Current Pharmaceutical Design - Volume 10, Issue 8, 2004
Volume 10, Issue 8, 2004
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Modulating the Hypoxia-Inducible Factor Signaling Pathway: Applications From Cardiovascular Disease to Cancer
Authors: K. S. Hewitson, L. A. McNeill and C. J. SchofieldHumans, like other complex aerobic organisms, possess highly evolved systems for the delivery of dioxygen to all the cells of the body. These systems are regulated since excessive levels of dioxygen are toxic. In animals hypoxia causes an increase in the transcription levels of specific genes, including those encoding for vascular endothelial growth factor and erythropoietin. At the transcriptional level, the hypoxic response is mediated by hypoxia-inducible factor (HIF), an α,β-heterodimeric protein. HIF-β is constitutively present, but HIF-α levels are regulated by dioxygen. Under hypoxic conditions, levels of HIF-a rise, allowing its dimerization with HIF-b and enabling transcriptional activation. Under normoxic conditions both the level of HIF-α and its ability to enable transcription are directly controlled by its post-translational oxidation by oxygenases. Hydroxylation of HIF-α at either of two conserved prolyl residues enables its recognition by the von Hippel-Lindau tumour suppressor protein which targets it for proteasomal degradation. Hydroxylation of an asparaginyl residue in the C-terminal transactivation domain of HIF-a directly prevents its interaction with the coactivator p300 from the transcription complex. Hydroxylation of HIF-α is catalysed by members of the iron (II) and 2-oxoglutarate dependent oxygenase family. In humans, three prolyl-hydroxylase isozymes (PHD1-3, for prolyl hydroxylase domain enzymes) and an asparaginyl hydroxylase (FIH, for factor inhibiting HIF) have been identified. Recent studies have identified additional post-translational modifications of HIF-α including acetylation and phosphorylation. Modulation of the HIF mediated hypoxic response is of potential use in a wide range of disease states including cardiovascular disease and cancer. Here we review current knowledge of the HIF pathway focusing on its regulation by dioxygen and discussion of potential targets and challenges in attempts to modulate the pathway for medicinal application.
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B Cell Responses to Oxidative Stress
Authors: Yumi Tohyama, Tomoko Takano and Hirohei YamamuraB-lymphocytes are exposed to a reduction / oxidation environment during activation or inflammatory process, and the antioxidant systems are functional to protect themselves against harmful reactive oxygen species (ROS). The crucial roles of thioredoxin-2 (Trx-2) and a DNA repair enzyme APE / Ref-1 in mitochondria are reported in B-lymphocytes. Furthermore, ROS stimulate different signaling pathways in many cellular responses. Their effects often cause some diseases or are utilized for the treatment of other diseases. For example, the cells derived from Fanconi anemia (FA) patients are intolerant of oxidative stress and the therapeutic effect of anti-CD20 monoclonal antibody rituximab on B cell lymphoproliferative disorders is due to the generation of ROS. To clarify the oxidative stress-induced signaling pathways, we stimulated a B cell line with various concentrations of H2 O2 . As a result, a protein tyrosine kinase, Syk was involved in the induction of G2 / M arrest and protection of cells from apoptosis. Syk might inhibit the activation of caspase-9 through Akt thereby protecting cells from oxidative stress-induced apoptosis. On the other hand, Syk-dependent PLC-γ2 activation was required for acceleration towards apoptosis following oxidative stress. These findings suggest that oxidative stress-induced Syk activation triggers the activation of different pathways, such as pro-apoptotic or survival pathways, and that the balance of these pathways is a key factor in determining the fate of the cells exposed to oxidative stress. In contrast, the stimulation with the millimolar concentrations of H2 O2 rapidly led to necrosis in which tyrosine phosphorylation of FAK was involved at the downstream of Lyn and Syk.
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Cytotoxic Effects on B Lymphocytes Mediated by Reactive Oxygen Species
Authors: Neus Villamor, Emili Montserrat and Dolors ColomerReactive oxygen species (ROS) are produced in all mammalian cells as a result of normal cellular metabolism and due to the activation of oxidant-producing enzymes in response to exogenous stimuli. The balance between ROS production and antioxidant defenses determines the degree of oxidative stress. Generation of ROS has been associated with cell signaling, stress responses, cell proliferation, aging and cancer development. The ability of ROS to induce cellular damage and to cause cell death opens the possibility to exploit this property in the treatment of cancer through a free radical-mediated mechanism.
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The Role of ROS and RNS in Regulating Life and Death of Blood Monocytes
Authors: Christopher P. Baran, Mandy M. Zeigler, Susheela Tridandapani and Clay B. MarshThe ability to target and accumulate monocytes and macrophages in areas of tissue inflammation plays an important role in innate and humoral immunity. However, when this process becomes uncontrolled, tissue injury and dysfunction may ensue. This paper will focus on understanding the role and action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in regulating the molecular and biochemical pathways responsible for the regulation of the survival of human monocytes. We and others have found that ROS and RNS serve as important intracellular signaling molecules that influence cellular survival. Human monocytes are influenced by intracellular production of ROS and RNS, which affects both monocyte survival and death, depending on the form of nitric oxide presented to the cell. This review will address potential mechanisms by which ROS and RNS promote the survival of human monocytes and macrophages.
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Provoking Neuroprotection by Peroxynitrite
Authors: Juan P. Bolanos, Paula Garcia-Nogales and Angeles AlmeidaPeroxynitrite, the product of the reaction between nitric oxide and superoxide, is spontaneouly formed within most mammalian cells under physiological conditions. Initial work addressing the pathophysiology of peroxynitrite afforded the generally accepted notion that this compound would be the long-term neurotoxic nitric oxide-derivative. However, over the past six years a number of interesting studies have reported direct in vivo and in vitro evidence that, at nanomolar-low micromolar concentrations, peroxynitrite is actively involved in triggering cellular survival signals. Most such evidence came from studies demonstrating protection against myocardial ischemia-reperfusion injury and neuronal apoptosis. Although full elucidation of the precise mechanism responsible for such protection still requires further research, peroxynitrite has been shown to promote the nitration and / or phosphorylation of regulatory sites at tyrosine kinase receptors coupled to well-known antiapoptotic pathways, such as those involving phosphoinositide 3-kinase / Akt or mitogen-activated protein kinases. In addition, peroxynitrite-mediated transient protection of neurons against apoptotic death is associated with rapid stimulation of glucose metabolism and glutathione regeneration. In view of the potential cytoprotective function of peroxynitrite, further studies specifically focused on elucidating the possible therapeutic potential of peroxynitrite are sure to appear.
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Induction of Cytoprotective Genes Through Nrf2 / Antioxidant Response Element Pathway: A New Therapeutic Approach for the Treatment of Inflammatory Diseases
Authors: Xi-Lin Chen and Charles KunschIn the last decade, it has become recognized that reactive oxygen species (ROS) play important roles in the multiple biological processes involved in the pathophysiology of chronic inflammation such as cell proliferation, adhesion molecule expression, cytokine and chemoattractant production and matrix metalloproteinase generation. Intracellular redox homeostasis is maintained by balancing the production of ROS with their removal through cellular antioxidant defense systems. The antioxidant response element (ARE) is a cis-acting DNA regulatory element located in the regulatory regions of multiple genes including phase II detoxification enzymes as well as antioxidant proteins including glutathione-S-transferases, NAD(P)H:quinone oxidoreductase-1, γ-glutamylcysteine synthase, ferritin, and heme oxygenase-1. Nrf2 is the primary transcription factor that binds to the ARE, and through heterodimerization with other leucine-zipper containing transcription factors, activates the expression of these genes. It is evident that activation of ARE-regulated genes contributes to the regulation of cellular antioxidant defense systems. More importantly, there is a growing body of evidence suggesting that modulation of these cytoprotective genes has profound effects on immune and inflammatory responses. Activation of cytoprotective Nrf2 / ARE-regulated genes can suppress inflammatory responses, whereas decreased expression of these genes results in autoimmune disease and enhanced inflammatory responses to oxidant insults. Thus, coordinate induction of cytoprotective genes through Nrf2 / ARE pathway may represent a novel therapeutic approach for the treatment of immune and inflammatory diseases.
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Inhibition of MHC II Gene Transcription by Nitric Oxide and Antioxidants
Authors: Olivier Harari and James K. LiaoMHC class II molecules are expressed on the surface of antigen presenting cells and are loaded with peptides processed from the phagosomal compartment of these cells. Such complexes interact with the CD4 positive T lymphocyte receptor for antigen and a strong interaction is followed by T cell activation and proliferation. As class II expression is critical for antigen specific immunity its expression mostly restricted to a few cell types but can be induced on others in response to interferon γ. This expansion of antigen presenting ability plays a role in increasing the duration and intensity of the immune response. Nitric oxide and antioxidants attenuate this class II induction through negative effects on the induction of class II transactivator protein expression and on the binding of transcription factor NF-Y to the class II promoter.
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Reactive Oxygen Species in the Initiation of IL-4 Driven Autoimmunity as a Potential Therapeutic Target
Authors: Z. Wu, I. A. M. MacPhee and D. B. G. OliveiraHelper T-lymphocytes have been shown to differentiate into two mutually regulatory subsets. Cells primarily secreting interleukin-2 (IL-2) and interferon-g are known as Th1 cells and mediate classical cell-mediated immune responses such as delayed-type hypersensitivity. Cells secreting interleukin-4 (IL-4) are known as Th2 cells and promote humoral immune responses, in particular the production of IgE and IgG4 (human) or IgG1 (rodents). Over-activity of either cell type can result in tissue-damaging autoimmune disease. A number of human diseases including asthma and some kidney diseases are thought to be caused by a Th-2 type autoimmune response. Study of an animal model of Th2-driven autoimmunity (mercuric chloride-induced autoimmunity in Brown Norway rats) has yielded insights into a possible role for oxidant stress in the generation of Th-2 driven autoimmune responses. Mercuric chloride probably causes oxidant stress by the generation of free-radicals, activating NK-kB, a transcription factor for the IL-4 gene. Treatment with the antioxidants N-acetlcysteine and desferrioxamine has been shown to suppress vasculitis and IgE production in this model. These findings suggest a possible clinical role for antioxidants in the therapy of human autoimmune disease.
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Regulation of Inflammatory Responses by Oxidized Phospholipids: Structure-Function Relationships
Authors: A. Furnkranz and N. LeitingerIncreasing evidence points to the role of oxidized phospholipids as modulators of inflammatory processes. These modified phospholipids are derived from lipoproteins or cellular membranes and accumulate at sites of inflammation such as atherosclerotic lesions. It has been shown that oxidized phospholipids influence a variety of cellular functions such as chemokine production and expression of adhesion molecules. Furthermore, recent reports indicate that oxidized phospholipids act as ligands for pattern-recognition receptors which detect conserved pathogen-associated molecular patterns during innate immune defense. Thus, the diversity of individual phospholipid oxidation products reflects the many aspects of the inflammatory process they influence. In this review, we focus on structural features used to classify different oxidized phospholipids and how they relate to specific biological responses. As the chemical identification of oxidized phospholipid products proceeds, distinctive structural motifs emerge that can help us to understand the mechanism of action of these unique compounds and how to intervene for therapeutic purposes.
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The Relationship Between Inflammation and the Anticoagulant Pathway: The Emerging Role of Endothelial Nitric Oxide Synthase (eNOS)
By W. C. HooperInflammation represents the interaction of the immune and coagulation systems in an attempt to restore normal hemostasis following injury. The underlying basis of the interrelationship between these two physiological systems revolves around the following: a) the activation of coagulation by inflammation, b) the augmentation of the inflammatory response by coagulation, c) the significant attenuation of inflammation by the anticoagulant response and d) the separate influence of the vascular endothelium on coagulation and inflammation as well as its mediation or control of the cross-talk between these two physiological systems. In hemostasis, the protein C anticoagulant pathway is a major mechanism that functions to prevent the development of a pathological thrombus through the regulation of the procoagulant pathway. The endothelium is essential in maintaining a physiological balance between the anticoagulant and procoagulant pathways with proinflammatory cytokines functioning, in part, to regulate endothelial-cell- surface associated coagulation and anticoagulation proteins. In addition to its anticoagulant properties, activated protein C can also function as a regulator of proinflammatory cytokine production. Current evidence suggests that activated protein C may act to control inflammation through NF-kB and / or nitric oxide synthase. A better understanding of the relationship between APC and inflammation may provide new targets for drug design.
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Natural Anticoagulant Proteins in the Regulation of Autoimmunity: Potential Role of Protein S
Authors: Howard A. Anderson and Emily ShacterAutoimmunity results when the immune system fails to distinguish between self and non-self factors in the body. The cellular and biochemical mechanisms that underlie development of autoimmunity are only partly understood. One current theory is that autoimmunity can result when there is a failure to clear dying cells from a tissue before they undergo lysis of the plasma membrane. That is, cells that die by apoptosis are thought to be cleared from a tissue by neighboring phagocytic cells, such as macrophages, before the cells have lost their plasma membrane integrity. This rapid removal of early apoptotic cells is thought to prevent induction of an inflammatory response to intracellular macromolecules, thereby allowing for an immunologically silent removal of the dying cells. Hence, any factor or condition that inhibits phagocytosis of early apoptotic cells may trigger or promote an autoimmune response to intracellular components. Depletion of factors required for the efficient phagocytosis of dying cells would have a similar outcome. The recent discovery that the natural anticoagulant protein S is required for efficient uptake of apoptotic cells (Anderson, H.A., Maylock, C.A., Williams, J.A., Paweletz, C.P., Shu, H., and Shacter, E. (2003) Nature Immunology 4, 87-91) reveals a potential new linkage between autoimmunity and coagulation systems. This article will review the dual roles of protein S as an anticoagulant and in regulating phagocytosis of apoptotic cells, with emphasis on exposing a possible novel role in regulating autoimmunity.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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