quality.ResultsCompared to HCs, the expression levels of BMAL1, CRY1, and PER3 were significantly decreased in the IBD group (P<0.05). In Ulcerative Colitis (UC) patients, the expression levels of CRY1 and PER3 were reduced (P<0.01), and in Crohn’s Disease (CD) patients, the expression level of CRY1 was decreased (P<0.05). Among IBD patients, BMAL1, CLOCK, PER3, and CRY2 were negatively correlated with C-reactive protein (R<-0.40, P<0.05), while CRY2 was positively correlated with albumin (R=0.38, P=0.03). PER2 was positively correlated with hematocrit and hemoglobin (R=0.36, P<0.05). In UC patients, the expression level of PER3 was negatively correlated with CRP (R=-0.70, P=0.03). The ISI scores were higher in IBD patients who completed the questionnaire compared to HCs (P= 0.03). Participants with an ISI score greater than 7 (indicating insomnia issues) exhibited lower expression levels of the CLOCK gene compared to others (P = 0.04) (IDDF2025-ABS-0040 figure 1).Abstract IDDF2025-ABS-0040 Figure 1Comparison of circadin gene mRNA expression levels between inflammatory bowel disease (IBD), ulcerative colitis(UC), crohn’s disease (CD) patients and healthy controls (HCs)[Figure omitted. See PDF]ConclusionsThe downregulation of circadian clock genes may constitute the molecular basis for sleep disturbances and the exacerbation of inflammation in IBD patients.

BackgroundCircadian rhythm is a 24-hour cycle that regulates physiological processes in the brain and peripheral tissues in the body through a transcription-translation feedback loop system. Proximal colon is a major site of fermentation in the digestive system, where produces anti-inflammatory short-chain fatty acids that provide numerous health benefits. Recent studies have shown that circadian disruption can be triggered by systemic inflammation, which is closely associated with various metabolic diseases. In our previous study, we suggested prebiotics as a novel dietary strategy to address light-shift-induced circadian misalignment. With reference to our previous study, we investigate the effects of prebiotic polysaccharides, specifically yeast β-glucan and chicory inulin, on reducing systemic inflammation-induced circadian misalignment in the proximal colon of C57BL/6J mice in this study. Melatonin, a chronobiotic, and ibuprofen, an anti-inflammatory drug, were included as positive controls.MethodsIntraperitoneal injection of lipopolysaccharide (LPS) was performed to induce systemic inflammation in the wild-type C57BL/6J mice, which further triggered inflammation in the proximal colon (figure 1). Two days later, proximal colon tissues were harvested and RNA extraction at four different time points (Zeitgeber time (ZT) 3, ZT 9, ZT 15, and ZT 21) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis were performed. We analysed the expression of seven core circadian clock genes (Bmal1, Clock, Cry1, Cry2, Per1, Per2, Per3) and pro-inflammatory cytokine genes (IL-1β, IL-6, MCP-1, TNF-α) in the proximal colon.ResultsOur results indicate that β-glucan demonstrated distinct immunomodulatory effects in the proximal colon, maintaining the rhythmic expression of the pro-inflammatory cytokine TNF-α, with a reduced phase shift compared to the LPS group (p < 0.05; figure 2a). Moreover, β-glucan restored the rhythmic expression of IL-1β to levels similar to those observed with melatonin treatment (p < 0.05; figure 2b). Interestingly, inulin treatment also modulated circadian rhythm by restoring rhythmicity of Per1 expression, comparable to melatonin (p < 0.05; figure 2c).Abstract IDDF2025-ABS-0340 Figure 1Abstract IDDF2025-ABS-0340 Figure 2ConclusionsIn summary, our findings demonstrate the therapeutic potential of prebiotics in modulating both inflammatory responses and circadian rhythms in the digestive system.

Traditionally, circadian clocks have been thought of as a neurobiological phenomenon. This view changed somewhat over recent years with the discovery of peripheral tissue circadian oscillators. In mammals, however, the suprachiasmatic nucleus (SCN) in the hypothalamus still retains the critical role of a central synchronizer of biological timing. Zebrafish, in contrast, have always reflected a more highly decentralized level of clock organization, as individual cells and tissues contain directly light responsive circadian pacemakers. As a consequence, clock function in the zebrafish brain has remained largely unexplored, and the precise organization of rhythmic and light-sensitive neurons within the brain is unknown. To address this issue, we used the period3 (per3)-luciferase transgenic zebrafish to confirm that multiple brain regions contain endogenous circadian oscillators that are directly light responsive. In addition, in situ hybridization revealed localised neural expression of several rhythmic and light responsive clock genes, including per3, cryptochrome1a (cry1a) and per2. Adult brain nuclei showing significant clock gene expression include the teleost equivalent of the SCN, as well as numerous hypothalamic nuclei, the periventricular grey zone (PGZ) of the optic tectum, and granular cells of the rhombencephalon. To further investigate the light sensitive properties of neurons, expression of c-fos, a marker for neuronal activity, was examined. c-fos mRNA was upregulated in response to changing light conditions in different nuclei within the zebrafish brain. Furthermore, under constant dark (DD) conditions, c-fos shows a significant circadian oscillation. Taken together, these results show that there are numerous areas of the zebrafish central nervous system, which contain deep brain photoreceptors and directly light-entrainable circadian pacemakers. However, there are also multiple brain nuclei, which possess neither, demonstrating a degree of pacemaker complexity that was not previously appreciated.

Disruptions to circadian rhythm in mice and humans have been associated with an increased risk of obesity and metabolic syndrome. The gut microbiota is known to be essential for the maintenance of circadian rhythm in the host suggesting a role for microbe-host interactions in the regulation of the peripheral circadian clock. Previous work suggested a role for gut bacterial bile salt hydrolase (BSH) activity in the regulation of host circadian gene expression. Here we demonstrate that unconjugated bile acids, known to be generated through the BSH activity of the gut microbiota, are potentially chronobiological regulators of host circadian gene expression. We utilised a synchronised Caco-2 epithelial colorectal cell model and demonstrated that unconjugated bile acids, but not the equivalent tauro-conjugated bile salts, enhance the expression levels of genes involved in circadian rhythm. In addition oral administration of mice with unconjugated bile acids significantly altered expression levels of circadian clock genes in the ileum and colon as well as the liver with significant changes to expression of hepatic regulators of circadian rhythm (including Dbp) and associated genes (Per2, Per3 and Cry2). The data demonstrate a potential mechanism for microbe-host crosstalk that significantly impacts upon host circadian gene expression.

Attention-deficit/hyperactivity disorder (ADHD) is a frequently observed condition, with about 70% of individuals diagnosed with ADHD experiencing irregular sleep–wake patterns. Beyond the primary symptoms of ADHD, there is a significant overlap with sleep-related issues, indicating that disrupted sleep patterns may exacerbate ADHD symptoms. ADHD-related sleep problems can be traced to a delayed circadian rhythm and a later onset of melatonin production. Therefore, normalizing circadian rhythms has been proposed as a potential therapeutic target for psychiatric disorders. Recent animal studies have provided compelling evidence linking peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of energy metabolism, to the regulation of physiological and behavioral rhythms. In this study, we hypothesized that treating fibroblasts from ADHD patients, which exhibit disturbances in circadian rhythmicity that are replicated in peripheral fibroblasts, with rosiglitazone may restore their circadian rhythmicity to that of the controls. To this end, we used cultures of fibroblasts obtained from skin biopsy explants of ADHD patients and controls and investigated the temporal patterns of clock gene expression over a period of 24 h. We report that the administration of the PPARγ agonist, rosiglitazone significantly realigns the chronobiological patterns of ADHD patient samples and control groups by inducing phase shifts in the expression of the BMAL1 , PER3 , and CRY1 clock genes. Nevertheless, rosiglitazone showed limited impact on the amplitude and phase of CLOCK1, NPAS2, and PER1 . No notable changes were observed in PER2 and PER3 gene expression. The data from cultured human dermal fibroblasts indicate that PPARγ-agonists may help regulate circadian molecular mechanisms. Given the shared genetic pathways between ADHD and obesity, future studies could investigate the potential of RSG as a treatment for circadian rhythm disorders, particularly in obese patients with ADHD.

Dysregulation of circadian rhythm genes is related to the increased risk of development of various human cancers. This study investigated the biological roles of Period circadian regulator 3 (PER3) in the development and progression of lung adenocarcinoma and related underlying mechanisms. The expression of PER3 was decreased in lung adenocarcinoma and its low expression was correlated with advanced disease stages. Lentiviral-transduced overexpression of PER3 inhibited but PER3 silencing promoted proliferation, migration and invasion of lung adenocarcinomatous cells, suggesting that it played an anti-carcinogenic role in the development and progression of lung adenocarcinoma. Mechanistically, PER3 overexpression elevated the phosphorylation level of AMPK and reduced the phosphorylation level of mTOR, but PER3 silencing produced the opposite effects. More importantly, the inhibitory effects of PER3 overexpression on cellular proliferation, migration and invasion were partially reversed by the AMPK/mTOR pathway inhibitor. Correspondingly, the promoting effects of PER3 silencing on proliferation, migration and invasion was partially reversed by the AMPK/mTOR pathway activator. These findings collectively suggest that PER3 regulated biological behaviors of lung adenocarcinomatous cells through activating the AMPK/mTOR pathway. PER3 may be a promising biomarker and therapeutic target for lung adenocarcinoma.