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Mechanisms of neurodegeneration in Alzheimer’s disease  [PDF]
Jovanovi? Zorica
Medicinski Pregled , 2012, DOI: 10.2298/mpns1208301j
Abstract: Introduction. Recent research into mechanisms of neurodegeneration in Alzheimer’s disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer’s disease is a complex disease with multiple etiological factors involved in disease pathogenesis. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Amyloid-β peptide toxicity is mediated at least in part by oxidative stress. Amyloid-β peptide directly generates reactive oxygen species in the presence of redox-active metal ions. In Alzheimer’s disease, oxidative stress is present early in pathogenesis and contributes to disease pathogenesis. Unlike other organs, the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants. Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death. Microglial activation and nicotinamide adenine dinucleotide phosphate oxidase in Alzheimer’s disease. There is a wealth of evidence demonstrating that microglia, the resident innate immune cells in the brain, can become deleterious and damage neurons. Microglial activation causes neuron damage through the production of neurotoxic factors, such as reactive oxygen species and cytokines that are toxic to neurons. The neuron also has strong homeostatic mechanisms that can delay or prevent activation of apoptosis and necrosis. Insulin resistance and Alzheimer’s disease. Insulin plays a role in Alzheimer’s disease, as it is involved in the metabolism of β-amyloid. Hyperinsulinemia and type-2 diabetes mellitus results in an increased risk of developing Alzheimer’s disease, but its implications when the disease is already well established remain unknown. Treatment of central insulin resistance may be a promising avenue, not only in metabolic syndrom, but also in Alzheimer’s disease. Conclusion. Increasing evidence suggests a role for oxidative stress, mitochondrial dysfunction, microglial activation and insulin resistance in pathogenesis of neurodegenerative diseases including Alzheimer’s disease.
Escherichia coli Shiga Toxin Mechanisms of Action in Renal Disease  [PDF]
Tom G. Obrig
Toxins , 2010, DOI: 10.3390/toxins2122769
Abstract: Shiga toxin-producing Escherichia coli is a contaminant of food and water that in humans causes a diarrheal prodrome followed by more severe disease of the kidneys and an array of symptoms of the central nervous system. The systemic disease is a complex referred to as diarrhea-associated hemolytic uremic syndrome (D+HUS). D+HUS is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. This review focuses on the renal aspects of D+HUS. Current knowledge of this renal disease is derived from a combination of human samples, animal models of D+HUS, and interaction of Shiga toxin with isolated renal cell types. Shiga toxin is a multi-subunit protein complex that binds to a glycosphingolipid receptor, Gb3, on select eukaryotic cell types. Location of Gb3 in the kidney is predictive of the sites of action of Shiga toxin. However, the toxin is cytotoxic to some, but not all cell types that express Gb3. It also can cause apoptosis or generate an inflammatory response in some cells. Together, this myriad of results is responsible for D+HUS disease.
Pathogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease
Levin MC, Lee S, Gardner LA, Shin Y, Douglas JN, Groover CJ
Degenerative Neurological and Neuromuscular Disease , 2012, DOI: http://dx.doi.org/10.2147/DNND.S38353
Abstract: thogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease Review (986) Total Article Views Authors: Levin MC, Lee S, Gardner LA, Shin Y, Douglas JN, Groover CJ Published Date December 2012 Volume 2012:2 Pages 175 - 187 DOI: http://dx.doi.org/10.2147/DNND.S38353 Received: 20 September 2012 Accepted: 30 October 2012 Published: 05 December 2012 Michael C Levin,1–3 Sangmin Lee,1,2 Lidia A Gardner,1,2 Yoojin Shin,1,2 Joshua N Douglas,1,3 Chassidy J Groover1,2 1Veterans Administration Medical Center, Memphis, TN, USA; 2Departments of Neurology, 3Neuroscience, University of Tennessee Health Science Center, Memphis, TN, USA Abstract: Considering there are no treatments for progressive forms of multiple sclerosis (MS), a comprehensive understanding of the role of neurodegeneration in the pathogenesis of MS should lead to novel therapeutic strategies to treat it. Many studies have implicated viral triggers as a cause of MS, yet no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Importantly, HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS. Interestingly, both MS and HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an RNA-binding protein overexpressed in neurons. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting the autoantibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. Taken together, these data begin to clarify mechanisms of neurodegeneration related to the clinical presentation of patients with chronic immune-mediated neurological disease of the central nervous system, which will give insights into the design of novel therapies to treat these neurological diseases.
Pathogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease  [cached]
Levin MC,Lee S,Gardner LA,Shin Y
Degenerative Neurological and Neuromuscular Disease , 2012,
Abstract: Michael C Levin,1–3 Sangmin Lee,1,2 Lidia A Gardner,1,2 Yoojin Shin,1,2 Joshua N Douglas,1,3 Chassidy J Groover1,21Veterans Administration Medical Center, Memphis, TN, USA; 2Departments of Neurology, 3Neuroscience, University of Tennessee Health Science Center, Memphis, TN, USAAbstract: Considering there are no treatments for progressive forms of multiple sclerosis (MS), a comprehensive understanding of the role of neurodegeneration in the pathogenesis of MS should lead to novel therapeutic strategies to treat it. Many studies have implicated viral triggers as a cause of MS, yet no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Importantly, HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS. Interestingly, both MS and HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an RNA-binding protein overexpressed in neurons. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting the autoantibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. Taken together, these data begin to clarify mechanisms of neurodegeneration related to the clinical presentation of patients with chronic immune-mediated neurological disease of the central nervous system, which will give insights into the design of novel therapies to treat these neurological diseases.Keywords: human T-lymphotropic virus type 1 (HTLV-1), multiple sclerosis, neurodegeneration, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), autoimmunity, spastic paraparesis, RNA-binding protein
Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies  [cached]
Massimo C Fantini, Francesco Pallone, Giovanni Monteleone
World Journal of Gastroenterology , 2009,
Abstract: Spondyloarthropathies (SpA) are commonly observed extra-intestinal manifestations of both Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD). However, the immunological link between these two clinical entities is still poorly understood. Several lines of evidence indicate that SpA may originate from the relocation to the joints of the immune process primarily induced in the gut. The transfer of the intestinal inflammatory process into the joints implicates that immune cells activated in the gut-draining lymph nodes can localize, at a certain point of the intestinal disease, either into the gut or into the joints. This is indicated by the overlapping expression of adhesion molecules observed on the surface of intestinal and synovial endothelial cells during inflammation. Moreover bacterial antigens and HLA-B27 expression may be implicated in the reactivation of T cells at the articular level. Finally, accumulating evidence indicates that a T helper 17 cell-mediated immune response may contribute to IBD and IBD-related SpA with a crucial role played by tumor necrosis factor-α in CD and to a lesser extent in UC.
Immune mechanisms and natural history of inflammatory bowel disease
K.H. Katsanos,E.V. Tsianos
Annals of Gastroenterology , 2007,
Abstract: The gastrointestinal tract uses a system of tolerance and controlled inflammation to limit the response to dietary or bacteria-derived antigens in the gut. The triggering factor for this and cascade whether it represents an auto-antigen or an heteroantigen is still to be elucidated. It has been also demonstrated that a serologic anti-microbial response in CD patients exists. This response includes antibodies against saccharomyces cerevisiae (ASCA), E.coli outer membrane porin C (Omp-C), flagelin (cBir1) and pseudomonas aeroginosa (l2). Host response to microbial pathogens includes self-defense mechanisms such as defensins, pattern recognition receptors (PRRs) and TLRs (Toll Like Receptors). Natural history of IBD has been described mainly through studies in American and north European IBD cohorts. In general, 50-60% of IBD patients are in remission during any given year. The likelihood of steroid dependency remains high in IBD. The prediction of disease location seems quite safe as the location of the disease remains stable over time. By contrast the disease behaviour changes over time with increasing risk for structuring/penetrating disease with longer disease duration. The question whether currently available therapies are able to alter natural history of IBD still remains unanswered. The risk of colorectal cancer in UC patients begins to increase 8 years from diagnosis and high risk groups are patients with extensive colitis, young age at UC onset, familial cancer history and co-existing primary sclerosing cholangitis. In CD the risk of cancer seems to be comparatively smaller. Life expectancy of CD patients is slightly lower compared to healthy subjects while life expectancy in UC patients is generally normal.
Mechanisms of Brain Aging Regulation by Insulin: Implications for Neurodegeneration in Late-Onset Alzheimer's Disease  [PDF]
Artur F. Schuh,Carlos M. Rieder,Liara Rizzi,Márcia Chaves,Matheus Roriz-Cruz
ISRN Neurology , 2011, DOI: 10.5402/2011/306905
Abstract: Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation. 1. Introduction Aging can be defined as a process that invariably causes a decline in the abilities of the individuals to face environmental stressors, leading to a dysfunction in homeostasis and an increased incidence of chronic degenerative diseases [1]. Cognitive decline, which is an important aspect of aging, is a leading cause of morbidity and mortality among the elderly, since it greatly impairs their activities of daily living and quality of life [2]. Some patterns of neurodegeneration involved in cognitive impairment are highly preserved phylogenetically in mammals—such as reduced synaptic activity in neurons, alterations in glial metabolism, and accumulation of specific metabolic products [3]. In this chapter we will review the relationships between some disorders of metabolism related to insulin dysfunction and cognitive decline and the importance of these alterations to the neurodegenerative process in aging-related disorders, particularly Alzheimer’s disease. 2. Interactions between Aging and Insulin Regulation The ultimate cause of senescence remains unknown. However, Some specific mechanisms possess major roles in regulating the aging process [4, 5]. Presently, reconciliation between the two main theories of aging would be the proposal that the cumulative effects of the Reactive Oxygen Species (ROS) and Advanced Glycation End products (AGE) leads to aging. In another
The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease  [cached]
Keane Michael,Strieter Robert
Respiratory Research , 2002,
Abstract: The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance.
Oxidative Stress Mechanisms Underlying Parkinson’s Disease-Associated Neurodegeneration in C. elegans  [PDF]
Sudipta Chakraborty,Julia Bornhorst,Thuy T. Nguyen,Michael Aschner
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms141123103
Abstract: Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of oxidative stress in neurodegeneration. In addition to its extensive use as an aging model, some researchers have turned to the invertebrate model Caenorhabditis elegans ( C. elegans) in order to further investigate molecular mediators that either exacerbate or protect against reactive oxygen species (ROS)-mediated neurodegeneration. Due to their fully characterized genome and short life cycle, rapid generation of C. elegans genetic models can be useful to study upstream markers of oxidative stress within interconnected signaling pathways. This report will focus on the roles of C. elegans homologs for the oxidative stress-associated transcription factor Nrf2, as well as the autosomal recessive, early-onset Parkinson’s disease (PD)-associated proteins Parkin, DJ-1, and PINK1, in neurodegenerative processes.
Duality and Complexity of Allergic Type Inflammatory Mechanisms in Determining the Outcome of Malaria Disease  [PDF]
Ulrich Blank,Salaheddine Mécheri
Frontiers in Immunology , 2011, DOI: 10.3389/fimmu.2011.00078
Abstract: One of the effector arms of the pathogenesis of severe forms of malaria disease is the development of uncontrolled or excessive inflammatory responses. A characteristic inflammatory response may arise from the propensity of some individuals to produce IgE antibodies against environmental antigens or against parasite components. We believe that an allergic inflammatory response which develops concomitantly with a malaria episode may drive the disease course toward severe forms. The role of the IgE–FcεRI complex in malaria severity in Plasmodium falciparum-hosting patients is unknown. Subsequently, except a very limited number of reports, study of effector cells that express this complex such as mast cells and basophils and that may contribute to malaria pathogenesis have been particularly neglected. A better understanding of this type of inflammatory response and its implication in malaria disease and how it impacts Plasmodium parasite development may provide additional tools to alleviate or to cure this deadly disease.
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