418 research outputs found

    Posttranslational Truncation of E-Cadherin and Significance for Tumour Progression

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    Stable intraepithelial adhesion complexes are essential for the maintenance of epithelial integrity. Alterations in these complexes are key events in the development and progression of many diseases. One of the major proteins involved in maintaining epithelial cell-cell adhesion is the cell-adhesion junction protein E-cadherin, a member of the cadherin family of transmembrane adhesion proteins. E-cadherin is involved in many cellular processes including morphogenesis, adhesion, recognition, communication and oncogenesis. Inactivation of its adhesive properties is often a key step in tumour progression and metastasis, leading to its recent description as a tumour suppressor gene. Mutations of the Ecadherin gene CDH1 in gastric and mammary cancers have been well documented and reports of transcriptional repression during tumour progression are increasing. This review examines the role of posttranslational truncation of Ecadherin in cancer cells focusing on implications for tumour progression. The various proteins involved in the directed cleavage of E-cadherin and consequences of these truncations are discussed

    Eosinophils, probiotics, and the microbiome

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    There is currently substantial interest in the therapeutic properties of probiotic microorganisms as recent research suggests that oral administration of specific bacterial strains may reduce inflammation and alter the nature of endogenous microflora in the gastrointestinal tract. Eosinophils are multifunctional tissue leukocytes, prominent among the resident cells of the gastrointestinal mucosa that promote local immunity. Recent studies with genetically altered mice indicate that eosinophils not only participate in maintaining gut homeostasis, but that the absence of eosinophils may have significant impact on the nature of the endogenous gut microflora and responses to gut pathogens, notably Clostridium difficile. Furthermore, in human subjects, there is an intriguing relationship between eosinophils, allergic inflammation, and the nature of the lung microflora, notably a distinct association between eosinophil infiltration and detection of bacteria of the phylum Actinobacteria. Among topics for future research, it will be important to determine whether homeostatic mechanisms involve direct interactions between eosinophils and bacteria or whether they involve primarily eosinophil-mediated responses to cytokine signaling in the local microenvironment. Likewise, although is it clear that eosinophils can and do interact with bacteria in vivo, their ability to discern between pathogenic and probiotic species in various settings remains to be explored

    Mucosal associated invariant T cells are altered in patients with Hidradenitis Suppurativa and contribute to the inflammatory milieu

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    Mucosal Associated Invariant T cells are a population of “innate” T cells, which express the invariant T cell receptor (TCR) a chain Va7.2-Ja33 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-g and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin. On-going research has highlighted their involvement in numerous inflammatory diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is currently unknown. In this study we show for the first time, that MAIT cells are altered in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17 cytokine bias. We show that CCL20 expression is elevated in lesions of patients with H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT cells can accumulate in the lesionsfrom patients with H.S. when compared to adjacent skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation of dermal fibroblasts, promoting the expression of chemotactic signals including CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively our data detailsIL-17 producing MAIT cells as a novel player in the pathogenesis of H.S and highlights the potential of RORyt inhibition as a novel therapeutic strategy

    Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

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    MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation

    5-Bromo-2-deoxyuridine activates DNA damage signalling responses and induces a senescence-like phenotype in p16-null lung cancer cells

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    5-Bromo-2-deoxyuridine (BrdU) is a thymidine analogue that is incorporated into replicating DNA. Although originally designed as a chemotherapeutic agent, sublethal concentrations of BrdU have long been known to alter the growth and phenotype of a wide range of cell types. Mechanisms underlying these BrdU-mediated effects remain unknown, however. We have characterized the effects of BrdU on A549 lung cancer cells by examining DNA damage responses, cell cycle effects and phenotypic changes. A549 cells express wild-type p53, but are p16- null. Sublethal concentrations of BrdU evoke a DNA damage response in these cells that involves the activation of Chk1, Chk2 and p53. Increased numbers of enlarged nuclei and multinucleated cells are evident in the treated populations. Cell cycle inhibition occurs, resulting in reduced proliferation and accumulation of cells in the S, G2/M and G0 phases. BrdU induces an early inhibition of p21 expression that coincides with nuclear localization of proliferating cell nuclear antigen. Subsequently, p21 levels increase, whereas proliferating cell nuclear antigen levels decrease compared with control cells. Upregulation of p27 and p57 expression also occurs. By day 7 of exposure to BrdU, treated cells acquire a senescent-like phenotype with an increase in cell size, granularity and bgalactosidase activity. We conclude that BrdU induces a DNA damage response in A549 cells, which results in reduced proliferation mitotic exit and phenotypic changes that resemble senescence

    Posttranslational Truncation of E-Cadherin and Significance for Tumour Progression

    No full text
    Stable intraepithelial adhesion complexes are essential for the maintenance of epithelial integrity. Alterations in these complexes are key events in the development and progression of many diseases. One of the major proteins involved in maintaining epithelial cell-cell adhesion is the cell-adhesion junction protein E-cadherin, a member of the cadherin family of transmembrane adhesion proteins. E-cadherin is involved in many cellular processes including morphogenesis, adhesion, recognition, communication and oncogenesis. Inactivation of its adhesive properties is often a key step in tumour progression and metastasis, leading to its recent description as a tumour suppressor gene. Mutations of the Ecadherin gene CDH1 in gastric and mammary cancers have been well documented and reports of transcriptional repression during tumour progression are increasing. This review examines the role of posttranslational truncation of Ecadherin in cancer cells focusing on implications for tumour progression. The various proteins involved in the directed cleavage of E-cadherin and consequences of these truncations are discussed

    5-Bromo-2-deoxyuridine activates DNA damage signalling responses and induces a senescence-like phenotype in p16-null lung cancer cells

    Get PDF
    5-Bromo-2-deoxyuridine (BrdU) is a thymidine analogue that is incorporated into replicating DNA. Although originally designed as a chemotherapeutic agent, sublethal concentrations of BrdU have long been known to alter the growth and phenotype of a wide range of cell types. Mechanisms underlying these BrdU-mediated effects remain unknown, however. We have characterized the effects of BrdU on A549 lung cancer cells by examining DNA damage responses, cell cycle effects and phenotypic changes. A549 cells express wild-type p53, but are p16- null. Sublethal concentrations of BrdU evoke a DNA damage response in these cells that involves the activation of Chk1, Chk2 and p53. Increased numbers of enlarged nuclei and multinucleated cells are evident in the treated populations. Cell cycle inhibition occurs, resulting in reduced proliferation and accumulation of cells in the S, G2/M and G0 phases. BrdU induces an early inhibition of p21 expression that coincides with nuclear localization of proliferating cell nuclear antigen. Subsequently, p21 levels increase, whereas proliferating cell nuclear antigen levels decrease compared with control cells. Upregulation of p27 and p57 expression also occurs. By day 7 of exposure to BrdU, treated cells acquire a senescent-like phenotype with an increase in cell size, granularity and bgalactosidase activity. We conclude that BrdU induces a DNA damage response in A549 cells, which results in reduced proliferation mitotic exit and phenotypic changes that resemble senescence

    Eosinophilic Esophagitis - Pathophysiology and its Clinical Implications

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    Eosinophilic Esophagitis is an antigen mediated chronic disease that is distinct from gastroesophageal reflux disease. EoE an emerging clinical problem that is rapidly growing in incidence and in recognition. It is characterized clinically by feeding dysfunction, dysphagia and reflux-like symptoms. Histologically EoE is identifiable by a dense epithelial eosinophilic infiltrate. Experimental modeling and clinical studies over the last decade have greatly improved our understanding of this disease and led to improvements in clinical understanding and the assessment of therapeutic options for patients and their clinicians who manage this disease. In this review we review the cliniopathologic diagnostic criteria and our understanding of EoE as an allergic disease with genetic and immunological components in the pathophysiology. We make note of the berth of studies defining the importance of the epithelial barrier and discuss the concept of barrier function as an initiating or perpetuating factor for this disease. The relationship between the symptoms of dysphagia, feeding dysfunction and our current knowledge of the underlying pathophysiologic mechanisms of these clinical indicators, as well as advances in clinical assessment of decreased esophageal distensibility and narrowing in EoE patients. Lastly, therapeutic implications relating to the advances that have led to our current understanding of the pathophysiology of EoE are explored

    Epithelial Claudin Proteins and Their Role in Gastrointestinal Diseases

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    Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body as well as controlling the absorption of nutrients, fluid and solutes (1, 2). A series of protein complexes including the adherens junction, desmosomes, and tight junctions (TJ) function as the principal barrier in paracellular diffusion (3) as well as regulators of intracellular solute, protein and lipid transport (4). TJs are composed of a series of proteins called occludins, junctional adhesion molecules (JAM), and claudins (5, 6) that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases
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