Bacteriophage Therapy: An Alternative for the Treatment of Staphylococcus aureus Infections in Animals and Animal Models

Staphylococcus aureus causes hospital-acquired (HA), community-acquired (CA) and companion animal and livestock-associated (LA) infections. Molecular epidemiology studies suggest that although host specificity may be associated with specific genetic lineages, recent human-to-animal and animal-to-human transmissions related to mobile genetic elements have been described. Gene transfers include virulence and antibiotic resistance genes, thus making it difficult to control multidrug resistance S. aureus infections. Bacteriophages (phages) and endolysins, the enzymes responsible for bacterial lysis by phages, are alternatives to the use of antibiotics for the control of S. aureus infections. In this work, we review current advances in the development of phage therapy and the study and design of recombinant endolysins to treat S. aureus infections. Preliminary results of bacteriophage isolation based on molecular epidemiology knowledge show that bacteriophages are specific of genetic lineages and that this strategy may be used as an approach to isolate and evaluate new bacteriophages for therapy

Control and resolution mechanisms of the inflammatory response

Inflammation is beneficial to the organism because it represents one of the first barriers against external and internal stimuli. It is a complex process in which a number of cells and molecules play different roles in a coordinated and well-controlled manner. However, a failure of the mechanism that self-regulates and resolves the process may lead to chronic inflammation, and this in turn may cause degenerative diseases such as cancer, diabetes, and autoimmune and cardiovascular diseases. Therefore, a deep knowledge about the cellular and molecular mechanisms used to resolve inflammation is mandatory to design tools and strategies to control it. This task is not easy taking into account that different signaling pathways activate several molecules involved in the resolution of the inflammatory response and some of them interfere with cellular activities unrelated to the resolution phenomenon. In addition, many reports have shown that several molecules activate or inhibit inflammation depending on the tissue or the physiological context. Furthermore, it has been observed that inhibition of several molecules considered as proinflammatory has resulted in the intensification of the inflammatory response. Having this is mind, this special issue has gathered original and review articles that will help us to expand our knowledge on the complex process of the inflammation control and resolution. More importantly, the papers presented in this special issue are a good reference to recognize what type of studies is missing and the way we could fill the gaps.Fil: Baizabal Aguirre, Víctor M.. Universidad Michoacana de San Nicolás de Hidalgo; MéxicoFil: Rosales, Carlos. Universidad Nacional Autónoma de México; MéxicoFil: López Macías, Constantino. Instituto Mexicano del Seguro Social; México. University of Oxford; Reino UnidoFil: Gomez, Marisa Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

Control and Resolution Mechanisms of the Inflammatory Response 2016

In the last 20 years the field of the innate immunity has advanced notably since the pioneering work on the discovery of Toll-like receptors. A considerable number of studies on the molecular mechanisms triggering the inflammatory response have been described. A search in PubMed with the words ?inflammatory response? for the current year gives 11,000 articles, which means an approximate 917 articles per month and 30 per day. This amount of information reflects the interest of the scientific community not only to understand the essential mechanisms involved in the inflammatory response but also to translate this knowledge for the treatment of chronic and degenerative human diseases. Now that the main participating molecules and signaling transduction mechanisms activated during the inflammatory response have been established, researchers have begun to elucidate how a tissue is able to control/resolve inflammation and regain homeostasis. This is because a failure of the mechanisms that self-regulate and resolve the inflammatory process may lead to chronic inflammation, and this in turn may cause degenerative diseases such as cancer, diabetes, and autoimmune and cardiovascular diseases. Although many investigations have described synthetic or natural molecules that inhibit inflammation, no clear picture on the control and resolution mechanisms have emerged. This special issue is an attempt to contribute to our knowledge of the molecular programs used by the cell to control and resolve inflammation. We hope this issue may be a good reference to all interested in the complex process of the inflammation control and resolution.Fil: Baizabal Aguirre, Víctor M.. Universidad Michoacana de San Nicolás de Hidalgo; MéxicoFil: Rosales, Carlos. Universidad Nacional Autónoma de México; MéxicoFil: López Macías, Constantino. Instituto Mexicano del Seguro Social; México. University of Oxford; Reino UnidoFil: Gomez, Marisa Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer

The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer’s disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3β kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α

Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens

Abstract Glycogen synthase kinase 3β (GSK3β) plays a fundamental role during the inflammatory response induced by bacteria. Depending on the pathogen and its virulence factors, the type of cell and probably the context in which the interaction between host cells and bacteria takes place, GSK3β may promote or inhibit inflammation. The goal of this review is to discuss recent findings on the role of the inhibition or activation of GSK3β and its modulation of the inflammatory signaling in monocytes/macrophages and epithelial cells at the transcriptional level, mainly through the regulation of nuclear factor-kappaB (NF-κB) activity. Also included is a brief overview on the importance of GSK3 in non-inflammatory processes during bacterial infection.</p

Glycogen Synthase Kinase 3α Is the Main Isoform That Regulates the Transcription Factors Nuclear Factor-Kappa B and cAMP Response Element Binding in Bovine Endothelial Cells Infected with Staphylococcus aureus

Glycogen synthase kinase 3 (GSK3) is a constitutive enzyme implicated in the regulation of cytokine expression and the inflammatory response during bacterial infections. Mammals have two GSK3 isoforms named GSK3α and GSK3β that plays different but often overlapping functions. Although the role of GSK3β in cytokine regulation during the inflammatory response caused by bacteria is well described, GSK3α has not been found to participate in this process. Therefore, we tested if GSK3α may act as a regulatory isoform in the cytokine expression by bovine endothelial cells infected with Staphylococcus aureus because this bacterium is one of the major pathogens that cause tissue damage associated with inflammatory dysfunction. Interestingly, although both isoforms were phosphorylated–inactivated, we consistently observed a higher phosphorylation of GSK3α at Ser21 than that of GSK3β at Ser9 after bacterial challenge. During a temporal course of infection, we characterized a molecular switch from pro-inflammatory cytokine expression (IL-8), promoted by nuclear factor-kappa B (NF-κB), at an early stage (2 h) to an anti-inflammatory cytokine expression (IL-10), promoted by cAMP response element binding (CREB), at a later stage (6 h). We observed an indirect effect of GSK3α activity on NF-κB activation that resulted in a low phosphorylation of CREB at Ser133, a decreased interaction between CREB and the co-activator CREB-binding protein (CBP), and a lower expression level of IL-10. Gene silencing of GSK3α and GSK3β with siRNA indicated that GSK3α knockout promoted the interaction between CREB and CBP that, in turn, increased the expression of IL-10, reduced the interaction of NF-κB with CBP, and reduced the expression of IL-8. These results indicate that GSK3α functions as the primary isoform that regulates the expression of IL-10 in endothelial cells infected with S. aureus