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Search results for: bMAL1

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#33652118   2021/02/27 To Up

Circadian Clock Disruption Suppresses PDL1+ Intraepithelial B-cells in Experimental Colitis and Colitis Associated Colorectal Cancer.

Circadian clock is crucial for physiological homeostasis including gut homeostasis. Disorder of circadian clock may contribute to many diseases including inflammatory bowel disease (IBD). However, the role and the mechanisms of circadian clock involved in IBD are still unclear.
Jing-Lin Liu, Chu-Yi Wang, Tian-Yu Cheng, Youlutuziayi Rixiati, Cheng Ji, Min Deng, Su Yao, Li-Hua Yuan, Yuan-Yuan Zhao, Tong Shen, Jian-Ming Li

2324 related Products with: Circadian Clock Disruption Suppresses PDL1+ Intraepithelial B-cells in Experimental Colitis and Colitis Associated Colorectal Cancer.



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#33650487   2021/03/02 To Up

Loss of circadian protection against influenza infection in adult mice exposed to hyperoxia as neonates.

Adverse early-life exposures have a lasting negative impact on health. Neonatal hyperoxia that is a risk factor for bronchopulmonary dysplasia confers susceptibility to influenza A virus (IAV) infection later in life. Given our previous findings that the circadian clock protects against IAV, we asked if the long-term impact of neonatal hyperoxia vis-à-vis IAV infection includes circadian disruption. Here, we show that neonatal hyperoxia abolishes the clock-mediated time of day protection from IAV in mice, independent of viral burden through host tolerance pathways. We discovered that the lung intrinsic clock (and not the central or immune clocks) mediated this dysregulation. Loss of circadian protein, , in alveolar type 2 (AT2) cells recapitulates the increased mortality, loss of temporal gating, and other key features of hyperoxia-exposed animals. Our data suggest a novel role for the circadian clock in AT2 cells in mediating long-term effects of early-life exposures to the lungs.
Yasmine Issah, Amruta Naik, Soon Y Tang, Kaitlyn Forrest, Thomas G Brooks, Nicholas Lahens, Katherine N Theken, Mara Mermigos, Amita Sehgal, George S Worthen, Garret A FitzGerald, Shaon Sengupta

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#33649466   2021/03/01 To Up

Amelioration of circadian disruption and calcium-handling protein defects by choline alleviates cardiac remodeling in abdominal aorta coarctation rats.

The key pathophysiological process leading to heart failure is cardiac remodeling, a term referring to cardiac hypertrophy, fibrosis, and apoptosis. We explored circadian rhythm disruption and calcium dyshomeostasis in cardiac remodeling and investigated the cardioprotective effect of choline. The experiments were conducted using a model of cardiac remodeling by abdominal aorta coarctation (AAC) in Sprague-Dawley rats. In vitro cardiomyocyte remodeling was induced by exposing neonatal rat cardiomyocytes to angiotensin II. The circadian rhythms of the transcript levels of the seven major components of the mammalian clock (Bmal1, Clock, Rev-erbα, Per1/2, and Cry1/2) were altered in AAC rat hearts during a normal 24 h light/dark cycle. AAC also upregulated the levels of proteins that mediate store-operated Ca entry/receptor-operated Ca entry (stromal interaction molecule 1 [STIM1], Orai1, and transient receptor potential canonical 6 [TRPC6]) in rat hearts. Moreover, choline ameliorated circadian rhythm disruption, reduced the upregulated protein levels of STIM1, Orai1, and TRPC6, and alleviated cardiac dysfunction and remodeling (evidenced by attenuated cardiac hypertrophy, fibrosis, and apoptosis) in AAC rats. In vitro analyses showed that choline ameliorated calcium overload, downregulated STIM1, Orai1, and TRPC6, and inhibited thapsigargin-induced store-operated Ca entry and 1-oleoyl-2-acetyl-sn-glycerol-induced receptor-operated Ca entry in angiotensin II-treated cardiomyocytes. In conclusion, choline attenuated AAC-induced cardiac remodeling and cardiac dysfunction, which was related to amelioration of circadian rhythm disruption and attenuation of calcium-handling protein defects. Modulation of vagal activity by choline targeting the circadian rhythm and calcium homeostasis may have therapeutic potential for cardiac remodeling and heart failure.
Xi He, Si Yang, Juan Deng, Qing Wu, Wei-Jin Zang

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#33647263   2021/02/26 To Up

The role of clock genes in sleep, stress and memory.

Circadian clock genes serve as the molecular basis for animals' ∼24-h internal timekeeping. Clock gene expression inside and outside of the mammalian brain's circadian pacemaker (i.e. the SCN) integrates temporal information into a wealth of physiological processes. Ample data suggests that in addition to canonical cellular timekeeping functions, clock proteins also interact with proteins involved in cellular processes not related to timekeeping, including protein regulation and the interaction with other signaling mechanisms not directly linked to the regulation of circadian rhythms. Indeed, recent data suggests that clock genes outside the SCN are involved in fundamental brain processes such as sleep/wakefulness, stress and memory. The role of clock genes in these brain processes are complex and divers, influencing many molecular pathways and phenotypes. In this review, we will discuss recent work on the involvement of clock genes in sleep, stress, and memory. Moreover, we raise the controversial possibility that these functions may be under certain circumstances independent of their circadian timekeeping function.
Youri G Bolsius, Matias D Zurbriggen, Jae Kyoung Kim, Martien J Kas, Peter Meerlo, Sara J Aton, Robbert Havekes

2589 related Products with: The role of clock genes in sleep, stress and memory.

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#33643814   2020/09/19 To Up

Phosphorylation regulates cullin-based ubiquitination in tumorigenesis.

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.
Yifan Chen, Xuejing Shao, Ji Cao, Hong Zhu, Bo Yang, Qiaojun He, Meidan Ying

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#33641746   2020/12/07 To Up

Genomic perspectives on the circadian clock hypothesis of psychiatric disorders.

Circadian rhythm disturbances are frequently described in psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia. Growing evidence suggests a biological connection between mental health and circadian rhythmicity, including the circadian influence on brain function and mood and the requirement for circadian entrainment by external factors, which is often impaired in mental illness. Mental (as well as physical) health is also adversely affected by circadian misalignment. The marked interindividual differences in this combined susceptibility, in addition to the phenotypic spectrum in traits related both to circadian rhythms and mental health, suggested the possibility of a shared genetic background and that circadian clock genes may also be candidate genes for psychiatric disorders. This hypothesis was further strengthened by observations in animal models where clock genes had been knocked out or mutated. The introduction of genome-wide association studies (GWAS) enabled hypothesis-free testing. GWAS analysis of chronotype confirmed the prominent role of circadian genes in these phenotypes and their extensive polygenicity. However, in GWAS on psychiatric traits, only one clock gene, ARNTL (BMAL1) was identified as one of the few loci differentiating bipolar disorder from schizophrenia, and macaque monkeys where the ARNTL gene has been knocked out display symptoms similar to schizophrenia. Another lesson from genomic analyses is that chronotype has an important genetic correlation with several psychiatric disorders and that this effect is unidirectional. We conclude that the effect of circadian disturbances on psychiatric disorders probably relates to modulation of rhythm parameters and extend beyond the core clock genes themselves.
Malcolm von Schantz, Mario A Leocadio-Miguel, Michael J McCarthy, Sergi Papiol, Dominic Landgraf

1638 related Products with: Genomic perspectives on the circadian clock hypothesis of psychiatric disorders.

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#33630038   2021/02/25 To Up

The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development?

The circadian clock is a specialised cell signalling pathway present in all cells. Loss of clock function leads to tissue degeneration and premature aging in animal models demonstrating the fundamental importance of clocks for cell, tissue and organism health There is now considerable evidence that the chondrocyte circadian clock is altered in osteoarthritis (OA). The purpose of this review is to summarise current knowledge regarding the nature of the change in the chondrocyte clock in OA and the implications of this change for disease development. Expression of the core clock component, BMAL1, has consistently been shown to be lower in OA chondrocytes. This may contribute to changes in chondrocyte differentiation and extracellular matrix turnover in disease. Circadian clocks are highly responsive to environmental factors. Mechanical loading, diet, inflammation and oxidative insult can all influence clock function. These factors may contribute to causing the change in the chondrocyte clock in OA.
Raewyn C Poulsen, James I Hearn, Nicola Dalbeth

2989 related Products with: The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development?

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#33620678   2021/02/23 To Up

The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats.

Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats.
Zhen Qiu, Hao Ming, Yi Zhang, Yanli Yu, Shaoqing Lei, Zhong-Yuan Xia

1730 related Products with: The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats.

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#33617843   2021/02/19 To Up

From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach.

We present ten insights that can be gained from computational models based on molecular mechanisms for the mammalian circadian clock. These insights range from the conditions in which circadian rhythms occur spontaneously to their entrainment by the light-dark (LD) cycle and to clock-related disorders of the sleep-wake cycle. Endogenous oscillations originate spontaneously from transcription-translation feedback loops involving clock proteins such as PER, CRY, CLOCK and BMAL1. Circadian oscillations occur in a parameter domain bounded by critical values. Outside this domain the circadian network ceases to oscillate and evolves to a stable steady state. This conclusion bears on the nature of arrhythmic behavior of the circadian clock, which may not necessarily be due to mutations in clock genes. Entrainment by the LD cycle occurs in a certain range of parameter values, with a phase that depends on the endogenous period of the circadian clock. A decrease in PER phosphorylation is accompanied by a decrease in endogenous period and a phase advance of the clock; this situation accounts for the familial, advanced sleep phase syndrome (FASPS). The mirror delayed sleep phase syndrome (DSPS) can be accounted for, similarly, by an increase in PER phosphorylation and a rise in autonomous period. Failure of entrainment by the LD cycle in the model corresponds to the non-24h sleep-wake cycle syndrome, in which the phase of the circadian clock drifts in the course of time. Quasi-periodic oscillations that develop in these conditions sometimes correspond to long-period patterns in which the circadian clock is nearly entrained for long bouts of time before its phase rapidly drifts until a new regime of quasi-entrainment is re-established. In regard to jet lag, the computational approach accounts for the two modes of re-entrainment observed after an advance or delay which correspond, respectively, to an eastward or westward flight: the clock adjusts in a direction similar (orthodromic) or opposite (antidromic) to that of the shift in the LD cycle. Computational modeling predicts that in the vicinity of the switch between orthodromic and antidromic re-entrainment the circadian clock may take a very long time to resynchronize with the LD cycle. Repetitive perturbations of the circadian clock due, for example, to chronic jet lag -a situation somewhat reminiscent of shift work- may lead to quasi-periodic or chaotic oscillations. The latter irregular oscillations can sometimes be observed in normal LD cycles, raising the question of their possible relevance to fragmented sleep patterns observed in narcolepsy. The latter condition, however, appears to originate from disorders in the orexin neural circuit, which promotes wakefulness, rather than from an irregular operation of the circadian clock.
Albert Goldbeter, Jean-Christophe Leloup

2404 related Products with: From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach.

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#33602006   2021/02/18 To Up

Longterm effects of rotational night shift work on expression of circadian genes and its association with postprandial triglyceride levels - A pilot study.

Abnormalities of lipid metabolism in the form of high fasting as well as postprandial triglyceride levels immediately after night shift work and under simulated night shift conditions have been reported in the literature. Whether dysregulation of circadian genes in the long term is associated with abnormal triglyceride metabolism has not been previously investigated. This pilot study aimed to investigate the long-term effect of rotational night shift work on the expression of circadian genes among healthcare workers and to ascertain the association between the expression of circadian genes and postprandial triglyceride and insulin resistance parameters. The study was conducted on two groups of healthcare workers (n = 20/group). Group 1 included day shift workers who had not done night shift duty during the past one year or ever. Group 2 included healthcare workers doing rotational night shift duties (≥4 night shift duties/month). Fasting blood samples were collected at 08:00 h to study the expression of circadian genes CLOCK, NPAS2, BMAL1, CRY1, CRY2, PER1, PER2, PER3, REVERBα, and biochemical parameters after which a standardized fat challenge test was done to measure postprandial triglyceride levels. Study of Group 2 individuals was conducted after a minimum of one week after the last night shift duty. Expression of CLOCK, NPAS2, PER1, PER3, and REV-ERBα genes was higher in Group 2 compared to Group 1 subjects, and expression of BMAL1 and CRY1 genes were lower in Group 2 compared to Group 1. Several of these genes showed significant correlations with postprandial triglyceride and insulin resistance parameters in Group 2 but not in Group 1 subjects. The present study showed altered expression of several circadian genes in healthcare workers involved in rotational night shift duties associated with postprandial triglyceride and insulin resistance parameters. This study therefore suggests that long term circadian gene dysregulation could have serious metabolic consequences in individuals engaged in rotational night shift duties.
M Aslama, S V Madhua, K Keithellakpama, M Mehndirattab, B K Mishraa, V Neha

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