scholarly journals Phase-dependent resetting of the adrenal clock by ACTH in vitro

2014 ◽  
Vol 306 (6) ◽  
pp. R387-R393 ◽  
Author(s):  
J. Marina Yoder ◽  
Megan Brandeland ◽  
William C. Engeland
Keyword(s):  
Circadian Rhythms ◽  
Molecular Clock ◽  
Clock Gene ◽  
External Environment ◽  
Phase Delay ◽  
Melanocyte Stimulating Hormone ◽  
Circadian Time ◽  
Acth Receptor ◽  
Acth Fragments

The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoids, yet how the clock is synchronized to the external environment is unknown. Using mPER2::Luciferase (mPER2Luc) knockin mice, in which luciferase is rhythmically expressed under the control of the mouse Per2 clock gene, we hypothesized that ACTH transmits entrainment signals to the adrenal. Adrenal explants were administered ACTH at different phases of the mPER2Luc rhythm. Treatment with ACTH 1–39 produced a phase delay that was phase-dependent, with a maximum at circadian time (CT)18; ACTH did not alter the period or amplitude of the rhythm. Forskolin produced a parallel response, suggesting that the phase delay was cAMP-mediated. The response to ACTH was concentration-dependent and peptide-specific. Pulse administration (60 min) of ACTH 1–39 also produced phase delays restricted to late CTs. In contrast to ACTH 1–39, other ACTH fragments, including α-melanocyte-stimulating hormone, which do not activate the melanocortin 2 (MC2/ACTH) receptor, had no effect. The finding that ACTH in vitro phase delays the adrenal mPER2luc rhythm in a monophasic fashion argues for ACTH as a key resetter, but not the sole entrainer, of the adrenal clock.

scholarly journals Cell-intrinsic, Bmal1-dependent Circadian Regulation of Temozolomide Sensitivity in Glioblastoma

2017 ◽  
Vol 32 (2) ◽  
pp. 121-129 ◽  
Author(s):  
Emily A. Slat ◽  
Jasmin Sponagel ◽  
Luciano Marpegan ◽  
Tatiana Simon ◽  
Najla Kfoury ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Growth Inhibition ◽  
Clock Gene ◽  
Daily Rhythms ◽  
The Core ◽  
Circadian Time ◽  
Damage Response ◽  
Human And Mouse ◽  
Core Clock Gene

The safety and efficacy of chemotherapeutics can vary as a function of the time of their delivery during the day. This study aimed to improve the treatment of glioblastoma (GBM), the most common brain cancer, by testing whether the efficacy of the DNA alkylator temozolomide (TMZ) varies with the time of its administration. We found cell-intrinsic, daily rhythms in both human and mouse GBM cells. Circadian time of treatment affected TMZ sensitivity of murine GBM tumor cells in vitro. The maximum TMZ-induced DNA damage response, activation of apoptosis, and growth inhibition occurred near the daily peak in expression of the core clock gene Bmal1. Deletion of Bmal1 (Arntl) abolished circadian rhythms in gene expression and TMZ-induced activation of apoptosis and growth inhibition. These data indicate that tumor cell-intrinsic circadian rhythms are common to GBM tumors and can regulate TMZ cytotoxicity. Optimization of GBM treatment by timing TMZ administration to daily rhythms should be evaluated in prospective clinical trials.

scholarly journals Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus

2017 ◽  
Vol 313 (2) ◽  
pp. E213-E221 ◽  
Author(s):  
Jingyi Qian ◽  
Anthony P. Thomas ◽  
Analyne M. Schroeder ◽  
Kuntol Rakshit ◽  
Christopher S. Colwell ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Rat Model ◽  
Clock Gene ◽  
Transgenic Rat ◽  
Circadian Activity ◽  
Melatonin Secretion ◽  
Clock Gene Expression

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.

scholarly journals Dissection of central clock function in Drosophila through cell-specific CRISPR-mediated clock gene disruption

2019 ◽  
Author(s):  
Rebecca Delventhal ◽  
Meghan Pantalia ◽  
Reed M. O’Connor ◽  
Matthew Ulgherait ◽  
Han X. Kim ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Circadian Rhythms ◽  
Molecular Clock ◽  
Gene Disruption ◽  
Clock Gene ◽  
Distributed Network ◽  
Circadian Activity ◽  
Clock Proteins ◽  
Central Clock ◽  
Circadian Behavior

AbstractIn Drosophila, ~150 neurons expressing molecular clock proteins regulate circadian behavior. Sixteen of these clock neurons secrete the neuropeptide Pdf and have been called “master pacemakers” because they are essential for circadian rhythms. A subset of Pdf+ neurons (the morning oscillator) regulates morning activity and communicates with other non-Pdf+ neurons, including a subset called the evening oscillator. It is assumed that the molecular clock in Pdf+ neurons is required for these functions. To test this, we developed and validated Gal4-UAS based CRISPR tools for cell-specific disruption of key molecular clock components, period and timeless. While loss of the molecular clock in both the morning and evening oscillators eliminates circadian locomotor activity, the molecular clock in either oscillator alone is sufficient for circadian locomotor activity. This suggests that clock neurons do not act in a hierarchy but as a distributed network to regulate circadian activity.

scholarly journals mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

2016 ◽  
Vol 113 (21) ◽  
pp. E2965-E2972 ◽  
Author(s):  
Xiao Chen ◽  
Michael Rosbash
Keyword(s):  
Circadian Rhythms ◽  
Molecular Clock ◽  
Posttranscriptional Regulation ◽  
Clock Gene ◽  
Constant Darkness ◽  
Transcription Activator ◽  
Behavioral Rhythms ◽  
Culture Cells ◽  
Tissue Culture Cells ◽  
The Central Nervous System

Circadian rhythms in metazoan eukaryotes are controlled by an endogenous molecular clock. It functions in many locations, including subsets of brain neurons (clock neurons) within the central nervous system. Although the molecular clock relies on transcription/translation feedback loops, posttranscriptional regulation also plays an important role. Here, we show that the abundant Drosophila melanogaster microRNA mir-276a regulates molecular and behavioral rhythms by inhibiting expression of the important clock gene timeless (tim). Misregulation of mir-276a in clock neurons alters tim expression and increases arrhythmicity under standard constant darkness (DD) conditions. mir-276a expression itself appears to be light-regulated because its levels oscillate under 24-h light–dark (LD) cycles but not in DD. mir-276a is regulated by the transcription activator Chorion factor 2 in flies and in tissue-culture cells. Evidence from flies mutated using the clustered, regularly interspaced, short palindromic repeats (CRISPR) tool shows that mir-276a inhibits tim expression: Deleting the mir-276a–binding site in the tim 3′ UTR causes elevated levels of TIM and ∼50% arrhythmicity. We suggest that this pathway contributes to the more robust rhythms observed under light/dark LD conditions than under DD conditions.

Circadian rhythms in the absence of the clock gene Bmal1

Science ◽  
2020 ◽  
Vol 367 (6479) ◽  
pp. 800-806 ◽  
Author(s):  
Sandipan Ray ◽  
Utham K. Valekunja ◽  
Alessandra Stangherlin ◽  
Steven A. Howell ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Circadian Rhythms ◽  
Molecular Clock ◽  
Knockout Mice ◽  
Clock Gene ◽  
Skin Fibroblasts ◽  
Temperature Cycles ◽  
Ets Family

Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether Bmal1 function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.

Organ-specific development characterizes circadian clock gene Per2 expression in rats

2014 ◽  
Vol 306 (1) ◽  
pp. R67-R74 ◽  
Author(s):  
Shin-ya Nishide ◽  
Kazuaki Hashimoto ◽  
Takuya Nishio ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Developmental Stages ◽  
Phase Relationship ◽  
Developmental Changes ◽  
Circadian Phase ◽  
Peripheral Oscillators ◽  
Clock Gene Expression ◽  
Organ Specific

To explore developmental changes in circadian organization of central and peripheral oscillators, circadian rhythms in clock gene expression were examined in 12 organs in transgenic rats carrying a bioluminescence reporter for Per2. Organ slices were obtained from different developmental stages starting at postnatal day 5 and tissue was cultured for more than 6 days. In addition, four organs were examined from embryonic day 20. Robust circadian rhythms in bioluminescence were detected in all organs examined. The circadian period in vitro was specific to each organ and remained essentially the same during development. The circadian peak phase on the first day of culture was significantly different not only among organs but also in the same organ. Three patterns in circadian phase were detected during development. Thus, during development, circadian phase did not change in the suprachiasmatic nucleus, adrenal gland, and liver, whereas delay shifts were seen in the pineal, lung, heart, kidney, spleen, thymus, and testis. Finally, circadian phase advanced at postnatal day 10–15 and subsequently delayed in skeletal muscle and stomach.Circadian amplitude also showed developmental changes in several organs. These findings indicate that the temporal orders of physiological functions of various organs change during development. Such age-dependent and organ-specific changes in the phase relationship among circadian clocks most likely reflect entrainment to organ-specific time cues at different developmental stages.

scholarly journals Polymorphism T3111C of the Clock gene in ethnic groups of women from Russia and Buryatia

2018 ◽  
Vol 22 (2) ◽  
pp. 212-216
Author(s):  
O. V. Kaluzhnaya ◽  
N. V. Semenova ◽  
T. A. Bairova ◽  
I. M.  Madaeva ◽  
E. V. Belyaeva ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Biological Clock ◽  
External Environment ◽  
Biological Rhythms ◽  
Eastern Siberia ◽  
Chain Reaction ◽  
Irkutsk Region ◽  
Menopausal Women ◽  
Polymerase Chain

Biological rhythms of organisms depend on both changing conditions of the external environment and internal “biological clock”. Circadian rhythms are the response of the organism to the change of day and night. They are some of the most important biological rhythms of organisms. Circadian rhythms are regulated by the group of circadian genes. It is known that women suffer from sleep disorders more often than men. Up to 50 % of menopausal women complain of problems associated with sleeping. The study involved 403 menopausal women aged from 45 to 60 years: 214 Russians (the average age is 52.74±6.28 years) and 189 Buryats (the average age is 51.95±5.13 years) living in Eastern Siberia (Irkutsk region, Irkutsk and Republic of Buryatia, Ulan-Ude). The prevalence of genotypes and alleles of the polymorphism T3111C of the circadian rhythm gene Clock (rs1801260) was studied in these groups. To this end, we conducted genotyping of DNA samples by polymerase chain reaction. It was shown that the compared groups have statistically significant differences in genotypes frequency (р = 0.001). It was found that in the group of Russian women the frequency of the TC genotype (p = 0.004) was significantly higher and the frequency of the TT genotype (p = 0.0001) was significantly lower than those in the sample of women of Buryatia. It was shown that in the group of Russian women allele 3111C is found in 30.4 % of cases, which is statistically significantly more often than in the group of Buryat women, where the frequency of allele 3111C was 19.3 % (p = 0.014).

scholarly journals Roles for ClpXP in regulating the circadian clock in Synechococcus elongatus

2018 ◽  
Vol 115 (33) ◽  
pp. E7805-E7813 ◽  
Author(s):  
Susan E. Cohen ◽  
Briana M. McKnight ◽  
Susan S. Golden
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Cell Division ◽  
Circadian Rhythms ◽  
External Environment ◽  
Long Period ◽  
Protein Synthesis And Degradation ◽  
Synthesis And Degradation

In cyanobacteria, the KaiABC posttranslational oscillator drives circadian rhythms of gene expression and controls the timing of cell division. The Kai-based oscillator can be reconstituted in vitro, demonstrating that the clock can run without protein synthesis and degradation; however, protein degradation is known to be important for clock function in vivo. Here, we report that strains deficient in the ClpXP1P2 protease have, in addition to known long-period circadian rhythms, an exaggerated ability to synchronize with the external environment (reduced “jetlag”) compared with WT strains. Deletion of the ClpX chaperone, but not the protease subunits ClpP1 or ClpP2, results in cell division defects in a manner that is dependent on the expression of a dusk-peaking factor. We propose that chaperone activities of ClpX are required to coordinate clock control of cell division whereas the protease activities of the ClpXP1P2 complex are required to maintain appropriate periodicity of the clock and its synchronization with the external environment.

scholarly journals Response to Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽  
2021 ◽  
Vol 372 (6539) ◽  
pp. eabf1941
Author(s):  
Sandipan Ray ◽  
Utham K. Valekunja ◽  
Alessandra Stangherlin ◽  
Steven A. Howell ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Statistical Significance ◽  
Statistical Measures ◽  
Statistical Algorithm ◽  
Low Amplitude ◽  
Lines Of Evidence

Abruzzi et al. argue that transcriptome oscillations found in our study in the absence of Bmal1 are of low amplitude, statistical significance, and consistency. However, their conclusions rely solely on a different statistical algorithm than we used. We provide statistical measures and additional analyses showing that our original analyses and observations are accurate. Further, we highlight independent lines of evidence indicating Bmal1-independent 24-hour molecular oscillations.

scholarly journals Marliolide Derivative Induces Melanosome Degradation via Nrf2/p62-Mediated Autophagy

2021 ◽  
Vol 22 (8) ◽  
pp. 3995
Author(s):  
Cheong-Yong Yun ◽  
Nahyun Choi ◽  
Jae Un Lee ◽  
Eun Jung Lee ◽  
Ji Young Kim ◽  
...  
Keyword(s):  
Related Factor ◽  
Melanin Pigmentation ◽  
Microtubule Associated Proteins ◽  
Melanocyte Stimulating Hormone ◽  
Associated Proteins ◽  
Autophagy Pathway ◽  
Nrf2 Activator ◽  
Promising Therapeutic Agent

Nuclear factor erythroid 2-related factor 2 (Nrf2), which is linked to autophagy regulation and melanogenesis regulation, is activated by marliolide. In this study, we investigated the effect of a marliolide derivative on melanosome degradation through the autophagy pathway. The effect of the marliolide derivative on melanosome degradation was investigated in α-melanocyte stimulating hormone (α-MSH)-treated melanocytes, melanosome-incorporated keratinocyte, and ultraviolet (UV)B-exposed HRM-2 mice (melanin-possessing hairless mice). The marliolide derivative, 5-methyl-3-tetradecylidene-dihydro-furan-2-one (DMF02), decreased melanin pigmentation by melanosome degradation in α-MSH-treated melanocytes and melanosome-incorporated keratinocytes, evidenced by premelanosome protein (PMEL) expression, but did not affect melanogenesis-associated proteins. The UVB-induced hyperpigmentation in HRM-2 mice was also reduced by a topical application of DMF02. DMF02 activated Nrf2 and induced autophagy in vivo, evidenced by decreased PMEL in microtubule-associated proteins 1A/1B light chain 3B (LC3)-II-expressed areas. DMF02 also induced melanosome degradation via autophagy in vitro, and DMF02-induced melanosome degradation was recovered by chloroquine (CQ), which is a lysosomal inhibitor. In addition, Nrf2 silencing by siRNA attenuated the DMF02-induced melanosome degradation via the suppression of p62. DMF02 induced melanosome degradation in melanocytes and keratinocytes by regulating autophagy via Nrf2-p62 activation. Therefore, Nrf2 activator could be a promising therapeutic agent for reducing hyperpigmentation.

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