N6-methyladenosine (m6A) is the most abundant epitranscriptomic mark that regulates the fate of RNA molecules. Recent studies have revealed a bidirectional interaction between m6A modification and the circadian clock. However, the precise temporal dynamics of m6A global enrichment in the central circadian pacemaker have not been fully elucidated. Our study investigates the relationship between FTO demethylase and molecular clocks in primary cells of the suprachiasmatic nucleus (SCN). In addition, we examined the effects of lipopolysaccharide (LPS) on Fto expression and the role of FTO in LPS-induced reactive oxygen species (ROS) production in primary SCN cell culture. We observed circadian rhythmicity in the global m6A levels, which mirrored the rhythmic expression of the Fto demethylase. Silencing FTO using siRNA reduced the mesor of Per2 rhythmicity in SCN primary cells and extended the period of the PER2 rhythm in SCN primary cell cultures from PER2::LUC mice. When examining the immune response, we discovered that exposure to LPS upregulated global m6A levels while downregulating Fto expression in SCN primary cell cultures. Interestingly, we found a loss of circadian rhythmicity in Fto expression following LPS treatment, indicating that the decrease of FTO levels may contribute to m6A upregulation without directly regulating its circadian rhythm. To explore potential protective mechanisms against neurotoxic inflammation, we examined ROS production following LPS treatment in SCN primary cell cultures pretreated with FTO siRNA. We observed a time-dependent pattern of ROS induction, with significant peak at 32 h but not at 20 h after synchronization. Silencing the FTO demethylase abolished ROS induction following LPS exposure, supporting the hypothesis that FTO downregulation serves as a protective mechanism during LPS-induced neuroinflammation in SCN primary cell cultures.

• MeSH
• adenosin * analogy a deriváty   metabolismus   MeSH
• cirkadiánní hodiny * účinky léků   fyziologie   genetika   MeSH
• cirkadiánní proteiny Period metabolismus   genetika   MeSH
• cirkadiánní rytmus účinky léků   fyziologie   MeSH
• gen pro FTO * metabolismus   genetika   MeSH
• kultivované buňky MeSH
• lipopolysacharidy * farmakologie   MeSH
• methylace RNA MeSH
• metylace účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neurozánětlivé nemoci metabolismus   MeSH
• nucleus suprachiasmaticus * metabolismus   účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• RNA genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that drives circadian rhythms in physiology and behavior and adjusts their timing to external cues. Neurotransmitter glutamate and glutamatergic receptors sensitive to N-methyl-d-aspartate (NMDA) play a dual role in the SCN by coupling astrocytic and neuronal single cell oscillators and by resetting their phase in response to light. Recent reports suggested that signaling by endogenous cannabinoids (ECs) participates in both of these functions. We have previously shown that ECs, such as 2-arachidonoylglycerol (2-AG), act via CB1 receptors to affect the SCN response to light-mimicking NMDA stimulus in a time-dependent manner. We hypothesized that this ability is linked to the circadian regulation of EC signaling. We demonstrate that circadian clock in the rat SCN regulates expression of 2-AG transport, synthesis and degradation enzymes as well as its receptors. Inhibition of the major 2-AG synthesis enzyme, diacylglycerol lipase, enhanced the phase delay and lowered the amplitude of explanted SCN rhythm in response to NMDAR activation. Using microscopic PER2 bioluminescence imaging, we visualized how individual single cell oscillators in different parts of the SCN respond to the DAGL inhibition/NMDAR activation and shape response of the whole pacemaker. Additionally, we present strong evidence that the zero amplitude behavior of the SCN in response to single NMDA stimulus in the middle of subjective night is the result of a loss of rhythm in individual SCN cells. The paper provides new insights into the modulatory role of endocannabinoid signaling during the light entrainment of the SCN.

• MeSH
• agonisté excitačních aminokyselin farmakologie   MeSH
• cirkadiánní rytmus účinky léků   fyziologie   MeSH
• endokanabinoidy fyziologie   MeSH
• krysa rodu rattus MeSH
• lipoproteinlipasa antagonisté a inhibitory   metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• N-methylaspartát farmakologie   MeSH
• nucleus suprachiasmaticus cytologie   účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The circadian clock in the suprachiasmatic nucleus (SCN) regulates daily rhythms in physiology and behaviour and is an important part of the mammalian homeostatic system. Previously, we have shown that systemic inflammatory stimulation with lipopolysaccharide (LPS) induced the daytime-dependent phosphorylation of STAT3 in the SCN. Here, we demonstrate the LPS-induced Stat3 mRNA expression in the SCN and show also the circadian rhythm in Stat3 expression in the SCN, with high levels during the day. Moreover, we examined the effects of LPS (1mg/kg), applied either during the day or the night, on the rhythm in locomotor activity of male Wistar rats. We observed that recovery of normal locomotor activity patterns took longer when the animals were injected during the night. The clock genes Per1, Per2 and Nr1d1, and phosphorylation of kinases ERK1/2 and GSK3β are sensitive to external cues and function as the molecular entry for external signals into the circadian clockwork. We also studied the immediate changes in these clock genes expressions and the phosphorylation of ERK1/2 and GSK3β in the suprachiasmatic nucleus in response to daytime or night-time inflammatory stimulation. We revealed mild and transient changes with respect to the controls. Our data stress the role of STAT3 in the circadian clock response to the LPS and provide further evidence of the interaction between the circadian clock and immune system.

• MeSH
• cirkadiánní rytmus účinky léků   MeSH
• krysa rodu rattus MeSH
• lipopolysacharidy toxicita   MeSH
• lokomoce účinky léků   MeSH
• MAP kinasový signální systém účinky léků   MeSH
• mitogenem aktivovaná proteinkinasa 3 metabolismus   MeSH
• nucleus suprachiasmaticus metabolismus   patologie   MeSH
• potkani Wistar MeSH
• regulace genové exprese účinky léků   MeSH
• transkripční faktor STAT3 biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Circadian clock plays an essential role in orchestrating daily physiology, and its disruption can evoke metabolic diseases such as obesity. L-Carnitine can reduce blood lipid levels, and ameliorate fatty liver through regulating lipid metabolism. However, whether L-Carnitine administration may affect the disturbance of lipid metabolism and circadian rhythm of mice induced by prolonged circadian disruption is still unknown. Herein, we investigated the effects of L-Carnitine on conditions of circadian clock and lipid metabolism through a chronic jet-lag mice model which was developed by reversing 12 h light/12 h dark cycle every 4 days for a continuous 12 weeks. Results showed that L-Carnitine administration significantly decreased levels of serum glutamic-oxaloacetic transaminase (GOT) and triglycerides (TG), which were remarkably elevated by chronic jet-lag. More importantly, quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that L-Carnitine supplementation would effectively counteract the negative alterations in gene expression which related to lipid metabolism (Srebp1, Acaca, Fasn, and Scd1), metabolic regulator (mTOR) and circadian rhythm (Bmal1, Per1, Cry1 and Dec1) in the liver of mice subjected to the chronic jet-lag. As a conclusion, L-Carnitine was partly effective in preventing the disruption of circadian clock and lipid metabolic disorders induced by the chronic jet-lag.

• MeSH
• chronická nemoc MeSH
• cirkadiánní hodiny účinky léků   fyziologie   MeSH
• cirkadiánní rytmus účinky léků   fyziologie   MeSH
• jet lag syndrom krev   farmakoterapie   genetika   MeSH
• karnitin farmakologie   terapeutické užití   MeSH
• metabolismus lipidů účinky léků   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• náhodné rozdělení MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• Cílový krevní tlak, Analýza výsledků studie SPRINT,
• MeSH
• ambulantní monitorování metody   trendy   využití   MeSH
• antihypertenziva terapeutické užití   MeSH
• cirkadiánní rytmus fyziologie   účinky léků   MeSH
• kardiovaskulární nemoci etiologie   prevence a kontrola   MeSH
• klinické zkoušky jako téma metody   využití   MeSH
• komorbidita MeSH
• krevní tlak fyziologie   účinky léků   MeSH
• lidé MeSH
• měření krevního tlaku * metody   normy   využití   MeSH
• metaanalýza jako téma MeSH
• prospektivní studie MeSH
• statistika jako téma MeSH
• tělesná hmotnost fyziologie   účinky léků   MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH

Plant growth regulating properties of brevicompanines (Brvs), natural products of the fungus Penicillium brevicompactum, have been known for several years, but further investigations into the molecular mechanism of their bioactivity have not been performed. Following chemical synthesis of brevicompanine derivatives, we studied their activity in the model plant Arabidopsis by a combination of plant growth assays, transcriptional profiling, and numerous additional bioassays. These studies demonstrated that brevicompanines cause transcriptional misregulation of core components of the circadian clock, whereas other biological read-outs were not affected. Brevicompanines thus represent promising chemical tools for investigating the regulation of the plant circadian clock. In addition, our study also illustrates the potential of an unbiased -omics-based characterization of bioactive compounds for identifying the often cryptic modes of action of small molecules.

• MeSH
• Arabidopsis účinky léků   fyziologie   MeSH
• biologické přípravky chemická syntéza   farmakologie   MeSH
• cirkadiánní rytmus účinky léků   MeSH
• cyklické peptidy chemická syntéza   farmakologie   MeSH
• fyziologie rostlin účinky léků   MeSH
• genetická transkripce účinky léků   MeSH
• indoly chemická syntéza   farmakologie   MeSH
• kořeny rostlin účinky léků   růst a vývoj   MeSH
• Penicillium chemie   MeSH
• Publikační typ
• časopisecké články MeSH

Signal transducers and activators of transcription (STAT) proteins regulate many aspects of cellular physiology from growth and differentiations to immune responses. Using immunohistochemistry, we show the daily rhythm of STAT3 protein in the rat suprachiasmatic nucleus (SCN), with low but significant amplitude peaking in the morning. We also reveal the strong expression of STAT5A in astrocytes of the SCN and the STAT5B signal in nonastrocytic cells. Administration of lipopolysaccharide (LPS) acutely induced phosphorylation of STAT3 on Tyr705 during both the day and the night and induced phosphorylation on Ser727 but only after the daytime application. The LPS-induced phospho-STAT3 (Tyr705) remained elevated for 24 hr after the daytime application but declined within 8 hr when LPS was applied at night.

• MeSH
• analýza rozptylu MeSH
• časové faktory MeSH
• cirkadiánní rytmus účinky léků   MeSH
• fosforylace účinky léků   MeSH
• gliový fibrilární kyselý protein metabolismus   MeSH
• krysa rodu rattus MeSH
• lipopolysacharidy farmakologie   MeSH
• nucleus suprachiasmaticus cytologie   účinky léků   MeSH
• potkani Wistar MeSH
• regulace genové exprese účinky léků   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• transkripční faktor STAT5 metabolismus   MeSH
• tyrosin-3-monooxygenasa metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The role of melatonin in maintaining proper function of the circadian system has been proposed but very little evidence for such an effect has been provided. To ascertain the role, the aim of the study was to investigate impact of long-term melatonin absence on regulation of circadian system. The parameters of behavior and circadian clocks of rats which were devoid of the melatonin signal due to pinealectomy (PINX) for more than one year were compared with those of intact age-matched controls. PINX led to a decrease in spontaneous locomotor activity and a shortening of the free-running period of the activity rhythm driven by the central clock in the suprachiasmatic nuclei (SCN) in constant darkness. However, the SCN-driven rhythms in activity and feeding were not affected and remained well entrained in the light/dark cycle. In contrast, in these conditions PINX had a significant effect on amplitudes of the clock gene expression rhythms in the duodenum and also partially in the liver. These results demonstrate the significant impact of long-term melatonin absence on period of the central clock in the SCN and the amplitudes of the peripheral clocks in duodenum and liver and suggest that melatonin might be a redundant but effective endocrine signal for these clocks.

• MeSH
• cirkadiánní rytmus * účinky léků   fyziologie   MeSH
• epifýza mozková metabolismus   chirurgie   MeSH
• fotoperioda MeSH
• krysa rodu rattus MeSH
• lokomoce fyziologie   MeSH
• melatonin metabolismus   fyziologie   MeSH
• nucleus suprachiasmaticus metabolismus   MeSH
• potkani Wistar MeSH
• signální transdukce fyziologie   MeSH
• světlo MeSH
• tma MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine.

• MeSH
• abstinenční syndrom metabolismus   MeSH
• arginin vasopresin metabolismus   MeSH
• cirkadiánní proteiny Period metabolismus   MeSH
• cirkadiánní rytmus účinky léků   MeSH
• hybridizace in situ MeSH
• methadon škodlivé účinky   MeSH
• morfin škodlivé účinky   MeSH
• narkotika škodlivé účinky   MeSH
• nucleus suprachiasmaticus účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• anestetika farmakologie   MeSH
• anestezie * MeSH
• cirkadiánní rytmus účinky léků   MeSH
• elektrokardiografie účinky léků   MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• úvodníky MeSH