scholarly journals Protein Kinase R in Bacterial Infections: Friend or Foe?

2021 ◽  
Vol 12 ◽  
Author(s):  
Robin Smyth ◽  
Jim Sun
Keyword(s):  
Immune Response ◽  
Protein Kinase ◽  
Bacterial Infections ◽  
Current Knowledge ◽  
Bacterial Pathogens ◽  
Treatment Strategies ◽  
Protein Translation ◽  
Protein Kinase R ◽  
Cell Functions ◽  
Pharmacological Modulators

The global antimicrobial resistance crisis poses a significant threat to humankind in the coming decades. Challenges associated with the development of novel antibiotics underscore the urgent need to develop alternative treatment strategies to combat bacterial infections. Host-directed therapy is a promising new therapeutic strategy that aims to boost the host immune response to bacteria rather than target the pathogen itself, thereby circumventing the development of antibiotic resistance. However, host-directed therapy depends on the identification of druggable host targets or proteins with key functions in antibacterial defense. Protein Kinase R (PKR) is a well-characterized human kinase with established roles in cancer, metabolic disorders, neurodegeneration, and antiviral defense. However, its role in antibacterial defense has been surprisingly underappreciated. Although the canonical role of PKR is to inhibit protein translation during viral infection, this kinase senses and responds to multiple types of cellular stress by regulating cell-signaling pathways involved in inflammation, cell death, and autophagy – mechanisms that are all critical for a protective host response against bacterial pathogens. Indeed, there is accumulating evidence to demonstrate that PKR contributes significantly to the immune response to a variety of bacterial pathogens. Importantly, there are existing pharmacological modulators of PKR that are well-tolerated in animals, indicating that PKR is a feasible target for host-directed therapy. In this review, we provide an overview of immune cell functions regulated by PKR and summarize the current knowledge on the role and functions of PKR in bacterial infections. We also review the non-canonical activators of PKR and speculate on the potential mechanisms that trigger activation of PKR during bacterial infection. Finally, we provide an overview of existing pharmacological modulators of PKR that could be explored as novel treatment strategies for bacterial infections.

scholarly journals Exploring the Therapeutic Potential of Membrane Transport Proteins: Focus on Cancer and Chemoresistance

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1624 ◽  
Author(s):  
Shekoufeh Almasi ◽  
Yassine El Hiani
Keyword(s):  
Cancer Treatment ◽  
Membrane Transport ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Functional Expression ◽  
Transport Proteins ◽  
Cell Functions ◽  
Membrane Transport Proteins ◽  
Druggable Targets

Improving the therapeutic efficacy of conventional anticancer drugs represents the best hope for cancer treatment. However, the shortage of druggable targets and the increasing development of anticancer drug resistance remain significant problems. Recently, membrane transport proteins have emerged as novel therapeutic targets for cancer treatment. These proteins are essential for a plethora of cell functions ranging from cell homeostasis to clinical drug toxicity. Furthermore, their association with carcinogenesis and chemoresistance has opened new vistas for pharmacology-based cancer research. This review provides a comprehensive update of our current knowledge on the functional expression profile of membrane transport proteins in cancer and chemoresistant tumours that may form the basis for new cancer treatment strategies.

scholarly journals Cytosolic Sensors for Pathogenic Viral and Bacterial Nucleic Acids in Fish

2020 ◽  
Vol 21 (19) ◽  
pp. 7289
Author(s):  
Miriam Mojzesz ◽  
Krzysztof Rakus ◽  
Magdalena Chadzinska ◽  
Kentaro Nakagami ◽  
Gouranga Biswas ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nucleic Acids ◽  
Current Knowledge ◽  
Innate Immune ◽  
Rna Helicases ◽  
Protein Kinase R ◽  
Evolutionarily Conserved ◽  
Different Types ◽  
Molecular Patterns ◽  
Inducible Gene

Recognition of the non-self signature of invading pathogens is a crucial step for the initiation of the innate immune mechanisms of the host. The host response to viral and bacterial infection involves sets of pattern recognition receptors (PRRs), which bind evolutionarily conserved pathogen structures, known as pathogen-associated molecular patterns (PAMPs). Recent advances in the identification of different types of PRRs in teleost fish revealed a number of cytosolic sensors for recognition of viral and bacterial nucleic acids. These are DExD/H-box RNA helicases including a group of well-characterized retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and non-RLR DExD/H-box RNA helicases (e.g., DDX1, DDX3, DHX9, DDX21, DHX36 and DDX41) both involved in recognition of viral RNAs. Another group of PRRs includes cytosolic DNA sensors (CDSs), such as cGAS and LSm14A involved in recognition of viral and intracellular bacterial dsDNAs. Moreover, dsRNA-sensing protein kinase R (PKR), which has a role in antiviral immune responses in higher vertebrates, has been identified in fish. Additionally, fish possess a novel PKR-like protein kinase containing Z-DNA binding domain, known as PKZ. Here, we review the current knowledge concerning cytosolic sensors for recognition of viral and bacterial nucleic acids in teleosts.

A Journey through the Cytoskeleton with Protein Kinase CK2

2019 ◽  
Vol 20 (6) ◽  
pp. 547-562 ◽  
Author(s):  
Claudio D'Amore ◽  
Valentina Salizzato ◽  
Christian Borgo ◽  
Luca Cesaro ◽  
Lorenzo A. Pinna ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Shape ◽  
Protein Kinase Ck2 ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Consensus Sequence ◽  
Cell Movement ◽  
Mechanical Integrity ◽  
Cell Functions ◽  
Kinase Ck2

Substrate pleiotropicity, a very acidic phosphorylation consensus sequence, and an apparent uncontrolled activity, are the main features of CK2, a Ser/Thr protein kinase that is required for a plethora of cell functions. Not surprisingly, CK2 appears to affect cytoskeletal structures and correlated functions such as cell shape, mechanical integrity, cell movement and division. This review outlines our current knowledge of how CK2 regulates cytoskeletal structures, and discusses involved pathways and molecular mechanisms.

scholarly journals Redox Regulation of the Immune Response: Nitro-Oxidative Stress and Antioxidants Regulate Macrophage, Neutrophil, and T and B Lymphocyte, and Dendritic and Natural Killer Cell Functions

2021 ◽  
Author(s):  
Gerwyn Morris ◽  
Michael Maes
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Protein Kinase ◽  
Natural Killer ◽  
Immune Cells ◽  
Metabolic Reprogramming ◽  
Antioxidant Systems ◽  
Nuclear Factor ◽  
Cell Functions ◽  
Mitochondrial Functions

An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-κB, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

scholarly journals Mitochondrial dsRNAs activate PKR and TLR3 to promote chondrocyte degeneration in osteoarthritis

2020 ◽  
Author(s):  
Sujin Kim ◽  
Keonyong Lee ◽  
Yong Seok Choi ◽  
Jayoung Ku ◽  
Yun Jong Lee ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Kinase ◽  
Inflammatory Cytokines ◽  
Degenerative Diseases ◽  
Toll Like Receptor ◽  
Protein Kinase R ◽  
Molecular Identity ◽  
Synovial Fluids ◽  
Elevated Expression

ABSTRACTProtein kinase R (PKR) is an immune response protein that becomes activated by long double-stranded RNAs (dsRNAs). Several studies reported the misactivation of PKR in patients of degenerative diseases including primary osteoarthritis (OA). However, the molecular identity of PKR-activating dsRNAs remains unknown. Here, we investigate the role of mitochondrial dsRNAs (mt-dsRNAs) in the development of OA. We find that in response to OA-mimicking stressors, cytosolic efflux of mt-dsRNAs is increased, leading to PKR activation and subsequent induction of inflammatory cytokines and apoptosis. Moreover, mt-dsRNAs are exported to the extracellular space where they activate toll-like receptor 3. Elevated expression of mt-dsRNAs in the synovial fluids of OA patients further supports our data. Lastly, we show that autophagy protects chondrocytes from mitochondrial dysfunction partly by removing cytosolic mt-dsRNAs. Together, these findings establish the PKR-mt-dsRNA as a critical regulatory axis in OA development and suggest mt-dsRNAs as a potential target in fighting OA.

Development of Peptides that Inhibit Aminoglycoside-Modifying Enzymes and β-Lactamases for Control of Resistant Bacteria

2020 ◽  
Vol 21 (10) ◽  
pp. 1011-1026
Author(s):  
Bruna O. Costa ◽  
Marlon H. Cardoso ◽  
Octávio L. Franco
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Specific Chemical ◽  
Target Interaction ◽  
Multiresistant Bacteria ◽  
Acute Bacterial Infections

: Aminoglycosides and β-lactams are the most commonly used antimicrobial agents in clinical practice. This occurs because they are capable of acting in the treatment of acute bacterial infections. However, the effectiveness of antibiotics has been constantly threatened due to bacterial pathogens producing resistance enzymes. Among them, the aminoglycoside-modifying enzymes (AMEs) and β-lactamase enzymes are the most frequently reported resistance mechanisms. AMEs can inactivate aminoglycosides by adding specific chemical molecules in the compound, whereas β-lactamases hydrolyze the β-lactams ring, preventing drug-target interaction. Thus, these enzymes provide a scenario of multidrug-resistance and a significant threat to public health at a global level. In response to this challenge, in recent decades, several studies have focused on the development of inhibitors that can restore aminoglycosides and β-lactams activity. In this context, peptides appear as a promising approach in the field of inhibitors for future antibacterial therapies, as multiresistant bacteria may be susceptible to these molecules. Therefore, this review focused on the most recent findings related to peptide-based inhibitors that act on AMEs and β-lactamases, and how these molecules could be used for future treatment strategies.

scholarly journals COVID-19: a review of current knowledge regarding exposure, quarantine, isolation and other preventive measures

2021 ◽  
Vol 8 ◽  
pp. 204993612110320
Author(s):  
Robert Rosolanka ◽  
Andres F. Henao-Martinez ◽  
Larissa Pisney ◽  
Carlos Franco-Paredes ◽  
Martin Krsak
Keyword(s):  
Immune Response ◽  
Severe Acute Respiratory Syndrome ◽  
Clinical Response ◽  
Preventive Measures ◽  
Current Knowledge ◽  
Therapeutic Options ◽  
Exposure Control ◽  
Knowledge Gaps ◽  
Vaccination Strategies ◽  
Speed Up

Deeper understanding of the spread, morbidity, fatality, and development of immune response associated with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is necessary in order to establish an appropriate epidemiological and clinical response. Exposure control represents a key part of the combat against COVID-19, as the effectiveness of current therapeutic options remains partial. Since the preventive measures have not been sufficiently able to slow down this pandemic, in this article we explore some of the pertinent knowledge gaps, while overall looking to effective vaccination strategies as a way out. Early on, such strategies may need to rely on counting the convalescents as protected in order to speed up the immunization of the whole population.

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