Dissertations / Theses on the topic 'Fibrotic and inflammatory conditions'
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Pustilnik, Leslie Royce 1964. "The pulmonary inflammatory and fibrotic response induced by glass fibers." Thesis, The University of Arizona, 1987. http://hdl.handle.net/10150/276624.
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The present study was initiated to evaluate the pulmonary inflammatory and fibrotic responses induced by single and repeated exposures to glass fibers. Single and repeated intratracheal injections of glass fibers induced an acute inflammatory response which progressed to a chronic inflammatory and fibrotic response. Mice exposed to glass fibers in single or repeated doses demonstrated elevated numbers of eosinophils, neutrophils and macrophages and increases in cell-free protein in lung lavage fluid at five days post-exposure. These parameters, in addition to relative lung/body weight ratios and lung tissue hydroxyproline levels, were elevated in comparison to saline control animals at five weeks post-exposure. Although repeated exposures to glass fibers did not potentiate the cellular inflammatory response, they did induce a marked infiltration of eosinophils, a response not observed with either asbestos or silica exposures. These observations suggest that glass fibers may be more toxic to the lungs than previously thought.
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Montague, Samantha J. "Platelet activation in trauma and other inflammatory conditions." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7147/.
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Platelets play critical roles in thrombosis, inflammation, and wound healing, which are essential in response to trauma. These processes are primarily driven through the immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2). This study aimed to investigate; (i) the effects of Alarmins released following trauma on platelet reactivity and the mechanisms involved; (ii) establish whether soluble GPVI (sGPVI), a platelet activation marker is elevated in trauma and other inflammatory conditions; (iii) determine whether the CLEC-2 ligand, podoplanin, is elevated in inflammatory conditions and (iv) establishing the role of GPVI and platelets in cutaneous wound healing. The nuclear-related Alarmin, histones, induced robust platelet activation both in vitro and in vivo. Histone-induced platelet activation was mediated through GPVI in vitro However, this pathway was found not to underlie histone-induced lowering of platelet count in vivo and is most likely to result from mediators released following vascular damage. GPVI shedding was shown to be induced following activation by thrombin, through a pathway dependent on fibrin generation. sGPVI was found to be a marker for platelet activation during a variety of inflammatory disorders, notably in association with sepsis. Furthermore, GPVI shedding reflects platelet activation by collagen and potentially thrombin-induced fibrin generation.
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Zhang, Qing, and 張清. "Comparison of mycophenolate mofetil and cyclophosphamide on inflammatory and fibrotic processes in the pathogenesis of lupusnephritis: animal and in vitro studies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085222.
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Htwe, Su Su. "Studying the role of spatial cell distribution and substrate stiffness in inflammatory and fibrotic responses in human lung using bioengineered platforms." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/48045/.
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The extracellular matrix (ECM) has emerged as a major regulator of cell behaviours. Changes in extracellular matrix, especially its composition, organization/ dimensionality, and rigidity have been implicated in various aspects of cellular functions including cell growth, migration, and differentiation. In my thesis, I have focused on the effect of two biophysical properties of the extracellular matrix namely dimensionality and rigidity in the inflammatory and fibrotic pathologies of human lung. To study the role of matrix dimensionality, firstly electrospun scaffold based three-dimensional (3D) culture with similar architecture of human lung was developed. By applying this 3D model, inflammatory response was studied in an in vivo like environment by using NF-κB transcription factor activation as a tool for probing inflammatory response in human lung fibroblasts. According to my observations, it was confirmed that the matrix dimensionality together with spatial organisation of cells is crucial in lung inflammatory response, evidenced by the observation of the differences in the level and pattern of inflammatory response between 2D and 3D culture systems. To study the role of matrix rigidity in progression of lung fibrosis, we developed the ECM-based hydrogel platform with tuneable stiffness level relevant to normal and fibrotic lung. By using this disease relevant platform, I have shown that stiff matrix but not soft matrix can induce the myofibroblast differentiation and fibroblast proliferation, the two major features of lung fibrosis. To date, the molecular mechanisms underpinning this cellular mechanosensing process in response to matrix stiffening remains unknown. To achieve this, I further investigated the involvement of two potential mechanosensitive signalling pathways namely, Rho associated coiled coil forming kinase (ROCK) signalling and talin- (focal adhesion adaptor) signalling in this process. Interestingly, my data show that ROCK signalling differentially regulated stiffness induced myofibroblast differentiation between soft normal and stiff fibrotic matrix. Moreover, both ROCK isoforms 1 and 2 are synergistically important in myofibroblast differentiation driven by rigid matrix and the absence of one ROCK isoform can exaggerate myofibroblast differentiation on stiff fibrotic matrix. Regarding talin signalling, my preliminary data confirms that talin1 can control both stiffness induced fibroblast proliferation and myofibroblasts differentiation on stiff matrix. In contrast to talin1, talin2 showed a protective role in controlling myofibroblast differentiation. In conclusion, we have successfully developed two in vitro lung models for studying the effect of matrix dimensionality and rigidity in lung inflammation and fibrosis. Overall my PhD work has elucidated the significant contribution of biophysical cues of external cellular environment in lung inflammation and fibrosis.
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Lee, Chung Bomy. "Theranostic nanoparticles for the management of inflammatory diseases and conditions." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/112504.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references.
Atherosclerosis, the gradual buildup of plaques within arteries, is the main cause of cardiovascular diseases (CVDs). The World Health Organization reports that CVDs are the number one cause of death in the world. In the United States alone, around 85 million people suffer from CVDs; this is associated with a cost of over $316 billion per year and responsible for about a third of all deaths in the US. Recent findings have shown that inflammation plays a pivotal role in atherosclerosis. Although statins have traditionally been prescribed for their lipid-lowering benefits, studies have indicated that they can have other effects as well (so-called "pleiotropic effects"), including anti-inflammatory, anti-oxidant, and anti-thrombotic benefits. This thesis presents a novel theranostic (therapeutic + diagnostic) nanoparticle platform for the treatment and diagnosis of atherosclerosis. Given the anti-inflammatory effects of statins when cells are directly treated, the aim of this nanoparticle platform was to target macrophages within plaques given their central role in plaque development and progression. First, simvastatin-loaded nanoparticles were designed and optimized. The particles consisted of a biodegradable polymer core and a lipid shell. Using bulk nanoprecipitation methods, as well as microfluidic devices, the physical characteristics of the particles could be controlled and fine-tuned to meet the desired specifications: 100 to 200 nm in size, -15 to -20 mV in zeta potential, and 70%+ simvastatin loading efficiency. Imaging agents, such as iron oxide nanocrystals used for magnetic resonance imaging (MRI), were successfully incorporated into the nanoparticles and can offer diagnostic capabilities to the nanoparticles. Next, various nanoparticle formulations were shown to be therapeutically effective in cell and mice models of atherosclerosis. For instance, in vitro treatment of macrophages led to decreases in the expression of TNF-a and MCP-1 by roughly 20% and 50%, respectively. This pattern has also been observed in murine models, with researchers showing that simvastatin-loaded particles can halt plaque development (and even decrease plaque area) while reducing the expression of pro-inflammatory genes (e.g., of TNF-a, IL- IP) by an order of magnitude. Overall, this thesis presents a new and innovative nanoparticle platform that has the potential for the simultaneous treatment and diagnosis of atherosclerosis. Given their anti-inflammatory benefits, these nanoparticles have the potential to impact the treatment of not only atherosclerosis but also various other inflammatory conditions and diseases as well.
by Bomy Lee Chung.
Ph. D.
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Zhang, Qing. "Comparison of mycophenolate mofetil and cyclophosphamide on inflammatory and fibrotic processes in the pathogenesis of lupus nephritis : animal and in vitro studies /." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43085222.
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Zhang, Chenzhu, and 张辰珠. "The effects of rapamycin and mycophenolic acid on inflammatory and fibrotic processes in the pathogenesis of lupus nephritis: animal and in vitro studies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B45898935.
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Collins, John Samuel Andrew. "A morphometric study of inflammatory conditions of the upper gastrointestinal tract." Thesis, Queen's University Belfast, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336208.
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Isebor, Peter. "Positive psychological interventions in chronic conditions : gratitude and inflammatory bowel disease." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/21308/.
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Petit, Maxime. "Residency and trafficking of ILC2 in steady steate and th2 induced inflammatory conditions." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7095.
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Les ILC2s sont retrouvées au niveau des muqueuses comme les poumons et l’intestin, ainsi que dans divers ganglions et organes liés au métabolisme comme les tissus adipeux (ATs). Elles jouent un rôle important dans l’induction des réponses immunitaires de type Th2 comme équivalents innées dans lymphocytes Th2. Elles sont activées par des alarmines (IL-25 et IL-33) et des activateurs environnementaux (allergènes, métabolites et neuromédiateurs). Les ILC2s sécrètent des cytokines de type Th2 permettant de recruter et d’activer des cellules myéloïdes, d’augmenter la production de mucus et la contraction musculaire, ainsi que d’initier la réparation et le renouvellement des tissus. Cependant, une activation non contrôlée des ILC2s participe au développement de maladies chroniques. Les ILCs sont généralement considérées comme des cellules résidentes. Cependant, plusieurs études ont suggéré que la migration pourrait être un processus important pour la maturation des capacités effectrices. La circulation des ILCs reste peu documentée, et aucun mécanisme n’est pour l’instant capable d’expliquer le renouvellement des ILC2s pour agir dans de nombreux tissus suite à une stimulation. Nous avons montré que des quantités significatives d’ILC2s matures et immatures peuvent être collectées dans la lymphe du canal thoracique de souris canulées durant plusieurs heures. Les ILC2s circulantes forment 3 groupes distincts avec des expressions de molécules d’adhésion et récepteurs de migration spécifiques. Nos expériences de transferts cellulaires montrent que ces groupes spécifiques de molécules exprimées sont liés à des tropismes particuliers pour l’intestin, les poumons ou les ATs. Pour analyser le comportement des ILC2s dans un contexte de réponse de type Th2, nous avons injecter les cytokines IL-25 et IL-33 et étudié la lymphe de ces souris. La stimulation à l’IL-33 augmente le nombre de cellules ILC2s circulants dans la lymphe. Les différents groupes d’ILC2s montrent des réponses différentes à l’IL-33. Ainsi, les ILC2s migrants vers l’intestin sont majoritairement prolifératives tandis que le groupe migrant vers les poumons et les ATs secrètent de l’IL-5, de l’IL-13 et de l’Areg. Cela suggère que les ILC2s migrants de façon spécifique possèdent une empreinte fonctionnelle. Nous confirmons les fonctions des groupes d’ILC2s circulants en utilisant des modèles plus physiologiques mimant des réactions allergiques et des infections parasitaires (stimulation par la papaïne et le succinate). Les migrations vers l’intestin et les poumons jouent un rôle primordial dans l’induction de réponse de type Th2 par sécrétion d’IL-5 et d’IL-13, et à l’initiation de la réparation tissulaire par production d’Areg. De façon intéressante, les ILC2s migrants vers les poumons participent au renouvellement des populations résidentes participant principalement à la production d’Areg. Finalement, nous caractérisons un rôle important du trafic des ILC2s à différents temps suivant l’infection par Nippostrongulus brasiliensis, confirmant la fonction des ILC2s migrantesILC2s are found in mucosal tissues as lung and intestine, in lymph nodes, and in metabolic tissues such as the adipose tissues. They play important role in maintaining or inducing type-2 immune responses as innate equivalent of Th2 lymphocytes. They are activated by alarmins (IL-25 and IL-33) and by external activators (allergens, metabolites and neuromediators). ILC2s are secreting type-2 cytokines to facilitate the activation of other cells and to induce an important repair program. Their activation allows large type of events as diverse as myeloid cells recruitment and activation, mucus production, muscle contractility and tissue repair. They have key role in lung and adipose tissue development and maintain their homeostasis by early responding against parasitic pathogens. Abnormal activation of ILC2s is also participating to chronic diseases.ILCs are mostly considered as resident cells. However, different studies suggested that migration could be important for the maturation of their effector capacities and to correctly target the injured tissue. Circulation and trafficking of ILC subsets is still unclear. No mechanism is yet available to explain the turnover of ILC2s and how they can act in many tissues following stimuli.We found that large numbers of mature and immature ILC2s could be collected in the thoracic duct lymph of mice perfused over several hours, showing that ILC2s are in fact actively circulating through the hemo-lymphatic circuit. Furthermore, circulating mature ILC2s could be separated into three distinct subsets depending on their pattern of receptor and adhesion molecule expression. Cell transfer experiments proved that specific patterns are representative of specific tropism for gut, lung and adipose tissues.To analyse ILC2 behaviour in the context of a type-2 response, we injected IL-25 and IL-33 before lymph collection. IL-33 stimulation largely enhanced the number of circulating ILC2s in the lymph. These different ILC2 tissue targeted subsets responded differently to IL-33. Specifically, gut-trafficking ILC2s were mainly stimulated to proliferate whereas lung and adipose tissue subsets were stimulated to produce IL-13, IL-5 and Areg. This suggests that, in ILC2s, specific tissue targeting is associated with already imprinted functions while transiting through the hemo-lymphatic system. We confirmed these functions of circulating ILC2 subsets in more physiological context by mimicking allergy and helminth infection (stimulation by papain and succinate) where specific migration to lungs and intestine play important roles in mounting the type-2 response by IL-5/IL-13 secretion, and also initiating tissue repair by Areg production. Interestingly, we showed that lung migrating ILC2s participated to resident pool renewal that main function is Areg production. Finally, we characterized important trafficking of ILC2 at different stages of Nippostrongulus brasiliensis infection, confirming the functional relevance of ILC2 trafficking
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Ng, Yee-ching Claudia, and 吳綺菁. "Effects of anti-DNA antibodies and mycophenolic acid on inflammatory and fibrotic processes in proximal tubular epithelial cells and theimplications in the pathogenesis of lupus nephritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085234.
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Ng, Yee-ching Claudia. "Effects of anti-DNA antibodies and mycophenolic acid on inflammatory and fibrotic processes in proximal tubular epithelial cells and the implications in the pathogenesis of lupus nephritis." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43085234.
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Müller, Gerrit [Verfasser]. "The Impact of Inflammatory Conditions on the Immunological Responses of Cutaneous Dendritic Cells / Gerrit Müller." Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1180388135/34.
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Kulmatycki, Kenneth M. "Disease-drug interactions, pharmacokinetics and pharmacodynamics of sotalol and lidocaine in the presence of inflammatory conditions." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0012/NQ59615.pdf.
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Farrell, Kurt W. "Role of Matrix Microenviroment on Neural Stem Cell Phenotype and Differentiation under Healthy and Inflammatory Conditions." Cleveland State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=csu1462009482.
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Cedergren, Jan. "Radical aspects on arthritis : the role of neutrophil generation of nitric oxide and superoxide in inflammatory conditions." Doctoral thesis, Linköping : Univ, 2007. http://www.bibl.liu.se/liupubl/disp/disp2007/med984s.pdf.
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Duckworth, Phoebe E. "Nociceptive behaviours evoked by intrathecal (R, S)-3,5-dihydroxyphenylglycine to rats with neuropathic and inflammatory pain conditions." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=99369.
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Spontaneous nociceptive behaviours (SNBs) are an important but under-studied component of chronic pain conditions. The group I metabotropic glutamate receptor (mGluR) agonist DHPG produces SNBs when injected intrathecally and group I mGluR antagonists are effective at reducing symptoms of neuropathic and inflammatory pain. The present experiments tested whether rats with sciatic nerve injury or persistent inflammation exhibit greater SNBs following intrathecal DHPG compared with control animals. SNBs were observed following intrathecal injection of DHPG between the L4 and L5 vertebrae. When DHPG was injected in rats with chronic constriction injury (CCI) of the sciatic nerve, they showed increased paw stamping behaviour compared to DHPG-injected sham controls. Results of the complementary experiment in rats with complete Freund's adjuvant (CFA)-induced inflammation did not show significant effects. Both CCI and CFA rats injected with DHPG showed increased paw licking and biting behaviour in the ipsilateral paws. These results provide evidence for behaviourally relevant contributions of group I mGluRs to SNBs in models of neuropathic and inflammatory pain.
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Danks, Lynett. "The effect of inflammatory cells and humoral factors on osteoclast differentiation in rheumatoid arthritis and other joint conditions." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408685.
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Orlowski, Gregory M. "Cathosis: Cathepsins in Particle-induced Inflammatory Cell Death: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/770.
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Sterile particles underlie the pathogenesis of numerous inflammatory diseases. These diseases can often become chronic and debilitating. Moreover, they are common, and include silicosis (silica), asbestosis (asbestos), gout (monosodium urate), atherosclerosis (cholesterol crystals), and Alzeihmer’s disease (amyloid Aβ). Central to the pathology of these diseases is a repeating cycle of particle-induced cell death and inflammation. Macrophages are the key cellular mediators thought to drive this process, as they are especially sensitive to particle-induced cell death and they are also the dominant producers of the cytokine responsible for much of this inflammation, IL-1β. In response to cytokines or microbial cues, IL-1β is synthesized in an inactive form (pro-IL-1β) and requires an additional signal to be secreted as an active cytokine. Although a multimolecular complex, called the NLRP3 inflammasome, controls the activation/secretion of IL-1β (and has been thought to also control cell death) in response to particles in vitro, the in vivo inflammatory response to particles occurs independently of inflammasomes. Therefore, I sought to better understand the mechanisms governing IL-1β production and cell death in response to particles, focusing specifically on the role of lysosomal cathepsin proteases. Inhibitor studies have suggested that one of these proteases, cathepsin B, plays a role in promoting inflammasome activation subsequent to particle-induced lysosomal damage, however genetic models of cathepsin B deficiency have argued otherwise. Through the use of inhibitors, state-of-the-art biochemical tools, and multi-cathepsin-deficient genetic models, I found that multiple redundant cathepsins promote pro-IL-1β synthesis as well as particle-induced NLRP3 activation and cell death. Importantly, I also found that particle-induced cell death does not depend on inflammasomes, suggesting that this may be why inflammasomes do not contribute to particle-induced inflammation in vivo. Therefore, my observations suggest that cathepsins may be multifaceted therapeutic targets involved in the two key pathological aspects of particle-induced inflammatory disease, IL-1β production and cell death.
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Orlowski, Gregory M. "Cathosis: Cathepsins in Particle-induced Inflammatory Cell Death: A Dissertation." eScholarship@UMMS, 2005. http://escholarship.umassmed.edu/gsbs_diss/770.
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Sterile particles underlie the pathogenesis of numerous inflammatory diseases. These diseases can often become chronic and debilitating. Moreover, they are common, and include silicosis (silica), asbestosis (asbestos), gout (monosodium urate), atherosclerosis (cholesterol crystals), and Alzeihmer’s disease (amyloid Aβ). Central to the pathology of these diseases is a repeating cycle of particle-induced cell death and inflammation. Macrophages are the key cellular mediators thought to drive this process, as they are especially sensitive to particle-induced cell death and they are also the dominant producers of the cytokine responsible for much of this inflammation, IL-1β. In response to cytokines or microbial cues, IL-1β is synthesized in an inactive form (pro-IL-1β) and requires an additional signal to be secreted as an active cytokine. Although a multimolecular complex, called the NLRP3 inflammasome, controls the activation/secretion of IL-1β (and has been thought to also control cell death) in response to particles in vitro, the in vivo inflammatory response to particles occurs independently of inflammasomes. Therefore, I sought to better understand the mechanisms governing IL-1β production and cell death in response to particles, focusing specifically on the role of lysosomal cathepsin proteases. Inhibitor studies have suggested that one of these proteases, cathepsin B, plays a role in promoting inflammasome activation subsequent to particle-induced lysosomal damage, however genetic models of cathepsin B deficiency have argued otherwise. Through the use of inhibitors, state-of-the-art biochemical tools, and multi-cathepsin-deficient genetic models, I found that multiple redundant cathepsins promote pro-IL-1β synthesis as well as particle-induced NLRP3 activation and cell death. Importantly, I also found that particle-induced cell death does not depend on inflammasomes, suggesting that this may be why inflammasomes do not contribute to particle-induced inflammation in vivo. Therefore, my observations suggest that cathepsins may be multifaceted therapeutic targets involved in the two key pathological aspects of particle-induced inflammatory disease, IL-1β production and cell death.
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Rosenbaum, Corinna [Verfasser], Heike [Gutachter] Walles, Erhard [Gutachter] Wischmeyer, and Beate [Gutachter] Niesler. "The role of enteric glial cells under inflammatory conditions of the intestine / Corinna Rosenbaum ; Gutachter: Heike Walles, Erhard Wischmeyer, Beate Niesler." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1118317777/34.
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Fell, Benjamin. "Organotypic human skin disease models for the assessment of novel therapeutic approaches." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/24594.
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Comprehensive in vitro modelling of inflammatory human skin conditions is an essential first step in the development and assessment of potential therapeutic approaches. Mouse models or monolayer keratinocyte cultures come with distinct limitations which might be complimented or overcome by the use of human-specific organotypic 3D culture models. Over the course of this thesis, an organotypic culture system, based on patientderived immortalised keratinocyte cell lines on a dermal equivalent collagen 1 gel, was established and used to recapitulate phenotypical features for two hereditary skin diseases, Harlequin ichthyosis and Tylosis with oesophageal cancer. Small molecular compounds, supplied via the medium, or RNA interference were used to modulate disease-specific changes in histology and marker expression of the skin equivalent. Since hyperproliferative skin conditions can be associated with an aberrant wound healing phenotype, the organotypic system was manipulated to obtain a basic in vitro wound healing model. This model displays typical features of re-epithelialisation over time (both normal and disease-specific) which can further be manipulated via shRNAmediated knockdown or the exogenous supply of compounds. In parallel, a non-disease model was used to assess the topical application of novel nanopolymeric drug delivery systems in regard to their ability to penetrate across the permeability barrier. Penetrance profiles for the organotypic model (in dependence of co-application with chemical enhancers) showed a similar pattern as for topical applications performed in parallel on explant skin. In conclusion, a highly adaptable human organotypic keratinocyte culture model was developed and used to recapitulate (and manipulate) skin disease phenotypes and epidermal wound healing in vitro, as well as perform first essential assessments of novel drug delivery systems.
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Thirlwell, Kayleigh. "Tissue origin dictates mesenchymal stromal cell chemokine and chemokine receptor repertoire and predicts in vitro chemotactic activity under homeostatic and inflammatory conditions." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8951/.
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Due to their anti-inflammatory and immunomodulatory properties, mesenchymal stromal cells (MSCs) are under intense investigation in many pre-clinical and clinical trials as a potential cellular therapy to be used in an array of clinical settings. The majority of the literature surrounding MSC phenotype and function is derived from studies focusing on bone marrow (BM) derived MSCs. Recently however, it has become apparent that MSCs can be isolated in a less invasive manner, from the majority of tissues in the human body. In light of this, many studies have been published promoting the use of alternative tissue sources for MSC isolation with no thorough standardised comparison of the phenotype or potential in vivo function of these MSCs. The advanced therapeutics department within the Scottish National Blood Transfusion Service (SNBTS) is involved in the development and optimisation of several cellular therapies including the use of MSCs within various clinical settings. SNBTS has access to fully consented human tissues rich in MSCs including; pancreatic islets, visceral adipose tissue, liposuction aspirate, bone marrow and umbilical cord. Therefore this study aimed to objectively compare the phenotype and potential in vivo function of MSCs isolated from the aforementioned tissues in a stringent, standardised manner in order to assess if MSCs isolated from one specific tissue source might be optimal for use within the clinic. The beneficial therapeutic effect of MSCs often depends on their ability to migrate to target tissues and interact with residing or migratory immune and non-immune cells, frequently within an inflammatory environment. Therefore this study focussed on how MSCs might migrate in vivo by assessing and comparing MSC chemokine receptor expression, whilst also assessing and comparing MSC chemokine secretion profiles to understand which immune cells MSCs might attract, and therefore potentially interact with, in vivo. This study found that chemokine receptor expression by MSCs isolated from islet, visceral adipose, adipose, bone marrow and umbilical cord tissues was very low, with CXCR4, CCR7 and ACKR3 expression being restricted to visceral adipose and bone marrow derived MSCs. Inflammatory chemokines were secreted at very high levels by MSCs isolated from all of the aforementioned tissues, which induced migration of target immune cells towards all MSCs tested in vitro and in vivo, importantly however, the tissue origin of MSCs dictated the quantities of immune cells attracted. This study highlighted that the tissue origin of MSCs could affect MSC in vivo migratory capacity and their ability to chemoattract surrounding immune cells, thereby potentially influencing their clinical performance.
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Bezugla, Yevgeniya. "Production of prostaglandin E2 and thromboxane A2 by rat liver macrophages and involvement of nitric oxide and cytokines in mediator pathways under inflammatory conditions." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2008. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1200655847867-69951.
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The pathogenesis of inflammatory liver diseases and development of liver fibrosis involves hepatocytes as well as non-parenchymal liver cells like resident liver macrophages (Kupffer cells (KC)), Stellate cells and endothelial cells. Kupffer cells play a critical role in liver (patho)physiology and in the defense of the liver during inflammation. They constitute about 50% of non-parenchymal cells and are the largest population of tissues macrophages in the body. Infections, toxins (lipopolysacharide (LPS)), parenchymal damage and stresses stimulate the inflammatory response of Kupffer cells with the following secretion of bioactive factors, cytotoxicity, antigen processing, etc. Resident liver macrophages are the main producers of inflammatory mediators in the liver. Among them there are prostanoids (prostaglandin (PG) E2 and thromboxane (Tx) A2), cytokines (e.g. interleukin (IL)-1,-6, -10, tumor necrosis factor (TNF) α) and inorganic mediators like nitric oxide (NO). Macrophages-derived products play opposing roles in the development of liver fibrogenesis: IL-1β, TNFα, IL-6, transforming growth factor (TGF)-β and TxA2 (pro-fibrogenic mediators) promote whereas PGE2, IL-10 and nitric oxide (anti-fibrogenic mediators) suppress liver fibrogenesis. The present study shows the production of PGE2 and TxA2 by resident liver macrophages upon prolonged activation by LPS and the characterization of biosynthesis pathways. The production of PGE2 and TxA2 is followed during 24 h after stimulation of macrophages with LPS. The involvement of enzymes is measured on the RNA level (RT-PCR), protein level (Western blot analysis) and activity (activity assays), respectively. The amounts of released prostanoids are measured at time points 2, 4, 8 and 24 h after LPS stimulation. The production of PGE2 is very low without stimulation, shows a delay within the first few hours after stimulation with LPS, and thereafter linearly increases up to 24 h. TxA2 production is very low without stimulation, and increases without a time-delay after the addition of LPS. Prostanoid biosynthesis is inhibited by dexamethasone. The present study shows the involvement and regulation of the AA cascade by the following enzymes: cPLA2: is expressed in resting Kupffer cells; cPLA2 expression and phosphorylation is increased by LPS, dexamethasone suppresses the LPS effect, localization in membrane fraction. COX-1: is expressed in resting Kupffer cells; COX-1 expression is not influenced by LPS and dexamethasone. The COX-1 inhibitor SC560 suppresses the LPS-induced production of PGE2 and TxA2 (8h and 24h), localization predominantly in membrane fraction. COX-2: is almost not expressed in resting Kupffer cells; COX-2 expression is highly increased by LPS, dexamethasone suppresses the LPS effect. The COX-2 inhibitor SC236 inhibits the production of PGE2 and TxA2 at 8h by about 77% and 20%, and at 24h by about 42% and 34%, respectively, localization predominantly in membrane fraction. mPGES-1: is almost not expressed in resting cells; mPGES-1 expression is highly increased by LPS, dexamethasone suppresses the LPS effect, localization in membrane fraction. mPGES-2: is expressed in resting Kupffer cells; mPGES-2 expression is slightly increased by LPS, localization predominantly in membrane fraction. cPGES: is expressed in resting Kupffer cells; LPS has no effect, localization predominantly in soluble fraction. TxA2 synthase: is expressed in resting Kupffer cells; LPS and dexamethasone have no effect, localization predominantly in membrane fraction. Treatment of Kupffer cells with IL-1ß and TNF-α leads to an enhanced release of PGE2 and TxA2 and upregulate the expression of cPLA2, COX-2 and mPGES-1. IL-6 has no effect on prostanoid production. In contrast, IL-10 suppresses the LPS-induced production of PGE2 and TxA2 and expression of cPLA2, COX-2 and mPGES-1. Resting Kupffer cells release very low amounts of NO and do not express iNOS, nNOS and eNOS. LPS, TNF-α and IL-1ß upregulate NO release and the expression of iNOS whereas dexamethasone and IL-10 downregulate NO release and the expression of iNOS. PGE2 suppresses the LPS-induced release of NO but enhances the cytokine-induced release of NO. NO induces a release of PGE2. Thus, the study demonstrates a crosstalk between prostanoids, nitric oxide and cytokines in Kupffer cells under inflammatory conditions and demonstrates a possible anti-fibrogenic effect of PGE2 in the process of liver fibrogenesis.
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Bezugla, Yevgeniya. "Production of prostaglandin E2 and thromboxane A2 by rat liver macrophages and involvement of nitric oxide and cytokines in mediator pathways under inflammatory conditions." Doctoral thesis, Technische Universität Dresden, 2007. https://tud.qucosa.de/id/qucosa%3A24025.
Full textAbstract:
The pathogenesis of inflammatory liver diseases and development of liver fibrosis involves hepatocytes as well as non-parenchymal liver cells like resident liver macrophages (Kupffer cells (KC)), Stellate cells and endothelial cells. Kupffer cells play a critical role in liver (patho)physiology and in the defense of the liver during inflammation. They constitute about 50% of non-parenchymal cells and are the largest population of tissues macrophages in the body. Infections, toxins (lipopolysacharide (LPS)), parenchymal damage and stresses stimulate the inflammatory response of Kupffer cells with the following secretion of bioactive factors, cytotoxicity, antigen processing, etc. Resident liver macrophages are the main producers of inflammatory mediators in the liver. Among them there are prostanoids (prostaglandin (PG) E2 and thromboxane (Tx) A2), cytokines (e.g. interleukin (IL)-1,-6, -10, tumor necrosis factor (TNF) α) and inorganic mediators like nitric oxide (NO). Macrophages-derived products play opposing roles in the development of liver fibrogenesis: IL-1β, TNFα, IL-6, transforming growth factor (TGF)-β and TxA2 (pro-fibrogenic mediators) promote whereas PGE2, IL-10 and nitric oxide (anti-fibrogenic mediators) suppress liver fibrogenesis. The present study shows the production of PGE2 and TxA2 by resident liver macrophages upon prolonged activation by LPS and the characterization of biosynthesis pathways. The production of PGE2 and TxA2 is followed during 24 h after stimulation of macrophages with LPS. The involvement of enzymes is measured on the RNA level (RT-PCR), protein level (Western blot analysis) and activity (activity assays), respectively. The amounts of released prostanoids are measured at time points 2, 4, 8 and 24 h after LPS stimulation. The production of PGE2 is very low without stimulation, shows a delay within the first few hours after stimulation with LPS, and thereafter linearly increases up to 24 h. TxA2 production is very low without stimulation, and increases without a time-delay after the addition of LPS. Prostanoid biosynthesis is inhibited by dexamethasone. The present study shows the involvement and regulation of the AA cascade by the following enzymes: cPLA2: is expressed in resting Kupffer cells; cPLA2 expression and phosphorylation is increased by LPS, dexamethasone suppresses the LPS effect, localization in membrane fraction. COX-1: is expressed in resting Kupffer cells; COX-1 expression is not influenced by LPS and dexamethasone. The COX-1 inhibitor SC560 suppresses the LPS-induced production of PGE2 and TxA2 (8h and 24h), localization predominantly in membrane fraction. COX-2: is almost not expressed in resting Kupffer cells; COX-2 expression is highly increased by LPS, dexamethasone suppresses the LPS effect. The COX-2 inhibitor SC236 inhibits the production of PGE2 and TxA2 at 8h by about 77% and 20%, and at 24h by about 42% and 34%, respectively, localization predominantly in membrane fraction. mPGES-1: is almost not expressed in resting cells; mPGES-1 expression is highly increased by LPS, dexamethasone suppresses the LPS effect, localization in membrane fraction. mPGES-2: is expressed in resting Kupffer cells; mPGES-2 expression is slightly increased by LPS, localization predominantly in membrane fraction. cPGES: is expressed in resting Kupffer cells; LPS has no effect, localization predominantly in soluble fraction. TxA2 synthase: is expressed in resting Kupffer cells; LPS and dexamethasone have no effect, localization predominantly in membrane fraction. Treatment of Kupffer cells with IL-1ß and TNF-α leads to an enhanced release of PGE2 and TxA2 and upregulate the expression of cPLA2, COX-2 and mPGES-1. IL-6 has no effect on prostanoid production. In contrast, IL-10 suppresses the LPS-induced production of PGE2 and TxA2 and expression of cPLA2, COX-2 and mPGES-1. Resting Kupffer cells release very low amounts of NO and do not express iNOS, nNOS and eNOS. LPS, TNF-α and IL-1ß upregulate NO release and the expression of iNOS whereas dexamethasone and IL-10 downregulate NO release and the expression of iNOS. PGE2 suppresses the LPS-induced release of NO but enhances the cytokine-induced release of NO. NO induces a release of PGE2. Thus, the study demonstrates a crosstalk between prostanoids, nitric oxide and cytokines in Kupffer cells under inflammatory conditions and demonstrates a possible anti-fibrogenic effect of PGE2 in the process of liver fibrogenesis.
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Vital, Daiana Morelli 1987. "Efeito da hidroxiureia na adesão in vitro de neutrófilos, sob condições inflamatórias = Effect of hydroxyurea on the adhesion of neutrophil under in vitro inflammatory conditions." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312964.
Full textAbstract:
Orientador: Nicola Amanda Conran ZorzettoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A inflamação é uma resposta fisiológica normal à infecção ou lesão tecidual que permite a sobrevivência do indivíduo a diversos agentes lesivos e mantém a homeostase dos tecidos sob uma variedade de condições nocivas. Os neutrófilos têm um papel importante em processos inflamatórios e, na presença de estímulos inflamatórios, como citocinas e quimiocinas, são recrutados da circulação para o tecido inflamado por uma sequência de interações adesivas. Recentemente, novas técnicas in vitro têm levado a importantes avanços no entendimento de patologias vasculares e hematológicas e sistemas microfluídicos, que mimetizam a microcirculação humana, demonstrando a utilidade para o estudo de interações adesivas de células inflamatórias. As interações dos neutrófilos e outros leucócitos com a parede vascular tem contribuição importante para as doenças inflamatórias crônicas, como a anemia falciforme (AF) e aterosclerose, pois podem participar em processos de oclusão vascular. O objetivo deste trabalho foi avaliar se a hidroxiureia (HU), uma droga utilizada como terapia na AF, modula as propriedades adesivas de neutrófilos quando incubados in vitro com a droga e frente um estímulo inflamatório. Os neutrófilos, isolados do sangue periférico de indivíduos saudáveis, foram estimulados com a citocina TNF-? (Fator de Necrose Tumoral alfa) e tratados com HU em três concentrações (100, 500, 1000 ?M); as propriedades adesivas das células foram avaliadas por ensaios de adesão estática e por ensaios microfluídicos, utilizando como ligantes proteínas expressas no endotélio (ICAM-1 e E-selectina), proteínas da matriz extracelular (fibronectina - FN) e células endoteliais (HUVEC). Além disso, foi analisada a ativação celular (spreading celular, observado como o espalhamento das células redondas que se tornam achatadas sobre um substrato sólido 2D). Observamos que os neutrófilos, quando estimulados com TNF-?, demonstram aumentos significantes na adesão e spreading celular. O pré-tratamento das células com HU reduziu significativamente o spreading dos neutrófilos nas três proteínas estudas (FN, ICAM-1 e E-selectina). Sob condições estáticas, o pré e o pós-tratamento dos neutrófilos com a HU diminuiu significativamente a adesão à FN quando comparados ao estimulados por TNF-?. Nos ensaios de adesão em fluxo, foi possível observar que o pré-tratamento com HU nas três concentrações (100, 500 e 1000 ?M) diminuiu significativamente a adesão dos neutrófilos a FN e o pós-tratamento com HU diminuiu apenas na concentração de 100 ?M. Avaliamos a adesão em fluxo de neutrófilos aderidos a proteínas de adesão presentes no endotélio, ICAM-1 e E-selectina; o pré e o pós-tratamento de neutrófilos com HU diminuiu a suas propriedades adesivas frente ao estímulo inflamatório de TNF-? à proteína E-selectina, enquanto que o pré-tratamento nas três concentrações diminuiu a adesão dos neutrófilos ao ICAM-1 e ao ICAM-1 e E-selectina adicionados juntos ao chip. A técnica de citometria de fluxo demonstrou que as integrinas LFA-1 (CD11a) e Mac-1 (CD11b), mostraram-se aumentadas na superfície dos neutrófilos após estímulo com TNF-?. Todavia, a expressão da L-selectina, mostrou-se diminuída com este potente estímulo inflamatório, provavelmente devido o mecanismo de "shedding" celular. A incubação dos neutrófilos com HU, após o estímulo com o TNF-?, reduziu significativamente a expressão de CD11a nos neutrófilos tratados com HU nas concentrações de 100 e 1000 ?M para níveis de expressão equivalentes ao grupo de neutrófilos não estimulados com TNF-?. Observamos também que houve aumento da presença da integrina LFA-1 (CD11a) na sua conformação ativada, após estímulo com TNF-? e que a pós-incubação das células estimuladas com HU na concentração de 1000 ?M, reduziu a ativação da subunidade CD11a da molécula de adesão LFA-1, comparado ao grupo apenas estimulado com TNF-?. Diante destes resultados, é possível concluir que o tratamento de neutrófilos com HU foi capaz de proteger ou até reverter algumas das ações inflamatórias do TNF-?. A HU é utilizada como uma terapia de uso crônico em pacientes com AF, mas estes dados indicam que a HU também pode exercer efeitos imediatos que são independentes da elevação de hemoglobina fetal. Dados melhor clarificam o mecanismo de ação de HU na AF e sugerem que a droga pode ter potencial para uso em outras doenças inflamatórias. Ainda será necessário entender como a HU exerce estes efeitos anti-inflamatórios nos neutrófilos
Abstract: Inflammation is a normal physiological response to infection or tissue injury that defends against various damaging agents and maintains tissue homeostasis in a variety of deleterious conditions. Neutrophils play an important role in inflammatory processes and, in the presence of inflammatory stimuli, such as cytokines and chemokines, are recruited from the circulation into the inflamed tissue by a sequence of adhesive interactions. Recently, new in vitro techniques have led to significant advances in our understanding of vascular and hematological conditions and microfluidic systems that mimic the human microcirculation have been shown to be useful for the study of adhesive interactions in inflammatory cells. The interaction of neutrophils and other leukocytes with the vascular wall makes an important contribution to chronic inflammatory diseases, such as sickle cell anemia (SCA) and atherosclerosis, as these may participate in vascular occlusion processes. The aim of this study was to evaluate whether hydroxyurea (HU), a drug used as a therapy in SCA, modulates the adhesive properties of neutrophils in vitro under an inflammatory stimulus. The neutrophils isolated from the peripheral blood of healthy subjects were stimulated with the cytokine TNF-? (Tumor Necrosis Factor alpha) and treated with HU in three concentrations (100, 500, 1000 ?M); the adhesive properties of the cells were evaluated by static adhesion assays and microfluidic assays using ligands such as proteins expressed on the endothelium (ICAM-1 and E-selectin), extracellular matrix proteins (fibronectin - FN) and endothelial cells (HUVEC). Furthermore, cellular activation was evaluated as cell spreading (observed when round cells become flattened and spread on a 2D solid substrate). When stimulated with TNF-?, neutrophils presented a significant increase in cell adhesion and spreading. Pre-treatment of cells with HU significantly reduced neutrophil spreading on all three proteins studied (FN, ICAM-1 and E-selectin). Under static conditions, the pre-treatment and post-treatment of neutrophils with HU significantly decreased adhesion to FN, compared to TNF-?-stimulated cells. In the flow adhesion assays, pre-treatment of neutrophils with HU at three concentrations (100, 500 and 1000 ?M) significantly reduced the adhesion of neutrophils to FN and post-treatment with HU decreased only at the concentration of 100 ?M. We evaluated the in vitro flow adhesion of neutrophils to proteins present on endothelial cells, ICAM-1 and E-selectin; pre-treatment and post-treatment of neutrophils with HU decreased their adhesive properties after TNF-? inflammatory stimulus to the E-selectin ligand, while pre-treatment in the three concentrations decreased neutrophil adherence to ICAM-1 ligand and ICAM-1/E-selectin ligands added together to the chip. Flow cytometry demonstrated that the expressions of the integrins LFA-1 (CD11a) and Mac-1 (CD11b) were elevated on the surface of neutrophils after a TNF-? stimulus. However, L-selectin expression was reduced with this potent inflammatory stimulus, probably due to the mechanism of "shedding". Incubation of neutrophils with HU (100 and 1000 ?M), after stimulation with TNF-?, significantly reduced the CD11a expression on neutrophils to levels similar to those found on the neutrophils of the non-TNF-?-stimulated group. We also observed that there was an increased expression of the LFA-1 (CD11a) integrin in its active conformation after stimulation with TNF-? and that, post-incubation with HU (1000 ?M) was able to reduce the activation of the adhesion molecule CD11a (LFA-1 subunit), compared to the group with TNF-? stimulus only. Given these results, it is possible to conclude that treatment of neutrophils with HU was able to protect or even reverse some of the inflammatory actions of TNF-?. HU is used as a chronic therapy in patients with SCA, but our data indicate that HU may also have immediate effects that are independent of the increase in fetal hemoglobin usually observed in patients in therapy. Our results further clarify the mechanism of action of HU in SCA and suggest that this drug may have potential for use in other inflammatory diseases. Further studies will be needed to better comprehend how these HU anti-inflammatory effects act on neutrophils
Mestrado
Fisiopatologia Médica
Mestra em Ciências
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Silva, Fernando Oliveira Catanho da. "Treinamento fisico, processo inflamatorio e adaptação." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314731.
Full textAbstract:
Orientador: Denise Vaz de MacedoTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O exercício físico e um conhecido indutor agudo de traumas sobre as estruturas biológicas como músculos esqueléticos, articulações, ossos e demais tecidos. O treinamento físico, de maneira cronica e respeitando a relacao estimulo-recuperação pode levar a uma seqüência coerente de traumas e conseqüentemente a adaptação (Overreaching Funcional - FOR). Por outro lado, desequilíbrios persistentes na relação estimulo-recuperação podem levar a condições não-adaptativas refletidas em perda de performance e sintomatologia variada (Overreaching Não-Funcional - _FOR e Síndrome do Overtraining - OTS). Existe na literatura a proposta do envolvimento de marcadores antiinflamatórios e pro-inflamatorios na diferenciação entre esses dois estados. O objetivo central do presente trabalho foi investigar a relação entre treinamento físico e os estados FOR e _FOR através da analise de performance e de marcadores sericos e teciduais imunológicos, bioquímicos e hematológicos em ratos submetidos a um protocolo de indução ao overtraining desenvolvido recentemente em nosso laboratório. O presente trabalho esta dividido em dois capítulos escritos na forma de artigos científicos. O capitulo 1 consiste em um artigo de revisão da literatura sobre processo inflamatório e treinamento físico. Anexo ao artigo segue o roteiro de estudos que será utilizado como ferramenta didática em sala de aula quando da discussão do processo inflamatório desencadeado pelo exercício e treinamento físico. No capitulo 2 apresentamos os dados de performance e as concentrações hepática e muscular das citocinas Fator de Necrose Tumoral (TNFa), Interleucina 1 (IL-1ß), Interleucina 6 (IL-6) e Interleucina 10 (IL-10); concentracao muscular dos aminoácidos Glutamina (Gln) e Glutamato (Glu); concentração serica de Proteína C-reativa (PCR), Albumina, Acido Urico (AU), FRAP (Ferric Reducing Ability of Plasma), Creatina Quinase (CK), Ureia, Proteínas Totais e Creatinina, alem do hemograma completo de ratos alimentados ad libitum e submetidos a um protocolo controlado de treinamento em esteira, contendo um período de desequilíbrio entre o estimulo do exercício e o tempo de recuperação entre os estímulos. O protocolo teve a duração de 11 semanas, sendo: treinos 1x/dia da 1ª a 8ª semana, treinos 2x/dia na 9ª semana, treinos 3x/dia na 10ª semana e treinos 4x/dia na 11ª semana. A performance e os biomarcadores foram analisados apos a 9ª semana e apos a 11ª semana. Os animais sacrificados apos a 9ª semana constituíram o grupo treinado (Tr). Os animais do grupo controle (CO) também foram sacrificados na 9ª semana. Os resultados mostraram que a performance da maioria dos ratos melhorou significativamente (p<0,05) apos a 11ª semana em relação ao grupo Tr, sendo estes caracterizados como grupo FOR. Corroborando com o dado de performance o grupo FOR mostrou um maior padrão antiinflamatório muscular (?[IL6] e ??[TNFa ?e IL-1 ß]), antiinflamatório serico (?[PCR]) e antioxidante serico (?[AU e FRAP]) (p<0,05). Ao mesmo tempo apresentou um maior padrão pró-inflamatório no fígado (?[TNFa ?e IL-1 ß]) (p<0,05). Exibiu ainda tendência de queda (p>0,05) da concentração serica da CK e dos leucocitos, assim como dos componentes de sua contagem diferencial (neutrofilos, linfocitos e bastonetes) e queda (p<0,05) na razao Gln/Glu em relação ao grupo Tr. O grupo FOR apresentou tambem queda (p<0,05) do numero de hemaceas e do hematocrito. Os resultados apresentados sugerem que os ratos do grupo FOR apresentavam-se mais adaptados que os ratos dos grupos CO e Tr, exibindo um padrao antiinflamatorio serico e muscular alem de adaptacao antioxidante serica.
Abstract: Physical exercise can cause trauma to biological structures as skeletal muscle, joints, bone and several other tissues. Training in a chronic way and considering training-recovery relationship can lead to a coherent sequence of trauma and consequently to organic adaptive condition (Functional Overreaching - FOR). On the other hand an imbalance between training-recovery can lead to organic non-adaptive condition, directed by performance decrease and several other symptoms (Non-Functional Overreaching - NFOR and/or Overtraining Syndrome - OTS). Literature suggested that anti and pro-inflammatory markers are involved in the differentiation of these states. Our main goal was to investigate the relationship among exercise training, FOR and NFOR through performance added to serum and tissue immunologic, biochemical and hematological biomarkers in rats submitted to an overtraining inducing protocol recently developed in our laboratory. This work was divided in two chapters written as scientific articles. Chapter 1 consists in literature data review about inflammatory process and exercise training. A study guidebook follows this review to be used as a teaching tool to discuss the relationship between inflammatory process and exercise training. Chapter 2 presents data as performance added to muscle and hepatic cytokines concentration: Tumor Necrosis Factor-Alpha (TNFa), Interleukin 1-Beta (IL-1ß), Interleukin 6 (IL-6) and Interleukin 10 (IL-10); muscle aminoacids concentration: Glutamine (Gln) and Glutamate (Glu); serum concentration of C-reactive Protein (CRP), Albumin, Uric Acid (UA), Ferric Reducing Ability of Plasma (FRAP), Creatine Kinase (CK), Urea, Total Proteins, Creatinine and hemogram from rats submitted to a treadmill training protocol containing an imbalance between exercise and rest. Protocol consisted in 11 weeks training 1x/day from week 1 to week 8; training 2x/day at week 9; training 3x/day at week 10; training 4x/day at week 11. Performance and biomarkers were analyzed after week 9 and week 11. The rats sacrificed at 9th week constituted trained group (Tr). The control group (CO) was also sacrificed at 9th week. Results showed that performance of mostly rats were significantly increased after 11th week (p<0,05) and then characterized group FOR. The FOR group showed a greater anti-inflammatory pattern in muscle (?[IL6] and ??[TNFa ?and IL-1 ß]) and serum (?[CRP]) beyond a greater serum antioxidant status (?[UA and FRAP]) (p<0,05). The liver analysis showed a greater pro-inflammatory status (?[TNFa ?and IL-1 ß]) (p<0,05). There was a decrease tendency in CK serum concentration and WBC total and relative count (neutrophils, lymphocytes, band cells) added to a decrease (p<0,05) in Gln/Glu ratio when compared to Tr group. There was also a decrease in RBC and HCT at FOR (p<0,05) in relation to Tr group. We concluded that rats from FOR group were more adapted than CO and Tr rats, exhibiting muscle and serum antiinflammatory and antioxidant pattern.
Doutorado
Bioquimica
Doutor em Biologia Funcional e Molecular
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Kabbert, Johanna Verfasser], Oliver [Akademischer Betreuer] Pabst, and Lars Mathias [Akademischer Betreuer] [Blank. "Investigation of the binding profile and specificity of monoclonal IgA to microbiota communities under steady state and inflammatory conditions / Johanna Kabbert ; Oliver Pabst, Lars M. Blank." Aachen : Universitätsbibliothek der RWTH Aachen, 2021. http://d-nb.info/123913083X/34.
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Bergmann, Hanna [Verfasser], Jürgen [Akademischer Betreuer] Ruland, Dieter K. M. [Akademischer Betreuer] Saur, and Roland R. [Akademischer Betreuer] Rad. "Card9 signaling in the innate immune system drives carcinogenesis in the colon under inflammatory conditions / Hanna Bergmann. Gutachter: Dieter K. M. Saur ; Roland R. Rad. Betreuer: Jürgen Ruland." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1074999371/34.
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Milanez, de Lima Almeida Pedro [Verfasser], and Michael [Akademischer Betreuer] Steinert. "Contribution of Foxp3+ regulatory T cells and myeloid-derived suppressor cells to immune homeostasis in the steady state and under inflammatory conditions / Pedro Milanez de Lima Almeida ; Betreuer: Michael Steinert." Braunschweig : Technische Universität Braunschweig, 2014. http://d-nb.info/1175821101/34.
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Diallo, Ibrahima. "Potentiels anti-oxydants et anti-inflammatoires de sporophores de Lentinula edodes (Shiitake) sous différentes conditions de culture." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTG042.
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Lentinula edodes est un champignon comestible cultivé et commercialisé depuis des siècles en raison de ses propriétés nutritionnelles et médicinales. Riche en protéines, en fibres, en minéraux et pauvre en calories, le Shiitake a de multiples propriétés pharmacologiques (propriétés antimicrobiennes, antioxydantes, anti-inflammatoires, hypoglycémiques, anticancéreuses). Peu d'études ont été effectuées tenant compte de l'influence des conditions de culture sur les effets santé de ce champignon. Nos travaux ont porté sur la comparaison des propriétés antioxydantes et anti-inflammatoires de sporophores de différents producteurs : A et C non bio et B bio, tous issus d’une souche identique de Shiitake (Mycelia-3782) et achetés à trois (3) producteurs de la région Occitanie Française. Une extraction séquentielle sous sonication (cyclohexane, chloroforme, éthanol et eau) a été réalisée sur ces champignons suivie d’une caractérisation qui a permis d’identifier des molécules dont: l’ergostérol dans les extraits apolaires, l’acide ascorbique et des acides aminés dans les extraits polaires. La capacité antioxydante de chaque extrait a été évaluée en utilisant le DPPH et l’ORAC. L’activité anti-inflammatoire des extraits éthanoliques et aqueux de tous les producteurs a été évaluée in vitro sur un modèle de macrophages inflammatoires J774.A1.Les résultats montrent qu’à 1 mg/ml, tous les extraits présentent une activité antioxydante quantifiable mais modérée avec un potentiel antioxydant plus prononcé dans les extraits aqueux, par contre, la teneur en polyphénol dosé par le réactif de Folin Ciocalteu était plus importante dans les extraits cyclohexaniques. A 50 µg/ml les extraits éthanoliques des trois producteurs inhibent fortement la production du NO de manière dose dépendante (29.66% ; 31.30% et 27.56 % respectivement pour les producteurs A, B et C) lorsque les cellules sont prétraitées pendant 4 heures avec un temps de stimulation par le LPS/IFNγ de 24 heures sans affecter la viabilité cellulaire. Par contre, l’inhibition observée pour les extraits aqueux est très faible. Cette activité constatée n’était pas due à une activité du NO Scavenging des extraits. Les résultats ont montrés également que le TNFα sécrété dans les surnageants cellulaires des macrophages prétraités par les extraits éthanoliques de Shiitake était inhibé de manière concentration dépendante, contrairement aux extraits aqueux qui n’ont pas un effet inhibiteur sur la molécule.Cette étude préliminaire montre que les conditions de culture du Shiitake (bio et non bio) n’influencent pas son potentiel antioxydant et anti-inflammatoire in vitroLentinula edodes is an edible mushroom grown and marketed for centuries due to its nutritional and medicinal properties. Rich in protein, fiber, minerals and low in calories, Shiitake has mainly antimicrobial, antioxidant, anti-inflammatory, hypoglycemic and anticancer activities. Few studies have been done considering the influence of Shiitake growing conditions on biological activities. Our work focused on the comparison of the antioxidant and anti-inflammatory properties of Shiitake cultivated by different producers (from the French region Occitanie), i.e., A and C non-organic and B organic mushroom professionals, using an identical strain of Shiitake (Mycelia-3782). A sequential extraction under sonication (cyclohexane, chloroform, ethanol and water) was carried out on the fungal materials. The antioxidant capacity of the four extracts was evaluated using DPPH and ORAC. The anti-inflammatory activity of the ethanolic and aqueous extracts of all the producers was evaluated in vitro on a model of J774.A1 inflammatory macrophages. The results show that at 1 mg/ml, all the extracts have a quantifiable but moderate antioxidant activity with a more pronounced antioxidant potential in the aqueous extracts, whereas the polyphenol content assayed by the Folin Ciocalteu reagent was greater in cyclohexane extracts. At 50 μg/ml, the ethanolic extracts of the three producers strongly inhibit the production of the NO in a dose-dependent manner (29.66%, 31.30% and 27.56% for the producers A, B and C, respectively) when the cells are pre-treated for 4 hours with a LPS / IFNγ stimulation time of 24 hours without affecting cell viability. On the other hand, the inhibition observed for the aqueous extracts is very low. This activity was not due to a NO scavenging activity of the extracts. The results also showed that TNFα secreted in cell supernatants of macrophages pretreated with ethanolic extracts of Shiitake was inhibited in a concentration-dependent manner, in contrast to aqueous extracts which do not have an inhibitory effect on the molecule. This preliminary study shows that the growing conditions of Shiitake (organic and non-organic) do not influence its antioxidant and anti-inflammatory potentials in vitro
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Silveira, Angélica Aparecida Antoniellis 1987. "Investigação do papel do óxido nítrico e de Rho GTPases na adesão de neutrófilos sob condições inflamatórias = Investigation of the role of nitric oxide and Rho GTPases in neutrophils adhesion under inflammatory conditions." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311498.
Full textAbstract:
Orientador: Nicola Amanda Conran ZorzettoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-21T05:53:22Z (GMT). No. of bitstreams: 1 Silveira_AngelicaAparecidaAntoniellis_M.pdf: 1268408 bytes, checksum: 22c750391706cfa07cb1fd66d9e8a9c1 (MD5) Previous issue date: 2012
Resumo: Durante a resposta inflamatória, os neutrófilos e outros leucócitos aderem ao endotélio, deixando os vasos sanguíneos e movimentando-se ativamente em direção ao foco inflamatório. A migração dos neutrófilos para sítios inflamatórios depende de uma série de eventos adesivos e quimiotáticos, resultantes da ativação de moléculas de adesão como as selectinas e integrinas e receptores de quimiocinas. Devido às suas propriedades, os neutrófilos podem ser ativados por proteínas de sinalização intracelular, as Rho GTPases, que auxiliam os neutrófilos a desempenhar esta função por interferirem em mudanças no citoesqueleto. Estas proteínas também estão envolvidas na adesão e proliferação celular. Os neutrófilos são capazes de sintetizar óxido nítrico (NO), sendo que esta produção de NO é um importante componente da resposta imune inata durante a inflamação. Estudos demonstraram que os neutrófilos têm papel indutor na geração de inflamação e esforços visando compreender o mecanismo adesivo destas células nos processos inflamatórios podem ser um ponto chave para intervenções farmacológicas em doenças que são caracterizadas por inflamação vascular com consequente obstrução de fluxo sanguíneo. Diante disso, este estudo objetivou avaliar o papel da via do NO e das Rho GTPases no mecanismo pelo qual os estímulos inflamatórios aumentam a adesão de neutrófilos. Também foi avaliado os efeitos da sinvastatina na modulação das propriedades adesivas de neutrófilos, como ferramenta para auxiliar no estudo do envolvimento das Rho GTPases, Rac1 e RhoA, no processo adesivo destas células. Este mecanismo foi estudado a partir de neutrófilos isolados do sangue periférico por ensaios de adesão estática e em fluxo e citometria de fluxo. Além disso, foi analisada a expressão gênica das Rho GTPases, Rac1 e RhoA, através de PCR em tempo real. Sob potente estímulo de TNF-?, as propriedades adesivas dos neutrófilos aumentam significativamente. Inibidores de NO sintase e doadores de NO não alteraram as propriedades adesivas de neutrófilos quando estimulados com TNF-?. Não observamos grande diferença quanto à adesão e expressão das moléculas de adesão na superfície dos neutrófilos usando inibidor de Rac1, porém o composto Y-27632, inibidor de ROCK (Rho-associated coiled coil forming protein serine/threonine kinase), proteína efetora de RhoA, mostrou aumentar a adesão dos neutrófilos sob condições basais. O uso da sinvastatina modulou as propriedades adesivas e a expressão de Mac-1 nos neutrófilos na presença de um estímulo inflamatório, apoiando evidências de seu uso como anti-inflamatório. Em destaque foi observado que o Y-27632 reverteu o efeito da sinvastatina sob estímulo de TNF-? e que o mevalonato e os isoprenóides intermediários da via do colesterol, GGPP e FPP, não foram capazes de reverter o efeito da sinvastatina. Dados indicam que a via de sinalização dependente em NO-GMPc aparentemente não modula as propriedades adesivas dos neutrófilos sob condições inflamatórias. Por outro lado, resultados indicam que as Rho GTPases parecem estar envolvidas na regulação das propriedades adesivas dos neutrófilos sob condições inflamatórias. O envolvimento de ROCK na adesão celular ainda não está completamente compreendido, mas de acordo com nossos resultados podemos sugerir a hipótese de que esta enzima efetora tenha um papel na inducão de adesão dos neutrófilos na presença de um estímulo inflamatório. A sinvastatina foi capaz de inibir as propriedades adesivas de neutrófilos quando ativados indicando mais uma utilidade desta classe de drogas no tratamento de doenças inflamatórias. O papel das Rho GTPases nas propriedades adesivas dos neutrófilos sob condições inflamatórios ainda precisa ser melhor elucidado
Abstract: During the inflammatory response, neutrophils and other leukocytes adhere to the endothelium leaving the blood vessels and actively moving towards the inflammatory focus. The migration of neutrophils to inflammatory sites depends on a variety of chemotactic and adhesive events resulting from the activation of adhesion molecules such as selectins and integrins and chemokine receptors. Due to its properties, neutrophils may be activated by small intracellular signaling proteins, the Rho GTPases, which help neutrophils to fulfill this function by interfering in cytoskeletal changes. These proteins are also involved in cell adhesion and proliferation. The neutrophils are able to synthesize nitric oxide (NO), and this production of NO is an important component of innate immunity during inflammation. Studies have shown that neutrophils play a role in inducing inflammation and generation of efforts to understand the adhesive mechanism exerted by neutrophils in inflammatory processes may be a key point for pharmacological interventions for diseases that are characterized by vascular inflammation with consequent obstruction of blood flow. Thus, this study aimed to evaluate the role of the NO pathway and the Rho GTPases in the mechanism by which inflammatory stimuli increases neutrophil adhesion. We also assessed the effects of simvastatin on neutrophil adhesive properties as a tool to aid in studying the involvement of Rho GTPases, RhoA and Rac1 in these mechansims. Neutrophils were isolated from peripheral blood and aspects of adhesion studied by static and flow adhesion assays as well as flow cytometry. In addition, we analyzed the gene expression of Rho GTPases, Rac1 and RhoA by real time - PCR. Following a strong stimulation with TNF-?, the adhesive properties of neutrophils increase significantly. NO synthase inhibitors and NO donors did not modify the adhesive properties of neutrophils when stimulated with TNF-?. We did not observe any significant differences in the adhesion of neutrophils and the expression of adhesion molecules on their surface in the presence of a Rac1 inhibitor. However, an inhibitor of ROCK (Rho-associated coiled coil forming protein serine/threonine kinase, an efector protin for the RhoA), Y-27632, was shown to increase the adhesion of neutrophils under basal conditions. The use of simvastatin decreased adhesive properties and modulated the expression of Mac-1 of neutrophils in the presence of an inflammatory stimulus, supporting the use of this class of drugs as anti-inflammatory agents. Importantly, the attenuating effects of simvastatin on TNF-? stimulated neutrophil adhesion were reversed by Y-27632, whereas the cholesterol pathway intermediates, mevalonate, and the isoprenoids, GGPP FPP, were unable to reverse the effects of this drug. Data indicate that the NO-cGMP signaling pathway does not appear to modulate the adhesive properties of neutrophils under inflammatory conditions. Moreover, results suggest that Rho GTPases may be involved in the regulat ion of the adhesive properties of neutrophils. The involvement of ROCK in cellular adhesion is not yet fully understood but, according to our findings, it may be hypothesized that this protein effector has a role in the induction of neutrophil adhesion. Simvastatin was able to inhibit the adhesive properties of neutrophils when activated, indicating another use of this class of drugs for the treatment of inflammatory diseases. The role of Rho GTPases in the adhesive properties of neutrophils under inflammatory conditions should be further elucidated
Mestrado
Ciencias Biomedicas
Mestra em Ciências Médicas
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Amamou, Asma. "Le récepteur minéralocorticoide : une cible potentielle dans la fibrose intestinale ? Mineralocorticoid receptor antagonisl improves inflammation and fibrosis in chronic DSS colitis mouse model Neutrophil gelatinas-associated lipocalin (NGAL) is a mineralocorticoid receptor target involved in intestinal inflammation and fibrosis Inflammatory bowel diseases and food additives : to add fuel on the flames Dietary salt activates intestinal fibroblasts, thereby contributing to exacerbation of intestinal fibrosis Dietary aryl hydrocarbon receptor ligands have no anti-fibrotic properties in transforming growth factor-β1-stimulated human colonic fibroblasts Effet d'un régime riche en sel sur la fibrose intestinale dans un modèle murin de colite chronique Etude de l'interaction entre des dérivés du tryptophane et le récepteur aryl hydrocarbone dans un modèle in vitro de fibrose intestinale." Thesis, Normandie, 2020. http://www.theses.fr/2020NORMR079.
Full textAbstract:
Les maladies inflammatoires chroniques de l’intestin (MICI) se développent chez des individus génétiquement prédisposés sous l’influence de facteurs environnementaux. La fibrose intestinale est une complication fréquente de ces MICI sans traitement spécifique, qui se caractérise par une accumulation de matrice extracellulaire synthétisée par les cellules mésenchymateuses. Le récepteur minéralocorticoïde (RM) est l’effecteur terminal du système hormonal rénineangiotensine-aldostérone (SRAA). Le RM et l’ensemble des composants du SRAA sont exprimés dans le tractus gastro-intestinal et leur expression est augmentée dans l’intestin des patients atteints de MICI. L’antagonisme du RM exerce des effets bénéfiques sur la réduction de l’inflammation et de la fibrose extra-intestinales.L’objectif principal de ce travail de thèse était de déterminer si l’antagonisme du RM exerce des effets bénéfiques sur la fibrogenèse intestinale et d’en identifier les mécanismes sous-jacents. Un modèle de colite chronique induite chez la Souris et des modèles cellulaires de fibrose intestinale ont été utilisés. L’antagonisme du RM a été étudiée par des approches pharmacologiques et par invalidation génétique. Nous avons montré que l’inhibition pharmacologique ou génétique du RM diminue l’inflammation et la fibrose intestinales dans le modèle de colite chronique chez la Souris. L’activation du RM par l’aldostérone augmente la prolifération ainsi que l’expression de TGF-β1 des fibroblastes coliques humains et promeut la transition endothélio-mésanchymateuse, des cellules endothéliales vasculaires intestinales humaines. Nous avons également montré que la lipocaline associée à la gélatinase des neutrophiles (NGAL) est une cible du RM au niveau de l’intestin et est responsable des effets pro-fibrotiques médiés par l’activation du RM. L’invalidation génétique de la NGAL inhibe la voie de signalisation du TGF-β1 dépendante des SMAD, qui joue un rôle central dans l’initiation et le développement de la fibrose. En conclusion, nous avons d’une part démontré l’implication du RM dans la fibrose intestinale et d’autre part montré que ses effets étaient dépendants de la NGAL. Ainsi, l’antagonisme du RM pourrait constituer une nouvelle cible thérapeutique dans la fibrose intestinale associée aux MICI et permettrait de repositionner des molécules déjà disponibles dans le contexte des MICIInflammatory bowel diseases (IBD) occur in people with a genetic predisposition under the influence of environmental factors. Intestinal fibrosis is a common complication in IBD with no specific therapy which is characterized by an accumulative deposit of extra-cellular matrix produced by mesenchymal cells. Mineralocorticoid receptor (MR) is the final effector of renin-angiotensin-aldosterone system (RAAS). MR and all components of RAAS are expressed in the gastrointestinal tract and are up-regulated in the intestine from IBD patients. MR antagonism exerts beneficial properties in inflammation and fibrosis from extra-intestinal organs. We aimed to investigate whether MR antagonism had beneficial effects in intestinal fibrogenesis using murine chronic colitis and cellular models of intestinal fibrosis. MR antagonism was investigated by a dual approach using pharmacological inhibition and genetic invalidation. In the present study, we have demonstrated that pharmacological or genetic MR antagonism reduced inflammation and intestinal fibrosis in murine DSS chronic chemically-induced colitis. MR activation by aldosterone increased cell proliferation and TGF-β1 production in human colonic fibroblasts and human intestinal endothelial cells. Lipocalin associated with neutrophil gelatinase (NGAL) mediated pro-fibrotic effects via the activation of RM by aldosterone. Genetic invalidation of NGAL also reduced the SMAD-dependent TGF-β1 signaling pathway. In conclusion, we have demonstrated the MR involvement in intestinal fibrosis and these effects are mediated through NGAL. Thus, MR antagonism may represent a novel attractive approach in the treatment of intestinal fibrosis associated with IBD and may allow the repositioning molecules already available in the field of IBD
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Behzad, Ali Reza. "Regulation of inflammatory and fibrotic mediators by adenovirus E1A in guinea pig lung cells." Thesis, 2003. http://hdl.handle.net/2429/14791.
Full textAbstract:
Results from our laboratory have shown that guinea pigs with latent adenovirus
infection develop excess lung inflammation and greater amounts of emphysema when
chronically challenged with cigarette smoke. In this model the adenoviral E1A is
expressed in peripheral lung epithelial (PLE) cells. We sought to establish PLE cell
lines that stably express adenoviral E1A protein in culture and use these cells to
investigate mechanisms by which E1A contributes to inflammatory and fibrotic
responses. Primary PLE cultures were established on either plastic or on polycarbonate
filters that were coated with extracellular matrix. Transfection of primary PLE cells
grown on either substrate resulted in E1A-expressing PLE cell lines with epithelial
characteristics of cytokeratin expression, cuboidal morphology and junctional
complexes, but these cell lines failed to show more specific markers of PLE cells such
as surfactant mRNA expression, lamellar bodies or microvilli. The suspicion that E1A
transfection may have induced mesenchymal to epithelial transformation (MET) of
contaminating normal lung fibroblasts (NLF) led us to compare E1A-PLE with E1A-NLF
cell lines. E1A-expressing PLE and NLF cell lines showed similar epithelial
characteristics and similar levels of mRNA and protein expression of IL-8 and MCP-1
before and after stimulation with LPS and TGF-pi and of CTGF in the absence of
stimulation. These overlapping characteristics suggest that either E1A caused both
PLE and NLF to converge to an intermediate phenotype or that E1A-expressing PLE
cell lines are the result of E1A-induced MET of contaminating fibroblasts. E1A's
enhancement of TGF-(31 mRNA expression in fibroblasts implicates this viral protein in
the pathogenesis of fibrosis while the E1 A-induced suppression of IL-8 and MCP-1 may
imply that E1A is acting as a negative regulator of inflammation. This suppression may
reflect redirection of the host transcriptional apparatus by E1A to upregulate fibrotic
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Yang, Ting-Yu, and 楊庭瑜. "Antioxidant, anti-inflammatory, and anti-fibrotic potential of flavokawain A, a major component of Kava-Kava." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/s8r2s4.
Full textAbstract:
碩士中國醫藥大學
營養學系碩士班
102
Abnormal regulation of inflammatory response caused various pathological conditions, including the development of cardiovascular disease, cancer, and metabolic syndromes. However, strict regulation of inflammation can reduce the incidence of disease and the impact of life. Flavokawain A (FKA), a chalcone isolated from the rhizomes of Piper methysticum, also known as “Kawa” by the Pacific Islanders. Recent studies reported that FKA possesses anti-tumor and anti-inflammatory effect in vitro and in vivo. However, the anti-inflammatory effect of Flavokawain A on spleenocytes, a immune cell regulating systemic inflammation was poorly understood. Spleen is part of the immune system, which contain variety of immune cells regulating systemic inflammation. In this thesis research, we investigated the anti-inflammatory, anti-pancreatitis and anti-vascular fibrosis effects of FKA utilizing various in vitro and in vivo models. The experimental design was divided into three parts. The result of first experiment was designed shows that FKA treatment significantly decreased production of pro-inflammatory cytokines such as IL-1β, IL-2, and TNF-α and increased the anti-inflammatory cytokine IL-10. This data suggest that FKA possessed strong anti-inflammatory effect. To further examine, the inflammation in spleenocytes were induced by LPS and then the anti-inflammatory effect of FKA was examined. Treatment with FKA significantly inhibited intracellular ROS generation and pro-inflammatory cytokines (IL-2, IL-6, IL-1β, TNF-α) production. In addition FKA treatment significantly inhibited the protein expression levels of inflammatory genes such as iNOS, COX-2, TNF-??, and IL-1?? in a dose-dependent manner. The inhibition of pro-inflammatory genes by FKA was mediated by suppression of their corresponding transcription factor NF-?羠. In addition, several studies reported that regulating redox-sensitive transcription factor Nrf2 to achieve the effect of anti-inflammation. In the present study, we also found that FKA can stimulate basal ROS, thus prompting the transcriptional activation of Nrf2 and transcription of antioxidant genes including NQO-1, γ-GCLC, HO-1. Based on the results, FKA has antioxidant and anti-inflammatory capabilities. In the second set of experiment, we investigated the functional alteration of splenocytes in severe acute pancreatitis of FKA treated. Treatment with FKA significantly decreased blood lipase activity in CCK-8-induced acute pancreatitis in experimental mice. Appropriate pro / anti-inflammatory cytokines and Th1/Th2 cytokines will maintain a balance in human, but this model will cause unnormal immune response with spleen injury, and then pro/anti-inflammatory cytokines is a tendency to inhibit pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α. Moreover, FKA significantly increased pro-inflammatory cytokines including IL-1??, IL-6, and TNF-??. In the third set of experiment, the anti-vascular fibrosis effect of FKA was examined. Vascular smooth muscle cells (A7r5) were pretreated with FKA and fibrosis was induced by TGF??1. Result shows that FKA treatment significantly inhibited the TGF??1-induced ??-SMA and fibronectin expression in a dose-dependent manner. The inhibition of ??-SMA and fibronection by FKA was mediated by suppression of smad2/smad3 activation. FKA also significantly reduced nuclear translocation of smad3 but not smad2 and inhibits transcriptional activity of Smad3. We also observed that treatment with FKA significantly inhibited TGFβ1-induced migration and invasion of smooth muscle cells. The inhibition of migration and invasion by FKA is associated with down-regulation of MMP-2 and MMP-9 protein expression in smooth muscle cells. Taken together, the present study demonstrated that FKA has a potential anti-inflammatory and antioxidant agent. By acute pancreatitis in animal experiments, FKA also proved that it reduce the immune function and protects spleen function. FKA inhibited TGFβ1-induced vascular fibrosis, which support that it is potential agent for cardiovascular diseases. We believe that FKA may be an attracting candidate for the development of function food and nuetraceutical supplement.
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"EQUINE NEUTROPHIL APOPTOSIS IN INFLAMMATORY CONDITIONS." Thesis, 2015. http://hdl.handle.net/10388/ETD-2015-11-2368.
Full textAbstract:
Horses are at high risk to develop systemic inflammation due to the release of bacterial endotoxin from an inflamed gastrointestinal tract. Neutrophils are critical for mounting an immune response to bacterial endotoxins. Neutrophil activation following engagement of bacterial endotoxin expands their lifespan through suppression of their constitutive apoptosis. The prolonged lifespan of neutrophils propagates acute inflammation and delays the resolution of inflammation. Since equine neutrophil lifespan has not been well-studied, I investigated the occurrence of equine neutrophil apoptosis in vitro and in vivo.
First, I investigated the effect of Escherichia coli lipopolysaccharide (LPS) treatment on the occurrence of equine neutrophil apoptosis in vitro. LPS treatment delayed in vitro equine neutrophil apoptosis in a dose-dependent manner at concentrations of 0.1-10 μg/ml through toll-like receptor (TLR)-4 signaling and down-regulation of the intrinsic pathway of apoptosis, specifically through reduced caspase-9 activity.
Next, I found that ex vivo neutrophil apoptosis was delayed in two models of intestinal inflammation, jejunal ischemia and reperfusion (IR) and oligofructose-induced colitis, through down-regulation of both the intrinsic and extrinsic apoptosis pathways via reduced caspase-3, -8, and -9 activities. Pulmonary intravascular macrophages (PIMs) depletion with systemic gadolinium chloride (GC) prevented the prolongation of ex vivo neutrophil lifespan in horses undergoing jejunal IR through modulation of caspase-3, -8 and -9 activities. PIM depletion in IR horses resulted in an earlier and greater increase in tumor necrosis factor-alpha and a concomitant decrease in interleukin-10 to suggest an enhanced systemic pro-inflammatory response.
I examined the effect of neutrophil concentration and co-incubation with aged, apoptotic neutrophils on the occurrence of neutrophil apoptosis in vitro. Neutrophil apoptosis was delayed with increasing concentrations of neutrophils in vitro, which may contribute to delayed neutrophil apoptosis in systemic inflammation. However, co-incubation with aged, apoptotic neutrophils did not alter in vitro neutrophil lifespan.
Taken together, the data show that LPS delays equine neutrophils apoptosis in vitro in a TLR4-dependent manner through inhibition of caspase-9. Ex vivo neutrophil apoptosis was also delayed with systemic inflammation via down-regulation of caspase activity. A novel finding of this work was the reversal of delayed neutrophil apoptosis by depletion of PIMs in horses experiencing intestinal IR.
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Silva, Rafaela Inês Pedro da. "Adenosine exerts a pro-fibrotic and pro-inflammatory effect on rat subcutaneous fibroblasts via A2A receptors activation." Master's thesis, 2020. https://hdl.handle.net/10216/132157.
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Silva, Rafaela Inês Pedro da. "Adenosine exerts a pro-fibrotic and pro-inflammatory effect on rat subcutaneous fibroblasts via A2A receptors activation." Dissertação, 2020. https://hdl.handle.net/10216/132157.
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Ezequiel, Catarina Alexandra Barbosa. "Balance between pro-inflammatory/anti-inflammatory indicators of SOD1G93A microglia in steady conditions and modification by immunomodulation." Master's thesis, 2017. http://hdl.handle.net/10451/34248.
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Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017Amyotrophic Lateral Sclerosis (ALS) is the third most common neurodegenerative disease, mostly sporadic, with limited identified targets, biomarkers and therapeutic options. The most widely used animal model and experimental cellular models to study ALS pathological mechanisms are based on mutations in the anti-oxidant protein SOD1, particularly that of G93A. ALS affects mainly motor neurons, but it is widely accepted that immune unbalance plays a crucial role in the ALS disease, and microglial dysfunction is described to be associated with neuronal injury influencing disease onset and progression. As the immune cells of the central nervous system, microglia produce inflammatory responses towards an insult by secreting pro-inflammatory mediators to the extracellular milieu in the form of soluble factors, or in membrane-bound vesicles called exosomes, an important component in intercellular communication and in disease dissemination. In this thesis we aimed to better understand the role of microglia in ALS disease using the mutant SOD1G93A microglia, and assessing their reactivity upon the immunostimulation by lipopolysaccharide (LPS), and immunomodulation by glycoursodeoxycholic acid (GUDCA) and vinyl sulfone (VS), having in mind the goal of fighting ALS neurodegeneration. For that, we assessed microglia function/dysfunction and reactivity after human SOD1 overexpression in the N9 cell line, either wild type (hSOD1WT) or mutated in G93A (hSOD1G93A), alone or treated with LPS, and when exposed to GUDCA and VS, known for their potential anti-inflammatory effects. Data showed that overexpression of hSOD1WT in N9 cells leads to a decrease in all analyzed pro- and anti-inflammatory markers, whereas hSOD1G93A increases both pro-inflammatory TNF-α, IL-1β, MHCII and HMGB1 gene expression levels, together with anti-inflammatory Arg1 and SOCS1 indicators, and reduces iNOS, Fizz1, IL-10, TLR4, miR-125b and miR-21. Interestingly we found an elevated cargo of miR-155 and miR-146a in hSOD1G93A microglia-derived exosomes. Upon LPS exposure, all cells switched from ramified into amoeboid morphology. LPS-treated transgenic microglia showed equivalent pro-inflammatory markers, when compared to LPS-treated naïve cells. However, they revealed decreased levels of the anti-inflammatory Arg1, Fizz1 and IL-10, thus reducing the ability to later balance the microglia reactivity to the insult. Surprisingly, cells also evidenced reduced miR-155 expression, what may even compromise an adequate pro-inflammatory response. In contrast with hSOD1WT cells, SOD1G93A microglia displayed decreased gene expression of S100B and equal of TNF-α mRNA, when compared to naïve cells. Additionally, the ability of ingesting a high number of beads (≥ 11) was found diminished. Treatment with GUDCA or VS decreased the cell body area of reactive microglia, and SOCS1 and Arg1 mRNA expression. Nevertheless, both immunomodulators increased TLR4, as well as reduced IL-1β and S100B gene expression, which may represent benefits for response to selected insults, while protecting from destructive secondary damage, respectively. In addition, though it decreased cellular MFG-E8 and enhanced miR-125b in exosomes, GUDCA markedly increased the cellular gene expression of the anti-inflammatory IL-10. On the other hand, VS was the only one able to reduce the pro-inflammatory MMP-9 activity and to elevate the exosomal cargo in the anti-inflammatory miR-21. In conclusion, this work demonstrates the advantageous hSOD1WT overexpression in balancing pro- and anti-inflammatory mediators in microglial cells, but overall that upregulation of hSOD1G93A increases their reactivity and may have a detrimental role in reducing their wound repair ability after insult, thus causing homeostatic imbalance between anti-inflammatory and pro-inflammatory gene expression mediators. In addition, the study also highlights that, although with different potential roles, both VS and GUDCA may have benefits over specific hSOD1G93A polarized microglia subtypes.
A Esclerose Lateral Amiotrófica (ELA) é a terceira doença neurodegenerativa mais comum, sendo maioritariamente esporádica, e limitada em termos de alvos, biomarcadores e opções terapêuticas. Os modelos animais e celulares mais usados no estudo dos mecanismos envolvidos na patogénese da ELA consideram mutações na enzima antioxidante SOD1, particularmente, a mutação G93A. A ELA afeta maioritariamente neurónios motores. No entanto, é considerado que existe uma desregulação inflamatória nesta doença que contribui para a sua progressão. A disfunção de células microgliais é associada ao dano neuronal, o que consequentemente leva ao início e progressão da doença. No Sistema Nervoso Central (CNS), as células da microglia são responsáveis pela produção da resposta inflamatória em consequência da presença de moléculas estranhas no ambiente extracelular. Esta resposta baseia-se na secreção de mediadores pro-inflamatórios para o meio extracelular sob a forma de fatores solúveis ou incorporados em vesículas membranares denominadas de exossomas, um importante meio de comunicação intercelular na disseminação da patologia. Na presente tese, pretendeu-se compreender melhor o papel da microglia na ELA, utilizando células da microglia sobreexpressando SOD1G93A, e avaliando a sua reatividade após estimulação com lipopolissacárido (LPS), e após tratamento com os imunomoduladores ácido glicoursodesoxicólico (GUDCA) e vinil sulfona (VS), com o objetivo de combater a neurodegeneração na ELA. Para isso, avaliámos a função/disfunção e reatividade microglial após a sobreexpressão da enzima SOD1 na linha celular N9, na conformação WT (hSOD1WT) ou mutada em G93A (hSOD1G93A) da enzima, em células sem tratamento ou tratadas com LPS. Adicionalmente, avaliámos o potencial anti-inflamatório dos compostos GUDCA e VS nas células sobreexpressando hSOD1G93A. Os nossos resultados demonstraram que a sobreexpressão de hSOD1WT em células N9 leva a uma diminuição de todos os parâmetros pro- e anti-inflamatórios analisados, enquanto que da sobreexpressão de hSOD1G93A leva a um aumento da expressão génica dos marcadores pro-inflamatórios TNF-α, IL-1β, MHCII e HMGB1 em conjunto com os marcadores anti-inflamatórios Arg1 e SOCS1, reduzindo iNOS, Fizz1, IL-10, TLR4, miR-125b e miR-21. Curiosamente, exossomas derivados de microglia sobreexpressando hSOD1G93A revelaram transportar maiores quantidades de miR-155 e miR-146a. Após exposição ao LPS, todas as células modificaram a sua morfologia ramificada para uma forma ameboide. Células N9 hSOD1G93A tratadas com LPS demonstraram marcadores pro-inflamatórios com níveis equivalentes ao das células controlo. No entanto, revelaram também uma diminuição dos marcadores pró-inflamatórios Arg1, Fizz1 e IL-10, reduzindo assim a capacidade da microglia de resposta ao insulto. Surpreendentemente, estas células demonstraram ainda uma diminuição de miR-155, o que pode sugerir uma resposta pró-inflamatória adequada. Ao contrário de células sobreexpressando hSOD1WT, microglia SOD1G93A apresentou uma diminuição nos níveis de expressão génica de S100B e igual expressão de TNF-α quando comparadas ao controlo. Adicionalmente, estas células evidenciaram uma diminuição da capacidade de ingestão de um elevado número de beads [≥11]. O tratamento com GUDCA ou VS demonstrou diminuir a área do corpo celular das células reativas da microglia, em conjunto com uma diminuição da expressão génica de SOCS1 e Arg1. Contudo, ambos os imunomoduladores aumentaram a expressão de TLR4, diminuindo a expressão de IL-1β e S100B, o que pode sugerir o efeito benéfico destes compostos na resposta a insultos, protegendo contra efeitos secundários destrutivos, respetivamente. Adicionalmente, apesar da diminuição da expressão de MFG-E8 e aumento da expressão de miR-125b em exossomas, o composto GUDCA evidenciou um aumento significativo da expressão do marcador anti-inflamatório IL-10. Por outro lado, apenas o tratamento com VS foi bem-sucedido na diminuição da atividade da MMP-9 e aumento do transporte do anti-inflamatório miR-21 em exossomas. Em conclusão, este trabalho demonstra o benefício da sobreexpressão de hSOD1WT no equilíbrio de marcadores pro- e anti-inflamatórios nas células da microglia, enquanto a sobreexpressão de hSOD1G93A aumenta a reatividade microglial, podendo ter um papel prejudicial na redução da sua capacidade de resposta a estímulos externos, causando assim um desequilíbrio na expressão génica de marcadores pro- e anti-inflamatórios. Adicionalmente, este estudo foca ainda que, apesar de com diferentes funções, os compostos GUDCA e a VS que podem ser benéficos para as células da microglia hSOD1G93A com diferentes polarizações.
The studies presented in this master thesis were performed in the Neuron Glia Biology in Health and Disease Group, at the Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, under the supervision of Dora Brites, Ph.D. (group leader) and Ana Rita Vaz, Ph.D.
Work presented in this master thesis was supported by Santa Casa da Misericórdia de Lisboa [Ela Project 2015-002 (DB)] and in part by Fundação para a Ciência e Tecnologia [project Pest-UID/DTP/04138/2013 iMed.ULisboa project].
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Choi, Hyun Beom. "Roles of microglial purinergic receptors in inflammatory conditions of the brain." Thesis, 2006. http://hdl.handle.net/2429/18271.
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Microglia, the resident immune cells of brain, mediate inflammatory responses leading to progressive neuronal damage in neurodegenerative diseases. Binding of ATP to purinergic receptors activates microglia thereby inducing cellular responses in inflamed brain cells. The two families of purinergic receptors, labelled P2XR (ionotropic) and P2YR (metabotropic) contribute to inflammatory responses in microglia. The first two parts of my study focused on the involvement and role of the ionotropic purinergic receptor, P2X₇R in mediating inflammatory responses such as secretion of pro-inflammatory factors in vitro and in vivo. The final part of my study concentrated on purinergic receptor-dependent intracellular Ca²⁺([Ca²⁺]i) mobilization and functional responses in human fetal microglia [i.e. foetal microglia]. A detailed in vivo study was carried out on the involvement of P2X₇R in mediating lipopolysaccharide (LPS)-induced inflammatory responses and neuronal damage in rat striatum. LPS-injected striatum exhibited a marked increase in the expression and production of P2X₇R compared with control (saline)-injected animals. Additionally, LPS injection upregulated a host of pro-inflammatory mediators and reduced neuronal viability. The P2X₇R antagonist, oxidized ATP (oxATP) was effective in attenuating expressions of all inflammatory mediators; most importantly oxATP was protective for striatal neurons. In vitro, I found LPS stimulation of cultured human microglia enhanced cellular expressions of inflammatory mediators and increased [Ca²⁺]i mobilization which were blocked with oxATP treatment. Overall, the results from this work indicate that P2X₇R plays a critical role in LPS-induced inflammatory responses including induction of neuronal damage. Subsequently a series of studies was designed to examine putative roles of P2X₇R in mediating inflammatory responses with relevance to the pathology typical of Alzheimer’s disease (AD). First, I found microglia isolated from AD brains expressed enhanced P2X₇R compared with microglia obtained from non-demented individuals. In a second study, human fetal microglia stimulated with Aβ₁₋₄₂ peptide exhibited markedly elevated levels of P2X₇R compared with untreated cells. Also, P2X₇R-mediated Ca²⁺ responses were increased with Aβ₁₋₄₂ pretreatment of cells relative to untreated cells. Finally, in vivo double immunostaining analysis showed considerable P2X₇R co-localized with microglia following injection of Aβ₁₋₄₂ into rat hippocampus. The overall results from this section of study show the involvement of P2X₇R in mediating microglial purinergic inflammatory responses in AD brain. We were also interested in the contribution of purinergic receptors other than P2X₇R in mediating inflammatory responses. I focused on cyclooxygenase-2 (COX-2) since this enzyme is highly elevated in inflamed brain and contributes to inflammation-induced cytotoxicity. In this research, we used a low concentration of ATP (100 μM) to eliminate contributions of P2X₇R since activation of this purinergic subtype receptor requires concentrations of ATP in excess of 1mM. In summary, we found that the block of P2XR (candidate P2X₄R) increased the duration of ATP-mediated [Ca²⁺]i responses and upregulated expression and production of COX-2. The prolonged response involved influx of Ca²⁺ through store-operated channels (SOC) and was suggested as a consequence of removal of cell depolarization by the block of P2XR. Inhibition of SOC was then shown to be effective in attenuating COX-2 expression in human microglia. These novel results link inhibition of P2XR, other than P2X₇R, with upregulation of COX-2 in human microglia with the link involving SOC-mediated Ca²⁺ influx. The overall findings from this study suggest that pharmacological manipulation of P2X₇R and other purinergic receptors could serve as a potential therapeutic intervention in modulating inflammatory responses in microglia.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Fang, Yi-Ting, and 方怡婷. "Isolation conditions immunomodulatory and anti-inflammatory activites of rice bran feruloylated oligosaccharides." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/78511314853398292418.
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碩士中華醫事科技大學
生物科技研究所
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This study was to investigate the optimization conditions of feruloylated oligosaccharides preparation from rice bran by acid hydrolysis and to evaluate the immunomodulatory function of feruloylated oligosaccharides. To obtain the optimization conditions of feruloylated oligosaccharides preparation, response surface methodology (RSM) was introduced in this study. The optimal condition of 193 mM of TFA and 1.36 h of hydrolysis time was derived from canonical analysis. 2.2% of feruloylated oligosaccharides recovery was verified from predicted optimal condition and confirmed the fitness and applicability of this model. The immunomodulatory activity of feruloylated oligosaccharides was evaluated through RAW264.7 macrophage cells model. Inflammatory mediators, including the nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and prostaglandins E2 (PGE2) were surveyed separately. The results showed that the increasing of NO releasing and TNF-α, IL-1β, IL-6 and PGE2 secretion were in proportion to the increasing concentrations of feruloylated oligosaccharides. Furthermore, inflammation-prevent model (Model A) and inflammation-repairing model (Model B) of feruloylated oligosaccharides were both investigated to clarify anti-inflammatory activity in the LPS-induced RAW264.7 macrophage cells model. The data from model A and model B revealed that feruloylated oligosaccharides could significantly reduce the LPS-induced NO secretion and increased IL-10 production, but inhibited pro-inflammatory cytokine and PGE2 production. Therefore, feruloylated oligosaccharides could reveal the immunomodulatory activity. In addition, it also had the inflammation-prevent and inflammation-repair abilities against LPS-induced inflammatory effect.
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Niu, Shuo. "Regulation Of Innate Immune Cell Response Under Sub-acute/Chronic Inflammatory Conditions." 2017. http://scholarworks.gsu.edu/biology_diss/191.
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Sub-acute/chronic inflammatory diseases are often associated with altered inflammatory response, leading to increased host vulnerability to secondary inflammatory challenges. In the first study, by employing streptozotocin (STZ)-induced diabetes in mice, we further investigate mechanisms leading to enhanced polymorphonuclear leukocytes (PMN) response under hyperglycemia. We show that existence of a proinflammatory state associated with broad increases of macrophages in various organs plays a dominant role in promoting PMN response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment through increasing F4/80+ macrophages in the peritoneal cavity. Insulin reversal of hyperglycemia reduces peritoneal macrophage numbers and ameliorates PMN infiltration. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and are attributable to exacerbated nephropathy and colitis when respective inflammatory conditions are induced. We also find that significant monocytosis of inflammatory F4/80+Gr-1+ monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic/diabetic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages. In the second study, we focus on the identification of the carrier that binds to and delivers Shiga toxin 2(Stx2) to the target organ causing hemolytic uremic syndrome (HUS). By employing a murine HUS model through co-injection of LPS-Stx2, we show that, adoptive transfer of CD11b+ leukocytes, but not CD11b- leukocytes, RBC, platelets or plasma, isolated from mice with HUS induces HUS in healthy recipients. Interestingly, we find that LPS priming of mice significantly promotes CD11b+ leukocytes binding to Stx2. Compared to CD11b+ leukocytes from mice without LPS priming, CD11b+ leukocytes isolated from mice after LPS priming demonstrate higher frequencies of toxin binding and augmented potency to induce HUS. In sum, our results demonstrate peripheral CD11b+ myeloid leukocytes act as effective Stx2 carriers that deliver toxin to kidneys causing HUS and that LPS-induced inflammation enhances the carrier capacity and aggravates HUS.
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Rosenbaum, Corinna. "The role of enteric glial cells under inflammatory conditions of the intestine." Doctoral thesis, 2016. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-138946.
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The enteric nervous system (ENS) innervates the gastrointestinal (GI) tract and controls central aspects of GI physiology including contractility of the intestinal musculature, glandular secretion and intestinal blood flow. The ENS is composed of neurons that conduct electrical signals and of enteric glial cells (EGCs). EGCs resemble central nervous system (CNS) astrocytes in their morphology and in the expression of shared markers such as the intermediate filament protein glial fibrillary acidic protein (GFAP). They are strategically located at the interface of ENS neurons and their effector cells to modulate intestinal motility, epithelial barrier stability and inflammatory processes. The specific contributions of EGCs to the maintenance of intestinal homeostasis are subject of current research. From a clinical point of view EGC involvement in pathophysiological processes such as intestinal inflammation is highly relevant. Like CNS astrocytes ECGs can acquire a reactive, tissue-protective phenotype in response to intestinal injury. In patients with chronic inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis, alterations in the EGC network are well known, particularly a differential expression of GFAP, which is a hallmark of reactive gliosis in the CNS. With increasing recognition of the role of EGCs in intestinal health and disease comes the need to study the glial population in its complexity. The overall aim of this thesis was to comprehensively study EGCs with focus on the reactive GFAP-expressing subpopulation under inflammatory conditions in vivo and in vitro. In a first step, a novel in vivo rat model of acute systemic inflammation mimicking sepsis was employed to investigate rapidly occuring responses of EGCs to inflammation. This study revealed that within a short time frame of a few hours, EGCs responded to the inflammation with an upregulation of Gfap gene expression. This inflammation-induced upregulation was confined to the myenteric plexus and varied in intensity along the intestinal rostro-caudal axis. This highly responsive myenteric GFAP-expressing EGC population was further characterized in vivo andin vitro using a transgenic mouse model (hGFAP-eGFP mice). Primary purified murine GFAP-EGC cultures in vitro were established and it was assessed how the transcriptomic and proteomic profiles of these cells change upon inflammatory stimulation. Here, myenteric GFAP-EGCs were found to undergo a shift in gene expression profile that predominantly affects expression of genes associated with inflammatory responses. Further, a secretion of inflammatory mediators was validated on protein level. The GFAP+ subpopulation is hence an active participant in inflammatory pathophysiology. In an acute murine IBD model in vivo, GFAP-EGCs were found to express components of the major histocompatibility complex (MHC) class II in inflamed tissue, which also indicates a crosstalk of EGCs with the innate and the adaptive lamina propria immune system in acute inflammation. Taken together, this work advances our knowledge on EGC (patho-)physiology by identifying and characterizing an EGC subpopulation rapidly responsive to inflammation. This study further provides the transcriptomic profile of this population in vivo and in vitro, which can be used to identify targets for therapeutic intervention. Due to the modulating influence of EGCs on the intestinal microenvironment, the study further underlines the importance of integrating EGCs into in vitro test systems that aim to model intestinal tissues in vitro and presents an outlook on a potential strategyDas enterische Nervensystem (ENS) innerviert den gastrointestinalen Trakt und kontrolliert zentrale Aspekte der gastrointetinalen Physiologie, wie die Kontraktilität der intestinalen Muskulatur, Sekretion und den intestinalen Blutfluss. Das ENS setzt sich aus elektrisch leitenden Neuronen und enterischen Gliazellen (EGZ) zusammen. EGZ ähneln Astrozyten des zentralen Nervensystems (ZNS) hinsichtlich ihrer Morphologie und der Expression gemeinsamer Marker wie dem Intermediärfilament Saures Gliafaserprotein (GFAP von engl. glial fibrillary acidic protein). EGZ sind strategisch an der Kontaktstelle zwischen ENS-Neuronen und deren Effektorzellen positioniert, um die intestinale Motilität, die epitheliale Barrierestabilität sowie inflammatorischen Prozesse zu modulieren. Die spezifische Beteiligung der EGZ an der Aufrechterhaltung der Darmhomöostase wird gegenwärtig erforscht. Aus klinischer Sicht ist die Beteiligung von EGZ an pathophysiologischen Prozessen wie der intestinalen Entzündung besonders relevant. Wie ZNS-Astrozyten können EGZ bei intestinalen Schädigungen einen reaktiven, gewebe-protektiven Phänotyp annehmen. Bei Patienten mit chronisch-entzündlichen Darmerkrankungen (IBD, von engl. inflammatory bowel disease) wie Morbus Crohn und Colitis ulcerosa sind Veränderungen im EGZ-Netzwerk bekannt, besonders eine veränderte Expression von GFAP, welches ein prominentes Kennzeichen der reaktiven Gliose im ZNS ist. Nachdem sich die Bedeutung der EGZ im gesunden und kranken Darm zunehmend herausgestellt hat, muss ein stärkerer Fokus auf die Erforschung der glialen Population gelegt werden. Die Zielsetzung dieser Arbeit war die umfassende Untersuchung der EGZ mit Fokus auf die reaktive GFAP-exprimierende Population unter entzündlichen Bedingungen in vivo und in vitro}. In einem ersten Schritt wurde ein neuartiges in vivo-Rattenmodell einer akuten systemischen Entzündung verwendet, um die schnell stattfindenden Veränderungen der EGZ unter entzündlichen Bedingungen zu untersuchen. Diese Studie ergab, dass innerhalb von wenigen Stunden EGZ mit einer Hochregulation der Gfap-Genexpression auf die Entzündung reagieren. Diese entzündungsinduzierte Hochregulation war lokal auf den myenterischen Plexus begrenzt und entlang der rostro-kaudalen Achse des Darms unterschiedlich stark ausgeprägt. Die responsive, GFAP-exprimierende myenterische EGZ-Population wurde daraufhin in vivo und in vitro charakterisiert unter Zuhilfenahme eines transgenen Mausmodells (hGFAP-eGFP-exprimierende Mäuse). Primäre, aufgereinigte GFAP-EGZ-Zellkulturen wurden etabliert und dahingehend untersucht, wie sich das transkriptomische und proteomische Profil der Population unter entzündlichen Bedingungen verändert. Hierbei wurde reproduzierbar eine Verschiebung des transkriptomischen Profils myenterischer GFAP-exprimierender EGZ gefunden. Die davon betroffenen Gene sind vorwiegend mit Immunantworten assoziiert. Weiterhin wurde die Sekretion solcher Immunmediatoren auf Proteinebene validiert. Die GFAP+ Subpopulation ist somit ein aktiver Modulator entzündlicher pathophysiologischer Prozesse. In einem akuten IBD-Mausmodell konnte weiterhin gezeigt werden, dass GFAP-EGZ verstärkt Komponenten des Haupthistokompatibilitätskomplex (MHC) Klasse II im entzündeten Gewebe exprimieren. Dies weist auf eine direkt Interaktion der EGZ mit dem Immunsystem in der Lamina propria hin. Insgesamt konnte mit dieser Arbeit das Wissen über die (Patho-)Physiologie von EGZ erweitert werden, indem eine schnell responsive EGZ-Subpopulation identifizert und charakterisiert wurde. Weiterhin wurde im Rahmen dieser Arbeit das gesamte Transkriptomprofil der GFAP-Subpopulation in vivo und in vitro veröffentlicht, welches für weitere Studien zur Identifikation möglicher therapeutischer Anwendungen genutzt werden kann. Aufgrund des modulierenden Einflusses der EGZ auf die Darmphysiologie betont diese Studie die Notwendigkeit EGZs in in-vitro-Gewebemodelle des Darms zu integrieren und präsentiert einen Ausblick auf eine mögliche Strategie
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"Changes in endomorphin-2-like immunoreactivity in inflammatory and nerve injury conditions." Tulane University, 2001.
Find full textAbstract:
Inflammation and nerve injury often lead to chronic, sometimes excruciating pain. The mechanisms contributing to this syndrome include neurochemical plasticity in neurons involved in the earliest stages of pain transmission. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2) is an endogenous morphine-like substance that binds to the mu-opioid receptor with high affinity and selectivity. EM2-like immunoreactivity (EM2-LI) is present in the superficial layers of the dorsal horn in the spinal cord and in primary afferents, suggesting a role for this peptide in pain transmission Immunocytochemical studies revealed that unilateral sciatic nerve ligation (Seltzer model) produced dramatic reductions in EM2-LI and substance P-LI (SP-LI) ipsilateral to the injury from 4--14 days after injury in mice. Calcitonin gene-related peptide-LI (CGRP-LI) remained unchanged throughout the study. Control animals did not show any side-to-side changes. The neuropeptide changes were accompanied by significant thermal hyperalgesia. In rats, a novel triple-ligature nerve injury model was sufficient to produce significant reductions in EM2-LI and SP-LI ipsilateral to the injury from 4--14 days after injury. Dynorphin-LI (DYN-LI) was significantly increased during this time. As with the mouse model, CGRP-LI was unchanged. The neuropetide alterations in this study were concurrent with both thermal hyperalgesia and thermal and mechanical allodynia In contrast to nerve injury, a unilateral inflammatory stimulus (CFA) failed to produce significant changes in SP-LI or EM2-LI at 2h, 24h, 3d or 7d after intraplantar injection of CFA in rats. These results are consistent with other studies which suggest that opioids may not be altered after inflammation The decrease in EM2-LI during the development of chronic pain is consistent with a loss of an inhibitory influence on pain transmission. The results provide the first evidence that reduction of an endogenous opioid in primary afferents is associated with injury-induced chronic painacase@tulane.edu
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Bu, So Young. "Bone protective effects of dried plum and its polyphenols under inflammatory and oxidative stress conditions." 2007. http://digital.library.okstate.edu/etd/umi-okstate-2223.pdf.
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Ferreira, Elisabete Priscila Pinto. "The role of polyphenols and reactive nitrogen species in inflammatory conditions of the gastrointestinal tract|." Master's thesis, 2011. http://hdl.handle.net/10316/25851.
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Dissertação de mestrado em Bioquímica apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra.Inflammatory Bowel Diseases (IBD) are a group of chronic inflammatory diseases of the gastrointestinal tract with a high degree of incidence worldwide. Nowadays, a specific treatment of IBD is still not available and the most currently drugs used in its treatment are associated with significant side effects that limit their use. The lack of effectiveness and the adverse effects of standard therapies have increased the need for searching new treatment strategies that combine efficacy and safety. Dietary polyphenols have been shown to exert beneficial effects on human health but the underlying mechanism are still a matter of controversy. Initially though to be antioxidants in vivo, because of extensive biotransformation and poor bioavailability, it is now widely accepted that this is an unlike activity mediating their biological impact. In fact, it has been shown that the anti-inflammatory effect of polyphenols (among others) cannot be merely explained on basis of their antioxidant capacity and it is now known that the redox regulation of several signal transduction pathways must be implied to explain their cellular effects. Red wine is very rich in these phenolic compounds and in the last years numerous studies described health-promoting effects of this beverage, including antiinflammatory proprieties, but the molecular mechanisms underlying its protective role remain largely unknown. A clear understanding of the molecular mechanisms of action of polyphenols is crucial in the valuation of these potent molecules as potential prophylactic and therapeutic agents in IBD. Given the fact that the gastrointestinal tract is a compartment where the dietary polyphenols reach high concentrations in a non-modified structure this work pretends to evaluate the potential anti-inflammatory effect of a red wine polyphenolic extract (RWE) in gastrointestinal inflammation and investigate which are the mechanisms involved in its anti-inflammatory action. Particularly, to determine if RWE have the capacity to modulate nitric oxide fluxes, activate the Nrf2 pathway leading to the induced expression of cytoprotective genes and also affect the NF-‐κB pathway using cultured intestinal cell models. Overall, results suport that RWE have a protective effect against inflammation not compromising cell viability. Mechanistically, this conclusion is supported by the interference with cellular inflammatory pathways, inhibiting the production of 10 inflammatory mediators. In fact, RWE inhibited IκB degradation induced by TNF-α, partially suppressed TNF-α -induced IL-8 overproduction and prevented the iNOS protein expression induced by cytokines, thus leading to a significant reduction in ●NO overproduction. RWE also reduce the levels of tyrosine nitration and alter occludin expression and distribution. Furthermore RWE also have an effect in the Nrf2 pathway increasing its translocation to the nucleus and the expression of its target genes.
As Doenças Inflamatórias Intestinais (DII) são um grupo de doenças inflamatórias graves do trato gastrointestinal com um elevado grau de incidência na população mundial. Atualmente ainda não existe um tratamento específico para DII e os fármacos mais frequentemente usados no seu tratamento estão associados a efeitos adversos significativos que limitam o seu uso. A falta de efetividade e os efeitos adversos das terapias atuais têm aumentado a necessidade de procurar novas estratégias terapêuticas que combinem eficácia e segurança. Os polifenóis da dieta têm vindo a demonstrar exercer efeitos benéficos para a saúde humana mas os mecanismos moleculares subjacentes são ainda tema de controvérsia. Inicialmente pensava-se que estes compostos atuassem como antioxidantes in vivo mas devido à sua extensa biotransformação e reduzida biodisponibilidade é agora aceite que o seu impacto biológico não se deve meramente a esta característica. De facto, foi provado que os efeitos anti-inflamatórios (entre outros) dos polifenóis não podem ser somente explicados pela sua capacidade antioxidante e sabe-se agora que a regulação redox de várias vias de transdução de sinal devem estar implicadas na explicação dos seus efeitos celulares. O vinho tinto é muito rico nestes compostos e nos últimos anos numerosos estudos descreveram efeitos benéficos para a saúde tais como propriedades antiinflamatórias, no entanto os aspectos fundamentais dos mecanismos de ação moleculares subjacentes à sua ação protetora permanecem ainda por esclarecer. Uma clara compreensão dos mecanismos moleculares de ação dos polifenóis é crucial na validação destas promissoras moléculas como potenciais agentes profiláticos e terapêuticos em DII. Dado que o trato gastrointestinal é um compartimento em que os polifenóis da dieta atingem concentrações elevadas numa estrutura não-modificada, este trabalho pretende avaliar o potencial efeito anti-inflamatório de um extrato polifenólico de vinho tinto (EVT) na inflamação gastrointestinal e investigar quais os mecanismos envolvidos neste efeito. Particularmente determinar se os EVT possuem a capacidade de modular fluxos de óxido nítrico, ativar a via do Nrf2 levando à indução da expressão de genes citoprotetivos e também afectar a via do NF-‐κB usando um modelo de células intestinais, as células HT-29. Globalmente, os resultados demonstram que os EVT possuem um papel protetor contra a inflamação não comprometendo a viabilidade celular. Esta conclsuão é mecanisticamente suportada pela intereferência com vias celulares de inflamação. De facto, o EVT inibiu a degradação de IκB induzida por TNF-α, suprimiu parcialmente a sobreprodução de IL-8 e preveniu a expressão de iNOS induzida por citocinas o que levou a uma significativa redução da sobreprodução de ●NO. O EVT também diminui os níveis de nitração de tirosina e a expressão de ocludina foi reduzida e alterada. Para além disso EVT também afectam a via de sinalização do Nrf2 aumentando a sua translocação para o núcleo e aumentando a expressão dos seus genes alvo.
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Woodbury, Maya Ellen. "The biology of microglia in neural development and synaptic maintenance in homeostatic and inflammatory conditions." Thesis, 2016. https://hdl.handle.net/2144/19166.
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Microglia, the innate immune cells of the brain, are not only immune surveyors, but also play important roles in neural development and maintenance. Microglial aberrations, including changes in morphology, gene expression, and phagocytic activity, have been observed in humans and animal models of pathologies involving cognitive and behavioral consequences. However, the precise contribution of microglial biology is not well characterized. Expression profiling of microglia and neural stem cells, co-culture assays, and transgenic mice were used to identify microglial micro-RNAs and genes, and study their roles in neural development. The results show that a specific micro-RNA, miR-155, participates in the neurogenic deficits induced by inflammation, and microglia-derived Wnt5a is essential for neural differentiation and maturation. This indicates the potential involvement of abnormal microglia in neurodevelopmental disorders such as autism spectrum disorders (ASDs). ASDs are group of debilitating disorders characterized by behavioral symptoms, including social and communication deficits and repetitive or restricted behaviors. I hypothesize that aberrant microglial biology plays a role in neurogenic and behavioral deficits in a mouse model of ASD. I performed a time-course study of microglial gene expression profiling, neural and microglial morphology, neurophysiology, and behavior in the maternal immune activation (MIA) model of ASD induced by the innate immunity ligand polyinosinic:polycytidylic acid. Microglia in MIA offspring displayed altered expression of 22 genes including 14 involved in cell-cell interaction, increased complexity of branching, and increased interactions with dendritic spines of cortical layer V pyramidal neurons. Microglial abnormalities were associated with neurophysiological alterations, measured by whole-cell patch clamp recordings, increased neuronal spine density, and ASD-like behaviors. MIA offspring treated with a colony stimulating factor -1 receptor inhibitor, to deplete and replenish microglia, showed correction of specific behaviors, microglial gene expression and branching, microglia-spine interactions, and spine density, and partial correction of neurophysiology. The data presented here shed new insight into the functional effects of microglia gene and microRNA expression in neurodevelopment. Furthermore, inflammation induces microglial aberrations that lead to altered neurodevelopment; this strongly supports the idea that targeting specific microglial genes and miRNAs will be a worthwhile approach to pursue for molecular intervention in ASD and related disorders.2018-11-02T00:00:00Z
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CHEW, WEN-QI, and WEN-QI CHEW. "Research on Anti-inflammatory and Anti-cancer Effects of Black Onions Derived From Different Fermentation Conditions." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/4h56u4.
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Yan, Jingya Jinni. "Metabolomics of cerebrospinal fluids to identity novel biomarkers as a predictive tool for brain inflammatory conditions." Thesis, 2020. http://hdl.handle.net/10453/149197.
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University of Technology Sydney. Faculty of Science.Inflammation of the brain is increasingly recognised as important in encephalitis. The high mortality and morbidity rates of acute neuroinflammatory diseases has directed significant interest in the investigation of biomarkers to define neuroinflammation and explore mechanisms involved in the regulation of central nervous system immune responses. Metabolomics is a rapidly emerging research field increasingly recognised as a powerful approach for addressing the gaps in knowledge underlying the pathophysiologic mechanisms involved in neuroinflammation and accurate diagnostic biomarkers. The advancements in analytical platforms followed by subsequent chemometrics tools have revolutionised untargeted metabolomics analyses. With liquid chromatography coupled to high resolution mass spectrometry moving to the forefront, an untargeted metabolomics analysis method was developed and optimised to identify multi-class metabolites in human cerebrospinal fluids. The detection of cerebrospinal fluid metabolites were determined based on a simple and rapid methanol precipitation sample preparation method. The chromatographic separation was achieved within a twenty minute gradient elution using hydrophilic interaction chromatography. The method exhibited good reproducibility, high efficiency chromatographic separation and strong mass resolving mass spectrometry analysis. The practicality and robustness of the developed method on a pilot study further demonstrated the potential of the untargeted metabolomics strategy to identify biomarkers and understand the biochemical pathways involved in neuroinflammation. With metabolites as the downstream products of cellular function, the application of metabolomics data is to understand the pathogenesis of neuroinflammatory mechanisms involved in encephalitis. Preliminary evidence showed statistically discriminative metabolites in the tryptophan-kynurenine pathway, nitric oxide pathway and elevation of neopterin. The use of the adjacent ratios such as kynurenine/tryptophan, anthranilic acid/3-hydroxyanthranilic acid and ADMA/arginine in combination with neopterin can serve as a potential cerebrospinal fluid biomarker panel to predict neuroinflammation, particularly when routine tests and neuroimaging return a negative result in encephalitis patients. The emergence of cerebrospinal metabolomics holds significant promise incorporating omics research into a clinical diagnostic service.
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Xin, Cuiyan. "Angiotensin II, extracellular nucleotides and sphingosine 1-phosphate : their effects on renal mesangial cells under inflammatory conditions /." 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014730839&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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