Circadian clock regulates hepatotoxicity of Tripterygium wilfordii through modulation of metabolism

2020 ◽  
Author(s):  
Huan Zhao ◽  
Yongbin Tong ◽  
Danyi Lu ◽  
Baojian Wu
Keyword(s):  
Circadian Clock ◽  
Diurnal Rhythm ◽  
Clock Gene ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Tripterygium Wilfordii ◽  
Circadian Expression ◽  
Circadian Time ◽  
Toxic Constituent

Abstract Objectives We aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity. Methods Hepatotoxicity was determined based on assessment of liver injury after dosing mice with TW at different circadian time points. Circadian clock control of metabolism, pharmacokinetics and hepatotoxicity was investigated using Clock-deficient (Clock−/−) mice. Key findings Hepatotoxicity of TW displayed a significant circadian rhythm (the highest level of toxicity was observed at ZT2 and the lowest level at ZT14). Pharmacokinetic experiments showed that oral gavage of TW at ZT2 generated higher plasma concentrations (and systemic exposure) of triptolide (a toxic constituent) compared with ZT14 dosing. This was accompanied by reduced formation of triptolide metabolites at ZT2. Loss of Clock gene sensitized mice to TW-induced hepatotoxicity and abolished the time-dependency of toxicity that was well correlated with altered metabolism and pharmacokinetics of triptolide. Loss of Clock gene also decreased Cyp3a11 expression in mouse liver and blunted its diurnal rhythm. Conclusions Tripterygium wilfordii chronotoxicity was associated with diurnal variations in triptolide pharmacokinetics and circadian expression of hepatic Cyp3a11 regulated by circadian clock. Our findings may have implications for improving TW treatment outcome with a chronotherapeutic approach.

The role of circadian clock gene BMAL1 in vascular proliferation

2020 ◽  
Vol 872 ◽  
pp. 172924
Author(s):  
Akira Takaguri ◽  
Jun Sasano ◽  
Oomiya Akihiro ◽  
Kumi Satoh
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Circadian Clock Gene ◽  
Vascular Proliferation

scholarly journals Role of Per3, a circadian clock gene, in brain development

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S81
Author(s):  
Koh-Ichi Nagata ◽  
Mariko Noda ◽  
Ikuko Iwamoto ◽  
Hidenori Tabata ◽  
Hidenori Ito
Keyword(s):  
Circadian Clock ◽  
Brain Development ◽  
Clock Gene ◽  
Circadian Clock Gene

scholarly journals Bmal1 regulates circadian expression of cytochrome P450 3a11 and drug metabolism in mice

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Yanke Lin ◽  
Shuai Wang ◽  
Ziyue Zhou ◽  
Lianxia Guo ◽  
Fangjun Yu ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Drug Exposure ◽  
Defense Mechanism ◽  
Critical Role ◽  
The Body ◽  
Cellular Regulation ◽  
Circadian Expression ◽  
Distal Promoter ◽  
Daily Time

Abstract Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.

scholarly journals Circadian Pattern of Ion Channel Gene Expression in Failing Human Hearts

2020 ◽  
Author(s):  
Charles F. McTiernan ◽  
Bonnie H. Lemster ◽  
Kenneth C. Bedi ◽  
Kenneth B. Margulies ◽  
Christine Moravec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ion Channel ◽  
Circadian Clock ◽  
Expression Pattern ◽  
Clock Gene ◽  
Circadian Pattern ◽  
Circadian Clock Gene ◽  
Circadian Expression ◽  
Clock Gene Expression ◽  
Brain Dead

Background - Ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD) show a circadian pattern of occurrence in heart failure patients. In the rodent ventricle, a significant portion of genes, including some ion channels, shows a circadian pattern of expression. However genes that define electrophysiologic properties in failing human heart ventricles have not been examined for a circadian expression pattern. Methods - Ventricular tissue samples were collected from patients at the time of cardiac transplantation. Two sets of samples (n=37 and 46, one set with a greater arrhythmic history) were selected to generate pseudo-time series according to their collection time. A third set (n=27) of samples was acquired from the non-failing ventricles of brain-dead donors. The expression of 5 known circadian clock genes and 19 additional ion channel genes plausibly important to electrophysiologic properties were analyzed by RT-PCR, and then analyzed for the percentage of expression variation attributed to a 24 hour circadian pattern. Results - The 5 known circadian clock gene transcripts showed a strong circadian expression pattern. Compared to rodent hearts, the human circadian clock gene transcripts showed a similar temporal order of acrophases but with a ~ 7.6 hours phase shift. Five of the ion channel genes also showed strong circadian expression. Comparable studies of circadian clock gene expression in samples recovered from non-heart failure brain-dead donors showed acrophase shifts, or weak or complete loss of circadian rhythmicity, suggesting alterations in circadian gene expression. Conclusions - Ventricular tissue from failing human hearts display a circadian pattern of circadian clock gene expression, but phase-shifted relative to rodent hearts. At least 5 ion channels show a circadian expression pattern in the ventricles of failing human hearts, which may underlie a circadian pattern of VT/SCD. Non-failing hearts from brain-dead donors show marked differences in circadian clock gene expression patterns, suggesting fundamental deviations from circadian expression.

scholarly journals Breast cancer risk, nightwork, and circadian clock gene polymorphisms

2014 ◽  
Vol 21 (4) ◽  
pp. 629-638 ◽  
Author(s):  
Thérèse Truong ◽  
Benoît Liquet ◽  
Florence Menegaux ◽  
Sabine Plancoulaine ◽  
Pierre Laurent-Puig ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Circadian Clock ◽  
Postmenopausal Women ◽  
Gene Polymorphisms ◽  
Clock Gene ◽  
Gene Variants ◽  
Circadian Clock Gene

Night shift work has been associated with an increased risk of breast cancer pointing to a role of circadian disruption. We investigated the role of circadian clock gene polymorphisms and their interaction with nightwork in breast cancer risk in a population-based case–control study in France including 1126 breast cancer cases and 1174 controls. We estimated breast cancer risk associated with each of the 577 single nucleotide polymorphisms (SNPs) in 23 circadian clock genes. We also used a gene- and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs. Interactions with nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs inRORA(rs1482057 and rs12914272) were associated with breast cancer in the whole sample and among postmenopausal women. In this subpopulation, we also reported an association with rs11932595 inCLOCK, and withCLOCK,RORA, andNPAS2in the analyses at the gene level. Breast cancer risk in postmenopausal women was also associated with overall genetic variation in the circadian gene pathway (P=0.04), but this association was not detected in premenopausal women. There was some evidence of an interaction betweenPER1and nightwork in breast cancer in the whole sample (P=0.024), although the effect was not statistically significant after correcting for multiple testing (P=0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk.

scholarly journals Role of the circadian clock gene Per2 in adaptation to cold temperature

2013 ◽  
Vol 2 (3) ◽  
pp. 184-193 ◽  
Author(s):  
Sylvie Chappuis ◽  
Jürgen Alexander Ripperger ◽  
Anna Schnell ◽  
Gianpaolo Rando ◽  
Corinne Jud ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Cold Temperature ◽  
Circadian Clock Gene ◽  
Adaptation To Cold

scholarly journals RNAi of the circadian clock gene period disrupts the circadian rhythm but not the circatidal rhythm in the mangrove cricket

2012 ◽  
Vol 8 (4) ◽  
pp. 488-491 ◽  
Author(s):  
Hiroki Takekata ◽  
Yu Matsuura ◽  
Shin G. Goto ◽  
Aya Satoh ◽  
Hideharu Numata
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Molecular Basis ◽  
Clock Gene ◽  
Circadian Clock Gene ◽  
Double Stranded Rna ◽  
Activity Intensity ◽  
Significant Difference ◽  
Clock Mechanism

The clock mechanism for circatidal rhythm has long been controversial, and its molecular basis is completely unknown. The mangrove cricket, Apteronemobius asahinai , shows two rhythms simultaneously in its locomotor activity: a circatidal rhythm producing active and inactive phases as well as a circadian rhythm modifying the activity intensity of circatidal active phases. The role of the clock gene period ( per ), one of the key components of the circadian clock in insects, was investigated in the circadian and circatidal rhythms of A. asahinai using RNAi. After injection of double-stranded RNA of per , most crickets did not show the circadian modulation of activity but the circatidal rhythm persisted without a significant difference in the period from controls. Thus, per is functionally involved in the circadian rhythm but plays no role, or a less important role, in the circatidal rhythm. We conclude that the circatidal rhythm in A. asahinai is controlled by a circatidal clock whose molecular mechanism is different from that of the circadian clock.

scholarly journals Global Analysis of Circadian Expression in the Cyanobacterium Synechocystis sp. Strain PCC 6803

2005 ◽  
Vol 187 (6) ◽  
pp. 2190-2199 ◽  
Author(s):  
Ken-ichi Kucho ◽  
Kazuhisa Okamoto ◽  
Yuka Tsuchiya ◽  
Satoshi Nomura ◽  
Mamoru Nango ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Dna Microarrays ◽  
Global Analysis ◽  
Bacterial Species ◽  
Physiological State ◽  
Expression Patterns ◽  
Main Role ◽  
Circadian Expression ◽  
Pcc 6803

ABSTRACT Cyanobacteria are the only bacterial species found to have a circadian clock. We used DNA microarrays to examine circadian expression patterns in the cyanobacterium Synechocystis sp. strain PCC 6803. Our analysis identified 54 (2%) and 237 (9%) genes that exhibited circadian rhythms under stringent and relaxed filtering conditions, respectively. The expression of most cycling genes peaked around the time of transition from subjective day to night, suggesting that the main role of the circadian clock in Synechocystis is to adjust the physiological state of the cell to the upcoming night environment. There were several chromosomal regions where neighboring genes were expressed with similar circadian patterns. The physiological functions of the cycling genes were diverse and included a wide variety of metabolic pathways, membrane transport, and signal transduction. Genes involved in respiration and poly(3-hydroxyalkanoate) synthesis showed coordinated circadian expression, suggesting that the regulation is important for the supply of energy and carbon source in the night. Genes involved in transcription and translation also followed circadian cycling patterns. These genes may be important for output of the rhythmic information generated by the circadian clock. Our findings provided critical insights into the importance of the circadian clock on cellular physiology and the mechanism of clock-controlled gene regulation.

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