BRITISH JOURNAL OF PHARMACOLOGY
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2019
·Vol. 176
·期 24
·4639-4652
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IF 6.583
Mengjing Zhao,Huan Zhao,Jiangming Deng,Lianxia Guo,Baojian Wu
Background and Purpose Whether and how circadian clock proteins regulate drug detoxification are not known. Here, we have assessed the effects of CLOCK (a core circadian clock protein) on drug metabolism and detoxification. Experimental Approach Regulation by CLOCK protein of drug-metabolizing enzymes was assessed using Clock knockout ( Clock −/− ) mice and Hepa-1c1c7/AML-12 cells. The relative mRNA and protein levels were determined by qPCR and Western blotting respectively. Toxicity and pharmacokinetic experiments were performed with Clock −/− and wild-type mice after intraperitoneal injection of coumarin or cyclophosphamide. Transcriptional gene regulation was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Key Results Clock deletion disrupted hepatic diurnal expressions of a number of drug-metabolizing enzymes in mice. In particular, CYP2A4/5 expressions were markedly down-regulated, whereas CYP2B10 was up-regulated. Positive regulation of Cyp2a4/5 and negative regulation of Cyp2b10 by CLOCK were confirmed in Hepa-1c1c7 and AML-12 cells. Based on a combination of luciferase reporter, mobility shift, and ChIP assays, we found that CLOCK activated Cyp2a4/5 transcription via specific binding to E-box elements in promoter region and repressed Cyp2b10 transcription through REV-ERBα/β (two target genes of CLOCK and transcriptional repressors of Cyp2b10 ). Furthermore, Clock ablation sensitized mice to coumarin toxicity by down-regulating CYP2A4/5-mediated metabolism (a detoxification pathway) and to cyclophosphamide toxicity by up-regulating CYP2B10-mediated metabolism (generating the toxic metabolite 4-hydroxycyclophosphamide). Conclusion and Implications CLOCK protein regulates metabolism by the cytochrome P450 family and drug detoxification. The findings improve our understanding of the crosstalk between circadian clock and drug detoxification.
研究领域:
药理学
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分子生物学
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昼夜节律
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2020
·Vol. 72
·期 12
·1854-1864
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IF 2.571
Zhao Huan,Tong Yongbin,Lu Danyi,Wu Baojian
ObjectivesWe aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity.MethodsHepatotoxicity 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 findingsHepatotoxicity 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.ConclusionsTripterygium 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.
研究领域:
药理学
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毒理学
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时间生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2023
·
IF 7.3
Luyao Ma,Fangjun Yu,Di He,Lianxia Guo,Yu Yang,Wangchun Li,Tianpeng Zhang
Background and purpose The role of CLOCK in regulation of drug chronoefficacy and chronotoxicity remains elusive. Here, we aimed to uncover the impact of CLOCK and dosing time on clopidogrel efficacy and toxicity. Experimental Approach The antiplatelet effect, toxicity and pharmacokinetics experiments were conducted with Clock −/− and wild-type mice after gavage administration of clopidogrel at different circadian time points. The expression levels of drug metabolizing enzymes were determined by qPCR and Western blotting. Transcriptional gene regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays. Key Results The antiplatelet effect and toxicity of clopidogrel in wild-type mice showed a dosing-time dependent variation. Clock ablation reduced the antiplatelet effect of clopidogrel, increased clopidogrel-induced hepatotoxicity, and blunted their rhythms. This was associated with attenuated rhythms of clopidogrel active metabolite (Clop-AM) and clopidogrel, respectively. We further found that Clock regulated the diurnal variation of Clop-AM formation by modulating the rhythmic expression of CYP1A2 and CYP3A11, and altered clopidogrel chronopharmacokinetics by circadian regulation of CES1D expression. Mechanistic studies revealed that CLOCK activated Cyp1a2 and Ces1d transcription by directly binding to the E-box elements in their promoters, and promoted Cyp3a11 transcription through enhancing the transactivation activity of DBP and TEF. Conclusion and implication CLOCK regulates the diurnal rhythmicity in clopidogrel efficacy and toxicity through regulation of CYP1A2, CYP3A11 and CES1D expression. The findings may contribute to the optimization of dosing schedule for clopidogrel, and deepen understanding of the connection between the circadian clock and chronopharmacology.
研究领域:
药理学
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生物节律学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
NEUROBIOLOGY OF DISEASE
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2024
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IF 5.1
Lu Deng,Hong Jiang,Jingjing Lin,Di Xu,Ailin Qi,Qing Guo,Ping-Ping Li,Xinshi Wang,Judy S. Liu,Xiaoqin Fu,Peijun Li
Summary Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clock flox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clock flox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.
研究领域:
神经科学
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分子生物学
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昼夜节律
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癫痫学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
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2025
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IF 4.2
Qianru Xiang,Xiao Chen,Enhui Tang,Zhi Chen,Zijun Xia,Wenzhen Liao
Current research indicates that insulin secretion deficiency in β-cells contributes to Type 2 diabetes mellitus (T2DM), which is associated with neuropeptide Y 1 receptor (Npy1r) overexpression from neuropeptide Y (NPY) system dysregulation. To date, limited literature has explored nobiletin (NOB) as a circadian modulator for restoring β-cell function through Npy1r regulation. This study investigates NOB's stimulatory effects on insulin secretion via Npy1r and clock-modulatory signaling to elucidate its underlying mechanism. The findings demonstrated that NOB ameliorated hyperglycemia and promoted insulin secretion in two distinct mouse models: T2DM induced by a high-fat diet with low-dose streptozotocin, and acute hyperglycemia triggered by NPY. Moreover, NOB reduced NPY family peptides in the serum and suppressed Npy1r overexpression in β-cells. Comprehensive investigations revealed that NOB mitigated Npy1r-mediated β-cell dysfunction through activating clock-modulatory signaling, evidenced by restored Bmal1::Luc bioluminescence rhythmicity in mouse insulinoma6 (MIN6) cells. Molecular docking confirmed a direct NOB-Npy1r interaction, while mechanistic analyses demonstrated modulation of the retinoic acid-related orphan receptors (RORs)/Bmal1-Yes-associated protein (Yap) pathway via Yap suppression and Bmal1 activation, based on the interventions with palmitic acid, BMS 193885 (Npy1r antagonist), and NPY. Therefore, this study provides evidence that NOB can protect β-cells from insulin secretion dysfunction by downregulating Npy1r expression and activating the RORs/Bmal1-Yap pathway.
研究领域:
内分泌学
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分子生物学
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时间生物学
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糖尿病研究
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药理学
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产品关联
DOI
PubMed
高影响因子
Zebrafish
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2014
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IF 1.772
Ju Wang,Changhong Liu,Fei Ma,Wei Chen,Jian Liu,Bing Hu,Lei Zheng
Zebrafish (Danio rerio) has been a widely used vertebrate animal model in developmental biology and behavioral neuroscience, but knowledge about some of its basic behaviors, for example, light/dark preference, is still controversial. Appropriate preference for light or dark environments can be crucial for an animal's survival, so we hypothesize that zebrafish may have its light/dark preference varied with the circadian clock. In this present work, we tested the hypothesis by recording the light/dark preference in a two-compartment tank continuously for over 60 h. We found that the light avoidance of fish generally increases with time from morning (8:00am) to midnight (2:00am), and then decreases with time from midnight (2:00am) to morning (8:00am), exhibiting a clear circadian-like trend in the light/dark preference. As melatonin can mediate circadian clock output and promote sleep in zebrafish, by adding extra melatonin at around 9:00am on the third day, the mean proportion of time fish spent in the dark area was increased significantly. Our results demonstrate that the circadian clock plays a significant role in regulating the light/dark preference in zebrafish, which provides valuable insights into understanding the metabolism mechanism underlying the neurobehavior, and facilitate further studies related to the neurobiology of normal and pathological behavior.
研究领域:
行为神经科学
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时间生物学
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发育生物学
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神经生物学
✓ 已验证
DOI
高影响因子
Cell Metabolism
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2025
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IF 30.9
Lianxia Guo,Yifei Xiao,Zanjin Li,Yuwei Huang,Haobin Cen,Zicong Wu,Hongbo Wang,Xinyu Liu,Zhehan Yang,Caifeng Zhao,Tingying Hao,Hui Chen,Meng Jin,Danyi Lu,Min Chen,Baojian Wu
The intestinal clock plays a role in transmitting feeding signals and generating circadian events, but how this clock system may time homeostatic processes related to sleep-wake regulation is unknown. Our functional dissections of the circadian clock in intestinal epithelial cells (IECs) demonstrate that its integrity is required for maintenance of the diurnal sleep-wake cycle. In IECs, BMAL1 generates diurnal rhythmic SLC6A19 expression that promotes intestinal absorption of glutamine during the active phase, which enhances glutamatergic neuron activities in hypothalamic nuclei and contributes to increased wakefulness and decreased sleep. The involvement of glutamine homeostasis in sleep-wake regulation is also pronounced during the rest phase, as an elevation of glutamine in the rest phase caused by IEC deficiency of REV-ERBα is causally linked to sleep abnormalities characterized by reduced sleep. Overall, the intestinal clock shapes the diurnal sleep-wake cycle through temporally gating glutamine homeostasis and serves as a potential target for boosting the sleep rhythm and for managing sleep disorders.
研究领域:
时间生物学
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神经科学
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代谢学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ELECTROANALYTICAL CHEMISTRY
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2023
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IF 4.5
Zhuo Chen,Waqar Uddin,Gang Hu,Xiaofeng Shen,Jie Yang,Lin Hu,Zhaohui Fang
In this study, we report an electrochemical method for the identification of three halates (ClO 3 − , BrO 3 − , and IO 3 − ) by using a pH clock system composed of HCHO-NaHSO 3 -Na 2 SO 3 . When equal amounts of analytes (halates) are separately added to the clock system, the increase in the induction period for the clock system is observed to be IO 3 − > BrO 3 − > ClO 3 − . Three halates are then distinguished from each other by such different perturbation effects. Furthermore, there is a linear relationship between the concentration of halates and the induction period in the range of 5.0 × 10 −4 -2.0 × 10 −3 mol/L. The quantitative analysis for halates is then to be achieved. Finally, the perturbation mechanisms of the three halates on the pH clock system are explained in detail.
研究领域:
分析化学
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环境科学
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产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Pengxuan Wang,Yuming Gao,Haoyu Yan,Zhengwu Yang,Chaoping Xu,Dawei Tang,Bo Jiang
CO 2 methanation offers a practical solution for sustainable, renewable energy storage and long-term space exploration missions. However, conventional direct solar-driven photothermal systems suffer from thermal response hysteresis and dynamic temperature fluctuations, undermining methane yield stability and limiting their applicability under high gas hourly space velocity (GHSV) conditions. Herein, a round-the-clock CO 2 methanation system is pioneered that integrates photovoltaic power generation with induction heating by a rapid-response electromagnetic metamaterial (EEM), serving as both a catalyst and a susceptor. The EMM assembles single atoms, nanoclusters, and nanotubes into a macrostructure by a 3D-printed strategy and rapidly reaches the methanation temperature of 300 °C within just 36 s at a frequency of 297 kHz with an input power of 461 W, achieving a substantially great CH 4 space-time-yield of 821 mmol g cat −1 h −1 at an ultra-high GHSV of 150 000 mL g cat −1 h −1 . The outdoor photovoltaic-driven induction heating system maintains stable production with a cumulative CH 4 output of 1373.2 L over one week, shielding the system from environmental instability. Notably, this system exhibits a solar-to-chemical energy efficiency of 13% and achieves 20% energy savings compared with conventional electric heating technologies, offering a prospective avenue for efficient and stable CO 2 methanation.
研究领域:
能源材料
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催化
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可再生能源
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化学工程
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可持续技术
✓ 已验证
产品关联
DOI
高影响因子
CURRENT BIOLOGY
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2025
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IF 7.5
Mingmin Zhou,Meijun Zheng,Xiaohang Zhang,Xin Liu,Jing Guo,Xichu Cao,Aike Guo,Yan Li
Animals display rhythmic foraging behavior synchronized with the Earth’s 24-h cycle. However, the underlying neural mechanism remains poorly understood. In this study, we found that one group of olfactory inhibitory projection neurons (iPNs) in Drosophila , called mlPN3, exhibits circadian responses to food odor and plays an essential role in promoting rhythmic foraging. We show that this circadian activity of mlPN3 neurons is driven by a rhythmic inhibition from a group of dopaminergic neurons (DANs), PAM-β'2. Furthermore, PAM-β'2 DANs are activated in the early morning by a group of circadian neurons, called morning cells, through pigment-dispersing factor (PDF) neuropeptide. Suppressing either PAM-β'2 DANs or morning cells impairs morning foraging, which is fully rescued by inhibiting mlPN3 neurons. Together, our findings show that the constant inhibition on foraging behavior of these iPNs is lifted by the circadian signal through dopaminergic suppression, providing critical insights into the function of the disinhibition circuit in circadian regulation.
研究领域:
神经科学
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时间生物学
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行为遗传学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Xuejun Jiang,Pengcheng Wu,Hui Chen,Jialu Cui,Xiting Lv,Linna Ha,Mingyang Wu,Min Chen,Baojian Wu,Haiman Xu,Dong Dong
Intestinal bowel disease (IBD), prevalent among sleep-deprived populations, is closely associated with circadian rhythm disruptions. Evidence suggests that sleep deprivation (SD) exacerbates colitis; however, the mechanisms is remains poorly understood. We subjected mice with Dextran sulfate sodium (DSS) induced acute and chronic colitis to 6 h-SD per day. It was observed that mild SD significantly aggravated both acute and chronic colitis, involving progressive body weight loss, increased Disease Activity Index (DAI), shortened colon length, histopathological deterioration, and elevated levels of inflammatory cytokines. Circadian gene screening identified PER2 as a pivotal mediator in SD aggravating colitis. Both SD and colitis independently suppressed Per2 expression in mice colon. Notably, the inhibitory effect on PER2 was most pronounced in cases of colitis accompanied by SD. Consistent with this, Per2 deficiency heightened the susceptibility of mice to DSS-induced colitis. Furthermore, transcriptomic analysis revealed that the disordered arachidonic acid (AA) metabolism pathway was implicated in the exacerbation of colitis due to Per2 deficiency. Specifically, Ptgs2 , a gene coding AA metabolism enzyme COX-2, was significantly upregulated in both Per2 -/- colitis mice and SD colitis mice. The elevated PGE 2 levels in plasma and colon supported the involvement of COX-2 mediated proinflammatory conversion of AA during episodes of SD-related colitis aggravation. Mechanistically, in vitro experiments in CT-26 cells suggested Per2 suppressed COX-2 transcription via BMAL1. In summary, SD inhibited the expression of clock factor PER2 in colon, leading to disorder of COX-2-mediated AA metabolism; this process released more pro-inflammatory mediators thereby aggravating colitis
研究领域:
免疫学
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分子生物学
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胃肠病学
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时间生物学
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炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SURFACE & COATINGS TECHNOLOGY
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2023
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IF 5.4
Xia He,Yuanduo Qu,Siqi Liao,Junkai Wang,Jinling Hu,Lianfeng Duan
A WO 3 /BiVO 4 /CdS-CdSe multistage heterojunction film with a well-matched energy band was constructed to solve the bottleneck problem of photocathodic protection technology not being able to work in round-the-clock continuous operation in practical applications. The WO 3 nanoplate as optoelectronic storage was closely combined with the BiVO 4 , which demonstrated a faster electron transfer rate, to promote photoelectron separation and transfer. Meanwhile, sensitization of CdS-CdSe quantum dots could extend light absorption to the visible region. The photoelectrochemical experiment results showed that the potential of 304 stainless steel as the protected material was negatively shifted to −1.09 V (vs. Ag/AgCl), after coupling with WO 3 /BiVO 4 /CdS-CdSe in 3.5 wt% NaCl solution under simulated sunlight (AM 1.5 G). Notably, the lower potential in this system could also remain for 7 h without the sunlight to achieve round-the-clock photocathodic corrosion protection .
研究领域:
材料科学
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电化学
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能源科学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）