Disruptions of Circadian Rhythms and Thrombolytic Therapy During Ischemic Stroke Intervention

Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.

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Rhythmic Clock Gene Expression in Atlantic Salmon Parr Brain

Frontiers in Physiology ◽

10.3389/fphys.2021.761109 ◽

2021 ◽

Vol 12 ◽

Author(s):

Charlotte M. Bolton ◽

Michaël Bekaert ◽

Mariann Eilertsen ◽

Jon Vidar Helvik ◽

Herve Migaud

Keyword(s):

Atlantic Salmon ◽

Clock Genes ◽

Expression Patterns ◽

Circadian Expression ◽

Clock Gene Expression ◽

Sister Clade ◽

Before And After ◽

Salmon Parr ◽

Species Specific ◽

Atlantic Salmon Parr

To better understand the complexity of clock genes in salmonids, a taxon with an additional whole genome duplication, an analysis was performed to identify and classify gene family members (clock, arntl, period, cryptochrome, nr1d, ror, and csnk1). The majority of clock genes, in zebrafish and Northern pike, appeared to be duplicated. In comparison to the 29 clock genes described in zebrafish, 48 clock genes were discovered in salmonid species. There was also evidence of species-specific reciprocal gene losses conserved to the Oncorhynchus sister clade. From the six period genes identified three were highly significantly rhythmic, and circadian in their expression patterns (per1a.1, per1a.2, per1b) and two was significantly rhythmically expressed (per2a, per2b). The transcriptomic study of juvenile Atlantic salmon (parr) brain tissues confirmed gene identification and revealed that there were 2,864 rhythmically expressed genes (p < 0.001), including 1,215 genes with a circadian expression pattern, of which 11 were clock genes. The majority of circadian expressed genes peaked 2 h before and after daylight. These findings provide a foundation for further research into the function of clock genes circadian rhythmicity and the role of an enriched number of clock genes relating to seasonal driven life history in salmonids.

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Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4613.4613 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4613-4613

Author(s):

Ming-Yu Yang ◽

Pai-Mei Lin ◽

Jui-Feng Hsu ◽

Wen-Chi Yang ◽

Yi-Chang Liu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Circadian Rhythms ◽

Circadian Clock ◽

Myeloid Leukemia ◽

Clock Genes ◽

Expression Patterns ◽

Healthy Individuals ◽

Daily Pattern ◽

Genes Expression ◽

Circadian Clock Genes

Abstract Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Rev-erb-α: an integrator of circadian rhythms and metabolism

Journal of Applied Physiology ◽

10.1152/japplphysiol.00570.2009 ◽

2009 ◽

Vol 107 (6) ◽

pp. 1972-1980 ◽

Cited By ~ 83

Author(s):

Hélène Duez ◽

Bart Staels

Keyword(s):

Circadian Rhythms ◽

Regulatory Networks ◽

Animal Studies ◽

Clock Genes ◽

Metabolic Response ◽

Large Body ◽

Internal Clock ◽

Glucose And Lipid Metabolism ◽

Physiological Processes ◽

Clock Component

The endogenous circadian clock ensures daily rhythms in diverse behavioral and physiological processes, including locomotor activity and sleep/wake cycles, but also food intake patterns. Circadian rhythms are generated by an internal clock system, which synchronizes these daily variations to the day/night alternance. In addition, circadian oscillations may be reset by the time of food availability in peripheral metabolic organs. Circadian rhythms are seen in many metabolic pathways (glucose and lipid metabolism, etc.) and endocrine secretions (insulin, etc.). As a consequence, misalignment of the internal timing system vs. environmental zeitgebers (light, for instance), as experienced during jetlag or shift work, may result in disruption of physiological cycles of fuel utilization or energy storage. A large body of evidence from both human and animal studies now points to a relationship between circadian disorders and altered metabolic response, suggesting that circadian and metabolic regulatory networks are tightly connected. After a review of the current understanding of the molecular circadian core clock, we will discuss the hypothesis that clock genes themselves link the core molecular clock and metabolic regulatory networks. We propose that the nuclear receptor and core clock component Rev-erb-α behaves as a gatekeeper to timely coordinate the circadian metabolic response.

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Circadian Clock Genes and Photoperiodism: Comprehensive Analysis of Clock Gene Expression in the Mediobasal Hypothalamus, the Suprachiasmatic Nucleus, and the Pineal Gland of Japanese Quail under Various Light Schedules

Endocrinology ◽

10.1210/en.2003-0435 ◽

2003 ◽

Vol 144 (9) ◽

pp. 3742-3748 ◽

Cited By ~ 129

Author(s):

Shinobu Yasuo ◽

Miwa Watanabe ◽

Naritoshi Okabayashi ◽

Shizufumi Ebihara ◽

Takashi Yoshimura

Keyword(s):

Pineal Gland ◽

Circadian Clock ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Expression Patterns ◽

Hypothalamic Nucleus ◽

Mediobasal Hypothalamus ◽

Clock Gene Expression ◽

Circadian Clock Genes ◽

Important Center

Abstract In birds, the mediobasal hypothalamus (MBH) including the infundibular nucleus, inferior hypothalamic nucleus, and median eminence is considered to be an important center that controls the photoperiodic time measurement. Here we show expression patterns of circadian clock genes in the MBH, putative suprachiasmatic nucleus (SCN), and pineal gland, which constitute the circadian pacemaker under various light schedules. Although expression patterns of clock genes were different between long and short photoperiod in the SCN and pineal gland, the results were not consistent with those under night interruption schedule, which causes testicular growth. These results indicate that different expression patterns of the circadian clock genes in the SCN and pineal gland are not an absolute requirement for encoding and decoding of seasonal information. In contrast, expression patterns of clock genes in the MBH were stable under various light conditions, which enables animals to keep a steady-state photoinducible phase.

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Comparison of expression patterns of six canonical clock genes of follicular phase and luteal phase in Small-tailed Han sheep

Archives Animal Breeding ◽

10.5194/aab-64-457-2021 ◽

2021 ◽

Vol 64 (2) ◽

pp. 457-466

Author(s):

Qi Han ◽

Xiaoyun He ◽

Ran Di ◽

Mingxing Chu

Keyword(s):

Gene Expression ◽

Estrous Cycle ◽

Luteal Phase ◽

Clock Gene ◽

Clock Genes ◽

Expression Patterns ◽

Mrna Levels ◽

Clock Gene Expression ◽

The Relationship ◽

The Brain

Abstract. The circadian rhythm is a biological rhythm that is closely related to the rhythmic expression of a series of clock genes. Results from several studies have indicated that clock genes are associated with the estrous cycle in female animals. Until now, the relationship between estrus cycle transition and clock gene expression in reproductive-axis-related tissues has remained unknown in Small-tailed Han (STH) sheep. This study was conducted to analyze the expression patterns of six canonical clock genes (Clock, BMAL1, Per1, Per2, Cry1, and Cry2) in the follicle phase and luteal phase of STH sheep. We found that all six genes were expressed in the brain, cerebellum, hypothalamus, pituitary, ovary, uterus, and oviduct in follicle and luteal phases. The results indicated that Clock expression was significantly higher in the cerebellum, hypothalamus, and uterus of the luteal phase than that of the follicle phase, whereas BMAL1 expression was significantly higher in the hypothalamus of the luteal phase than that of the follicle phase. Per1 expression was significantly higher in the brain, cerebellum, hypothalamus, and pituitary of the luteal phase than that of the follicle phase, and Per2 expression was significantly higher in the hypothalamus, pituitary, and uterus of the luteal phase than that of the follicle phase. Cry1 expression was significantly higher in the brain, cerebellum, and hypothalamus of the luteal phase than that of the follicle phase, whereas Cry2 expression was significantly higher in the pituitary of the luteal phase than that of the follicle phase. The clock gene expression in all tissues was different between follicle and luteal phases, but all clock gene mRNA levels were found to exhibit higher expression among seven tissues in the luteal phase. Our results suggest that estrous cycles may be associated with clock gene expression in the STH sheep. This is the first study to systematically analyze the expression patterns of clock genes of different estrous cycle in ewes, which could form a basis for further studies to develop the relationship between clock genes and the estrous cycle.

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Circadian Variation in Placental and Hepatic Clock Genes in Rat Pregnancy

Endocrinology ◽

10.1210/en.2011-0081 ◽

2011 ◽

Vol 152 (9) ◽

pp. 3552-3560 ◽

Cited By ~ 36

Author(s):

Michaela D. Wharfe ◽

Peter J. Mark ◽

Brendan J. Waddell

Keyword(s):

Clock Genes ◽

Fetal Liver ◽

Circadian Variation ◽

Time Of Day ◽

Peripheral Tissues ◽

Clock Gene Expression ◽

Physiological Processes ◽

Maternal Liver ◽

Physiological Adaptations ◽

Circadian Patterns

Clock genes drive circadian rhythms in a range of physiological processes both centrally and in peripheral tissues such as the liver. The aims of this study were to determine whether the two functionally-distinct zones of the rat placenta (junctional and labyrinth) differentially express clock genes and, if so, whether these exhibit circadian patterns. Rats were sampled from d 21 of pregnancy (term = d 23) and from diestrus I of the estrous cycle. Adult liver (all animals), fetal liver, and placental zones (pregnant animals) were collected at 0800, 1400, 2000, and 0200 h. Both zones of the rat placenta expressed all seven canonical clock genes (Clock, Bmal1, Per1, Per2, Per3, Cry1, and Cry2), but there were marked zonal differences and, unlike in maternal liver, circadian variation in placenta was limited. Similarly, placental expression of Vegf varied with zone but not time of day. Pregnancy also led to marked changes in hepatic clock gene expression, with peak levels of Per1, Cry1, and Cry2 all reduced, Per3 increased, and circadian variation in Clock expression lost. All clock genes were expressed in fetal liver, but there was less circadian variation than in maternal liver. Similarly, fetal corticosterone levels remained stable across the day, whereas maternal corticosterone showed clear circadian variation. In conclusion, our data show that the rat placenta expresses all canonical clock genes in a highly zone-specific manner but with relatively little circadian variation. Moreover, pregnancy alters the expression and circadian variation of clock genes in maternal liver, possibly contributing to maternal physiological adaptations.

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Maternal Obesity during Pregnancy Alters Daily Activity and Feeding Cycles, and Hypothalamic Clock Gene Expression in Adult Male Mouse Offspring

International Journal of Molecular Sciences ◽

10.3390/ijms20215408 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5408

Author(s):

Jane K. Cleal ◽

Kimberley D. Bruce ◽

Jasmin L. Shearer ◽

Hugh Thomas ◽

Jack Plume ◽

...

Keyword(s):

Gene Expression ◽

Food Intake ◽

Molecular Clock ◽

Daily Activity ◽

Maternal Obesity ◽

Clock Genes ◽

Expression Patterns ◽

Altered Expression ◽

Clock Gene Expression ◽

Feeding Rhythms

An obesogenic diet adversely affects the endogenous mammalian circadian clock, altering daily activity and metabolism, and resulting in obesity. We investigated whether an obese pregnancy can alter the molecular clock in the offspring hypothalamus, resulting in changes to their activity and feeding rhythms. Female mice were fed a control (C, 7% kcal fat) or high fat diet (HF, 45% kcal fat) before mating and throughout pregnancy. Male offspring were fed the C or HF diet postweaning, resulting in four offspring groups: C/C, C/HF, HF/C, and HF/HF. Daily activity and food intake were monitored, and at 15 weeks of age were killed at six time-points over 24 h. The clock genes Clock, Bmal1, Per2, and Cry2 in the suprachiasmatic nucleus (SCN) and appetite genes Npy and Pomc in the arcuate nucleus (ARC) were measured. Daily activity and feeding cycles in the HF/C, C/HF, and HF/HF offspring were altered, with increased feeding bouts and activity during the day and increased food intake but reduced activity at night. Gene expression patterns and levels of Clock, Bmal1, Per2, and Cry2 in the SCN and Npy and Pomc in the ARC were altered in HF diet-exposed offspring. The altered expression of hypothalamic molecular clock components and appetite genes, together with changes in activity and feeding rhythms, could be contributing to offspring obesity.

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Diversified regulation of circadian clock gene expression following whole genome duplication

10.1101/2020.03.22.002162 ◽

2020 ◽

Author(s):

Alexander C. West ◽

Marianne Iversen ◽

Even H. Jørgensen ◽

Simen R. Sandve ◽

David G. Hazlerigg ◽

...

Keyword(s):

Gene Expression ◽

Whole Genome Duplication ◽

Clock Gene ◽

Genome Duplication ◽

Clock Genes ◽

Expression Patterns ◽

Whole Genome ◽

Functional Diversification ◽

Clock Gene Expression ◽

Multiple Copies

AbstractAcross taxa, circadian control of physiology and behavior arises from cell-autonomous oscillations in gene expression, governed by a networks of so-called ‘clock genes’, collectively forming transcription-translation feedback loops. In modern vertebrates, these networks contain multiple copies of clock gene family members, which arose through whole genome duplication (WGD) events during evolutionary history. It remains unclear to what extent multiple copies of clock gene family members are functionally redundant or have allowed for functional diversification. We addressed this problem through an analysis of clock gene expression in the Atlantic salmon, a representative of the salmonids, a group which has undergone at least 4 rounds of WGD since the base of the vertebrate lineage, giving an unusually large complement of clock genes. By comparing expression patterns across multiple tissues, and during development, we present evidence for gene- and tissue-specific divergence in expression patterns, consistent with functional diversification of clock gene duplicates. In contrast to mammals, we found no evidence for coupling between cortisol and circadian gene expression, but cortisol mediated non-circadian regulated expression of a subset of clock genes in the salmon gill was evident. This regulation is linked to changes in gill function necessary for the transition from fresh- to sea-water in anadromous fish. Overall, this analysis emphasises the potential for a richly diversified clock gene network to serve a mixture of circadian and non-circadian functions in vertebrate groups with complex genomes.Author SummaryThe generation of daily (circadian) rhythms in behaviour and physiology depends on the activities of networks of so-called clock genes. In vertebrates, these have become highly complex due to a process known as whole genome duplication, which has occurred repeatedly during evolutionary history, giving rise to additional copies of key elements of the clock gene network. It remains unclear whether this results in functional redundancy, or whether it has permitted new roles for clock genes to emerge. Here, based on studies in the Atlantic salmon, a species with an unusually large complement of clock genes, we present evidence in favour of the latter scenario. We observe marked tissue-specific, and developmentally-dependent differences in the expression patterns of duplicated copies of key clock genes, and we identify a subset of clock genes whose expression is associated with the physiological preparation to migrate to sea, but is independent of circadian regulation. Associated with this, cortisol secretion is uncoupled from circadian organisation, contrasting with the situation in mammals. Our results indicate that whole genome duplication has permitted clock genes to diversify into non-circadian functions, and raise interesting questions about the ubiquity of mammal-like coupling between circadian and endocrine function.

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Inhibition of IRS-1 Alters Retinal Circadian Clock

Proceedings of IMPRS ◽

10.18060/22655 ◽

2018 ◽

Vol 1 (1) ◽

Cited By ~ 1

Author(s):

Maaz Arif ◽

Deepa Mathew ◽

Ashay Bhatwadekar

Keyword(s):

Gene Expression ◽

Diabetic Retinopathy ◽

Circadian Rhythms ◽

Circadian Clock ◽

Insulin Signaling ◽

Clock Genes ◽

Regulatory Gene ◽

Molecular Clocks ◽

Temporal Dimension ◽

Clock Gene Expression

Background and Hypothesis: Life on Earth has adapted to a 24-hour cycle of light and darkness. Circadian physiology coordinates temporal metabolism, hormone cycling, and sleep using clock genes. It is documented that dysregulation of clock gene expression is a key factor in the pathogenesis of diabetic retinopathy. Our goal was to explore the relationship between clock genes and the retina in diabetic milieu, and we hypothesized that disrupting downstream insulin signaling in a manner similar to diabetes in the retina would also affect the circadian clock. Experimental Design or Project Methods: In this mouse study, we used a Per2::Luc fusion protein to perform real-time bioluminescent recording of circadian rhythms. We used SecinH3 to inhibit Insulin Receptor Signaling (IRS-1). In isolated retinas, we modulated IRS-1 to mimic the diabetic condition of impaired insulin signaling; this allowed us to directly quantify circadian rhythms in the retina. Results: Our results show that IRS-1 inhibition by SecinH3 altered the gene expression of Per2, a clock regulatory gene, over the controls. There was an increase in the period and an apparent phase shift in the presence of 100uM SecinH3. Conclusion and Potential Impact: Our findings can help us understand the role of insulin signaling on circadian rhythms of the retina and provide another temporal dimension to view diabetic retinopathy disease progression. Ultimately, further studies and a closer understanding of the roles of molecular clocks and insulin signaling may help to develop novel therapeutics for treating some of the harmful effects of diabetes.

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NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1

PLoS Genetics ◽

10.1371/journal.pgen.1009933 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1009933

Author(s):

Yang Shen ◽

Mehari Endale ◽

Wei Wang ◽

Andrew R. Morris ◽

Lauren J. Francey ◽

...

Keyword(s):

Circadian Clock ◽

Clock Genes ◽

Period Length ◽

Transactivation Domain ◽

Cis Element ◽

Clock Gene Expression ◽

Physiological Processes ◽

Data Support ◽

Mutual Regulation ◽

E Boxes

In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways.

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