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https://www.readbyqxmd.com/read/28817805/ltp-at-hilar-mossy-cell-dentate-granule-cell-synapses-modulates-dentate-gyrus-output-by-increasing-excitation-inhibition-balance
#1
Yuki Hashimotodani, Kaoutsar Nasrallah, Kyle R Jensen, Andrés E Chávez, Daniel Carrera, Pablo E Castillo
Excitatory hilar mossy cells (MCs) in the dentate gyrus receive inputs from dentate granule cells (GCs) and project back to GCs locally, contralaterally, and along the longitudinal axis of the hippocampus, thereby establishing an associative positive-feedback loop and connecting functionally diverse hippocampal areas. MCs also synapse with GABAergic interneurons that mediate feed-forward inhibition onto GCs. Surprisingly, although these circuits have been implicated in both memory formation (e.g., pattern separation) and temporal lobe epilepsy, little is known about activity-dependent plasticity of their synaptic connections...
August 16, 2017: Neuron
https://www.readbyqxmd.com/read/28817624/ephb4-ephrinb2-therapeutics-in-rhabdomyosarcoma
#2
Matthew E Randolph, Megan M Cleary, Zia Bajwa, Matthew N Svalina, Michael C Young, Atiya Mansoor, Pali Kaur, Carol J Bult, Martin W Goros, Joel E Michalek, Sunny Xiang, James Keck, Valery Krasnoperov, Parkash Gill, Charles Keller
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4...
2017: PloS One
https://www.readbyqxmd.com/read/28817416/nicotinic-modulation-of-descending-pain-control-circuitry
#3
Iboro C Umana, Claire A Daniele, Brooke A Miller, Keith Gallagher, Meghan A Brown, Chandrika Abburi, Peggy Mason, Daniel S McGehee
Along with the well-known rewarding effects, activation of nicotinic acetylcholine receptors (nAChRs) can also relieve pain, and some nicotinic agonists have analgesic efficacy similar to opioids. A major target of analgesic drugs is the descending pain modulatory pathway, including the ventrolateral periaqueductal gray (vlPAG) and the rostral ventromedial medulla (RVM). Although activating nAChRs within this circuitry can be analgesic, little is known about the subunit composition and cellular effects of these receptors, particularly within the vlPAG...
July 3, 2017: Pain
https://www.readbyqxmd.com/read/28817212/fingolimod-against-endotoxin-induced-fetal-brain-injury-in-a-rat-model
#4
And Yavuz, Mekin Sezik, Ozlem Ozmen, Halil Asci
AIM: Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis treatment and acts on cellular processes such as apoptosis, endothelial permeability, and inflammation. We hypothesized that fingolimod has a positive effect on alleviating preterm fetal brain injury. METHODS: Sixteen pregnant rats were divided into four groups of four rats each. On gestational day 17, i.p. endotoxin was injected to induce fetal brain injury, followed by i...
August 17, 2017: Journal of Obstetrics and Gynaecology Research
https://www.readbyqxmd.com/read/28815604/chronic-morphine-reduces-the-readily-releasable-pool-of-gaba-a-presynaptic-mechanism-of-opioid-tolerance
#5
Adrianne R Wilson-Poe, Hyo-Jin Jeong, Christopher W Vaughan
The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals...
August 16, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28815044/agonist-anti-gitr-antibody-significantly-enhances-the-therapeutic-efficacy-of-listeria-monocytogenes-based-immunotherapy
#6
Rajeev Shrimali, Shamim Ahmad, Zuzana Berrong, Grigori Okoev, Adelaida Matevosyan, Ghazaleh Shoja E Razavi, Robert Petit, Seema Gupta, Mikayel Mkrtichyan, Samir N Khleif
BACKGROUND: We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4(+) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28814238/structural-insights-for-drugs-developed-for-phospholipase-d-enzymes
#7
Kimberly Stieglitz
BACKGROUND: In recent years human phospholipase D enzymes (PLD1 and PLD2 isozymes) have emerged as drug targets for various diseases such as cardiovascular disease, cancer, infectious diseases and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The interest in PLD as a drug target is due to the fact that PLD enzymes belong to a superfamily of phospholipases that are essential to intracellular and extracellular signaling. Many bioactive lipid signaling molecules are generated by these enzymes including phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG)...
August 15, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28814230/virtual-screening-on-mmp-13-led-to-discovering-new-inhibitors-including-a-non-zinc-binding-and-a-micro-molar-one-a-successful-example-of-receptor-selection-according-to-cross-docking-results-for-a-flexible-enzyme
#8
Mohammad Ramezani, Jamal Shamsara
MMP-13 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type II collagen, the main structural protein of articular cartilage. The main pathologic role of MMP-13 over expression is to contribute to the development of osteoarthritis. To find new inhibitors with possible selectivity for MMP-13 a structure based virtual screening was employed. The inhibitory activities of 11 inhibitors among 19 purchased compounds were approved by enzyme inhibition assay. Our results demonstrated that the CADD (computer aided drug design) could be successfully applied to find new MMP-13 inhibitors using a receptor structure (PDB code: 3O2X) which had been demonstrated a good performance in a cross-docking study...
August 16, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28813782/urea-cycle-pathway-targeted-therapeutic-action-of-naringin-against-ammonium-chloride-induced-hyperammonemic-rats
#9
Arumugam Ramakrishnan, Natesan Vijayakumar
Ammonia is a well-known neurotoxin that causes liver disease and urea cycle disorder. Excessive ammonia content in the blood leads to hyperammonemic condition and affects both excitatory and inhibitory neurotransmission including brain edema and coma. Naringin, a plant bioflavonoid present in various citrus fruits and mainly extracted from the grape fruit. This study was designed to assess the protective effect of naringin on ammonium chloride (NH4Cl) induced hyperammonemic rats. Experimental hyperammonemia was induced by intraperitoneal injections (i...
August 12, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28813663/a-crispr-activation-screen-identifies-a-pan-avian-influenza-virus-inhibitory-host-factor
#10
Brook E Heaton, Edward M Kennedy, Rebekah E Dumm, Alfred T Harding, Matthew T Sacco, David Sachs, Nicholas S Heaton
Influenza A virus (IAV) is a pathogen that poses significant risks to human health. It is therefore critical to develop strategies to prevent influenza disease. Many loss-of-function screens have been performed to identify the host proteins required for viral infection. However, there has been no systematic screen to identify the host factors that, when overexpressed, are sufficient to prevent infection. In this study, we used CRISPR/dCas9 activation technology to perform a genome-wide overexpression screen to identify IAV restriction factors...
August 15, 2017: Cell Reports
https://www.readbyqxmd.com/read/28812547/lung-epithelial-cells-therapeutically-inducible-effectors-of-antimicrobial-defense
#11
REVIEW
M M Leiva-Juárez, J K Kolls, S E Evans
Lung epithelial cells are increasingly recognized to be active effectors of microbial defense, contributing to both innate and adaptive immune function in the lower respiratory tract. As immune sentinels, lung epithelial cells detect diverse pathogens through an ample repertoire of membrane-bound, endosomal, and cytosolic pattern-recognition receptors (PRRs). The highly plastic epithelial barrier responds to detected threats via modulation of paracellular flux, intercellular communications, mucin production, and periciliary fluid composition...
August 16, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28811973/nk-cell-dysfunction-in-chronic-lymphocytic-leukemia-is-associated-with-loss-of-the-mature-cells-expressing-inhibitory-killer-cell-ig-like-receptors
#12
Alexander W MacFarlane, Mowafaq Jillab, Mitchell R Smith, R Katherine Alpaugh, Marion E Cole, Samuel Litwin, Michael M Millenson, Tahseen Al-Saleem, Adam D Cohen, Kerry S Campbell
A prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56(dim) NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811575/biological-and-functional-characterization-of-bone-marrow-derived-mesenchymal-stromal-cells-from-patients-affected-by-primary-immunodeficiency
#13
Nadia Starc, Daniela Ingo, Antonella Conforti, Valeria Rossella, Luigi Tomao, Angela Pitisci, Fabiola De Mattia, Immacolata Brigida, Mattia Algeri, Mauro Montanari, Giuseppe Palumbo, Pietro Merli, Paolo Rossi, Alessandro Aiuti, Franco Locatelli, Maria Ester Bernardo
Mesenchymal stromal cells (MSCs) represent a key component of bone marrow (BM) microenvironment and display immune-regulatory properties. We performed a detailed analysis of biological/functional properties of BM-MSCs derived from 33 pediatric patients affected by primary immune-deficiencies (PID-MSCs): 7 Chronic Granulomatous Disease (CGD), 15 Wiskott-Aldrich Syndrome (WAS), 11 Severe Combined Immunodeficiency (SCID). Results were compared with MSCs from 15 age-matched pediatric healthy-donors (HD-MSCs). Clonogenic and proliferative capacity, differentiation ability, immunophenotype, immunomodulatory properties were analyzed...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811476/lyn-and-fyn-function-as-molecular-switches-that-control-immunoreceptors-to-direct-homeostasis-or-inflammation
#14
Sanae Ben Mkaddem, Amaya Murua, Héloise Flament, Dimitri Titeca-Beauport, Carine Bounaix, Luca Danelli, Pierre Launay, Marc Benhamou, Ulrich Blank, Eric Daugas, Nicolas Charles, Renato C Monteiro
Immunoreceptors can transduce either inhibitory or activatory signals depending on ligand avidity and phosphorylation status, which is modulated by the protein kinases Lyn and Fyn. Here we show that Lyn and Fyn control immune receptor signaling status. SHP-1 tyrosine 536 phosphorylation by Lyn activates the phosphatase promoting inhibitory signaling through the immunoreceptor. By contrast, Fyn-dependent phosphorylation of SHP-1 serine 591 inactivates the phosphatase, enabling activatory immunoreceptor signaling...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28810913/selinexor-kpt-330-demonstrates-anti-tumor-efficacy-in-preclinical-models-of-triple-negative-breast-cancer
#15
Natalia Paez Arango, Erkan Yuca, Ming Zhao, Kurt W Evans, Stephen Scott, Charissa Kim, Ana Maria Gonzalez-Angulo, Filip Janku, Naoto T Ueno, Debu Tripathy, Argun Akcakanat, Aung Naing, Funda Meric-Bernstam
BACKGROUND: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. METHODS: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy...
August 15, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28810810/reduced-expression-of-siglec-7-nkg2a-and-cd57-on-terminally-differentiated-cd56-cd16-nk-cell-subset-is-associated-with-nk-cell-dysfunction-in-chronic-hiv-1-clade-c-infection
#16
Michael Zulu, Kewreshini Naidoo, Zenele Mncube, Manjeetha Jaggernath, Philip Jr Goulder, Thumbi Ndung'u, Marcus Altfeld, Christina Fanesa Thobakgale
BACKGROUND: HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. METHODS: NK cell phenotypic profiles were characterized by assessing Siglec-7, NKG2A and NKG2C markers on frozen peripheral blood mononuclear cells (PBMCs) from viremic, antiretroviral therapy (ART)-naïve HIV-1 chronically infected participants (n=23), HIV-1 chronically infected participants who have been on combination antiretroviral therapy (cART) for at least 12 months (n=23) compared to healthy donors (n=23)...
August 16, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28810599/effects-of-niflumic-acid-on-%C3%AE-aminobutyric-acid-induced-currents-in-isolated-dorsal-root-ganglion-neurons-of-neuropathic-pain-rats
#17
Li-Jie Wang, Yang Wang, Meng-Jie Chen, Zhen-Pu Tian, Bi-Han Lu, Ke-Tao Mao, Liang Zhang, Lei Zhao, Li-Ya Shan, Li Li, Jun-Qiang Si
Niflumic acid (NFA) is a type of non-steroidal anti-inflammatory drug. Neuropathic pain is caused by a decrease in presynaptic inhibition mediated by γ-aminobutyric acid (GABA). In the present study, a whole-cell patch-clamp technique and intracellular recording were used to assess the effect of NFA on GABA-induced inward current in dorsal root ganglion (DRG) neurons of a chronic constriction injury (CCI) model. It was observed that 1-1,000 µmol/l GABA induced a concentration-dependent inward current in DRG neurons...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28810545/electroacupuncture-attenuates-learning-and-memory-impairment-via-activation-of-%C3%AE-7nachr-mediated-anti-inflammatory-activity-in-focal-cerebral-ischemia-reperfusion-injured-rats
#18
Jiao Liu, Chunyan Li, Hongwei Peng, Kunqiang Yu, Jing Tao, Ruhui Lin, Lidian Chen
Studies have reported that electroacupuncture (EA) may reduce learning and memory impairment following cerebral ischemic injury. However, the precise mechanism of action remains unclear. In the present study, the attenuation of focal cerebral ischemia/reperfusion injury by EA in rats was investigated. EA at the Baihui (DU 20) and Shenting (DU 24) acupoints was demonstrated to significantly improve performance in the Morris water maze task, with shortened latency time and increased frequency of passing the platform...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28810542/electroacupuncture-promotes-axonal-regeneration-in-rats-with-focal-cerebral-ischemia-through-the-downregulation-of-nogo-a-ngr-rhoa-rock-signaling
#19
Saie Huang, Danxia Huang, Jiapei Zhao, Lidian Chen
The purpose of the present study was to evaluate the effect of electroacupuncture (EA) on the axonal regeneration environment following cerebral ischemia injury and to investigate whether it was associated with Nogo-A/Nogo receptor (NgR)/RhoA/Rho-associated protein kinase (ROCK) signaling. Using a rat model of focal cerebral ischemia, the effects of EA at the Quchi (LI11) and Zusanli (ST36) acupoints on axonal growth inhibitory protein and axonal growth factors were assessed and the underlying molecular mechanisms were investigated...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28809547/quantitative-evaluation-of-viral-protein-binding-to-phosphoinositide-receptors-and-pharmacological-inhibition
#20
Seong-Oh Kim, Joshua Alexander Jackman, Menashe Elazar, Sang-Joon Cho, Jeffrey S Glenn, Nam-Joon Cho
There is significant interest in developing analytical methods to characterize molecular recognition events between proteins and phosphoinositides, which are a medically important class of carbohydrate-functionalized lipids. Within this scope, one area of high priority involves quantitatively evaluating drug candidates that pharmacologically inhibit protein-phosphoinositide interactions. As full-length proteins are oftentimes difficult to produce, establishing methods to study these interactions with shorter, bioactive peptides would be advantageous...
August 15, 2017: Analytical Chemistry
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