Circadian Gene Expression Research Articles

Effects of LED spectrum on circadian rhythmic expression of clock genes and Aanat2 in the brain of juvenile European seabass (Dicentrarchus labrax)

The circadian rhythm is a physiological phenomenon that occurs in various organisms with a cycle of about 24 hours. Light is one of the important environmental factors affecting biological rhythm. To clarify whether a shift in light spectrum can influence the circadian expression in fish brain, a total of 175 European seabasses [body weight: 32.5 ± 0.71) g; body length: (13.78 ± 0.35) cm] were exposed to white light (WL), red light (RL), yellow light (YL), green light (GL) or blue light (BL). After 50 days of exposure, circadian expressions of four core clock genes (Clock, Bmal1, Per2, Cry1) and Aanat2 gene in brain were examined. The results showed that the temporal expression patterns of positive clock gens (Clock and Bmal1) showed increases during the scotophase and decreases during the photophase, with peaks near the middle of the darkness. Clock gene expression showed a stable circadian rhythm (R2 = 0.578-0.824, P=0.000- 0.027) in all light groups while Bmal1 showed circadian rhythm in WL, GL and RL, not in BL and YL. Daily expression patterns of the negative clock genes oscillated in the opposite phase from the positive clock genes, showing increasing mRNA levels during the light, decreases during the dark, and peaks near the shift from night to day, except Per2 in RL and Cry1 in BL. Compared with WL, the acrophases of Clock and Bmal1 were delayed under all light treatments (BL: + 3.7h, +6.73h; RL: +2.4h,+1.35h; YL: + 4.94h, 2.00h; GL: +0.05, +0.16h). Cry1 showed advanced acrophase under all light treatments (BL: -10.74 h, GL: -3.81 h, RL: -3.93 h, YL: -7.56 h) but Per2 showed delayed acrophase in all light treatments (GL: +0.86 h, RL: +10.35 h, YL: +9.62 h), except in BL (-0.43 h). The acrophase of Aanat2 was advanced by all monochromatic light, the Aanat2 level was significantly increased in RL compared with other light treatment. Therefore, the results indicate that RL may regulate the expression of Aanat2 gene by affecting the expression of clock gene in fish brain. Spectrum can affect the biological clock system of fish, and unreasonable spectrum may disturb the rhythm of gene expression of biological clock of fish. Under the irradiation of light spectrum, some clock genes still maintain obvious circadian oscillation, while the rhythm of some clock genes is not obvious and may be destroyed. Our findings suggest a primary role of light spectrum information to the fish brain circadian system.

The structural and functional roles of the flavin cofactor FAD in mammalian cryptochromes.

The importance of circadian rhythms in human health and disease calls for a thorough understanding of the underlying molecular machinery, including its key components, the flavin adenine dinucleotide (FAD)-containing flavoproteins cryptochrome 1 and 2. Contrary to their Drosophila counterparts, mammalian cryptochromes are direct suppressors of circadian transcription and act independently of light. Light-independence poses the question regarding the role of the cofactor FAD in mammalian cryptochromes. The weak binding of the cofactor in vitro argues against its relevance and might be a functionless evolutionary remnant. From the other side, the FAD-binding pocket constitutes the part of mammalian cryptochromes directly related to their ubiquitylation by the ubiquitin ligase Fbxl3 and is the target for protein-stabilizing small molecules. Increased supplies of FAD stabilize cryptochromes in cell culture, and the depletion of the FAD precursor riboflavin with simultaneous knock-down of riboflavin kinase affects the expression of circadian genes in mice. This review presents the classical and more recent studies in the field, which help to comprehend the role of FAD for the stability and function of mammalian cryptochromes.

Synechocystis: A model system for expanding the study of cyanobacterial circadian rhythms.

The study of circadian rhythms in bacteria was transformed by studies of the cyanobacterium Synechococcus elongatus. However, in a number of respects S. elongatus is atypical, and while those unusual characteristics were helpful for rapid progress in the past, another commonly used cyanobacterial species, Synechocystis sp. PCC 6803, may be more representative and therefore more productive for future insights into bacterial clock mechanisms. In the past, circadian studies of Synechocystis have suffered from not having an excellent reporter of circadian gene expression, but we introduce here a new luminescence reporter that rivals the reporters that have been used so successfully in S. elongatus. Using this new system, we generate for the first time in Synechocystis circadian period mutants resulting from point mutations. The temperature compensation and dark-pulse resetting that mediates entrainment to the environment is characterized. Moreover, we analyse the complex organization of clock genes in Synechocystis and identify which genes are essential for circadian rhythmicity and adaptive fitness for entrainment and optimal phase alignment to environmental cycles (and which genes are not). These developments will provide impetus for new approaches towards understanding daily timekeeping mechanisms in bacteria.

Isorhynchophylline Regulates the Circadian Rhythm of the Hypothalamus in Spontaneously Hypertensive Rats to Treat Hypertension.

The neurotransmitter metabolism in spontaneously hypertensive rats (SHR) is disordered, and these disturbances in neurotransmitter levels can further exacerbate the development of hypertension. Neurotransmitters can affect the expression of circadian clock genes. To clarify the time-dependent internal mechanism of the imbalance of the target neurotransmitter metabolic rhythm of spontaneously hypertensive rats, the circadian research was carried out by the method of targeted metabolomics and molecular biology technology. We have explored the mechanism of isorhynchophylline regulating the circadian rhythm through the ERK signaling pathway and thus treating hypertension by detecting the changes of central hypothalamic biological clock rhythm genes after isorhynchophylline intervention, from hypothalamic neurotransmitter rhythmicity. The expression of rhythm genes in normal rats showed a certain rhythm at 6 time points, while the expression of rhythm genes in model rats decreased, and the gene rhythm returned to normal after isorhynchophylline treatment. Cosine analysis of 12 neurotransmitters in hypothalamus showed that there were 6 rhythmic neurotransmitters in the normal group, while in the model group, 4 of the 6 neurotransmitters lost their rhythmicity, and the rhythmicity returned to normal after isorhynchophylline intervention. Compared with the normal group, the expression of ERK protein in the model group increased significantly and decreased after isorhynchophylline treatment. The mechanism of isorhynchophylline treating hypertension is not only the regulation of serum neurotransmitters rhythm, but also acting on rhythm genes in the feedback loop of the central biological clock.

Identification of potential circadian genes and associated pathways in colorectal cancer progression and prognosis using microarray gene expression analysis.

Colorectal cancer (CRC) is third cancer causing death in the world. CRC is associated with disrupting the circadian rhythm (CR), closely associating the CRC progression and the dysregulation of genes involved in the biological clock. In this study, we aimed to understand the circadian rhythm changes in patients diagnosed with CRC. We used the GEO database with the ID GSE46549 for our analysis, which consists of 32 patients with CRC and one as normal control. Our study has identified five essential genes involved in CRC, HAPLN1, CDH12, IGFBP5, DCHS2, and DOK5, and had different enriched pathways, such as the Wnt-signaling pathway, at different time points of study. As a part of our study, we also identified various related circadian genes, such as CXCL12, C1QTNF2, MRC2, and GLUL, from the Circadian Gene Expression database, that played a role in circadian rhythm and CRC development. As circadian timing can influence the host tissue's ability to tolerate anticancer medications, the genes reported can serve as a potential drug target for treating CRC and become beneficial to translational settings.

Molecular characterization of circadian gene expression and its correlation with survival percentage in colorectal cancer patients.

Colorectal cancer (CRC) is a form of cancer characterized by many symptoms and readily metastasizes to different organs in the body. Circadian rhythm is one of the many processes that is observed to be dysregulated in CRC-affected patients. In this study, we aim to identify the dysregulated physiological processes in CRC-affected patients and correlate the expression profiles of the circadian clock genes with CRC-patients' survival rates. We performed an extensive microarray gene expression pipeline, whereby 471 differentially expressed genes (DEGs) were identified, following which, we streamlined our search to 43 circadian clock affecting DEGs. The Circadian Gene Database was accessed to retrieve the circadian rhythm-specific genes. The DEGs were then subjected to multi-level functional annotation, i.e., preliminary analysis using ClueGO/CluePedia and pathway enrichment using DAVID. The findings of our study were interesting, wherein we observed that the survival percentage of CRC-affected patients dropped significantly around the 100th-month mark. Furthermore, we identified hormonal activity, xenobiotic metabolism, and PI3K-Akt signaling pathway to be frequently dysregulated cellular functions. Additionally, we detected that the ZFYVE family of genes and the two genes, namely MYC and CDK4 were the significant DEGs that are linked to the pathogenesis and progression of CRC. This study sheds light on the importance of bioinformatics to simplify our understanding of the interactions of different genes that control different phenotypes.

The impact of biological clock and sex hormones on the risk of disease.

Molecular clocks are responsible for defining 24-h cycles of behaviour and physiology that are called circadian rhythms. Several structures and tissues are responsible for generating these circadian rhythms and are named circadian clocks. The suprachiasmatic nucleus of the hypothalamus is believed to be the master circadian clock receiving light input via the optic nerve and aligning internal rhythms with environmental cues. Studies using both in vivo and in vitro methodologies have reported the relationship between the molecular clock and sex hormones. The circadian system is directly responsible for controlling the synthesis of sex hormones and this synthesis varies according to the time of day and phase of the estrous cycle. Sex hormones also directly interact with the circadian system to regulate circadian gene expression, adjust biological processes, and even adjust their own synthesis. Several diseases have been linked with alterations in either the sex hormone background or the molecular clock. So, in this chapter we aim to summarize the current understanding of the relationship between the circadian system and sex hormones and their combined role in the onset of several related diseases.

Data-Efficient Inference of Nonlinear Oscillator Networks

Decoding the connectivity structure of a network of nonlinear oscillators from measurement data is a difficult yet essential task for understanding and controlling network functionality. Several data-driven network inference algorithms have been presented, but the commonly considered premise of ample measurement data is often difficult to satisfy in practice. In this paper, we propose a data-efficient network inference technique by combining correlation statistics with the model-fitting procedure. The proposed approach can identify the network structure reliably in the case of limited measurement data. We compare the proposed method with existing techniques on a network of Stuart-Landau oscillators, oscillators describing circadian gene expression, and noisy experimental data obtained from Rössler Electronic Oscillator network.

The circadian E3 ligase FBXL21 regulates myoblast differentiation and sarcomere architecture via MYOZ1 ubiquitination and NFAT signaling.

Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3β, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from yeast 2-hybrid screening. We show that FBXL21 binding to MYOZ1 led to ubiquitination-mediated proteasomal degradation. GSK-3β co-expression and inhibition were found to accelerate and decelerate FBXL21-mediated MYOZ1 degradation, respectively. Previously, MYOZ1 has been shown to inhibit calcineurin/NFAT signaling important for muscle differentiation. In accordance, Fbxl21 KO and MyoZ1 KO in C2C12 cells impaired and enhanced myogenic differentiation respectively compared with control C2C12 cells, concomitant with distinct effects on NFAT nuclear localization and NFAT target gene expression. Importantly, in Psttm mice, both the levels and diurnal rhythm of NFAT2 nuclear localization were significantly diminished relative to wild-type mice, and circadian expression of NFAT target genes associated with muscle differentiation was also markedly dampened. Furthermore, Psttm mice exhibited significant disruption of sarcomere structure with a considerable excess of MYOZ1 accumulation in the Z-line. Taken together, our study illustrates a pivotal role of FBXL21 in sarcomere structure and muscle differentiation by regulating MYOZ1 degradation and NFAT2 signaling.

Berberine increases stromal production of Wnt molecules and activates Lgr5+ stem cells to promote epithelial restitution in experimental colitis

BackgroundInflammatory bowel diseases (IBDs) are characterized by sustained inflammation and/or ulcers along the lower digestive tract, and have complications such as colorectal cancer and inflammation in other organs. The current treatments for IBDs, which affect 0.3% of the global population, mainly target immune cells and inflammatory cytokines with a success rate of less than 40%.ResultsHere we show that berberine, a natural plant product, is more effective than the frontline drug sulfasalazine in treating DSS (dextran sulfate sodium)-induced colitis in mice, and that berberine not only suppresses macrophage and granulocyte activation but also promotes epithelial restitution by activating Lgr5+ intestinal stem cells (ISCs). Mechanistically, berberine increases the expression of Wnt genes in resident mesenchymal stromal cells, an ISC niche, and inhibiting Wnt secretion diminishes the therapeutic effects of berberine. We further show that berberine controls the expression of many circadian rhythm genes in stromal cells, which in turn regulate the expression of Wnt molecules.ConclusionsOur findings suggest that berberine acts on the resident stromal cells and ISCs to promote epithelial repair in experimental colitis and that Wnt-β-Catenin signaling may be a potential target for colitis treatment.

The contraction-expansion behaviour in the demosponge Tethya wilhelma is light controlled and follows a diurnal rhythm.

Sponges (phylum Porifera) are metazoans which lack muscles and nerve cells, yet perform coordinated behaviours such as whole-body contractions. Previous studies indicate diurnal variability in both the number of contractions and the expression of circadian clock genes. Here, we show that diurnal patterns are present in the contraction-expansion behaviour of the demosponge Tethya wilhelma, by using infrared videography and a simulated night/day cycle including sunrise and sunset mimics. In addition, we show that this behaviour is at least strongly influenced by ambient light intensity and therefore indicates light-sensing capabilities in this sponge species. This is supported by our finding that T. wilhelma consistently contracts at sunrise, and that this pattern disappears both when the sponge is kept in constant darkness and when it is in constant light.

Changing winter climate and snow conditions induce various transcriptional stress responses in Scots pine seedlings.

In northern boreal forests the warming winter climate leads to more frequent snowmelt, rain-on-snow events and freeze-thaw cycles. This may be harmful or even lethal for tree seedlings that spend even a half of the year under snow. We conducted a snow cover manipulation experiment in a natural forest to find out how changing snow conditions affect young Scots pine (Pinus sylvestris L.) seedlings. The ice encasement (IE), absence of snow (NoSNOW) and snow compaction (COMP) treatments affected ground level temperature, ground frost and subnivean gas concentrations compared to the ambient snow cover (AMB) and led to the increased physical damage and mortality of seedlings. The expression responses of 28 genes related to circadian clock, aerobic and anaerobic energy metabolism, carbohydrate metabolism and stress protection revealed that seedlings were exposed to different stresses in a complex way depending on the thickness and quality of the snow cover. The IE treatment caused hypoxic stress and probably affected roots which resulted in reduced water uptake in the beginning of the growing season. Without protective snowpack in NoSNOW seedlings suffered from cold and drought stresses. The combination of hypoxic and cold stresses in COMP evoked unique transcriptional responses including oxidative stress. Snow cover manipulation induced changes in the expression of several circadian clock related genes suggested that photoreceptors and the circadian clock system play an essential role in the adaptation of Scots pine seedlings to stresses under different snow conditions. Our findings show that warming winter climate alters snow conditions and consequently causes Scots pine seedlings various abiotic stresses, whose effects extend from overwintering to the following growing season.

Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway.

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5'-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

Reduced branched-chain aminotransferase activity alleviates metabolic vulnerability caused by dim light exposure at night in Drosophila

The rhythmic pattern of biological processes controlled by light over 24 h is termed the circadian rhythm. Disturbance of circadian rhythm due to exposure to light at night (LAN) disrupts the sleep-wake cycle and can promote cardiovascular disease, diabetes, cancer, and metabolic disorders in humans. We studied how dim LAN affects the circadian rhythm and metabolism using male Drosophila. Wild-type flies exposed to the dim light of 10 lux at night displayed altered 24 h sleep-wake behavior and expression patterns of circadian rhythm genes. In addition, the flies became more vulnerable to metabolic stress, such as starvation. Whole-body metabolite analysis revealed decreased amounts of branched-chain amino acids (BCAAs), such as isoleucine and valine. The dim light exposure also increased the expression of branched-chain amino acid aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKDC) enzyme complexes that regulate the metabolism of BCAAs. Flies with the Bcat heterozygous mutation were not vulnerable to starvation stress, even when exposed to dim LAN, and hemolymph BCAA levels did not decrease in these flies. Furthermore, the vulnerability to starvation stress was also suppressed when the Bcat expression level was reduced in the whole body, neurons, or fat body during adulthood using conditional GAL4 and RNA interference. Finally, the metabolic vulnerability was reversed when BCAAs were fed to wild-type flies exposed to LAN. Thus, short-term dim light exposure at night affects the expression of circadian genes and BCAA metabolism in Drosophila, implying a novel function of BCAAs in suppressing metabolic stress caused by disrupted circadian rhythm.

Mucosal circadian rhythm pathway genes altered by aging and periodontitis.

Macaca mulatta were used with naturally-occurring and ligature-induced periodontitis. Gingival tissue samples were obtained from healthy, diseased, and resolved sites in four groups: young (≤3 years), adolescent (3-7 years), adult (12-26) and aged (18-23 years). Microarrays targeted circadian rhythm (n = 42), inflammation/tissue destruction (n = 11), bone biology (n = 8) and hypoxia pathway (n = 7) genes. The expression of many circadian rhythm genes, across functional components of the pathway, was decreased in healthy tissues from younger and aged animals, as well as showing significant decreases with periodontitis. Negative correlations of the circadian rhythm gene levels with inflammatory mediators and tissue destructive/remodeling genes were particularly accentuated in disease. A dominance of positive correlations with hypoxia genes was observed, except HIF1A, that was uniformly negatively correlated in health, disease and resolution. The chronic inflammation of periodontitis exhibits an alteration of the circadian rhythm pathway, predominantly via decreased gene expression. Thus, variation in disease expression and the underlying molecular mechanisms of disease may be altered due to changes in regulation of the circadian rhythm pathway functions.

Gene expression of circadian genes and CIART in bipolar disorder: A preliminary case-control study

Based on the observed circadian rhythms disruptions and sleep abnormalities in bipolar disorders (BD), a chronobiological model has been proposed suggesting that core clock genes play a central role in the vulnerability to the disorder. In this context, the analysis of circadian genes expression levels is particularly relevant, however studies focused on the whole set of core clock genes are scarce. We compared the levels of expression of 19 circadian genes (including the recently described circadian repressor (CIART)) in 37 euthymic individuals with BD and 20 healthy controls (HC), using data obtained by RNA sequencing of lymphoblastoid cell lines and validated the results using RT-qPCR. RNA sequencing data showed that CIART gene expression was correlated with those of ARNTL, ARNTL2, DBP, PER2 and TIMELESS. Data from RNA sequencing showed that the level of expression of four circadian genes (ARNTL, ARNTL2, BHLHE41 and CIART) discriminated individuals with BD from HC. We replicated this result using RT-qPCR for ARNTL and CIART. This study suggests that an imbalance between activation/repression of the transcription within the circadian system in individuals with BD as compared to HC and as such opens avenues for further research in larger independent samples combining both expression and epigenetic analyses.

BMAL1/FOXA2-induced rhythmic fluctuations in IL-6 contribute to nocturnal asthma attacks.

Inflammatory cytokine levels were measured in asthma patients with and without nocturnal symptoms. Allergic airway disease was induced in mice by ovalbumin (OVA), and different periods of light/dark cycles were used to induce circadian rhythm disorders. Serum shock was used to stimulate the rhythmic expression in human bronchial epidermal cells (16HBE). The expression and oscillation of circadian clock genes and inflammatory cytokines in 16HBE cells subjected to brain and muscle ARNT-like protein-1 (BMAL1) and Forkhead Box A2 (FOXA2) knockdown and treatment with a FOXA2 overexpression plasmid were assessed. Serum IL-6 was found to be significantly higher in asthmatic patients with nocturnal symptoms than those without nocturnal symptoms. The OVA-induced asthma model with a circadian rhythm disorder and 16HBE cells treated with serum shock showed an increase in IL-6 levels and a negative correlation with BMAL1 and FOXA2. The knockdown of BMAL1 resulted in a lower correlation between IL-6 and other rhythm clock genes. Furthermore, knockdown of the BMAL1 and FOXA2 in 16HBE cells reduced the expression and rhythmic fluctuations of IL-6. Our findings suggest that there are increased IL-6 levels in nocturnal asthma resulting from inhibition of the BMAL1/FOXA2 signalling pathway in airway epithelial cells.

Circadian gene Rev-erbα influenced by sleep conduces to pregnancy by promoting endometrial decidualization via IL-6-PR-C/EBPβ axis

BackgroundSleep disturbance can cause adverse pregnancy outcomes by changing circadian gene expression. The potential mechanisms remain unclear. Decidualization is critical for the establishment and maintenance of normal pregnancy, which can be regulated by circadian genes. Whether Rev-erbα, a critical circadian gene, affects early pregnancy outcome by regulating decidualization needs to be explored.MethodsQPCR, western blot and artificial decidualization mouse model were used to confirm the effect of sleep disturbance on Rev-erbα expression and decidualization. The regulatory mechanism of Rev-erbα on decidualization was assessed using QPCR, western blot, RNA-Seq, and Chip-PCR. Finally, sleep disturbance mouse model was used to investigate the effect of therapeutic methods targeting Rev-erbα and interleukin 6 (IL-6) on improving adverse pregnancy outcomes induced by sleep disturbance.ResultsDysregulation of circadian rhythm due to sleep disturbance displayed abnormal expression profile of circadian genes in uterine including decreased level of Rev-erbα, accompanied by defective decidualization. Rev-erbα could regulate decidualization by directly repressing IL-6, which reduced the expression of CCAAT/enhancer-binding protein β (C/EBPβ) and its target insulin-like growth factor binding protein 1 (IGFBP1), the marker of decidualization, by inhibiting progesterone receptors (PR) expression. Moreover, deficient decidualization, higher abortion rate and lower implantation number were exhibited in the mouse models with sleep disturbance compared with those in normal mouse. Pharmacological activation of Rev-erbα or neutralization of IL-6 alleviated the adverse effect of sleep disturbance on pregnancy outcomes.ConclusionsTaken together, Rev-erbα regulated decidualization via IL-6-PR-C/EBPβ axis and might be a connector between sleep and pregnancy outcome. Therapies targeting Rev-erbα and IL-6 might help improving adverse pregnancy outcomes induced by sleep disturbance.

Disrupting circadian control of peripheral myogenic reactivity mitigates cardiac injury following myocardial infarction.

Circadian rhythms orchestrate important functions in the cardiovascular system: the contribution of microvascular rhythms to cardiovascular disease progression/severity is unknown. This study hypothesized that (i) myogenic reactivity in skeletal muscle resistance arteries is rhythmic and (ii) disrupting this rhythmicity would alter cardiac injury post-myocardial infarction (MI). Cremaster skeletal muscle resistance arteries were isolated and assessed using standard pressure myography. Circadian rhythmicity was globally disrupted with the ClockΔ19/Δ19 mutation or discretely through smooth muscle cell-specific Bmal1 deletion (Sm-Bmal1 KO). Cardiac structure and function were determined by echocardiographic, hemodynamic and histological assessments. Myogenic reactivity in cremaster muscle resistance arteries is rhythmic. This rhythm is putatively mediated by the circadian modulation of a mechanosensitive signalosome incorporating tumour necrosis factor and casein kinase 1. Following left anterior descending coronary artery ligation, myogenic responsiveness is locked at the circadian maximum, although circadian molecular clock gene expression cycles normally. Disrupting the molecular clock abolishes myogenic rhythmicity: myogenic tone is suspended at the circadian minimum and is no longer augmented by MI. The reduced myogenic tone in ClockΔ19/Δ19 mice and Sm-Bmal1 KO mice associates with reduced total peripheral resistance (TPR), improved cardiac function and reduced infarct expansion post-MI. Augmented microvascular constriction aggravates cardiac injury post-MI. Following MI, skeletal muscle resistance artery myogenic reactivity increases specifically within the rest phase, when TPR would normally decline. Disrupting the circadian clock interrupts the MI-induced augmentation in myogenic reactivity: therapeutics targeting the molecular clock, therefore, may be useful for improving MI outcomes.

Association of circadian BMAL1 gene expression and its polymorphism and risk of breast cancer in females

ObjectiveBreast cancer as the principal reason for cancer mortality in females. Any abnormalities in the circadian might increase breast cancer progression. The aim was to examine the association between a genetic variant in the circadian gene BMAL1 and the chance of developing breast cancer, as well as the effect of gene expression of the circadian gene on breast cancer tissue. Patients and methodsThis study conducted on 100 subjects: 50 breast cancer cases and 50 age-matched healthy women. All subjects had a complete medical history, general clinical examination, mammography, and laboratory investigations, including serum CEA and serum CA15-3, and detection of circadian BMAL1 (rs2279287) genotypes and its MRNA expression by real-time PCR. ResultsSerum CA15.3 levels were greater in breast cancer cases than in controls. The frequency of T/C and T/T genotypes is considerably greater in breast cancer patients. BMAL1 expression was higher in breast cancer tissues with a TC/TT genetic variance. The expression of the circadian gene BMAL1 was found to be significantly related to tumor status, relapse status, and BMAL1 genotypes. BMAL1 genotypes were associated with pathological stage and grade. Women with the T/C genotype had a greater risk of ER-/PR-tumors than ER+/PR-tumors. ConclusionCircadian BMAL1 gene was more common TC/TT genotypes than CC genotypes. BMAL1 expression was lower in breast cancer tissues with a TC/TT genetic variance, so BMAL1 may have a role in the development of breast cancer.