The mammalian clock and chronopharmacology

Griffett, Kristine; Burris, Thomas P.

doi:10.1016/j.bmcl.2013.02.015

Cited by 33 publications

(18 citation statements)

References 55 publications

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“…Recent efforts have therefore sought to gain a mechanistic understanding of these pathways, such that the metabolic burdens imposed by a 24-h society might be mitigated. Posttranslational regulators, which play key roles in connecting circadian and metabolic processes, serve as likely targets for future therapeutics, demonstrated by the wealth of available circadian-active small molecules (2,3).…”

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confidence: 99%

Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock

John

Hirota

Kay

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Posttranslational regulation of clock proteins is an essential part of mammalian circadian rhythms, conferring sensitivity to metabolic state and offering promising targets for pharmacological control. Two such regulators, casein kinase 1 (CKI) and F-box and leucinerich repeat protein 3 (FBXL3), modulate the stability of closely linked core clock proteins period (PER) and cryptochrome (CRY), respectively. Inhibition of either CKI or FBXL3 leads to longer periods, and their effects are independent despite targeting proteins with similar roles in clock function. A mechanistic understanding of this independence, however, has remained elusive. Our analysis of cellular circadian clock gene reporters further differentiated between the actions of CKI and FBXL3 by revealing opposite amplitude responses from each manipulation. To understand the functional relationship between the CKI-PER and FBXL3-CRY pathways, we generated robust mechanistic predictions by applying a bootstrap uncertainty analysis to multiple mathematical circadian models. Our results indicate that CKI primarily regulates the accumulating phase of the PER-CRY repressive complex by controlling the nuclear import rate, whereas FBXL3 separately regulates the duration of transcriptional repression in the nucleus. Dynamic simulations confirmed that this spatiotemporal separation is able to reproduce the independence of the two regulators in period regulation, as well as their opposite amplitude effect. As a result, this study provides further insight into the molecular clock machinery responsible for maintaining robust circadian rhythms.identifiability analysis | gene regulation | sensitivity analysis C ircadian rhythms are autonomous, near-24-h oscillations that coordinate daily changes in physiology and metabolism. Because circadian and metabolic regulators are tightly integrated, circadian disruptions often manifest in metabolic disease (1). Recent efforts have therefore sought to gain a mechanistic understanding of these pathways, such that the metabolic burdens imposed by a 24-h society might be mitigated. Posttranslational regulators, which play key roles in connecting circadian and metabolic processes, serve as likely targets for future therapeutics, demonstrated by the wealth of available circadian-active small molecules (2, 3).Oscillations in circadian gene transcription are generated through a time-delayed transcription-translation negative-feedback loop. In mammals, transcription factors CLOCK and BMAL1 promote transcription of E box-containing genes Period (Per) and Cryptochrome (Cry) (Fig. 1A). PER and CRY protein products form heterodimers to accumulate in the nucleus, in which PER is stoichiometrically limiting (4), and subsequently close the negative feedback loop by inhibiting CLOCK-BMAL1-promoted gene expression. Although steady-state endpoint assays have shown the possibility of nuclear entry of CRY without PER (5-7), experiments from Per1 −/− Per2 −/− mice demonstrated that PER proteins are required for the timely nuclear accumulation of ...

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confidence: 99%

Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock

John

Hirota

Kay

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Usually, toxicity in the daylight is less than in darkness for humankind. That means rest phase administration is accompanied by greater risks [18].…”

Section: Discussionmentioning

confidence: 99%

Dosing‐time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics

Luan

Zhang

Liu

et al. 2016

The Kaohsiung J of Med Scie

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To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application.

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“…Takva promjena može rezultirati drugačijim odgovorom tkiva na vanjske signale i ubrzati oštećenje tkiva. Gubitak sinkronizacije može dovesti do različitih bolesti, među kojima je i povećana incidencija kardiovaskularnih bolesti 14 .…”

Section: Cirkadijalni Ritamunclassified

Circadian rhythm and myocardial infarction

Škrlec

2019

Med flum

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Sažetak. Cirkadijalni sat kontrolira cijeli niz fizioloških procesa, a njegovi poremećaji mogu dovesti do brojnih patofizioloških promjena. Središnji cirkadijalni sat smješten je u suprahijazmatskoj jezgri u hipotalamusu i reguliran je brojim genima cirkadijalnog ritma. Varijacije tih gena povezane su s pretilošću, poremećajima spavanja, metaboličkim i raznim psihičkim poremećajima te kardiovaskularnim događajima, poput infarkta miokarda, moždanog udara i vaskularne smrti. Mnogi kardiovaskularni procesi pokazuju jasne dnevne varijacije ovisne o cirkadijalnom ritmu (tlak, otkucaji srca), a cirkadijalni obrazac pojavnost karakterističan je za kardiovaskularne bolesti. Kronotip i dnevna pospanost, elementi cirkadijalnog ritma, važni su čimbenici rizika u procijeni nastanaka kardiovaskularnih bolesti, odnosno infarkta. Rad donosi pregled o najnovijim spoznajama utjecaja cirkadijalnog ritma, gena cirkadijalnog ritma i fenotipskih elemenata cirkadijalnog ritma, tj. kronotipa i dnevne pospanosti, na nastanak infarkta miokarda. U doba personalizirane medicine, znanje o cirkadijalnom ritmu pojedine osobe može biti važno za njezino liječenje, a može se uključiti i u dijagnostičke procese.

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The mammalian clock and chronopharmacology

Cited by 33 publications

References 55 publications

Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock

Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock

Dosing‐time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics

Circadian rhythm and myocardial infarction

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