418 research outputs found
Posttranslational Truncation of E-Cadherin and Significance for Tumour Progression
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
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
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
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
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
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
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
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
201 Claudin-7 Dysregulation in Pediatric Eosinophilic Esophagitis: A Role for TGF-β in Esophageal Epithelial Barrier Dysfunction
Epithelial Claudin Proteins and Their Role in Gastrointestinal Diseases
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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