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https://www.readbyqxmd.com/read/27893989/drug-discovery-targeting-heme-based-sensors-and-their-coupled-activities
#1
Eduardo Henrique Silva Sousa, Luiz Gonzaga de França Lopes, Gonzalo Gonzalez, Marie-Alda Gilles-Gonzalez
Heme-based sensors have emerged during the last 20years as being a large family of proteins that occur in all kingdoms of life. A myriad of biological adaptations are associated with these sensors, which include vasodilation, bacterial virulence, dormancy, chemotaxis, biofilm formation, among others. Due to the key activities regulated by these proteins along with many other systems that use similar output domains, there is a growing interest in developing small molecules as their regulators. Here, we review the development of potential activators and inhibitors for many of these systems, including human soluble guanylate cyclase, c-di-GMP-related enzymes, Mycobacterium tuberculosis DevR/DevS/DosT (differentially expressed in virulent strain response regulator/sensor/dormancysurvival sensorT), the Rev-erb-α and β nuclear receptor, among others...
November 20, 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/27760313/a-mathematical-model-of-the-liver-circadian-clock-linking-feeding-and-fasting-cycles-to-clock-function
#2
Aurore Woller, Hélène Duez, Bart Staels, Marc Lefranc
To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27726182/the-intrinsic-microglial-clock-system-regulates-interleukin-6-expression
#3
Ryota Nakazato, Shogo Hotta, Daisuke Yamada, Miki Kou, Saki Nakamura, Yoshifumi Takahata, Hajime Tei, Rika Numano, Akiko Hida, Shigeki Shimba, Michihiro Mieda, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada
Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells...
October 11, 2016: Glia
https://www.readbyqxmd.com/read/27706103/in-vitro-metabolic-studies-of-rev-erb-agonists-sr9009-and-sr9011
#4
Lore Geldof, Koen Deventer, Kris Roels, Eva Tudela, Peter Van Eeno
SR9009 and SR9011 are attractive as performance-enhancing substances due to their REV-ERB agonist effects and thus circadian rhythm modulation activity. Although no pharmaceutical preparations are available yet, illicit use of SR9009 and SR9011 for doping purposes can be anticipated, especially since SR9009 is marketed in illicit products. Therefore, the aim was to identify potential diagnostic metabolites via in vitro metabolic studies to ensure effective (doping) control. The presence of SR9009 could be demonstrated in a black market product purchased over the Internet...
October 3, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27603791/pharmacological-targeting-the-rev-erbs-in-sleep-wake-regulation
#5
Ariadna Amador, Salvador Huitron-Resendiz, Amanda J Roberts, Theodore M Kamenecka, Laura A Solt, Thomas P Burris
The circadian clock maintains appropriate timing for a wide range of behaviors and physiological processes. Circadian behaviors such as sleep and wakefulness are intrinsically dependent on the precise oscillation of the endogenous molecular machinery that regulates the circadian clock. The identical core clock machinery regulates myriad endocrine and metabolic functions providing a link between sleep and metabolic health. The REV-ERBs (REV-ERBα and REV-ERBβ) are nuclear receptors that are key regulators of the molecular clock and have been successfully targeted using small molecule ligands...
2016: PloS One
https://www.readbyqxmd.com/read/27592634/dim-light-at-night-prior-to-adolescence-increases-adult-anxiety-like-behaviors
#6
Yasmine M Cissé, Juan Peng, Randy J Nelson
Dim light at night (dLAN) disrupts circadian organization and influences adult behavior. We examined early dLAN exposure on adult affective responses. Beginning 3 (juvenile) or 5 weeks (adolescent) of age, mice were maintained in standard light-dark cycles or exposed to nightly dLAN (5 lx) for 5 weeks, then anxiety-like and fear responses were assessed. Hypothalami were collected around the clock to assess core clock genes. Exposure to dLAN at either age increased anxiety-like responses in adults. Clock and Rev-ERB expression were altered by exposure to dLAN...
2016: Chronobiology International
https://www.readbyqxmd.com/read/27462873/tissue-damage-drives-co-localization-of-nf-%C3%AE%C2%BAb-smad3-and-nrf2-to-direct-rev-erb-sensitive-wound-repair-in-mouse-macrophages
#7
Dawn Z Eichenfield, Ty Dale Troutman, Verena M Link, Michael T Lam, Han Cho, David Gosselin, Nathanael J Spann, Hanna P Lesch, Jenhan Tao, Jun Muto, Richard L Gallo, Ronald M Evans, Christopher K Glass
Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS)...
2016: ELife
https://www.readbyqxmd.com/read/27356935/nuclear-receptors-in-hepatic-glucose-and-lipid-metabolism-during-neonatal-and-adult-life
#8
Demin Cai, Haoyu Liu, Ruqian Zhao
Research efforts focusing on metabolic diseases have established a close conjunction between glucolipid abnormalities and nuclear receptors, a large superfamily of receptors including classic peroxisome proliferation-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs) and glucocorticoid receptors (GRs) together with burgeoning retinoic acid receptor-related orphan receptors (RORs) and REV-ERBs. Nuclear receptors are identified to control a series of physiological and pathological processes of glucose and lipid metabolism and also implicated to mediate the long-term effects of early environmental and nutritional experiences on the formation of adult chronic metabolic disorders in human and animals...
June 26, 2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/27324142/circadian-genes-and-lithium-response-in-bipolar-disorders-associations-with-ppargc1a-pgc-1%C3%AE-and-rora
#9
P A Geoffroy, B Etain, M Lajnef, E-H Zerdazi, C Brichant-Petitjean, U Heilbronner, L Hou, F Degenhardt, M Rietschel, F J McMahon, T G Schulze, S Jamain, C Marie-Claire, F Bellivier
Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted...
September 2016: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/27285327/the-regulation-of-fgf21-gene-expression-by-metabolic-factors-and-nutrients
#10
Anjeza Erickson, Régis Moreau
Fibroblast growth factor 21 (FGF21) gene expression is altered by a wide array of physiological, metabolic, and environmental factors. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain fatty acids (butyric acid and lipoic acid), and all-trans-retinoic acid were repeatedly shown to induce FGF21 expression and circulating levels. These effects are usually more pronounced in liver or isolated hepatocytes than in adipose tissue or isolated fat cells. Although peroxisome proliferator-activated receptor α (PPARα) is a key mediator of hepatic FGF21 expression and function, including the regulation of gluconeogenesis, ketogenesis, torpor, and growth inhibition, there is increasing evidence of PPARα-independent transactivation of the FGF21 gene by dietary molecules...
June 10, 2016: Hormone Molecular Biology and Clinical Investigation
https://www.readbyqxmd.com/read/27195801/correction-pharmacological-and-genetic-modulation-of-rev-erb-activity-and-expression-affects-orexigenic-gene-expression
#11
Ariadna Amador, Yongjun Wang, Subhashis Banerjee, Theodore M Kamenecka, Laura A Solt, Thomas P Burris
[This corrects the article DOI: 10.1371/journal.pone.0151014.].
2016: PloS One
https://www.readbyqxmd.com/read/27194331/identification-of-a-circadian-clock-in-the-inferior-colliculus-and-its-dysregulation-by-noise-exposure
#12
Jung-Sub Park, Christopher R Cederroth, Vasiliki Basinou, Inna Meltser, Gabriella Lundkvist, Barbara Canlon
UNLABELLED: Circadian rhythms regulate bodily functions within 24 h and long-term disruptions in these rhythms can cause various diseases. Recently, the peripheral auditory organ, the cochlea, has been shown to contain a self-sustained circadian clock that regulates differential sensitivity to noise exposure throughout the day. Animals exposed to noise during the night are more vulnerable than when exposed during the day. However, whether other structures throughout the auditory pathway also possess a circadian clock remains unknown...
May 18, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27171500/the-circadian-clock-regulates-autophagy-directly-through-the-nuclear-hormone-receptor-nr1d1-rev-erb%C3%AE-and-indirectly-via-cebpb-c-ebp%C3%AE-in-zebrafish
#13
Guodong Huang, Fanmiao Zhang, Qiang Ye, Han Wang
Autophagy is a highly conserved intracellular degradation system, and recently was shown to display circadian rhythms in mice. The mechanisms underlying circadian regulation of autophagy, however, are still unclear. Here, we observed that numbers of autophagosomes and autolysosomes exhibit daily rhythms in the zebrafish liver, and cebpb/(c/ebpβ) and various autophagy genes are rhythmically expressed in zebrafish larvae but significantly upregulated in per1b and TALEN-generated nr1d1/rev-erbα mutant fish, indicating that both Per1b and Nr1d1 play critical roles in autophagy rhythms...
August 2, 2016: Autophagy
https://www.readbyqxmd.com/read/27143721/nuclear-receptor-rev-erb%C3%AE-mediates-circadian-sensitivity-to-mortality-in-murine-vesicular-stomatitis-virus-induced-encephalitis
#14
Khatuna Gagnidze, Kaitlyn H Hajdarovic, Marina Moskalenko, Ilia N Karatsoreos, Bruce S McEwen, Karen Bulloch
Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0)...
May 17, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27132483/altered-circadian-clock-gene-expression-in-patients-with-schizophrenia
#15
Anne-Sofie Johansson, Björn Owe-Larsson, Jerker Hetta, Gabriella B Lundkvist
Impaired circadian rhythmicity has been reported in several psychiatric disorders. Schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα and DBP...
July 2016: Schizophrenia Research
https://www.readbyqxmd.com/read/27068699/diurnal-regulation-of-hypothalamic-kisspeptin-is-disrupted-during-mouse-pregnancy
#16
Cassandra C Yap, Michaela D Wharfe, Peter J Mark, Brendan J Waddell, Jeremy T Smith
Kisspeptin, the neuropeptide product of the Kiss1 gene, is critical in driving the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (Arc) of the hypothalamus mediate differential effects, with the Arc regulating negative feedback of sex steroids and the AVPV regulating positive feedback, vital for the preovulatory surge and gated under circadian control. We aimed to characterize hypothalamic Kiss1 and Kiss1r mRNA expression in nonpregnant and pregnant mice, and investigate potential circadian regulation...
June 2016: Journal of Endocrinology
https://www.readbyqxmd.com/read/27040510/altered-cellular-redox-status-sirtuin-abundance-and-clock-gene-expression-in-a-mouse-model-of-developmentally-primed-nash
#17
Kimberley D Bruce, Dawid Szczepankiewicz, Kiran K Sihota, Manoj Ravindraanandan, Hugh Thomas, Karen A Lillycrop, Graham C Burdge, Mark A Hanson, Christopher D Byrne, Felino R Cagampang
BACKGROUND: We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear. AIMS: Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life. METHODS: Female mice were fed either a control (C, 7%kcal fat) or HF (45%kcal fat) diet...
July 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27038650/a-validated-ultra-performance-liquid-chromatography-tandem-mass-spectrometry-method-to-identify-the-pharmacokinetics-of-sr8278-in-normal-and-streptozotocin-induced-diabetic-rats
#18
Dong Dong, Hua Sun, Zhufeng Wu, Baojian Wu, Yunxia Xue, Zhijie Li
There is a relationship between circadian rhythm and metabolic disorders. The active agent, SR8278, could competitively bind to and inhibit the nuclear receptor, Rev-erb (a major modulator of mammalian circadian clock system), to regulate the metabolism in organisms. However, we had limited knowledge of the pharmacokinetic (PK) characteristics of SR8278. Here, we describe a sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify SR8278 in vivo...
May 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27002153/the-nuclear-receptor-rev-erb%C3%AE-regulates-adipose-tissue-specific-fgf21-signaling
#19
Jennifer Jager, Fenfen Wang, Bin Fang, Hee-Woong Lim, Lindsey C Peed, David J Steger, Kyoung-Jae Won, Alexei Kharitonenkov, Andrew C Adams, Mitchell A Lazar
FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver...
May 13, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26972823/brown-adipose-tissue-exhibits-a-glucose-responsive-thermogenic-biorhythm-in-humans
#20
Paul Lee, Ron Bova, Lynne Schofield, Wendy Bryant, William Dieckmann, Anthony Slattery, Matt A Govendir, Louise Emmett, Jerry R Greenfield
High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms...
April 12, 2016: Cell Metabolism
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