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https://www.readbyqxmd.com/read/28628858/unravelling-the-structural-interactions-between-pkr-kinase-domain-and-its-small-molecule-inhibitors-using-computational-approaches
#1
Sagar Barage, Abhijeet Kulkarni, Jayanta K Pal, Manali Joshi
The RNA-dependent protein kinase (PKR), an eIF2α kinase plays an important role in anti-viral response, apoptosis and cell survival. It is also implicated to play a role in several cancers, metabolic and neurodegenerative disorders. A few ATP competitive inhibitors of the PKR have been reported in the literature with promising results in vitro and in vivo. The aim of this study was to unravel the structural interactions between these inhibitors and the PKR kinase domain using molecular simulations and docking...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28628829/ectromelia-virus-accumulates-less-double-stranded-rna-compared-to-vaccinia-virus-in-bs-c-1-cells
#2
Tiffany R Frey, Michael H Lehmann, Colton M Ryan, Marie C Pizzorno, Gerd Sutter, Adam R Hersperger
Most orthopoxviruses, including vaccinia virus (VACV), contain genes in the E3L and K3L families. The protein products of these genes have been shown to combat PKR, a host defense pathway. Interestingly, ectromelia virus (ECTV) contains an E3L ortholog but does not possess an intact K3L gene. Here, we gained insight into how ECTV can still efficiently evade PKR despite lacking K3L. Relative to VACV, we found that ECTV-infected BS-C-1 cells accumulated considerably less double-stranded (ds) RNA, which was due to lower mRNA levels and less transcriptional read-through of some genes by ECTV...
June 16, 2017: Virology
https://www.readbyqxmd.com/read/28624282/effect-of-endoplasmic-reticulum-stress-on-metabolic-and-stress-signaling-and-kidney-specific-functions-in-madin-darby-bovine-kidney-cells
#3
E Chiappisi, R Ringseis, K Eder, D K Gessner
Recent studies demonstrated induction of endoplasmic reticulum (ER) stress in tissues of cows after parturition, but knowledge about the effect of ER stress on important cellular processes, such as critical signaling and metabolic pathways, in cattle is scarce. Thus, the present study aimed to investigate the effect of ER stress induction on nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), and sterol regulatory element-binding protein (SREBF1) pathway in Madin-Darby bovine kidney (MDBK) cells, a widely used in vitro model in ruminant research...
June 14, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28623239/-ccug-n-rna-toxicity-in-a-drosophila-model-for-myotonic-dystrophy-type-2-dm2-activates-apoptosis
#4
Vildan Betul Yenigun, Mario Sirito, Alla Amcheslavky, Tomek Czernuszewicz, Jordi Colonques-Bellmunt, Irma García-Alcover, Marzena Wojciechowska, Clare Bolduc, Zhihong Chen, Arturo López Castel, Ralf Krahe, Andreas Bergmann
The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions -- (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length (n=16 and 106)...
June 16, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28615521/ier3ip1-deficiency-leads-to-increased-%C3%AE-cell-death-and-decreased-%C3%AE-cell-proliferation
#5
Juan Sun, Decheng Ren
Mutations in the gene for Immediate Early Response 3 Interacting Protein 1 (IER3IP1) cause permanent neonatal diabetes mellitus in human. The mechanisms involved have not been determined and the role of IER3IP1 in β-cell survival has not been characterized. In order to determine if there is a molecular link between IER3IP1 deficiency and β-cell survival and proliferation, we knocked down Ier3ip1 gene expression in mouse MIN6 insulinoma cells. IER3IP1 suppression induced apoptotic cell death which was associated with an increase in Bim and a decrease in Bcl-xL...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611419/interaction-of-pkr-with-single-stranded-rna
#6
Christopher B Mayo, James L Cole
Although the antiviral kinase PKR was originally characterized as a double-stranded RNA activated enzyme it can be stimulated by RNAs containing limited secondary structure. Single-stranded regions in such RNAs contribute to binding and activation but the mechanism is not understood. Here, we demonstrate that single-stranded RNAs bind to PKR with micromolar dissociation constants and can induce activation. Addition of a 5'-triphosphate slightly enhances binding affinity. Single-stranded RNAs also activate PKR constructs lacking the double-stranded RNA binding domain and bind to a basic region adjacent to the N-terminus of the kinase...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28602740/protective-immunity-against-rock-bream-iridovirus-rbiv-infection-and-tlr3-mediated-type-i-interferon-signaling-pathway-in-rock-bream-oplegnathus-fasciatus-following-poly-i-c-administration
#7
Myung-Hwa Jung, Sung-Ju Jung
In this study, we evaluated the potential of poly (I:C) to induce antiviral status for protecting rock bream from RBIV infection. Rock bream injected with poly (I:C) at 2 days before infection (1.1 × 10(4)) at 20 °C had significantly higher protection with RPS 13.4% and 33.4% at 100 and 200 μg/fish, respectively, through 100 days post infection (dpi). The addition of boost immunization with poly (I:C) at before/post infection at 20 °C clearly enhanced the level of protection showing 33.4% and 60.0% at 100 and 200 μg/fish, respectively...
June 8, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28601430/imiquimod-induced-autophagy-is-regulated-by-er-stress-mediated-pkr-activation-in-cancer-cells
#8
Shu-Hao Chang, Shi-Wei Huang, Sin-Ting Wang, Kai-Cheng Chung, Chia-Wei Hsieh, Jun-Kai Kao, Yi-Ju Chen, Chun-Ying Wu, Jeng-Jer Shieh
BACKGROUND: Autophagy is a highly conserved cellular catabolic pathway for degradation and recycling of intracellular components in response to nutrient starvation or environmental stress. Endoplasmic reticulum (ER) homeostasis can be disturbed by physiological and pathological influences, resulting in accumulation of misfolded and unfolded proteins in the ER lumen, a condition referred to as ER stress. Imiquimod (IMQ), a Toll-like receptor (TLR) 7 ligand, possesses anti-tumor and anti-viral activities in vitro and in vivo...
May 2, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28592527/zika-virus-hijacks-stress-granule-proteins-and-modulates-the-host-stress-response
#9
Shangmei Hou, Anil Kumar, Zaikun Xu, Adriana M Airo, Iryna Stryapunina, Cheung Pang Wong, William Branton, Egor Tchesnokov, Matthias Götte, Christopher Power, Tom C Hobman
Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2α and cellular translational arrest, stress granule (SG) formation was inhibited...
June 7, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28542506/impact-evaluation-of-different-cash-based-intervention-modalities-on-child-and-maternal-nutritional-status-in-sindh-province-pakistan-at-6-mo-and-at-1-y-a-cluster-randomised-controlled-trial
#10
RANDOMIZED CONTROLLED TRIAL
Bridget Fenn, Tim Colbourn, Carmel Dolan, Silke Pietzsch, Murtaza Sangrasi, Jeremy Shoham
BACKGROUND: Cash-based interventions (CBIs), offer an interesting opportunity to prevent increases in wasting in humanitarian aid settings. However, questions remain as to the impact of CBIs on nutritional status and, therefore, how to incorporate them into emergency programmes to maximise their success in terms of improved nutritional outcomes. This study evaluated the effects of three different CBI modalities on nutritional outcomes in children under 5 y of age at 6 mo and at 1 y. METHODS AND FINDINGS: We conducted a four-arm parallel longitudinal cluster randomised controlled trial in 114 villages in Dadu District, Pakistan...
May 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28539447/a-map-of-the-arenavirus-nucleoprotein-host-protein-interactome-reveals-that-jun%C3%A3-n-virus-selectively-impairs-the-antiviral-activity-of-pkr
#11
Benjamin R King, Dylan Hershkowitz, Philip L Eisenhauer, Marion E Weir, Christopher M Ziegler, Joanne Russo, Emily A Bruce, Bryan A Ballif, Jason Botten
Arenaviruses are enveloped negative-strand RNA viruses that cause significant human disease. Encoding only four proteins to accomplish the viral life cycle, each arenavirus protein likely plays unappreciated accessory roles during infection. Here, we used immunoprecipitation and mass spectrometry to identify human proteins that interact with the nucleoprotein (NP) of the Old World arenavirus lymphocytic choriomeningitis (LCMV) and the New World arenavirus Junín Candid #1 (JUNV). Bioinformatic analysis of the identified protein partners of NP revealed that host translation appears to be a key biological process engaged during infection...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28537876/activation-of-perk-branch-of-er-stress-mediates-homocysteine-induced-bkca%C3%A2-channel-dysfunction-in-coronary-artery-via-foxo3a-dependent-regulation-of-atrogin-1
#12
Wen-Tao Sun, Xiang-Chong Wang, Shiu-Kwong Mak, Guo-Wei He, Xiao-Cheng Liu, Malcolm John Underwood, Qin Yang
The molecular mechanism of endoplasmic reticulum (ER) stress in vascular pathophysiology remains inadequately understood. We studied the role of ER stress in homocysteine-induced impairment of coronary dilator function, with uncovering the molecular basis of the effect of ER stress on smooth muscle large-conductance Ca2+-activated K+ (BKCa) channels. The vasodilatory function of BKCa channels was studied in a myograph using endothelium-denuded porcine small coronary arteries. Primary cultured porcine coronary artery smooth muscle cells were used for mRNA and protein measurements and current recording of BKCa channels...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28527816/adar1-is-targeted-by-mir-143-to-regulate-il-1%C3%AE-induced-endothelial-activation-through-the-nf%C3%AE%C2%BAb-pathway
#13
Yuanzhuo Chen, Hu Peng, Shuqin Zhou, Yugang Zhuang
Excessive endothelial activation by inflammatory mediators is a critical contributing factor of sepsis pathophysiology. ADAR1 (adenosine deaminase acting on RNA), an enzyme that binds and edits double-stranded RNAs, exhibits immune regulatory properties. Whether ADAR1 is involved in the pathophysiology of sepsis is unclear. In the present study, we used human umbilical endothelial cells (HUVECs) as an in vitro model system to investigate the roles of ADAR1 in interleukin (IL)-1β-induced endothelial activation...
May 17, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28527062/the-prokineticin-system-an-interface-between-neural-inflammation-and-pain
#14
Silvia Franchi, Paola Sacerdote, Alberto Panerai
Prokineticins (PK) 1 and 2 belong to a new family of chemokines capable to interact with two different G coupled receptors: Prokineticin receptor (PKR)1 and 2. Both prokineticins and their receptors are widely distributed in different tissues and regulate several biological functions. In particular, a role of the PK system in inflammation and nociception has been established. PKRs are expressed in regions of the nervous system associated with pain and in primary sensitive neurons they colocalize with transient potential receptor vanilloid-TRPV1 providing an anatomical interaction in nociceptor sensitization...
May 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28522733/activation-of-perk-elicits-memory-impairment-through-inactivation-of-creb-and-downregulation-of-psd95-after-traumatic-brain-injury
#15
Tanusree Sen, Rajaneesh Gupta, Helen Kaiser, Nilkantha Sen
The PKR-like ER kinase (PERK), a transmembrane protein, resides in the endoplasmic reticulum (ER). Its activation serves as a key sensor of ER stress, which has been implicated in traumatic brain injury (TBI). The loss of memory is one of the most common symptoms after TBI, but the precise role of PERK activation in memory impairment after TBI has not been well elucidated. Here, we have shown that blocking the activation of PERK using GSK2656157 prevents the loss of dendritic spines and rescues memory deficits after TBI...
June 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28511573/inhibition-of-pkr-ameliorates-lipopolysaccharide-induced-acute-lung-injury-by-suppressing-nf-%C3%AE%C2%BAb-pathway-in-mice
#16
Yinjiao Li, Jinglei Xiao, Yongchang Tan, Jun Wang, Yan Zhang, Xiaoming Deng, Yan Luo
Acute lung injury (ALI) is characterized by dramatic lung inflammation and alveolar epithelial cell death. Although protein kinase R (PKR) (double-stranded RNA-activated serine/threonine kinase) has been implicated in inflammatory response to bacterial cell wall components, whether it plays roles in lipopolysaccharide (LPS)-induced ALI remains unclear. This study was aimed to reveal whether and how PKR was involved in LPS-induced ALI pathology and the potential effects of its specific inhibitor, C16 (C13H8N4OS)...
May 17, 2017: Immunopharmacology and Immunotoxicology
https://www.readbyqxmd.com/read/28507276/dicer-protein-levels-elevated-by-mild-hyperthermia-promote-a-pro-survival-phenotype
#17
Anand S Devasthanam, Thomas B Tomasi
Cellular exposure to mild stress (39.5°C-41.5°C) induces thermotolerance, rendering cells resistant to a subsequent heat shock (>42°C) insult. We found that mild hyperthermia at 39.5°C leads to elevations in dicer, a protein well-known for its role in microRNA processing and for its role in cellular stress responses. However, whether elevated dicer protein levels play a role in sustaining a thermotolerant phenotype has, to our knowledge, not been reported. Here we demonstrate that elevated dicer protein is linked to a thermotolerant phenotype in the cervical carcinoma cell line HeLa and in murine embryonic fibroblasts (MEF), and demonstrate that dicer plays a role in mediating PKR and eIF2α phosphorylation...
April 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28498443/silencing-of-both-atf4-and-perk-inhibits-cell-cycle-progression-and-promotes-the-apoptosis-of-differentiating-chondrocytes
#18
Zhimeng Wu, Meiling Li, Wei Zheng, Qin Hu, Zhi Cheng, Fengjin Guo
In the current study, we demonstrate that the silencing of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) and activating transcription factor 6 (ATF4) (using small interfering RNA expression constructs) inhibits the chondrocyte cell cycle and proliferation in vitro and ex vivo. The silencing of PERK alone using siRNA against PERK (siPERK) led to arrest in the G1 phase, it decreased the number of cells in the S phase, and delayed progressoin to the G2‑M phase. Co-transfection with siRNA against ATF (siATF4) led to a more profound inhibitory effect on cell cycle progression...
May 10, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28484023/coronavirus-nonstructural-protein-15-mediates-evasion-of-dsrna-sensors-and-limits-apoptosis-in-macrophages
#19
Xufang Deng, Matthew Hackbart, Robert C Mettelman, Amornrat O'Brien, Anna M Mielech, Guanghui Yi, C Cheng Kao, Susan C Baker
Coronaviruses are positive-sense RNA viruses that generate double-stranded RNA (dsRNA) intermediates during replication, yet evade detection by host innate immune sensors. Here we report that coronavirus nonstructural protein 15 (nsp15), an endoribonuclease, is required for evasion of dsRNA sensors. We evaluated two independent nsp15 mutant mouse coronaviruses, designated N15m1 and N15m3, and found that these viruses replicated poorly and induced rapid cell death in mouse bone marrow-derived macrophages. Infection of macrophages with N15m1, which expresses an unstable nsp15, or N15m3, which expresses a catalysis-deficient nsp15, activated MDA5, PKR, and the OAS/RNase L system, resulting in an early, robust induction of type I IFN, PKR-mediated apoptosis, and RNA degradation...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28445962/psma-homing-dsrna-chimeric-protein-vector-kills-prostate-cancer-cells-and-activates-anti-tumor-bystander-responses
#20
Yael Langut, Nufar Edinger, Efrat Flashner-Abramson, Naomi Melamed-Book, Mario Lebendiker, Yael Levi-Kalisman, Shoshana Klein, Alexander Levitzki
The treatment of metastatic androgen-resistant prostate cancer remains a challenge. We describe a protein vector that selectively delivers synthetic dsRNA, polyinosinic/polycytidylic acid (polyIC), to prostate tumors by targeting prostate specific membrane antigen (PSMA), which is overexpressed on the surface of prostate cancer cells.The chimeric protein is built from the double stranded RNA (dsRNA) binding domain of PKR tethered to a single chain anti-PSMA antibody. When complexed with polyIC, the chimera demonstrates selective and efficient killing of prostate cancer cells...
April 11, 2017: Oncotarget
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