24,974 research outputs found

    Mechanistic insights into the regulation of inflammatory pathology by A20

    Get PDF

    Comedians without a Cause: The Politics and Aesthetics of Humour in Dutch Cabaret (1966-2020)

    Get PDF
    Comedians play an important role in society and public debate. While comedians have been considered important cultural critics for quite some time, comedy has acquired a new social and political significance in recent years, with humour taking centre stage in political and social debates around issues of identity, social justice, and freedom of speech. To understand the shifting meanings and political implications of humour within a Dutch context, this PhD thesis examines the political and aesthetic workings of humour in the highly popular Dutch cabaret genre, focusing on cabaret performances from the 1960s to the present. The central questions of the thesis are: how do comedians use humour to deliver social critique, and how does their humour resonate with political ideologies? These questions are answered by adopting a cultural studies approach to humour, which is used to analyse Dutch cabaret performances, and by studying related materials such as reviews and media interviews with comedians. This thesis shows that, from the 1960s onwards, Dutch comedians have been considered ‘progressive rebels’ – politically engaged, subversive, and carrying a left-wing political agenda – but that this image is in need of correction. While we tend to look for progressive political messages in the work of comedians who present themselves as being anti-establishment rebels – such as Youp van ‘t Hek, Hans Teeuwen, and Theo Maassen – this thesis demonstrates that their transgressive and provocative humour tends to protect social hierarchies and relationships of power. Moreover, it shows that, paradoxically, both the deliberately moderate and nuanced humour of Wim Kan and Claudia de Breij, and the seemingly past-oriented nostalgia of Alex Klaasen, are more radical and progressive than the transgressive humour of van ‘t Hek, Teeuwen and Maassen. Finally, comedians who present absurdist or deconstructionist forms of humour, such as the early student cabarets, Freek de Jonge, and Micha Wertheim, tend to disassociate themselves from an explicit political engagement. By challenging the dominant image of the Dutch comedian as a ‘progressive rebel,’ this thesis contributes to a better understanding of humour in the present cultural moment, in which humour is often either not taken seriously, or one-sidedly celebrated as being merely pleasurable, innocent, or progressively liberating. In so doing, this thesis concludes, the ‘dark’ and more conservative sides of humour tend to get obscured

    Role of NLRP3 in the pathogenesis and treatment of gout arthritis

    Get PDF
    Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA

    Regulation of Phagocytosis in Macrophages

    Get PDF
    When the first line of defence—the integumentary system fails, the immune system protects us from infections by pathogens. Macrophages are crucial for mediating effects in the innate immune system by eliminating impaired cells and harmful micro-organisms through phagocytosis. Although other cells undergo phagocytosis, the cellular processes that regulate phagocytosis may vary from cell to cell. These include metabolic changes, signal transduction, and changes in molecular expression or post-translational modifications. This chapter will comprehensively review biological processes that regulate phagocytosis in macrophages, including; changes in metabolic processes, signal transduction, molecular expression, and post-translational modifications

    Neuroprotective Properties of Peptides

    Get PDF
    The development of a treatment strategy for neurodegenerative disorders is a serious issue for the healthcare world and a crucial subject of discussion. In the past two decades, a lot of focus has been placed on identifying the pathophysiological processes involved in neuronal death linked to neurodegenerative disorders and developing a variety of treatment options for neuroprotection. Numerous research teams have studied the use of peptides as neuroprotective treatments for different types of neurodegenerative disorders for a long time. The review aims to provide details about the roles of erythropoietin (EPO), glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), and oxytocin (OXT) in neurodegenerative disorders as well as what cellular and molecular mechanisms they trigger to elicit the neuroprotective action, with a focus on neurodegenerative disorders

    Advances in the role of STAT3 in macrophage polarization

    Get PDF
    The physiological processes of cell growth, proliferation, differentiation, and apoptosis are closely related to STAT3, and it has been demonstrated that aberrant STAT3 expression has an impact on the onset and progression of a number of inflammatory immunological disorders, fibrotic diseases, and malignancies. In order to produce the necessary biological effects, macrophages (M0) can be polarized into pro-inflammatory (M1) and anti-inflammatory (M2) types in response to various microenvironmental stimuli. STAT3 signaling is involved in macrophage polarization, and the research of the effect of STAT3 on macrophage polarization has gained attention in recent years. In order to provide references for the treatment and investigation of disorders related to macrophage polarization, this review compiles the pertinent signaling pathways associated with STAT3 and macrophage polarization from many fundamental studies

    The immunosuppressive effects and mechanisms of loureirin B on collagen-induced arthritis in rats

    Get PDF
    IntroductionRheumatoid arthritis (RA) is a common disease mainly affecting joints of the hands and wrists. The discovery of autoantibodies in the serum of patients revealed that RA belonged to the autoimmune diseases and laid a theoretical basis for its immunosuppressive therapy. The pathogenesis of autoimmune diseases mainly involves abnormal activation and proliferation of effector memory T cells, which is closely related to the elevated expression of Kv1.3, a voltage-gated potassium (Kv) channel on the effector memory T cell membrane. Drugs blocking the Kv1.3 channel showed a strong protective effect in RA model animals, suggesting that Kv1.3 is a target for the discovery of specific RA immunosuppressive drugs.MethodsIn the present study, we synthesized LrB and studied the effects of LrB on collagen- induced arthritis (CIA) in rats. The clinical score, paw volume and joint morphology of CIA model rats were compared. The percentage of CD3+, CD4+ and CD8+ T cells in rat peripheral blood mononuclear and spleen were analyzed with flow cytometry. The concentrations of inflammatory cytokines interleukin (IL)-1b, IL-2, IL-4, IL-6, IL-10 and IL-17 in the serum of CIA rats were analyzed with enzyme-linked immunosorbent assay. The IL-1b and IL-6 expression in joints and the Kv1.3 expression in peripheral blood mononuclear cells (PBMCs) were quantified by qPCR. To further study the mechanisms of immunosuppressive effects of LrB, western blot and immunofluorescence were utilized to study the expression of Kv1.3 and Nuclear Factor of Activated T Cells 1 (NFAT1) in two cell models - Jurkat T cell line and extracted PBMCs.ResultsLrB effectively reduced the clinical score and relieved joint swelling. LrB could also decrease the percentage of CD4+ T cells, while increase the percentage of CD8+ T cells in peripheral blood mononuclear and spleen of rats with CIA. The concentrations of inflammatory cytokines interleukin (IL)-1b, IL-2, IL-6, IL-10 and IL-17 in the serum of CIA rats were significantly reduced by LrB. The results of qPCR showed that Kv1.3 mRNA in the PBMCs of CIA rats was significantly higher than that of the control and significantly decreased in the LrB treatment groups. In addition, we confirmed in cell models that LrB significantly decreased Kv1.3 protein on the cell membrane and inhibited the activation of Nuclear Factor of Activated T Cells 1 (NFAT1) with immune stimulus.ConclusionIn summary, this study revealed that LrB could block NFAT1 activation and reduce Kv1.3 expression in activated T cells, thus inhibiting the proliferation of lymphocytes and the release of inflammatory cytokines, thereby effectively weakening the autoimmune responses in CIA rats. The effects of immunosuppression due to LrB revealed its potential medicinal value in the treatment of RA

    Perturbation of Cellular Redox Status: Role of Nrf2, a Master Regulator of Cellular Redox

    Get PDF
    Regulation of cellular redox homeostasis determines the fate of the cell. Perturbation in redox status is known to elicit multiple cellular pathways. Role of oxidative stress modulation in channelizing the cell towards apoptosis or rescuing the cell by activating pro-survival pathways, depends on the levels of generated oxidative stress. High levels of generated oxidative stress induce cell death pathways whereas mild and low levels are known to elicit the cell survival pathways. Generation of ROS for a short duration of time inducing Redox ticking also triggers the pro-survival pathways inside the cell. Nrf2 is the redox sensitive prosurvival transcription factor which acts as master regulator of redox equilibrium. Nrf2 and its dependent genes including HO-1, GCLC, NQO1 etc. are involved in maintaining the cellular redox homeostasis. Role of Nrf2 as dual edges sword has been highlighted in past decade. The cross talk between the Nrf2 and NF-κB is at the focal point of building the redox response network. The present chapter is aimed at providing the insight on the role of Nrf2 and NF-κB as redox sensitive transcription factors in regulating cellular redox status. Further, the chapter brings in light the therapeutic potential of targeting Nrf2 under multiple clinical settings

    A comprehensive review of the current and future role of the microbiome in pancreatic ductal adenocarcinoma

    Get PDF
    Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC

    A correlation between tellurite resistance and nitric oxide detoxification in Salmonella Typhimurium

    Get PDF
    Salmonella are important enteric pathogens that are responsible for causing various diseases from gastroenteritis to systemic typhoid fever. Salmonella are a major contributor to morbidity and mortality worldwide. Crucial to their pathogenesis is the survival in harmful conditions elicited by the host immune system, one of these being reactive oxygen and nitrogen species (ROS/RNS). These are produced by macrophages and neutrophils in an attempt to eliminate pathogens. Salmonella, have the unique ability to colonise macrophages and have dedicated nitric oxide (NO) detoxification systems. There are three prominent metalloenzymes (HmpA, NorVW and NrfA) heavily researched in the literature for NO detoxification. Previous work suggested that more proteins are responsible for the nitrosative stress response with these being regulated by the nitric oxide sensitive transcriptional repressor, NsrR. This study demonstrates a relationship between three putative tellurite resistance proteins regulated by NsrR (STM1808, YeaR and TehB) and NO detoxification. A Functional redundancy between these proteins was observed for anaerobic protection against NO and tellurite. Furthermore, this study identified that proteins responsible in NO protection such as HmpA and YtfE also provide resistance to tellurite during aerobic and anaerobic conditions, respectively. Tellurite resistant Salmonella strains were evolved by continued passage in this study that consequently had altered H2O2 resistance profiles and increased sensitivity to antibiotics. However, these strains were not significantly attenuated during macrophage survival or during the presence of NO in vitro. Additionally, the hypothetical protein YgbA, which has predicted roles in NO detoxification, was found to be important to Salmonella survival in macrophages. However, in vitro NO exposure with the NO donor deta NONOate only showed a role for anaerobic protection
    corecore