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Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Once a cell binds IFN-α or IFN-β, which use a common receptor, a cascade of cellular signaling occurs resulting in the transcription of several proteins that aid in conferring a hostile environment to viral infection. There are three key antiviral proteins that have been identified as a result of this transcriptional activation: 2′–5′ oligoadenylate synthetase, protein kinase PKR and Mx protein [31]. The 2′–5′ oligoadenylate synthetase polymerizes adenosine triphosphate into a series of 2′–5′ linked oligomers, which differs from normal nucleotides that are joined 3′–5′. These oligomers in turn activate RNase L, a constitutive endoribonuclease. This enzyme degrades viral RNA. Protein kinase PKR is activated by the presence of double-stranded RNA. Upon activation, PKR phosphorylates the cellular translation initiation factor eIF-2. The result of this is an inhibition of translation and protein synthesis, contributing to the inhibition of viral replication. The Mx protein is a protein that acts in the nucleus of an infected cell to confer resistance to influenza virus. The Mx protein acts in the nucleus of the cell infected with influenza and inhibits the synthesis of the influenza virus mRNA [32].
Cyclic Nucleotides
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Differentiation of MEL cells, as well as treatment of these cells with a cAMP analog (8-bromo-cAMP), elicit a large and selective increase in the rate of biosynthesis of only one type of RII subunit.70 The rat has at least three genes coding for R subunits of cAMP-dependent protein kinase, one gene for RI and two for RII (RII-α and RII-β).71-73 The RII isoform is present and regulated by hormones (FSH and estradiol) in rat ovarian granulosa cells. A cDNA encoding the hormonally regulated RII-β subunit isoform was cloned from these cells and its structure was determined, thus allowing the deduction of the amino acid sequence (415 residues) of the enzyme.74 A cAMP-resistant CHO cell line containing both wild-type and mutant species of RI has been characterized.75 It is possible that the two forms of RI detected in these cells occurred by mutation in one of the two alleles of a single gene coding for RI. Studies on the functional organization and activity of cAMP-dependent protein kinase R subunits may be facilitated by the collection of a series of mutants from sublines of S49 mouse lymphoma cells that are hemizygous for expression of the R subunit and possess structural lesions in the gene for the R subunit.76
Vaginal Immunology
Published in William J. Ledger, Steven S. Witkin, Vulvovaginal Infections, 2017
William J. Ledger, Steven S. Witkin
Components of innate immunity also are present within the cytoplasm. A protein kinase known as PKR is activated by double-stranded RNA, an intermediate produced during intracellular viral infections. Activated PKR blocks viral protein synthesis and induces production of the antiviral protein, interferon alpha.
Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis
Published in Expert Opinion on Investigational Drugs, 2023
Loreto Martinez-Gonzalez, Ana Martinez
(NCT04220021), a well-known antidiabetic agent, has been recently identified as a double-stranded RNA-dependent protein kinase R (PKR) inhibitor. PKR regulates repeat associated non-canonical start codon (RAN) translation present in several neurodegenerative diseases including ALS [62]. In fact, metformin blocks a key pathway for expression of toxic proteins produced from the C9orf72 repeat expansion and improves disease in C9orf72-ALS/FTD mice [63]. Based on that results, a clinical trial phase II is ongoing with the aim to confirm changes in RAN protein levels in CSF from the participants. The recruitment is focused only in C9orf72 positive ALS patients. It is important to notice that previously metformin has not shown any beneficial effects on survival in the SOD1G93A mouse model of ALS [64], being one of the first drug showing great genetical specificity in ALS models.
Microbiota, not host origin drives ex vivo intestinal epithelial responses
Published in Gut Microbes, 2022
Kaline Arnauts, Padhmanand Sudhakar, Sare Verstockt, Cynthia Lapierre, Selina Potche, Clara Caenepeel, Bram Verstockt, Jeroen Raes, Séverine Vermeire, João Sabino, Catherine Verfaillie, Marc Ferrante
To complement differential gene expression analysis, we used weighted gene co-expression network analysis (WGCNA) to assess clusters of genes with similar expression patterns. Comparison of epithelial cells from UC and non-IBD controls in both inflamed and non-inflamed conditions, resulted in the identification of 11 co-expression clusters ranging in size from 77 to 2015 genes. In absence of microbiota, three clusters significantly correlated with UC non-inflamed epithelium as compared to non-IBD epithelium; of which one cluster significantly correlated with inflamed UC epithelium (turquoise cluster). The significant clusters identified in absence of microbiota were involved in tight junction and integrin signaling, and DNA damage response (BRCA1). The pink cluster was linked to the role of PKR in interferon induction and antiviral responses. In contrast, upon exposure to microbiota from the healthy volunteer only one significant correlation (pink cluster) was identified in inflamed conditions (Supplementary Figure 4). Again, the highest number of involved clusters was detected in the control condition, indicating that differences between UC and non-IBD epithelial cells were mainly driven by baseline characteristics and not induced by exposure to microbiota of UC patients or the healthy volunteer.
Resveratrol inhibits neural apoptosis and regulates RAX/P-PKR expression in retina of diabetic rats
Published in Nutritional Neuroscience, 2022
Kaihong Zeng, Yuan Wang, Lujiao Huang, Yi Song, Xuemei Yu, Bo Deng, Xue Zhou
PKR is a serine/threonine protein-kinase expressed in mammalian cells. Activation of PKR is reported to be involved in the ganglion cells death caused by tunicamycin. PKR regulates many cellular progresses such as apoptosis, proliferation and differentiation response to diverse stimuli including endoplasmic reticulum stress, oxidative stress, and inflammation. The murine protein RAX or its human homologue, PACT, is the endogenous activator of PKR. RAX is a stress response protein that activates PKR under various stressful conditions. Activation of PKR by ethanol has been shown to induce neuroblastoma cellular apoptosis through enhancing the binding of RAX and PKR. Overexpression of RAX increases cellular sensitivity to ethanol by further activating PKR. In contrast, mutated RAX inhibits ethanol-promoted PKR activation as well as cellular apoptosis [16,17].