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REV-ERB agonist

Marie Pariollaud, Julie Gibbs, Thomas Hopwood, Sheila Brown, Nicola Begley, Ryan Vonslow, Toryn Poolman, Baoqiang Guo, Ben Saer, D Heulyn Jones, James P Tellam, Stefano Bresciani, Nicholas Co Tomkinson, Justyna Wojno-Picon, Anthony Wj Cooper, Dion A Daniels, Ryan P Trump, Daniel Grant, William Zuercher, Timothy M Willson, Andrew S MacDonald, Brian Bolognese, Patricia L Podolin, Yolanda Sanchez, Andrew Si Loudon, David W Ray
Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERB as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid, and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous pro-inflammatory mechanism in un-challenged cells...
March 13, 2018: Journal of Clinical Investigation
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
Chao Song, Peng Tan, Zheng Zhang, Wei Wu, Yonghui Dong, Liming Zhao, Huiyong Liu, Hanfeng Guan, Feng Li
REV-ERBs (REV-ERBα and REV-ERBβ) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs)...
January 22, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Ariadna Amador, Theodore M Kamenecka, Laura A Solt, Thomas P Burris
Circadian signaling regulates and synchronizes physiological and behavioral processes, such as feeding, metabolism, and sleep cycles. The endogenous molecular machinery that regulates circadian activities is located in the suprachiasmatic nucleus of the hypothalamus. The REV-ERBs are transcription factors that play key roles in the regulation of the circadian clock and metabolism. Using pharmacological methods, we recently demonstrated the involvement of the REV-ERBs in sleep architecture. Another group reported a delayed response to sleep deprivation and altered sleep cycles in REV-ERBα null mice, indicating a role of REV-ERBα in sleep...
January 17, 2018: Biochemical Pharmacology
(no author information available yet)
Disruption of the circadian clock components reduces cancer cell viability in vitro and in vivo.
January 19, 2018: Cancer Discovery
Sarbani Ghoshal, Joseph R Stevens, Cyrielle Billon, Clemence Girardet, Sadichha Sitaula, Arthur S Leon, D C Rao, James S Skinner, Tuomo Rankinen, Claude Bouchard, Marinelle V Nuñez, Kimber L Stanhope, Deborah A Howatt, Alan Daugherty, Jinsong Zhang, Matthew Schuelke, Edward P Weiss, Alisha R Coffey, Brian J Bennett, Praveen Sethupathy, Thomas P Burris, Peter J Havel, Andrew A Butler
OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models...
December 30, 2017: Molecular Metabolism
Gabriele Sulli, Amy Rommel, Xiaojie Wang, Matthew J Kolar, Francesca Puca, Alan Saghatelian, Maksim V Plikus, Inder M Verma, Satchidananda Panda
The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock...
January 18, 2018: Nature
Endin Nokik Stujanna, Nobuyuki Murakoshi, Kazuko Tajiri, DongZhu Xu, Taizo Kimura, Rujie Qin, Duo Feng, Saori Yonebayashi, Yukino Ogura, Fumi Yamagami, Akira Sato, Akihiko Nogami, Kazutaka Aonuma
Rev-erb α, known as nuclear receptor 1D1 (NR1D1), regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI) and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day) or vehicle was intraperitoneally administered...
2017: PloS One
Yvonne Westermaier, Sergio Ruiz-Carmona, Isabelle Theret, Françoise Perron-Sierra, Guillaume Poissonnet, Catherine Dacquet, Jean A Boutin, Pierre Ducrot, Xavier Barril
The knowledge of the free energy of binding of small molecules to a macromolecular target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a molecular dynamics (MD)-based approach can be used to predict the free energy of small molecules, and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERBα with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines molecular docking, molecular dynamics (MD), solvent-accessible surface area (SASA) and molecular mechanics poisson boltzmann surface area (MMPBSA) calculations...
August 2017: Journal of Computer-aided Molecular Design
Faisal J Alibhai, Jonathan LaMarre, Cristine J Reitz, Elena V Tsimakouridze, Jeffrey T Kroetsch, Steffen-Sebastian Bolz, Alex Shulman, Samantha Steinberg, Thomas P Burris, Gavin Y Oudit, Tami A Martino
The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. Clock(Δ19/Δ19) mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness...
April 2017: Journal of Molecular and Cellular Cardiology
Sadichha Sitaula, Jinsong Zhang, Fernanda Ruiz, Thomas P Burris
REV-ERBα and REV-ERBβ are heme regulated nuclear receptors that are known to regulate metabolic pathways. We previously demonstrated that treatment of mice with synthetic REV-ERB agonists suppressed plasma cholesterol levels and the hepatic levels of the rate limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-CoA reductase). Here, we characterize the role of REV-ERB on the cholesterol biosynthetic pathway in greater detail. The REV-ERB agonist SR9009 reduced plasma cholesterol levels in both wild type C57Bl/6 and low density lipoprotein receptor (LDLR) null mice as well as reducing the expression of an array of genes within the cholesterol biosynthetic pathway...
May 1, 2017: Biochemical Pharmacology
Paul G Thomes, Elizabeth Brandon-Warner, Ting Li, Terrence M Donohue, Laura W Schrum
Our data describe autophagic flux in primary rat hepatic stellate cells (rHSCs) treated with pro-fibrotic growth factor, transforming growth factor beta (TGF-β). An autophagy flux experiment determines the rate of synthesis and degradation of the autophagosome marker, LC3-II in the presence and absence of the lysosomal inhibitor bafilomcyin, which blocks LC3-II degradation in lysosomes. The effects of a test agent on LC3-II flux through the autophagic pathway is determined immunochemically by its relative amounts detected in lysates of cells treated with and without bafilomycin...
February 2017: Data in Brief
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
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
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
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
Yoshio Inouye
Animal defense mechanisms against both endogenous and exogenous toxic compounds function mainly through receptor-type transcription factors, including the constitutive androstane receptor (CAR). Following xenobiotic stimulation, CAR translocates into the nucleus and transactivates its target genes including oxygenic and conjugative enzymes and transporters in hepatocytes. We identified subcellular localization signals in the rat CAR: two nuclear localization signals (NLS1 and 2); two nuclear export signals (NES1 and 2); and a cytoplasmic retention region...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Jiyeon Lee, Seungbeom Lee, Sooyoung Chung, Noheon Park, Gi Hoon Son, Hongchan An, Jaebong Jang, Dong-Jo Chang, Young-Ger Suh, Kyungjin Kim
Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by an innate genetically determined time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, development of small molecule modulators targeting the core clock machinery has only recently been initiated. BMAL1, a core clock gene, is controlled by a ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock...
January 15, 2016: Biochemical and Biophysical Research Communications
Norimitsu Morioka, Mizuki Tomori, Fang Fang Zhang, Munenori Saeki, Kazue Hisaoka-Nakashima, Yoshihiro Nakata
Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF)...
January 8, 2016: Biochemical and Biophysical Research Communications
Yongjun Wang, Douglas Kojetin, Thomas P Burris
REV-ERBα and REV-ERBβ are nuclear receptors that are ligand-dependent transcriptional repressors. Heme is the natural ligand for these receptors, but several synthetic agonists and antagonists have been designed recently. The gene that encodes REV-ERBα, NR1D1, is closely associated with ERBB2, the gene that encodes the HER2 oncogene, which is amplified in HER2(+) breast cancers. We examined the effect of a synthetic REV-ERB agonist, SR9011, on a range of estrogen receptor positive (ER(+)), ER(-), HER2(+), HER2(-) and triple negative breast cancer cell lines...
August 15, 2015: Biochemical Pharmacology
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