1,721,004 research outputs found
“Pharmacological Targeting of Glutamine Synthetase Skews Macrophages Toward An Inflammatory Phenotype and Inhibits Metastasis”
No full textPharmacological Targeting of Glutamine Synthetase Skews Macrophages Toward An Inflammatory Phenotype and Inhibits Metastasi
Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death
No full textAmyloid β-peptide [Aβ(1-42)] is central to the pathogenesis of Alzheimer's disease (AD), and the AD brain is under intense oxidative stress, including membrane lipid peroxidation. Aβ(1-42) causes oxidative stress in and neurotoxicity to neurons in mechanisms that are inhibited by Vitamin E and involve the single methionine residue of this peptide. In particular, Aβ induces lipid peroxidation in ways that are inhibited by free radical antioxidants. Two reactive products of lipid peroxidation are the alkenals, 4-hydroxynonenal (HNE) and 2-propenal (acrolein). These alkenals covalently bind to synaptosomal protein cysteine, histidine, and lysine residues by Michael addition to change protein conformation and function. HNE or acrolein binding to proteins introduces a carbonyl to the protein, making the protein oxidatively modified as a consequence of lipid peroxidation. Immunoprecipitation of proteins from AD and control brain, obtained no longer than 4h PMI, showed selective proteins are oxidatively modified in the AD brain. Creatine kinase (CK) and β-actin have increased carbonyl groups, and Glt-1, a glutamate transporter, has increased binding of HNE in AD. Aβ(1-42) addition to synaptosomes also results in HNE binding to Glt-1, thereby coupling increased Aβ(1-42) in AD brain to increased lipid peroxidation and its sequelae and possibly explaining the mechanism of glutatmate transport inhibition known in AD brain. Aβ also inhibits CK. Implications of these findings relate to decreased energy utilization, altered assembly of cytoskeletal proteins, and increased excitotoxicity to neurons by glutamate, all reported for AD. The epsilon-4 allele of the lipid carrier protein apolipoprotein E (APOE) allele is a risk factor for AD. Synaptosomes from APOE knock-out mice are more vulnerable to Aβ-induced oxidative stress (protein oxidation, lipid peroxidation, and ROS generation) than are those from wild-type mice. Further, synaptosomes from allele-specific APOE knock-in mice have tiered vulnerability to Aβ(1-42)-induced oxidative stress, with APOE4 more vulnerable to Aβ(1-42) than are those from APOE2 or APOE3 mice. These results are consistent with the notion of a coupling of the oxidative environment in AD brain and increased risk of developing this disorder. Taken together, the findings from in-vitro studies of lipid peroxidation induced by Aβ(1-42) and postmortem studies of lipid peroxidation (and its sequelae) in AD brain may help explain the APOE allele-related risk for AD, some of the functional and structural alterations in AD brain, and strongly support a causative role of Aβ(1-42)-induced oxidative stress in AD neurodegeneration
BLOCKADE OF GLUTAMINE SYNTHETASE SKEWS MACROPHAGES TOWARDS AN M1-LIKE PHENOTYPE AND INHIBITS TUMOR METASTASIS
No full textGlutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls
important events including the release of inflammatory mediators, mTOR activation and
autophagy. However, its role in macrophages remains elusive. Here we report that pharmacologic
inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized
by reduced intracellular glutamine and increased succinate with enhanced glucose flux through
glycolysis and pyruvate carboxylase, and consequent HIF1α activation. These metabolic changes
and HIF1α accumulation in GS-inhibited macrophages promote M1 markers expression,
accompanied by the ability to boost T-cell proliferation and migration, and to impair endothelial
cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice
promotes tumor vessel pruning, vascular normalization and accumulation of cytotoxic T-cells,
leading to metastasis inhibition. These data identify GS activity as mediator of the proangiogenic,
immunosuppressive and prometastatic function of M2-like macrophages and highlight the
possibility to target this enzyme in the treatment of cancer metastasis
Glutamine Synthetase: Localization Dictates Outcome
Full text linkGlutamine synthetase (GS) is the adenosine triphosphate (ATP)-dependent enzyme that catalyses the synthesis of glutamine by condensing ammonium to glutamate. In the circulatory system, glutamine carries ammonia from muscle and brain to the kidney and liver. In brain reduction of GS activity has been suggested as a mechanism mediating neurotoxicity in neurodegenerative disorders. In cancer, the delicate balance between glutamine synthesis and catabolism is a critical event. In vitro evidence, confirmed in vivo in some cases, suggests that reduced GS activity in cancer cells associates with a more invasive and aggressive phenotype. However, GS is known to be highly expressed in cells of the tumor microenvironment, such as fibroblasts, adipocytes and immune cells, and their ability to synthesize glutamine is responsible for the acquisition of protumoral phenotypes. This has opened a new window into the complex scenario of the tumor microenvironment, in which the balance of glutamine consumption versus glutamine synthesis influences cellular function. Since GS expression responds to glutamine starvation, a lower glutamine synthesizing power due to the absence of GS in cancer cells might apply a metabolic pressure on stromal cells. This event might push stroma towards a GS-high/protumoral phenotype. When referred to stromal cells, GS expression might acquire a 'bad' significance to the point that GS inhibition might be considered a conceivable strategy against cancer metastasis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines
No full textSignificant metabolic changes occur in the shift from resting to activated cellular status in inflammation. Thus, changes in expression of a large number of genes and extensive metabolic reprogramming gives rise to acquisition of new functions (e.g. production of cytokines, intermediates for biosynthesis, lipid mediators, PGE, ROS and NO). In this context, mitochondrial carriers, which catalyse the transport of solute across mitochondrial membrane, change their expression to transport mitochondrially produced molecules, among which citrate and succinate, to be used as intracellular signalling molecules in inflammation. This review summarises the mitochondrial carriers studied so far that are, directly or indirectly, involved in inflammation
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