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H3 antagonist

Abhinav Adhikari, Judith Davie
BACKGROUND: JARID2 is a non-catalytic member of the polycomb repressive complex 2 (PRC2), which is known to regulate developmental target genes in embryonic stem cells. Here, we provide mechanistic insight into the modulation of Wnt signaling by JARID2 during murine skeletal muscle differentiation. RESULTS: We show that JARID2 is expressed in proliferating myoblasts, but downregulated upon muscle differentiation. Unexpectedly, depletion of JARID2 or the catalytic subunit of the PRC2 complex, EZH2, inhibited differentiation, suggesting that JARID2 and the PRC2 complex are required to initiate this process...
August 17, 2018: Epigenetics & Chromatin
Betina González, Oscar V Torres, Subramaniam Jayanthi, Natalia Gomez, Máximo H Sosa, Alejandra Bernardi, Francisco J Urbano, Edgar García-Rill, Jean-Lud Cadet, Verónica Bisagno
METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans. In contrast, modafinil enhances cognition by increasing PFC function. Accumulated evidence indicates that psychostimulant drugs, including modafinil and METH, regulate gene expression via epigenetic modifications. In this study, we measured the effects of single-dose injections of modafinil and METH on the protein levels of acetylated histone H3 (H3ac) and H4ac, deacetylases HDAC1 and HDAC2, and of the NMDA subunit GluN1 in the medial PFC (mPFC) of mice euthanized 1 h after drug administration...
July 26, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
Na Liu, Wenfang Zhou, Yue Guo, Junmei Wang, Weitao Fu, Huiyong Sun, Dan Li, Mojie Duan, Tingjun Hou
The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2...
July 20, 2018: Journal of Chemical Information and Modeling
Adam Schafer, Han Cheng, Rui Xiong, Veronica Soloveva, Cary Retterer, Feiyan Mo, Sina Bavari, Gregory Thatcher, Lijun Rong
Ebola and Marburg are filoviruses and biosafety level 4 pathogens responsible for causing severe hemorrhagic fevers in humans with mortality rates up to 90%. The most recent outbreak in West Africa resulted in approximately 11,310 deaths in 28,616 reported cases. Currently there are no FDA-approved vaccines or therapeutics to treat infections of these deadly viruses. Recently we screened an FDA-approved drug library and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties...
September 2018: Antiviral Research
Mohammad A Khanfar, David Reiner, Stefanie Hagenow, Holger Stark
Histamine H3 receptor (H3 R) is largely expressed in the CNS and modulation of the H3 R function can affect histamine synthesis and liberation, and modulate the release of many other neurotransmitters. Targeting H3 R with antagonists/inverse agonists may have therapeutic applications in neurodegenerative disorders, gastrointestinal and inflammatory diseases. This prompted us to design and synthesize azole-based H3 R ligands, i.e. having oxadiazole- or thiazole-based core structures. While ligands of oxadiazole scaffold were almost inactive, thiazole-based ligands were very potent and several exhibited binding affinities in a nanomolar concentration range...
June 21, 2018: Bioorganic & Medicinal Chemistry
Hanyang Cai, Man Zhang, Mengnan Chai, Qing He, Xinyu Huang, Lihua Zhao, Yuan Qin
The accumulation of anthocyanins in response to specific developmental cues or environmental conditions plays a vital role in plant development and protection against stresses. Extensive research has examined the regulation of anthocyanin biosynthetic genes at the transcriptional and post-transcriptional levels, but the role of chromatin in this regulation remains unknown. Chromatin immunoprecipitation and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were performed. Genetic interactions between trimethylation of lysine 4 on histone H3 (H3K4me3) and the chromatin remodeling complex SWR1 in the control of anthocyanin biosynthesis were further studied...
June 30, 2018: New Phytologist
Katsuya Nagai, Yoshiko Misonou, Yosiyuki Fujisaki, Risa Fuyuki, Yuko Horii
We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats...
June 20, 2018: Amino Acids
A Lesniak, A Jonsson, M Aarnio, T Norberg, F Nyberg, T Gordh
Aims In PET studies of patients suffering from chronic pain following whip lash trauma, d-deprenyl was shown to bind to painful sites in the neck [1]. High uptake points towards an existence of an inflammation-specific binding site. Thus, the aim of this study was to identify the binding site for d-deprenyl employing radioligand receptor binding and high-throughput analysis of its activity towards 165 G-protein coupled receptors and 84 enzyme targets commonly used in drug discovery and development. Methods D-Deprenyl activity towards GPCR targets was assessed by DiscoverX in CHO-K1 EDG1 β-arrest in EFC cell line utilizing the PathHunter™ technique...
December 29, 2017: Scandinavian Journal of Pain
Magdalena Kotańska, Kamil J Kuder, Katarzyna Szczepańska, Jacek Sapa, Katarzyna Kieć-Kononowicz
The pharmacological profile of pitolisant, a histamine H3 receptor antagonist/inverse agonist, indicates that this compound might reduce body weight and metabolic disturbances. Therefore, we studied the influence of pitolisant on body weight, water and sucrose intake as well as metabolic disturbances in the high-fat and high-sugar diet-induced obesity model in mice. To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat blend for 14 weeks, water and 30% sucrose solution available ad libitum...
August 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Ayami Sato, Haruka Ueno, Momoka Fusegi, Saki Kaneko, Kakeru Kohno, Nantiga Virgona, Akira Ando, Yuko Sekine, Tomohiro Yano
BACKGROUND: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1)...
May 15, 2018: Pharmacology
Alaa Alachkar, Gniewomir Latacz, Agata Siwek, Annamaria Lubelska, Ewelina Honkisz, Anna Gryboś, Dorota Łażewska, Jadwiga Handzlik, Holger Stark, Katarzyna Kiec-Kononowicz, Bassem Sadek
Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i...
July 2018: Pharmacology, Biochemistry, and Behavior
Hyunju Kim, Minsu Jang, Rackhyun Park, Daum Jo, Inho Choi, Joonho Choe, Won Keun Oh, Junsoo Park
Conessine, a steroidal alkaloid, is a potent histamine H3 antagonist with antimalarial activity. We recently reported that conessine treatment interferes with H₂O₂-induced cell death by regulating autophagy. However, the cellular signaling pathways involved in conessine treatment are not fully understood. Here, we report that conessine reduces muscle atrophy by interfering with the expression of atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Promoter reporter assay revealed that conessine treatment inhibits FoxO3a-dependent transcription, NF-κB-dependent transcription, and p53-dependent transcription...
April 28, 2018: Journal of Microbiology and Biotechnology
Katarzyna Szczepańska, Tadeusz Karcz, Szczepan Mogilski, Agata Siwek, Kamil J Kuder, Gniewomir Latacz, Monika Kubacka, Stefanie Hagenow, Annamaria Lubelska, Agnieszka Olejarz, Magdalena Kotańska, Bassem Sadek, Holger Stark, Katarzyna Kieć-Kononowicz
As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3 R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki  = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids...
May 25, 2018: European Journal of Medicinal Chemistry
Ying Liu, Hong Zeng, John D Pediani, Richard J Ward, Lu-Yao Chen, Nan Wu, Li Ma, Mei Tang, Yang Yang, Su An, Xiao-Xi Guo, Qian Hao, Tian-Rui Xu
Activation of the histamine-3 receptor (H3R) is involved in memory processes and cognitive action, while blocking H3R activation can slow the progression of neurological disorders, such as Alzheimer's disease, schizophrenia and narcolepsy. To date, however, no direct way to examine the activation of H3R has been utilized. Here, we describe a novel biosensor that can visualize the activation of H3R through an intramolecular fluorescence resonance energy transfer (FRET) signal. To achieve this, we constructed an intramolecular H3R FRET sensor with cyan fluorescent protein (CFP) attached at the C terminus and yellow fluorescent protein (YFP) inserted into the third intracellular loop...
June 2018: FEBS Journal
Cindy Weidmann, Julie Bérubé, Léo Piquet, Arnaud de la Fouchardière, Solange Landreville
Uveal melanoma (UM) is the most common primary tumor in the adult, and disseminates to the liver in half of patients. A 15-gene expression profile prognostic assay allows to determine the likelihood of metastasis in patients using their ocular tumor DNA, but a cure still remains to be discovered. The serotonin receptor 2B represents the discriminant gene of this molecular signature with the greatest impact on the prognosis of UM. However, its contribution to the metastatic potential of UM remains unexplored...
March 2018: Clinical & Experimental Metastasis
Dorota Łażewska, Maria Kaleta, Stefanie Hagenow, Szczepan Mogilski, Gniewomir Latacz, Tadeusz Karcz, Annamaria Lubelska, Ewelina Honkisz, Jadwiga Handzlik, David Reiner, Grzegorz Satała, Barbara Filipek, Holger Stark, Katarzyna Kieć-Kononowicz
A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50  = 312 nM) and in vivo in the rat dipsogenia model (ED50  = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED50  = 30...
May 15, 2018: Bioorganic & Medicinal Chemistry
Devendran A Sadasivam, Der-Hwa Huang
Drosophila Polycomb group (PcG) repressors confer epigenetically heritable silencing on key regulatory genes through histone H3 trimethylation on lysine 27 (H3K27me3). How the silencing state withstands antagonistic activities from co-expressed trithorax group (trxG) activators is unclear. Upon overexpression of Trx H3K4 methylase, to perturb the silenced state, we find a dynamic process triggered in a stepwise fashion to neutralize the inductive impacts from excess Trx. Shortly after Trx overexpression, there are global increases in H3K4 trimethylation and RNA polymerase II phosphorylation, marking active transcription...
May 9, 2018: Journal of Cell Science
Eric Conway, Emilia Jerman, Evan Healy, Shinsuke Ito, Daniel Holoch, Giorgio Oliviero, Orla Deevy, Eleanor Glancy, Darren J Fitzpatrick, Marlena Mucha, Ariane Watson, Alan M Rice, Paul Chammas, Christine Huang, Indigo Pratt-Kelly, Yoko Koseki, Manabu Nakayama, Tomoyuki Ishikura, Gundula Streubel, Kieran Wynne, Karsten Hokamp, Aoife McLysaght, Claudio Ciferri, Luciano Di Croce, Gerard Cagney, Raphaël Margueron, Haruhiko Koseki, Adrian P Bracken
The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2), little is known about their differential functions. Here, we report the discovery of a family of vertebrate-specific PRC2.1 proteins, "PRC2 associated LCOR isoform 1" (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively...
May 3, 2018: Molecular Cell
Amit K Behera, Aditya Bhattacharya, Madavan Vasudevan, Tapas K Kundu
Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a type I arginine methyltransferase that mediates transcriptional activation via methylation of histone H3 on R17, R26, and R42. CARM1 is also a coactivator of transcription of various transcription factors such as NF-kB, MEF2C, β-catenin, p53, PPAR-gamma etc. CARM1 has been functionally implicated in maintenance of pluripotency, cellular differentiation, and tumorigenesis; where its expression status plays an important role. Although its expression has been shown to be regulated by a few miRNAs in different contexts at post-transcriptional level, transcriptional regulation of CARM1 gene is still unexplored...
May 2018: FEBS Journal
Luana de Almeida-Pereira, Marinna Garcia Repossi, Camila Feitosa Magalhães, Rafael de Freitas Azevedo, Juliana da Cruz Corrêa-Velloso, Henning Ulrich, Ana Lúcia Marques Ventura, Lucianne Fragel-Madeira
Adenine nucleotides through P2Y1 receptor stimulation are known to control retinal progenitor cell (RPC) proliferation by modulating expression of the p57KIP2 , a cell cycle regulator. However, the role of Gi protein-coupled P2Y12 and P2Y13 receptors also activated by adenine nucleotides in RPC proliferation is still unknown. Gene expression of the purinergic P2Y12 subtype was detected in rat retina during early postnatal days (P0 to P5), while expression levels of P2Y13 were low. Immunohistochemistry assays performed with rat retina on P3 revealed P2Y12 receptor expression in both Ki-67-positive cells in the neuroblastic layer and Ki-67-negative cells in the ganglion cell layer and inner nuclear layer...
March 25, 2018: Molecular Neurobiology
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