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Aurore Quinault, Corinne Leloup, Geoffrey Denwood, Coralie Spiegelhalter, Marianne Rodriguez, Philippe Lefebvre, Nadia Messaddeq, Quan Zhang, Catherine Dacquet, Luc Pénicaud, Stephan C Collins
The rhythmic nature of insulin secretion over the 24h cycle in pancreatic islets has been mostly investigated using transcriptomics studies showing that modulation of insulin secretion over this cycle is achieved via distal stages of insulin secretion. We set out to measure β-cell exocytosis using in depth cell physiology techniques at several time points. In agreement with the activity and feeding pattern of nocturnal rodents, we find that C57/Bl6J islets in culture for 24h exhibit higher insulin secretion during the corresponding dark phase than in the light phase (Zeitgeber Time ZT20 and ZT8, respectively, in vivo)...
2018: PloS One
Jihwan Myung, Christoph Schmal, Sungho Hong, Yoshiaki Tsukizawa, Pia Rose, Yong Zhang, Michael J Holtzman, Erik De Schutter, Hanspeter Herzel, Grigory Bordyugov, Toru Takumi
Mammalian circadian clocks have a hierarchical organization, governed by the suprachiasmatic nucleus (SCN) in the hypothalamus. The brain itself contains multiple loci that maintain autonomous circadian rhythmicity, but the contribution of the non-SCN clocks to this hierarchy remains unclear. We examine circadian oscillations of clock gene expression in various brain loci and discovered that in mouse, robust, higher amplitude, relatively faster oscillations occur in the choroid plexus (CP) compared to the SCN...
March 14, 2018: Nature Communications
Ning Wei, Michelle L Gumz, Anita T Layton
Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock, and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na$^+$-H$^+$ exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins...
March 14, 2018: American Journal of Physiology. Renal Physiology
Jaebong Jang, Sooyoung Chung, Youjeong Choi, Hye Young Lim, Yeongeon Son, Sung Kook Chun, Gi Hoon Son, Kyungjin Kim, Young-Ger Suh, Jong-Wha Jung
AIMS: We have previously identified a chemical scaffold possessing 2-ethoxypropanoic acid (designated as KS15) that directly binds to the C-terminal region of cryptochromes (CRYs: CRY1 and CRY2) and enhances E-box-mediated transcription. However, it is still unclear how KS15 impairs the feedback actions of the CRYs and which chemical moieties are functionally important for its actions. MAIN METHODS: The E-box-mediated transcriptional activities were mainly used to examine the effects of KS15 and its derivatives...
March 10, 2018: Life Sciences
Deqiang Zhang, Xin Tong, Bradley B Nelson, Ethan Jin, Julian Sit, Nicholas Charney, Meichan Yang, M Bishr Omary, Lei Yin
Alcohol liver disease (ALD) is one of the major chronic liver diseases worldwide, ranging from fatty liver, alcoholic hepatitis, cirrhosis, and potentially hepatocellular carcinoma. Epidemiological studies suggest a potential link between ALD and impaired circadian rhythms, but the role of hepatic circadian proteins in the pathogenesis of ALD remains unknown. Here we show that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect mice from alcohol liver disease. Ethanol diet-fed mice with liver-specific knockout (Bmal1-LKO) or depletion of Bmal1 develop more severe liver steatosis and injury as well as a simultaneous suppression of both de novo lipogenesis and fatty acid oxidation, which can be rescued by the supplementation of synthetic PPARα ligands...
March 13, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Ha Kyun Kim, Hyun Jung Kim, Jae Hyung Kim, Tae Hoon Kim, Sang Hag Lee
Numerous peripheral tissues possess self-sustaining daily biologic rhythms that are regulated at the molecular level by clock genes such as PER1, PER2, CLOCK, and BMAL1. Physiological function of nasal mucosa exhibits rhythmic variability to a day-night environmental cycle. Nevertheless, little is known of the expression and distribution pattern of clock genes in nasal mucosa. The present study investigates the expression level and distribution pattern of PER1, PER2, CLOCK, and BMAL1 genes in nasal mucosa of healthy controls, allergic rhinitis patients, and normal rats...
2018: PloS One
Tim S Nawrot, Nelly D Saenen, Julie Schenk, Bram G Janssen, Valeria Motta, Letizia Tarantini, Bianca Cox, Wouter Lefebvre, Charlotte Vanpoucke, Cristina Maggioni, Valentina Bollati
In mammals, a central clock maintains the daily rhythm in accordance with the external environment. At the molecular level, the circadian rhythm is maintained by epigenetic regulation of the Circadian pathway. Here, we tested the role of particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM2.5 ) exposure during gestational life on human placental Circadian pathway methylation, as an important molecular target for healthy development. In 407 newborns, we quantified placental methylation of CpG sites within the promoter regions of the following genes: CLOCK, BMAL1, NPAS2, CRY1-2 and PER1-3 using bisulfite-PCR-pyrosequencing...
March 7, 2018: Environment International
Fuyuki Sato, Akira Kohsaka, Ujjal K Bhawal, Yasuteru Muragaki
The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism...
March 8, 2018: International Journal of Molecular Sciences
Yuki Ohba, Hajime Tei
Circadian rhythms are generated by the cyclic expression of several clock genes in mammals. The rhythmic expression of these genes is maintained by multiple transcriptional-translational feedback loops in addition to the posttranslational regulation of the clock proteins. Transcription of one of the key clock genes, Bmal1, which exhibits a nocturnal transcriptional rhythm in the suprachiasmatic nucleus of the mouse brain, is induced and repressed by RORs and REV-ERBs, respectively. Thus, the dynamics of the RORs and REV-ERBs expression, modification, subcellular localization and degradation of these transcriptional factors are critical for the transcriptional regulation of Bmal1...
March 6, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Guoyuan Qi, Rui Guo, Haoyu Tian, Lixia Li, Hua Liu, Yashi Mi, Xuebo Liu
SCOPE: Circadian clock plays a principal role in orchestrating our daily physiology and metabolism, and their perturbation can evoke metabolic diseases such as fatty liver and insulin resistance. Nobiletin (NOB) has been demonstrated to possess antitumor and neuroprotective activities. The objective of the current study is to determine potential effects of NOB on modulating the core clock gene Bmal1 regarding ameliorating glucolipid metabolic disorders. RESULTS: Our results revealed that NOB partially reverse the relatively shallow daily oscillations of circadian clock genes and reset phase-shifting circadian rhythms in primary hepatocytes under metabolic disorders conditions...
February 28, 2018: Biochimica et Biophysica Acta
Kuntol Rakshit, Jingyi Qian, Krutika Satish Gaonkar, Sangeeta Dhawan, Christopher S Colwell, Aleksey V Matveyenko
Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of β-cell maturation. Circadian clock regulates diverse cellular functions important for regulation of β-cell function and turnover. However postnatal ontogenesis of the islet circadian clock and its potential role in β-cell maturation remain unknown. To address this, we studied wild type Sprague Dawley as well as Period1 luciferase transgenic rats ( Per1 :LUC) to determine circadian clock function, clock protein expression and diurnal insulin secretion during islet development and maturation process...
March 2, 2018: Diabetes
Thomas W Hopwood, Sarah Hall, Nicola Begley, Ruth Forman, Sheila Brown, Ryan Vonslow, Ben Saer, Matthew C Little, Emma A Murphy, Rebecca J Hurst, David W Ray, Andrew S MacDonald, Andy Brass, David A Bechtold, Julie E Gibbs, Andrew S Loudon, Kathryn J Else
Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH 2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH 2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics...
February 28, 2018: Scientific Reports
Ryan S Wible, Chidambaram Ramanathan, Carrie Hayes Sutter, Kristin M Olesen, Thomas W Kensler, Andrew C Liu, Thomas R Sutter
Diurnal oscillation of intracellular redox potential is known to couple metabolism with the circadian clock, yet the responsible mechanisms are not well understood. We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells...
February 26, 2018: ELife
Vaskar Das, Ranjan Kc, Xin Li, Disha Varma, Sujun Qiu, Jeffrey S Kroin, Christopher B Forsyth, Ali Keshavarzian, Andre J van Wijnen, Thomas J Park, Gary S Stein, Insug O-Sullivan, Thomas P Burris, Hee-Jeong Im
Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee...
February 20, 2018: Gene
Dongkai Guo, Shun Zhang, Hongyang Sun, Xingyun Xu, Zongbing Hao, Chenchen Mu, Xingshun Xu, Guanghui Wang, Haigang Ren
Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders such as schizophrenia, depression, autism, and Joubert syndrome. Ahi1 deficiency in mice leads to behaviors typical of depression. However, the mechanisms by which AHI1 regulates behavior remain to be elucidated. Here, we found that down-regulation of expression of the rate-limiting enzyme in dopamine biosynthesis, tyrosine hydroxylase (TH), in the midbrains of Ahi1 -knockout (KO) mice is responsible for Ahi1 -deficiency-mediated depressive symptoms...
February 15, 2018: Journal of Biological Chemistry
Afaf Akladious, Sausan Azzam, Yufen Hu, Pingfu Feng
OBJECTIVE: To determine the effect of Bmal1 knockdown (KD) on sleep, activity, immobility, hypothalamic levels of orexin, corticotrophin-releasing hormone (CRH), and GABAergic glutamate decarboxylase (GAD). METHODS: We used Bmal1 siRNA, or control siRNA intracerebroventricular (ICV) injection to knock down Bmal1 in C57BL/6 mice. Sleep polysomnography, wheel-running activity, and tail suspension test were performed. Polysomnographic (PSG) recordings in both groups were preceded by ICV injection made during both the light phase and the dark phase...
February 14, 2018: CNS Neuroscience & Therapeutics
Hortensia Ferrero, Patricia Diaz-Gimeno, Patricia Sebastian-Leon, Amparo Faus, Raul Gómez, Antonio Pellicer
Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like Cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2...
February 9, 2018: Reproduction: the Official Journal of the Society for the Study of Fertility
Jenny Lutshumba, Shu Liu, Yu Zhong, Tianfei Hou, Alan Daugherty, Hong Lu, Zhenheng Guo, Ming C Gong
OBJECTIVE: Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development. APPROACH AND RESULTS: SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone when provided with high salt and (2) angiotensin II infusion in hypercholesterolemia mice...
February 8, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Jingkui Wang, Laura Symul, Jake Yeung, Cédric Gobet, Jonathan Sobel, Sarah Lück, Pål O Westermark, Nacho Molina, Felix Naef
The mammalian circadian clock coordinates physiology with environmental cycles through the regulation of daily oscillations of gene expression. Thousands of transcripts exhibit rhythmic accumulations across mouse tissues, as determined by the balance of their synthesis and degradation. While diurnally rhythmic transcription regulation is well studied and often thought to be the main factor generating rhythmic mRNA accumulation, the extent of rhythmic posttranscriptional regulation is debated, and the kinetic parameters (e...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Weiliang Jiang, Senlin Zhao, Jia Shen, Lihong Guo, Yi Sun, Yuntian Zhu, Zhixiong Ma, Xin Zhang, Yangyang Hu, Wenqin Xiao, Kai Li, Sisi Li, Li Zhou, Li Huang, Zhanjun Lu, Yun Feng, Junhua Xiao, Eric Erquan Zhang, Lijuan Yang, Rong Wan
Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3'-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies...
February 2, 2018: Cell Death & Disease
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