scholarly journals Chronic Corticosterone Disrupts The Circadian Rhythm of CRH Expression and m6A RNA Methylation In The Chicken Hypothalamus

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 Background: 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. Results: 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). Conclusions: 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.

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

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.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

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.

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

Hypertension ◽  
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.

scholarly journals New Insights Into Cancer Chronotherapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingxuan Zhou ◽  
Jiechen Wang ◽  
Xiaozhao Zhang ◽  
Qingming Tang
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Clock Genes ◽  
Biological Activities ◽  
Circadian Clocks ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Circadian Clock Genes ◽  
Specific Association ◽  
Mild Toxicity

Circadian clocks participate in the coordination of various metabolic and biological activities to maintain homeostasis. Disturbances in the circadian rhythm and cancers are closely related. Circadian clock genes are differentially expressed in many tumors, and accelerate the development and progression of tumors. In addition, tumor tissues exert varying biological activities compared to normal tissues due to resetting of altered rhythms. Thus, chronotherapeutics used for cancer treatment should exploit the timing of circadian rhythms to achieve higher efficacy and mild toxicity. Due to interpatient differences in circadian functions, our findings advocate an individualized precision approach to chronotherapy. Herein, we review the specific association between circadian clocks and cancers. In addition, we focus on chronotherapies in cancers and personalized biomarkers for the development of precision chronotherapy. The understanding of circadian clocks in cancer will provide a rationale for more effective clinical treatment of tumors.

scholarly journals BMAL1 but not CLOCK is associated with monochromatic green light-induced circadian rhythm of melatonin in chick pinealocytes

2019 ◽  
Vol 8 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Shuhui Ma ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Pineal Gland ◽  
Clock Genes ◽  
Critical Role ◽  
Green Light ◽  
Circadian Oscillator ◽  
Melatonin Secretion ◽  
Expression Levels

The avian pineal gland, an independent circadian oscillator, receives external photic cues and translates them for the rhythmical synthesis of melatonin. Our previous study found that monochromatic green light could increase the secretion of melatonin and expression of CLOCK and BMAL1 in chick pinealocytes. This study further investigated the role of BMAL1 and CLOCK in monochromatic green light-induced melatonin secretion in chick pinealocytes using siRNAs interference and overexpression techniques. The results showed that si-BMAL1 destroyed the circadian rhythms of AANAT and melatonin, along with the disruption of the expression of all the seven clock genes, except CRY1. Furthermore, overexpression of BMAL1 also disturbed the circadian rhythms of AANAT and melatonin, in addition to causing arrhythmic expression of BMAL1 and CRY1/2, but had no effect on the circadian rhythms of CLOCK, BMAL2 and PER2/3. The knockdown or overexpression of CLOCK had no impact on the circadian rhythms of AANAT, melatonin, BMAL1 and PER2, but it significantly deregulated the circadian rhythms of CLOCK, BMAL2, CRY1/2 and PER3. These results suggested that BMAL1 rather than CLOCK plays a critical role in the regulation of monochromatic green light-induced melatonin rhythm synthesis in chicken pinealocytes. Moreover, both knockdown and overexpression of BMAL1 could change the expression levels of CRY2, it indicated CRY2 may be involved in the BMAL1 pathway by modulating the circadian rhythms of AANAT and melatonin.

scholarly journals Circadian rhythms affect bone reconstruction by regulating bone energy metabolism

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Beibei Luo ◽  
Xin Zhou ◽  
Qingming Tang ◽  
Ying Yin ◽  
Guangxia Feng ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Energy Metabolism ◽  
Circadian Rhythms ◽  
Clock Genes ◽  
Therapeutic Potential ◽  
Bone Development ◽  
Feeding Time ◽  
Bone Reconstruction ◽  
Immune Functions ◽  
Tissue Specific

AbstractMetabolism 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.

scholarly journals Melatonin, Clock Genes, and Mammalian Reproduction: What Is the Link?

2021 ◽  
Vol 22 (24) ◽  
pp. 13240
Author(s):  
Amnon Brzezinski ◽  
Seema Rai ◽  
Adyasha Purohit ◽  
Seithikurippu R. Pandi-Perumal
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Molecular Clock ◽  
Reproductive Performance ◽  
Clock Genes ◽  
Current Knowledge ◽  
Reproductive Function ◽  
The Body ◽  
Molecular Clocks ◽  
Biological Regulation

Physiological processes and behaviors in many mammals are rhythmic. Recently there has been increasing interest in the role of circadian rhythmicity in the control of reproductive function. The circadian rhythm of the pineal hormone melatonin plays a role in synchronizing the reproductive responses of animals to environmental light conditions. There is some evidence that melatonin may have a role in the biological regulation of circadian rhythms and reproduction in humans. Moreover, circadian rhythms and clock genes appear to be involved in optimal reproductive performance. These rhythms are controlled by an endogenous molecular clock within the suprachiasmatic nucleus (SCN) in the hypothalamus, which is entrained by the light/dark cycle. The SCN synchronizes multiple subsidiary oscillators (clock genes) existing in various tissues throughout the body. The basis for maintaining the circadian rhythm is a molecular clock consisting of transcriptional/translational feedback loops. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance. This mini review summarizes the current knowledge regarding the interrelationships between melatonin and the endogenous molecular clocks and their involvement in reproductive physiology (e.g., ovulation) and pathophysiology (e.g., polycystic ovarian syndrome).

scholarly journals Simulated Space Environmental Factors of Weightlessness, Noise and Low Air Pressure Differentially Affect the Circadian Rhythm and Gut Microbiome

2021 ◽  
Author(s):  
Huan Ma ◽  
Xihui Gan ◽  
Jianwei Zhao ◽  
Yin Zhang ◽  
Silin Li ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Community Structure ◽  
Circadian Rhythms ◽  
Environmental Factors ◽  
Circadian Clock ◽  
Gut Microbiome ◽  
Atmospheric Pressure ◽  
Clock Genes ◽  
Low Atmospheric Pressure ◽  
Space Capsule

Abstract Backgroundhe circadian clock extensively regulates physiology and behavior. In space, the astronauts encounter many environmental factors that are dramatically different from those on earth, however, the effects of these factors on circadian rhythms and the mechanisms remain largely unknown. The present study aimed to investigate the changes in the mouse circadian rhythm and gut microbiome under simulated space capsule conditions, including microgravity, noise and low atmospheric pressure.ResultsNoise and low atmospheric pressure were loaded in the capsule while the conditions in the animal room remained constant. The mice in the capsule showed disturbed locomotor rhythms and faster adaptation to a 6-h phase advance. RNA sequencing of hypothalamus samples revealed that microgravity simulated by hind limb unloading (HU) and exposure to noise and low atmospheric pressure led to decreases in the quantities of differentially expressed genes (DEGs), including circadian clock genes. Changes in the rhythmicity of genes implicated in pathways of cardiovascular deconditioning and more concentrated circadian phases were found under HU or noise and low atmospheric pressure. Furthermore, 16S rRNA sequencing revealed dysbiosis in the gut microbiome, and noise and low atmospheric pressure may repress the temporal discrepancy in the microbiome community structure induced by microgravity. Changes in diel oscillation were observed in a number of gut bacteria with critical physiological consequences in metabolism and immunodefense.ConclusionsOur data demonstrate that in addition to microgravity, exposure to noise and low atmospheric pressure affect the robustness of circadian rhythms and the community structure of the gut microbiome, and these factors may interfere with each other in their adaptation to respective conditions. These findings are important to further our understanding of the alteration of circadian rhythms in the space complex environment.

scholarly journals Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population

GeroScience ◽  
2021 ◽  
Author(s):  
Maria Giulia Bacalini ◽  
Flavia Palombo ◽  
Paolo Garagnani ◽  
Cristina Giuliani ◽  
Claudio Fiorini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Successful Aging ◽  
Clock Genes ◽  
Association Studies ◽  
Italian Population ◽  
Age Related

AbstractMany physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

Circadian Rhythms of Whole Bone Marrow and Lineage Negative Stem Cells of the Mouse.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4188-4188
Author(s):  
Galatia Politopoulou ◽  
Mark S. Dooner ◽  
Gerald A. Colvin ◽  
Deborah Greer ◽  
Delia Demers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Stem Cell Factor ◽  
Clock Genes ◽  
Circadian Variation

Abstract Circadian rhythms underlie most biological processes. In mammals circadian control of physiology and behavior is mediated via a central master oscillator, in the supra-schismatic nuclei of the hypothalamus. At the cellular level this oscillator is composed of an auto-regulatory transcription-translation loop of clock genes. The Period2 (Per2) gene is one of the clock genes which plays a key role in controlling the circadian rhythm in mammals. Mice with mutations in Per2 become arrhythmic. Expression of clock genes is also present in many peripheral tissues, including the bone marrow. Stem cell engraftment has been shown to vary with cell cycle transit (Habibian et al, 1998). A diurnal circadian variation in the ability of bone marrow to engraft sub-lethally irradiated mice has been previously shown by our laboratory. An increase in numbers of progenitors in S-phase underlined the engraftment nadirs. The host’s ability to accept incoming cells did not show circadian variation. To further study the interplay of circadian rhythm with cell cycle in bone marrow and populations of engraftable stem cells, we utilized a transgenic mouse model for the Per2 gene. The mouse Period2 (mPer2) real time gene expression reporter of circadian dynamics, constructed by Takahashi et al., was employed for these studies. In this reporter a Luciferin (Luc) gene was fused in frame to the 3′ of the promoter of the endogenous mPer2 gene. This system allows for detection of Per2 gene expression in the presence of luciferase, by recording light given off, during the luciferase catalyzed conversion of Luciferin to Oxyluciferin. We have detected circadian rhythm in whole bone marrow and Lineage negative cells i.e. whole bone marrow mononuclear cells depleted of B220, Ter119, GR1, CD4, CD8 and CD11b, with one peak every 24 hours for up to 14 days, from as few as 500,000 cells. Dissociated lung cells also show a circadian rhythm as do Lineage Negative Sca+ marrow stem cells. The later show an intermittent rhythm, for up to 10 days. The best rhythms were obtained from cells grown on a 12mm dish bathed in 4 mls of media or a 1 ml drop of media, the later covered with mineral oil. The media was DMEM with L Glutamine, low glucose no phenol red, 1% Penicillin, 10,000 U/ml/streptomycin, 4.18mM NaHCO3, 10mM Hepes, 0.019mM D-glucose pH 7.2 supplemented with 1×B27, 5–15% HIFCS and either stem cell factor alone (50ng/ml) or IL3, IL6, IL11 and stem cell factor (steel) (50 ng or units/ml). Feeding of the cells after 7 days increased the amplitude of the rhythm. Absence of cytokines dampened the rhythm, especially for Lineage Negative Sca+ cells. Steel in the presence of HIFCS induces some rhythm, but is not as effective as a cocktail of IL3, IL6, IL11 and steel, together with HIFCS. Given work from our laboratory on synchronized progenitor cells entering and progressing through cell cycle in cytokine cocktails, including IL3, IL6, IL11 and steel, and the correlation of engraftment potential with cell cycle phase and adhesion molecule phenotype, the appearance of the best circadian rhythm in proliferating cytokine cocktails, in this system, is intriguing. The cell cycle kinetics of the marrow cells exhibiting circadian rhythmicity, are being explored further, in this culture system. The links between expression of cell cycle control molecules and adhesion molecules in Lineage Negative Sca+ cells and circadian rhythms for engraftment are also under investigation.

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