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https://www.readbyqxmd.com/read/29442228/effect-of-an-88-amino-acid-deletion-in-nsp2-of-porcine-reproductive-and-respiratory-syndrome-virus-on-virus-replication-and-cytokine-responses-in-vitro
#1
Wei He, Ying Wei, Jing Yao, Xin Xie, Jiabin Huang, Siyuan Lin, Kang Ouyang, Ying Chen, Weijian Huang, Zuzhang Wei
Previously, a spontaneous 88-amino-acid (aa) deletion in nsp2 was associated with cell-adaptation of porcine reproductive and respiratory syndrome virus (PRRSV) strain JXM100, which arose during passaging of the highly pathogenic PRRSV (HP-PRRSV) strain JX143 in MARC-145 cells. Here, to elucidate the biological role of this deletion, we specifically deleted the region of a cDNA clone of HP-PRRSV strain JX143 (pJX143) corresponding to these 88 amino acids. The effect of the deletion on virus replication in cultured cells and transcriptional activation of inflammatory cytokines and chemokines in pulmonary alveolar macrophages (PAMs) was examined...
February 13, 2018: Archives of Virology
https://www.readbyqxmd.com/read/29436711/evidence-for-dispensability-of-protein-kinase-r-in-host-control-of-tuberculosis
#2
Shashirekha Mundhra, Ruslana Bryk, Natalie Hawryluk, Tuo Zhang, Xiuju Jiang, Carl F Nathan
Genetic deficiency of protein kinase R (PKR) in mice was reported to enhance macrophage activation in vitro in response to interferon-γ (IFNγ) and to reduce the burden of Mycobacterium tuberculosis (Mtb) in vivo (Wu et al. PloS One. 2012 7:e30512). Consistent with this, treatment of wild-type (WT) macrophages in vitro with a novel PKR inhibitor (Bryk et al., Bioorg. Med. Chem. Lett. 2011 21:4108-4114) also enhanced IFNγ-dependent macrophage activation (Wu et al. PloS One. 2012 7:e30512). Here we show that co-treatment with IFNγ and a new PKR inhibitor identified herein to be highly but not completely selective likewise induced macrophages to produce more reactive nitrogen intermediates (RNI) and tumor necrosis factor alpha (TNFα) and less interleukin 10 (IL-10) than seen with IFNγ alone...
February 13, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29430716/imoxin-attenuates-high-fructose-induced-oxidative-stress-and-apoptosis-in-renal-epithelial-cell-via-downregulation-of-pkr-pathway
#3
Jaspreet Kalra, Suresh Babu Mangali, Audesh Bhat, Indu Dhar, Mary Priyanka Udumula, Arti Dhar
Double stranded RNA (dsRNA) activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase is a key inducer of inflammation, insulin resistance and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of high fructose (HF) in cultured renal tubular epithelial cells (NRK 52E) derived from rat kidney and to investigate whether inhibition of PKR could prevent any deleterious effects of HF in these cells...
February 11, 2018: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/29429924/the-tia1-rna-binding-protein-family-regulates-eif2ak2-mediated-stress-response-and-cell-cycle-progression
#4
Cindy Meyer, Aitor Garzia, Michael Mazzola, Stefanie Gerstberger, Henrik Molina, Thomas Tuschl
TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation...
February 15, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29427702/high-brain-distribution-of-a-new-central-nervous-system-drug-candidate-despite-its-p-glycoprotein-mediated-efflux-at-the-mouse-blood-brain-barrier
#5
Camille Taccola, Sylvaine Cartot-Cotton, Delphine Valente, Pascal Barneoud, Catherine Aubert, Valérie Boutet, Fabienne Gallen, Murielle Lochus, Sophie Nicolic, Agnès Dodacki, Maria Smirnova, Salvatore Cisternino, Xavier Declèves, Fanchon Bourasset
Efficacy of drugs aimed at treating central nervous system (CNS) disorders rely partly on their ability to cross the cerebral endothelium, also called the blood-brain barrier (BBB), which constitutes the main interface modulating exchanges of compounds between the brain and blood. In this work, we used both, conventional pharmacokinetics (PK) approach and in situ brain perfusion technique to study the blood and brain PK of PKRinh, an inhibitor of the double-stranded RNA-dependent protein kinase (PKR) activation, in mice...
February 7, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29422542/protection-of-nigral-dopaminergic-neurons-by-aav1-transduction-with-rheb-s16h-against-neurotoxic-inflammation-in-vivo
#6
Sehwan Kim, Gyeong Joon Moon, Yong-Seok Oh, Jungha Park, Won-Ho Shin, Jae Yeong Jeong, Kwang Shik Choi, Byung Kwan Jin, Nikolai Kholodilov, Robert E Burke, Hyung-Jun Kim, Chang Man Ha, Seok-Geun Lee, Sang Ryong Kim
We recently reported that adeno-associated virus serotype 1 (AAV1) transduction of murine nigral dopaminergic (DA) neurons with constitutively active ras homolog enriched in brain with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced the production of neurotrophic factors, resulting in neuroprotective effects on the nigrostriatal DA system in animal models of Parkinson's disease (PD). To further investigate whether AAV1-Rheb(S16H) transduction has neuroprotective potential against neurotoxic inflammation, which is known to be a potential event related to PD pathogenesis, we examined the effects of Rheb(S16H) expression in nigral DA neurons under a neurotoxic inflammatory environment induced by the endogenous microglial activator prothrombin kringle-2 (pKr-2)...
February 9, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29415027/picornavirus-2a-protease-regulates-stress-granule-formation-to-facilitate-viral-translation
#7
Xiaodan Yang, Zhulong Hu, Shanshan Fan, Qiang Zhang, Yi Zhong, Dong Guo, Yali Qin, Mingzhou Chen
Stress granules (SGs) contain stalled messenger ribonucleoprotein complexes and are related to the regulation of mRNA translation. Picornavirus infection can interfere with the formation of SGs. However, the detailed molecular mechanisms and functions of picornavirus-mediated regulation of SG formation are not clear. Here, we found that the 2A protease of a picornavirus, EV71, induced atypical stress granule (aSG), but not typical stress granule (tSG), formation via cleavage of eIF4GI. Furthermore, 2A was required and sufficient to inhibit tSGs induced by EV71 infection, sodium arsenite, or heat shock...
February 7, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29407611/functional-characterization-of-tumor-necrosis-factor-receptor-associated-factor-3-of-sea-perch-lateolabrax-japonicas-in-innate-immune
#8
Wanwan Zhang, Peng Jia, Wei Liu, Yunlong Li, Meisheng Yi, Kuntong Jia
Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a multifunctional regulator implicated in both bacterial defense and antiviral immunity. Here, a TRAF3 gene from the seawater fish sea perch, designated as LjTRAF3, was characterized. The full-length cDNA of LjTRAF3 was 2972 bp including a 5' untranslated region (UTR) of 243 bp, a 3'UTR of 941 bp and a putative open reading frame of 1608 bp encoding a putative protein of 536 amino acid. The deduced LjTRAF3 protein contained a RING finger, two zinc fingers, a coiled-coil, and a meprin and TRAF-C homology domain...
January 30, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29407574/pathogenicity-of-duck-hepatitis-a-virus-type-3-and-innate-immune-responses-of-the-ducklings-to-virulent-dhav-3
#9
Xuelian Zhang, Chong Cao, Zhehui Qu, Wenjing Zhang, Yue Liu, Haihui Qi, Chunxue Hao, Wenlong Zhang, Mingchun Gao, Junwei Wang, Bo Ma
Duck virus hepatitis caused by duck hepatitis A virus (DHAV) is an acute and contagious disease. To better understand the pathogenic mechanism of DHAV-3 in ducklings, an infection experiment was performed. Our results showed that typical symptoms were observed in the infected ducklings. DHAV-3 could infect many tissues, leading to pathological lesions, especially on the livers and spleen, and the host immune responses are activated in infection. Real-time quantitative PCR demonstrated that expression of many innate immune-related genes was mostly up-regulated in the livers and spleen, and antiviral innate immune response was established, but not sufficient to restrict the virus replication of lethal dose...
January 26, 2018: Molecular Immunology
https://www.readbyqxmd.com/read/29402958/cell-fate-in-antiviral-response-arises-in-the-crosstalk-of-irf-nf-%C3%AE%C2%BAb-and-jak-stat-pathways
#10
Maciej Czerkies, Zbigniew Korwek, Wiktor Prus, Marek Kochańczyk, Joanna Jaruszewicz-Błońska, Karolina Tudelska, Sławomir Błoński, Marek Kimmel, Allan R Brasier, Tomasz Lipniacki
The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-κB, a requirement for induction of IFNβ expression. Autocrine IFNβ initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-κB in first responder cells...
February 5, 2018: Nature Communications
https://www.readbyqxmd.com/read/29395325/human-adar1-prevents-endogenous-rna-from-triggering-translational-shutdown
#11
Hachung Chung, Jorg J A Calis, Xianfang Wu, Tony Sun, Yingpu Yu, Stephanie L Sarbanes, Viet Loan Dao Thi, Abigail R Shilvock, H-Heinrich Hoffmann, Brad R Rosenberg, Charles M Rice
Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus...
January 12, 2018: Cell
https://www.readbyqxmd.com/read/29352251/differential-effects-of-sumo1-and-sumo3-on-pkr-activation-and-stability
#12
Ghizlane Maarifi, Faten El Asmi, Mohamed Ali Maroui, Laurent Dianoux, Mounira K Chelbi-Alix
Double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is a serine/threonine kinase that exerts its own phosphorylation and the phosphorylation of the α subunit of the protein synthesis initiation factor eIF-2α. PKR was identified as a target of SUMOylation and the triple PKR-SUMO deficient mutant on Lysine residues K60-K150-K440 has reduced PKR activity. We report that SUMO1 and SUMO3 expression exert differential effects on PKR localization, activation and stability. SUMO1 or SUMO3 did not alter the repartition of PKR in the cytoplasm and the nucleus...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348831/aberrant-expression-of-mir-21-mir-376c-and-mir-145-and-their-target-host-genes-in-merkel-cell-polyomavirus-positive-non-small-cell-lung-cancer
#13
Ismini Lasithiotaki, Eliza Tsitoura, Anastasios Koutsopoulos, Eleni Lagoudaki, Chara Koutoulaki, George Pitsidianakis, Demetrios A Spandidos, Nikolaos M Siafakas, George Sourvinos, Katerina M Antoniou
Merkel Cell Polyoma Virus (MCPyV) infection has been associated with non-small cell lung cancer (NSCLC). Viruses can manipulate cellular miRNAs or have a profound impact on cellular miRNA expression to control host regulatory pathways. In this study, we evaluated the expression profiles of cancer-associated and virally affected host microRNAs miR-21, miR-145, miR-146a, miR-155, miR-302c, miR-367 and miR-376c in a series of NSCLC tissue samples as well as in samples from "healthy" sites, distant from the tumour region that were either positive or negative for MCPyV DNA...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348664/stress-induced-trbp-phosphorylation-enhances-its-interaction-with-pkr-to-regulate-cellular-survival
#14
Evelyn Chukwurah, Rekha C Patel
Transactivation response element RNA-binding protein (TRBP or TARBP2) initially identified to play an important role in human immunodeficiency virus (HIV) replication also has emerged as a regulator of microRNA biogenesis. In addition, TRBP functions in signaling pathways by negatively regulating the interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) during viral infections and cell stress. During cellular stress, PKR is activated and phosphorylates the α subunit of the eukaryotic translation factor eIF2, leading to the cessation of general protein synthesis...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348517/ndrg2-contributes-to-cisplatin-sensitivity-through-modulation-of-bak-to-mcl-1-ratio
#15
Soojong Park, Sang-Seok Oh, Ki Won Lee, Yeon-Kyeong Lee, Nae Yu Kim, Joo Heon Kim, Jiyun Yoo, Kwang Dong Kim
The downregulation of N-Myc downstream-regulated gene 2 (NDRG2) is known to be associated with the progression and poor prognosis of several cancers. Sensitivity to anti-cancer may be associated with a good prognosis in cancer patients, and NDRG2, which is induced by p53, sensitizes the cells to chemotherapy. However, the unique function of NDRG2 as an inducer of apoptosis under chemotreatment has not been sufficiently studied. In this study, we investigated the role of NDRG2 in chemo-sensitivity, focusing on cisplatin in U937 histiocytic lymphoma, which has the loss-of-functional mutation in p53...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29345572/breaking-the-dna-damage-response-via-serine-threonine-kinase-inhibitors-to-improve-cancer-treatment
#16
Wioletta Rozpedek, Dariusz Pytel, Alicja Nowak-Zdunczyk, Dawid Lewko, Radoslaw Wojtczak, John Alan Diehl, Ireneusz Majsterek
Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death...
January 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29337352/genetic-removal-of-eif2%C3%AE-kinase-perk-in-mice-enables-hippocampal-l-ltp-independent-of-mtorc1-activity
#17
Helena R Zimmermann, Wenzhong Yang, Brenna C Beckelman, Nicole P Kasica, Xueyan Zhou, Lucas Galli, Alexey G Ryazanov, Tao Ma
Characterization of the molecular signaling pathways underlying protein synthesis-dependent forms of synaptic plasticity, such as late long-term potentiation (L-LTP), can provide insights not only into memory expression/maintenance under physiological conditions but also potential mechanisms associated with the pathogenesis of memory disorders. Here, we report in mice that L-LTP failure induced by the mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) inhibitor rapamycin is reversed by brain-specific genetic deletion of PKR-like ER kinase, PERK (PERK KO), a kinase for eukaryotic initiation factor 2α (eIF2α)...
January 16, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29337245/hepatic-alcohol-dehydrogenase-deficiency-induces-pancreatic-injury-in-chronic-ethanol-feeding-model-of-deer-mice
#18
Samir M Amer, Kamlesh K Bhopale, Ramu D Kakumanu, Vsevolod L Popov, Bill A Rampy, Inas H El-Mehallawi, Magdy M Ashmawy, G A Shakeel Ansari, Bhupendra S Kaphalia
The single most common cause of chronic pancreatitis (CP, a serious inflammatory disease) is chronic alcohol abuse, which impairs hepatic alcohol dehydrogenase (ADH, a major ethanol oxidizing enzyme). Previously, we found ~5 fold greater fatty acid ethyl esters (FAEEs), and injury in the pancreas of hepatic ADH deficient (ADH-) vs. hepatic normal ADH (ADH+) deer mice fed 3.5g% ethanol via liquid diet daily for two months. Therefore, progression of ethanol-induced pancreatic injury was determined in ADH- deer mice fed ethanol for four months to delineate the mechanism and metabolic basis of alcoholic chronic pancreatitis (ACP)...
January 11, 2018: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/29325821/dna-vaccine-encoding-myristoylated-membrane-protein-mmp-of-rock-bream-iridovirus-rbiv-induces-protective-immunity-in-rock-bream-oplegnathus-fasciatus
#19
Myung-Hwa Jung, Chamilani Nikapitiya, Sung-Ju Jung
Rock bream iridovirus (RBIV) causes severe mass mortalities in rock bream (Oplegnathus fasciatus) in Korea. In this study, we investigated the potential of viral membrane protein to induce antiviral status protecting rock bream against RBIV infection. We found that fish administered with ORF008L (myristoylated membrane protein, MMP) vaccine exhibited significantly higher levels of survival compared to ORF007L (major capsid protein, MCP). Moreover, ORF008L-based DNA vaccinated fish showed significant protection at 4 and 8 weeks post vaccination (wpv) than non-vaccinated fish after infected with RBIV (6...
January 8, 2018: Vaccine
https://www.readbyqxmd.com/read/29317708/connexin-43-hemichannel-as-a-novel-mediator-of-sterile-and-infectious-inflammatory-diseases
#20
Wei Li, Guoqiang Bao, Weiqiang Chen, Xiaoling Qiang, Shu Zhu, Shuaiwei Wang, Mingzhu He, Gaifeng Ma, Mahendar Ochani, Yousef Al-Abed, Huan Yang, Kevin J Tracey, Ping Wang, John D'Angelo, Haichao Wang
Cytoplasmic membrane-bound connexin 43 (Cx43) proteins oligomerize into hexameric channels (hemichannels) that can sometimes dock with hemichannels on adjacent cells to form gap junctional (GJ) channels. However, the possible role of Cx43 hemichannels in sterile and infectious inflammatory diseases has not been adequately defined due to the lack of selective interventions. Here we report that a proinflammatory mediator, the serum amyloid A (SAA), resembled bacterial endotoxin by stimulating macrophages to up-regulate Cx43 expression and double-stranded RNA-activated protein kinase R (PKR) phosphorylation in a TLR4-dependent fashion...
January 9, 2018: Scientific Reports
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