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Chao Yu Zhen, Roubina Tatavosian, Thao Ngoc Huynh, Huy Nguyen Duc, Raibatak Das, Marko Kokotovic, Jonathan B Grimm, Luke D Lavis, Jun Lee, Frances J Mejia, Yang Li, Tingting Yao, Xiaojun Ren
The Polycomb PRC1 plays essential roles in development and disease pathogenesis. Targeting of PRC1 to chromatin is thought to be mediated by the Cbx family proteins (Cbx2/4/6/7/8) binding to histone H3 with a K27me3 modification (H3K27me3). Despite this prevailing view, the molecular mechanisms of targeting remain poorly understood. Here, by combining live-cell single-molecule tracking (SMT) and genetic engineering, we reveal that H3K27me3 contributes significantly to the targeting of Cbx7 and Cbx8 to chromatin, but less to Cbx2, Cbx4, and Cbx6...
October 10, 2016: ELife
Soshi Seike, Masaya Takehara, Keiko Kobayashi, Masahiro Nagahama
BACKGROUND: Beta-toxin produced by Clostridium perfringens is a key virulence factor of fatal hemorrhagic enterocolitis and enterotoxemia. This toxin belongs to a family of β-pore-forming toxins (PFTs). We reported recently that the ATP-gated P2X7 receptor interacts with beta-toxin. The ATP-release channel pannexin 1 (Panx1) is an important contributor to P2X7 receptor signaling. Hence, we investigated the involvement of Panx1 in beta-toxin-caused cell death. METHODS: We examined the effect of Panx1 in beta-toxin-induced cell death utilizing selective antagonists, knockdown of Panx1, and binding using dot-blot analysis...
October 5, 2016: Biochimica et Biophysica Acta
Patrycja Orlowska-Feuer, Jagoda S Jeczmien-Lazur, Hanna J Szkudlarek, Marian H Lewandowski
A subpopulation of olivary pretectal nucleus (OPN) neurons fire action potentials in a rhythmic manner with an eruption of activity occurring approximately every two minutes. These infra-slow oscillations depend critically on functional retinal input and are subject to modulation by light. Interestingly, the activity of photoreceptors is necessary for the emergence of the rhythm and while classic photoreceptors (rods and cones) are necessary in darkness and dim light, melanopsin photoreceptors are indispensable in bright light...
September 28, 2016: Neuroscience
Hiroki Koizumi, Shoji Ikezaki, Toyoaki Ohbuchi, Ba Hung Do, Nobusuke Hohchi, Rintaro Kawaguchi, Takuro Kitamura, Hideaki Suzuki
OBJECTIVE: The present study aimed at investigating ATP release in response to acetylcholine (Ach) and pharmacologically elucidating the intracellular signal transduction pathway of this reaction in an ex vivo experiment. METHODS: The inferior turbinate mucosa was collected from 21 patients with chronic hypertrophic rhinitis who underwent endoscopic turbinectomy. The mucosa was shaped into a filmy round piece, and incubated with chemical(s) in Hank's balanced salt solution for 10min...
September 27, 2016: Auris, Nasus, Larynx
Yutaka Shishikura, Akira Koarai, Hiroyuki Aizawa, Mutsuo Yamaya, Hisatoshi Sugiura, Mika Watanabe, Yuichiro Hashimoto, Tadahisa Numakura, Tomonori Makiguti, Kyoko Abe, Mituhiro Yamada, Toshiaki Kikuchi, Yasushi Hoshikawa, Yoshinori Okada, Masakazu Ichinose
BACKGROUND: In response to tissue damage or inflammation, adenosine-5'-triphosphate (ATP) is released into the extracellular compartment and has been demonstrated to augment inflammation via purinergic P2 receptors (P2Rs). Recently, ATP has been shown to be increased in the airways of COPD patients. In the present study, we examined the possible involvement of extracellular ATP in airway mucus hypersecretion during viral-induced COPD exacerbations. METHODS: The involvement of extracellular ATP in the release of a major airway mucin, MUC5AC, and its signal pathway was examined after stimulation with polyinosine-polycytidylic acid [poly(I:C)], a synthetic analog of dsRNA to mimic viral infection, and rhinovirus (RV) infection in NCI-H292 cells and differentiated airway epithelial cells from COPD patients...
September 27, 2016: Respiratory Research
Lluis Morey, Luciano Di Croce
PRC1 complexes contain four core subunits: Pcgf, Phc, Ring1, and Cbx proteins. Interestingly, mammalian genomes have several paralogues for each subunit, which are differentially expressed depending on the cell type, differentiation program, and cellular stimuli. Therefore, identification and characterization of the specific architecture of different PRC1 complexes during cellular differentiation are essential to better understand the function and recruitment mechanism of PRC1 complexes. In this chapter we describe several methods to study Polycomb architecture, and identification of novel interactors in both pluripotent and differentiating mouse embryonic stem cells...
2016: Methods in Molecular Biology
Mateus R Amorim, Leni G H Bonagamba, George M P R Souza, Davi J A Moraes, Benedito H Machado
Sino-aortic denervated (SAD) rats present mean arterial pressure (MAP) similar to control rats. Since respiration modulates MAP, we hypothesized that conscious SAD rats present respiratory changes associated with the normal MAP. In this study we evaluated the cardiovascular and respiratory activities and arterial blood gases in control and SAD rats. Male juvenile Wistar rats (P19-P21) were submitted to SAD, sham surgery, or selective carotid bodies removal (CBX) and the three groups were evaluated 10 days after the surgery (SAD, n = 21, Sham, n = 18, CBX, n = 13)...
September 12, 2016: Experimental Physiology
Xing-Yong Liu, Xian-Bo Zhang, Ming-Hui Li, Shu-Qing Zheng, Zhi-Long Liu, Yun-Ying Cheng, De-Shou Wang
Chromobox (Cbx) family proteins are transcriptional repressors that involved in epigenetic and developmental processes. In this study, comprehensive analyses of Cbxs were performed using available genome databases from representative animal species. The Cbx family were originated from one Polycomb (Pc) gene like the yeast Pc, which duplicated into two and gave rise to the Pc and the Heterochromatin protein 1 (Hp1) identified in invertebrates from protozoon to lancelet. Rapid expansion of Cbx family members was observed in vertebrates as ~8 (5 Pc and 3 Hp1) were identified in spotted gar, coelacanth and tetrapods...
September 7, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Xiaowei Tai, Yang Wang, Li Zhang, Yuting Yang, Kairong Shi, Shaobo Ruan, Yayuan Liu, Huile Gao, Zhirong Zhang, Qin He
Cabazitaxel (CBX) is an effective antineoplastic agent for the treatment of many kinds of cancers. However, the poor water solubility remains a serious deterrent to the utilization of CBX as a commercial drug. In this study, we designed a strategy that integrated CBX into albumin nanoparticles (ANs) formed with human serum albumin (HSA) to improve the water solubility and targeting ability. Meanwhile, we utilized a photothermal agent-indocyanine green (ICG), which could cooperate with CBX to enhance the antitumor effect...
October 2, 2016: Journal of Drug Targeting
Jacob I Stuckey, Catherine Simpson, Jacqueline L Norris-Drouin, Stephanie H Cholensky, Junghyun Lee, Ryan Pasca, Nancy Cheng, Bradley M Dickson, Kenneth H Pearce, Stephen V Frye, Lindsey I James
To better understand the contribution of methyl-lysine (Kme) binding proteins to various disease states, we recently developed and reported the discovery of 1 (UNC3866), a chemical probe that targets two families of Kme binding proteins, CBX and CDY chromodomains, with selectivity for CBX4 and -7. The discovery of 1 was enabled in part by the use of molecular dynamics simulations performed with CBX7 and its endogenous substrate. Herein, we describe the design, synthesis, and structure-activity relationship studies that led to the development of 1 and provide support for our model of CBX7-ligand recognition by examining the binding kinetics of our antagonists with CBX7 as determined by surface-plasmon resonance...
October 13, 2016: Journal of Medicinal Chemistry
Evan Kovac, Gregory Lieser, Ahmed Elshafei, J Stephen Jones, Eric A Klein, Andrew J Stephenson
PURPOSE: We analyzed the rates of disease reclassification at initial and subsequent surveillance prostate biopsy as well as the treatment outcomes of deferred therapy among men on active surveillance for prostate cancer. MATERIALS AND METHODS: From a prospective database we identified 300 men on active surveillance who had undergone initial surveillance prostate biopsy, with or without confirmatory biopsy, within 1 year of diagnosis. Of these men 261 (87%) were classified as having NCCN very low or low risk disease at diagnosis...
July 20, 2016: Journal of Urology
Renata Bocian, Bartosz Caban, Paulina Kłos-Wojtczak, Jan Konopacki, Tomasz Kowalczyk
Data obtained in in vitro experiments and urethane anaesthetized animals have revealed that the mechanisms responsible for the generation of hippocampal cholinergic theta rhythm are specifically affected by the administration of broad spectrum gap junctions (GJs) blocker - carbenoxolone (CBX). The aim of this study was to examine the effect of GJs modulation on the production of posterior hypothalamic theta. Specifically, we were interested in evaluating whether CBX could attenuate the theta rhythm recorded from the supramammillary nucleus and posterior hypothalamic nuclei, in both in vitro and in vivo preparations...
September 2016: European Journal of Neuroscience
Nicholas Mitrou, Branko Braam, William A Cupples
Renal autoregulation dynamics originating from the myogenic response (MR) and tubuloglomerular feedback (TGF) can synchronize over large regions of the kidney surface, likely through gap junction-mediated electrotonic conduction and reflecting distributed operation of autoregulation. We tested the hypotheses that inhibition of gap junctions reduces spatial synchronization of autoregulation dynamics, abrogates spatial and temporal smoothing of renal perfusion, and impairs renal autoregulation. In male Long-Evans rats, we infused the gap junction inhibitor carbenoxolone (CBX) or the related glycyrrhizic acid (GZA) that does not block gap junctions into the renal artery and monitored renal blood flow (RBF) and surface perfusion by laser speckle contrast imaging...
September 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Xu Wang, María-Aránzazu Martínez, Guyue Cheng, Zhaoying Liu, Lingli Huang, Menghong Dai, Dongmei Chen, María-Rosa Martínez-Larrañaga, Arturo Anadón, Zonghui Yuan
Quinoxaline 1,4-dioxide derivatives (QdNOs) have been widely used as growth promoters and antibacterial agents. Carbadox (CBX), olaquindox (OLA), quinocetone (QCT), cyadox (CYA) and mequindox (MEQ) are the classical members of QdNOs. Some members of QdNOs are known to cause a variety of toxic effects. To date, however, almost no review has addressed the toxicity and metabolism of QdNOs in relation to oxidative stress. This review focused on the research progress associated with oxidative stress as a plausible mechanism for QdNO-induced toxicity and metabolism...
May 2016: Drug Metabolism Reviews
Qianying Liu, Jianwu Zhang, Xun Luo, Awais Ihsan, Xianglian Liu, Menghong Dai, Guyue Cheng, Haihong Hao, Xu Wang, Zonghui Yuan
Quinoxaline-di-N-oxides (QdNOs) are potential antibacterial agents with a wide range of biological properties. Quinocetone (QCT), carbadox (CBX), olaquindox (OLA), mequindox (MEQ) and cyadox (CYA) are classical QdNOs. Though the genotoxicity of parent drugs has been evaluated, the genotoxicity of their primary N → O reduced metabolites remains unclear. In the present study, a battery of four different short-term tests, mouse lymphoma assay (MLA), Ames test, chromosomal aberration assay in vitro and bone marrow erythrocyte micronucleus assay in vivo was carried out to investigate the genotoxicity of the six primary N → O reduced metabolites...
July 2016: Food and Chemical Toxicology
Shuai Hou, Ping-Ping Shen, Ming-Ming Zhao, Xiu-Ping Liu, Hong-Yan Xie, Fang Deng, Jia-Chun Feng
We observed mitochondrial connexin43 (mtCx43) expression under cerebral ischemia-reperfusion (I/R) injury, analyzed its regulation, and explored its protective mechanisms. Wistar rats were divided into groups based on injections received before middle cerebral artery occlusion (MCAO). Cerebral infarction volume was detected by 2,3,5-triphenyltetrazolim chloride staining, and cell apoptosis was observed by transferase dUTP nick end labeling. We used transmission electron microscopy to observe mitochondrial morphology and determined superoxide dismutase (SOD) activity and malondialdehyde (MDA) content...
2016: International Journal of Molecular Sciences
Jieying Pu, Li He, Heping Xie, Siyu Wu, Yuye Li, Ping Zhang, Zhicong Yang, Xi Huang
As one of the most important mosquito-borne viral diseases, dengue infection is now becoming a global concern due to its rapid spread and rise in incidence. Currently, there is no approved vaccine or effective antiviral drug for dengue virus (DENV) infection. Glycyrrhetinic acid (GNa) and its related derivatives have been reported to inhibit a broad spectrum of viruses. However, it is unknown whether Carbenoxolone disodium (CBX), one of the GNa derivatives, affects DENV infection. Here, we found that the production of infectious DENV particles was significantly decreased by CBX treatment in DENV-permissive cells, while the viral RNA and viral protein synthesis were not affected...
May 7, 2016: Journal of Medical Virology
Haitao Wang, Bo Gao, Yaju Zhang, Hua Xu
OBJECTIVE: The aim of this study was to investigate the effect of connexin43(Cx43) on basic fibroblast growth factor (bFGF) expression by inhibiting Cx43 expression in prolactinomas in rats. METHODS: An experimental rat model of prolactinoma induced by estradiol (E2) treatment was used. Gap junction inhibitor was applied in through the arachnoid space by injection of carbenoxolone (CBX). Cx43 and bFGF expression was examined by both western blotting, respectively...
May 2016: Neurological Research
Natalia Milosevich, Michael C Gignac, James McFarlane, Chakravarthi Simhadri, Shanti Horvath, Kevin D Daze, Caitlin S Croft, Aman Dheri, Taylor T H Quon, Sarah F Douglas, Jeremy E Wulff, Irina Paci, Fraser Hof
The polycomb paralogs CBX2, CBX4, CBX6, CBX7, and CBX8 are epigenetic readers that rely on "aromatic cage" motifs to engage their partners' methyllysine side chains. Each CBX carries out distinct functions, yet each includes a highly similar methyllysine-reading chromodomain as a key element. CBX7 is the only chromodomain that has yet been targeted by chemical inhibition. We report a small set of peptidomimetic agents in which a simple chemical modification switches the ligands from one with promiscuity across all polycomb paralogs to one that provides selective inhibition of CBX6...
February 11, 2016: ACS Medicinal Chemistry Letters
P P Sanna, T Kawamura, J Chen, G F Koob, A J Roberts, L F Vendruscolo, V Repunte-Canonigo
The identification of new and more effective treatments for alcohol abuse remains a priority. Alcohol intake activates glucocorticoids, which have a key role in alcohol's reinforcing properties. Glucocorticoid effects are modulated in part by the activity of 11β-hydroxysteroid dehydrogenases (11β-HSD) acting as pre-receptors. Here, we tested the effects on alcohol intake of the 11β-HSD inhibitor carbenoxolone (CBX, 18β-glycyrrhetinic acid 3β-O-hemisuccinate), which has been extensively used in the clinic for the treatment of gastritis and peptic ulcer and is active on both 11β-HSD1 and 11β-HSD2 isoforms...
2016: Translational Psychiatry
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