Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: A DREAM trial ancillary study

The small GTPase RhoA, and its down-stream effector ROCK kinase, and the interacting Rac1 and mTORC2 pathways, are the principal regulators of the actin cytoskeleton and actin-related functions in all eukaryotic cells, including the immune cells. As such, they also regulate the phenotypes and functions of macrophages in the immune response and beyond. Here, we review the results of our and other’s studies on the role of the actin and RhoA pathway in shaping the macrophage functions in general and macrophage immune response during the development of chronic (long term) rejection of allografts in the rodent cardiac transplantation model. We focus on the importance of timing of the macrophage functions in chronic rejection and how the circadian rhythm may affect the anti-chronic rejection therapies.

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Sex Differences in Circadian Clock Genes and Myocardial Infarction Susceptibility

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8050053 ◽

2021 ◽

Vol 8 (5) ◽

pp. 53

Author(s):

Ivana Škrlec ◽

Jasminka Talapko ◽

Martina Juzbašić ◽

Robert Steiner

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Disease ◽

Circadian Rhythm ◽

Single Nucleotide Polymorphisms ◽

Clock Genes ◽

P Value ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Biological Sex ◽

Significant Difference

The growing body of evidence shows a significant difference in the circadian rhythm of cardiovascular disease based on biological sex. The incidence of cardiovascular disease varies between women and men. Additionally, biological sex is vital for the timely application of therapy—chronotherapy, which benefits both sexes. This study aimed to examine the potential difference of single nucleotide polymorphisms (SNPs) of the circadian rhythm genes ARNTL, CLOCK, CRY2 and PER2 in women and men with myocardial infarction. A cross-sectional study was conducted, including 200 patients with myocardial infarction. Altogether, ten single nucleotide polymorphisms in the ARNTL, CLOCK, CRY2 and PER2 genes were analyzed. The Chi-square test yielded statistically significant differences in CLOCK gene rs11932595 polymorphism in a recessive genotype model between women and men with a p-value of 0.03 and an odds ratio 2.66, and a corresponding 95% confidence interval of 1.07 to 6.66. Other analyzed polymorphisms of the circadian rhythm genes ARNTL, CRY2, and PER2 did not significantly differ between the sexes. According to the study’s current results, the CLOCK gene’s genetic variability might affect myocardial infarction concerning biological sex.

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Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

International Journal of Molecular Sciences ◽

10.3390/ijms22020676 ◽

2021 ◽

Vol 22 (2) ◽

pp. 676

Author(s):

Andy W. C. Man ◽

Huige Li ◽

Ning Xia

Keyword(s):

Circadian Rhythm ◽

Cardiovascular Diseases ◽

Circadian Rhythms ◽

Circadian Clock ◽

Therapeutic Target ◽

Environmental Changes ◽

Clock Genes ◽

Vascular System ◽

Peripheral Tissues ◽

Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

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Chronic Corticosterone Disrupts the Circadian Rhythm of CRH Expression and M6a RNA Methylation in the Chicken Hypothalamus

10.21203/rs.3.rs-919584/v1 ◽

2021 ◽

Author(s):

Yang Yang ◽

Wanwan Han ◽

Aijia Zhang ◽

Mindie Zhao ◽

Wei Cong ◽

...

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Chronic Stress ◽

Hpa Axis ◽

Clock Genes ◽

Diurnal Fluctuation ◽

Opposite Pattern ◽

Rna Methylation ◽

Diurnal Patterns ◽

M6a Rna Methylation

Abstract Corticotropin-releasing hormone (CRH), the major secretagogue of the hypothalamic-pituitary-adrenal (HPA) axis, is intricately intertwined with the clock genes to regulate the circadian rhythm of various body functions. N6-methyladenosine (m6A) RNA methylation is involved in the regulation of circadian rhythm, yet it remains unknown whether CRH expression and m6A modification oscillate with the clock genes in chicken hypothalamus and how the circadian rhythms change under chronic stress. Here, we show that chronic exposure to corticosterone (CORT) eliminated the diurnal patterns of plasma CORT and melatonin levels in the chicken. The circadian rhythms of clock genes in hippocampus, hypothalamus and pituitary are all disturbed to different extent in CORT-treated chickens. The most striking changes occur in hypothalamus in which the diurnal fluctuation of CRH mRNA is flattened, together with mRNA of other feeding-related neuropeptides. Interestingly, hypothalamic m6A level oscillates in an opposite pattern to CRH mRNA, with lowest m6A level after midnight (ZT18) corresponding to the peak of CRH mRNA before dawn (ZT22). CORT diminished the circadian rhythm of m6A methylation with significantly increased level at night. Further site-specific m6A analysis on 3’UTR of CRH mRNA indicates that higher m6A on 3’UTR of CRH mRNA coincides with lower CRH mRNA at night (ZT18 and ZT22). Our results indicate that chronic stress disrupts the circadian rhythms of CRH expression in hypothalamus, leading to dysfunction of HPA axis in the chicken. RNA m6A modification is involved in the regulation of circadian rhythms in chicken hypothalamus under both basal and chronic stress conditions.

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MECHANISMS IN ENDOCRINOLOGY: A sense of time of the glucocorticoid circadian clock: from the ontogeny to the diagnosis of Cushing’s syndrome

Acta Endocrinologica ◽

10.1530/eje-18-0102 ◽

2018 ◽

Vol 179 (1) ◽

pp. R1-R18 ◽

Cited By ~ 6

Author(s):

Ayrton Custodio Moreira ◽

Sonir Rauber Antonini ◽

Margaret de Castro

Keyword(s):

Circadian Rhythm ◽

Circadian Clock ◽

Clock Genes ◽

Circadian Variation ◽

Circadian System ◽

Feedback Loops ◽

Adrenal Axis ◽

Sense Of Time ◽

Pituitary Adrenal Axis ◽

Hierarchical Manner

The circadian rhythm of glucocorticoids has long been recognised within the last 75 years. Since the beginning, researchers have sought to identify basic mechanisms underlying the origin and emergence of the corticosteroid circadian rhythmicity among mammals. Accordingly, Young, Hall and Rosbash, laureates of the 2017 Nobel Prize in Physiology or Medicine, as well as Takahashi’s group among others, have characterised the molecular cogwheels of the circadian system, describing interlocking transcription/translation feedback loops essential for normal circadian rhythms. Plasma glucocorticoid circadian variation depends on the expression of intrinsic clock genes within the anatomic components of the hypothalamic–pituitary–adrenal axis, which are organised in a hierarchical manner. This review presents a general overview of the glucocorticoid circadian clock mechanisms, highlighting the ontogeny of the pituitary–adrenal axis diurnal rhythmicity as well as the involvement of circadian rhythm abnormalities in the physiopathology and diagnosis of Cushing’s disease.

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Abstract P160: Non-invasive Method to Assess Human Circadian Rhythms

Hypertension ◽

10.1161/hyp.68.suppl_1.p160 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Daian Chen ◽

S Justin Thomas ◽

David A Calhoun ◽

David M Pollock ◽

Jennifer S Pollock

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Salivary Cortisol ◽

Metabolic Diseases ◽

Clock Genes ◽

Light Exposure ◽

Rna Isolation ◽

Buccal Cells ◽

Non Invasive ◽

Salivary Melatonin

Circadian rhythms are controlled by an endogenous time-keeping system oscillating approximately on a 24-h cycle under constant conditions. These rhythms depend on a network of interacting genes and proteins, including transcriptional activators such as CLOCK, NPAS2, and ARNTL (BMAL1), which induce transcription of the clock genes Period ( Per1 , Per2 , and Per3 ) and Cryptochrome ( Cry1 and Cry2 ). Human salivary cortisol and melatonin follow a clear circadian rhythm as well. Disruption of the circadian rhythm and sleep-wake cycles are considered risk factors for a variety of health problems, especially hypertension and other cardiovascular and metabolic diseases. Here we put together practical methods for assessing circadian rhythms in adult subjects conducted by each individual. This method is non-invasive, inexpensive and provides a predictive profile of an individual’s circadian rhythm related to clock-controlled gene expression in buccal cells, salivary cortisol, salivary melatonin, and subject’s activity or sleep. Subjects are instructed on how to obtain buccal cells using swabs (Whatman OmniSwab) from the inside of their cheeks and collect saliva using salivettes (Sarstedt) every 4 hours starting at 6am, for 2 consecutive days. Subjects also wear actigraphy watches (Phillips Respironics) during the 2 days, to record their activity, light exposure and estimates of sleep times. To monitor adherence to correct time point collections, each subject is given an electronic vial called eCAP (Information Mediary Corp) that records the exact time the container is opened to place samples once collected. We demonstrate feasibility to extract up to 150ng/μl of RNA (Ambion RNAqueous-Micro Total RNA Isolation Kit) from buccal cells swabs. Salivary melatonin and cortisol are measured by radioimmunoassay (Buhlmann Lab) with melatonin peak levels ranging from 14 to 23 pg/ml and cortisol peak levels ranging from 10 to 24 ng/ml. We suggest that buccal cell expression of clock-controlled genes, salivary melatonin, salivary cortisol, and actigraphy data are valuable in providing reliable assessment of human circadian rhythm profiles under a variety of conditions.

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P–372 Maternal circadian disruption is associated with impaired rhythmic expression of molecular clock genes and IUGR during placenta development in mice

Human Reproduction ◽

10.1093/humrep/deab130.371 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

N I Bektas ◽

G Akcay ◽

N Derin ◽

D Adiguzel ◽

C Celik-Ozenci

Keyword(s):

Circadian Rhythm ◽

Locomotor Activity ◽

Molecular Clock ◽

Clock Genes ◽

Weight Ratio ◽

Circadian Disruption ◽

Control Group ◽

Shift Workers ◽

Rhythmic Expression ◽

Registration Number

Abstract Study question Are molecular clock genes (MCGs) expressed rhythmically in mouse placenta, and whether maternal circadian rhythm disruption (MCRD) is associated with intrauterine growth retardation (IUGR) through disturbing rhythmic expression of MCGs? Summary answer Maternal circadian disruption causes impaired rhythmic expression of MCGs (Bmal1, Clock, Npas2, Per1, Per2, Per3, Cry1, and Cry2) and IUGR during placenta development in mice. What is known already The world economy is based on a 24/7 society and shift work or jet travel across time zones disrupts circadian rhythm in pregnant women. Evidence indicates that gestational chrono-disruption results in IUGR. Mature mouse and human placenta express MCGs. There is no information in the literature on whether the MCG expression in the placenta is rhythmic or not and whether the rhythmic expression of MCGs is impaired due to MCRD during pregnancy. Also, it is not known whether the association with MCRD and IUGR is related to MCGs. Study design, size, duration Young adult female BALB/c mice were paired with males until vaginal plug formation was verified. Females were randomly assigned to two groups: control and phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-advanced mice were subjected to 6-hr advances in the LD cycle every 5 days. Placentae (n = 1329) and fetuses were obtained from 144 mice at Zeitgeber time (ZT)0, ZT6, ZT12, and ZT18 days 12, 14, and 16 of pregnancy. Participants/materials, setting, methods The following analysis was performed: (i) open field test was used for locomotor activity evaluations to confirm MCRD, (ii) placenta/fetus weight ratio for evaluation of IUGR development, (iii) morphometric evaluation of placental compartments utilizing H&E staining (iv) gene expression analysis of MCGs utilizing qRT-PCR. One-way and Two-way ANOVA test followed by Holm-Sidak posthoc test was used for multiple comparisons. Values are expressed as mean ± standard error, and values below p < 0.05 were considered statistically significant. Main results and the role of chance Expression of MCGs (Bmal1, Clock, Npas2, Per1, Per2, Per3, Cry1, and Cry2) was rhythmic in the early and mature placenta development stages (days 12, 14, 16). Locomotor activity tests reveal that the total distance covered on the 16th day of pregnancy significantly decreased compared to the control group (p = 0.000158). The ratio of the time spent in the outer/inner quadrant, an anxiety indicator, significantly increased in the MCRD group on the 14th (p = 0.0351) and 16th days of pregnancy (p = 0.000329). While the number of fetuses was similar in both groups for all gestational days (p = 0.896), in the MCRD group, the fetus/placenta weight ratio decreased significantly on the 12th and 16th days of pregnancy (p < 0.001). Thus, IUGR developed due to MCRD. Histomorphometry analysis of the placental compartments revealed a significant reduction in the spongiotrophoblast layer’s size on all days of pregnancy and the labyrinth layer on day 16 (p < 0.05). Finally, the rhythmic expression MCGs were impaired in placentas obtained from MCRD groups on days 12th, 14th, 6th of pregnancy (p < 0.001). In conclusion, we found a robust relationship with the disturbed MCGs expression and occurrence of IUGR during a chrono-disrupted gestation. Limitations, reasons for caution Since this study was conducted in mice, care should be taken when translating the results to humans. Wider implications of the findings: Our results in mice are important for initiating basic science knowledge regarding the outcomes of maternal chrono-disruption. Moreover, research in the placenta of gestational chrono-disrupted mothers, such as shift-workers, are urgently needed to translate our findings into the clinic. Trial registration number TUBITAK–119S121 and Akdeniz University Research Projects Unit TYL–2018–3960

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“Gut Microbiota-Circadian Clock Axis” in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism

International Journal of Endocrinology ◽

10.1155/2019/5893028 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Liyuan Zhou ◽

Lin Kang ◽

Xinhua Xiao ◽

Lijing Jia ◽

Qian Zhang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Circadian Rhythm ◽

Gut Microbiota ◽

Circadian Clock ◽

Early Life ◽

Metabolic Diseases ◽

Clock Genes ◽

Early Stage ◽

Adult Life ◽

Metabolic Memory

The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the “metabolic memory” and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of “metabolic memory” has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the “gut microbiota-circadian clock axis” might be a novel and crucial mechanism to decipher “metabolic memory.” The “gut microbiota-circadian clock axis” is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.

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