Targeting Host Sulphonyl Urea Receptor 2 Can Reduce Severity of Associated Gastritis.

Background And Aims: While most -infected individuals remain asymptomatic throughout their lifetime, in a significant proportion, the resulting severe chronic gastritis drives the development of gastric cancer. In this study, we examine a new therapeutic target, a host potassium channel regulatory subunit, SUR2 (encoded by ), with potential to protect against -associated diseases.

Methods: SUR2 gene (ABCC9) expression in human gastric biopsies was analyzed by quantitative polymerase chain reactions.

Choroid plexus-derived extracellular vesicles exhibit brain targeting characteristics.

The brain is protected against invading organisms and other unwanted substances by tightly regulated barriers. However, these central nervous system (CNS) barriers impede the delivery of drugs into the brain via the blood circulation and are therefore considered major hurdles in the treatment of neurological disorders. Consequently, there is a high need for efficient delivery systems that are able to cross these strict barriers.

IL-33 promotes gastric tumour growth in concert with activation and recruitment of inflammatory myeloid cells.

Interleukin-33 (IL-33) is an IL-1 family cytokine known to promote T-helper (Th) type 2 immune responses that are often deregulated in gastric cancer (GC). IL-33 is overexpressed in human gastric tumours suggesting a role in driving GC progression although a causal link has not been proven. Here, we investigated the impact of IL-33 genetic deficiency in the well-characterized mouse model of GC.

Postnatal inflammation in ApoE-/- mice is associated with immune training and atherosclerosis.

Background And Aims: Preterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis which complicate pregnancies delivering preterm, or recurrent early-life infections, which are common in preterm infants. We previously reported that experimental chorioamnionitis followed by postnatal inflammation has additive and deleterious effects on atherosclerosis in ApoE-/- mice.

Coordinate expression loss of and in gastric cancer via impairment of a glucocorticoid-responsive enhancer.

Gastrokines (GKNs) are anti-inflammatory proteins secreted by gastric epithelial (surface mucous and pit) cells, with their aberrant loss of expression causally linked to premalignant inflammation and gastric cancer (GC). Transcriptional mechanisms accounting for GKN expression loss have not been elucidated. Using human clinical cohorts, mouse transgenics, bioinformatics, and transfection/reporter assays, we report a novel mechanism of GKN gene transcriptional regulation and its impairment in GC.

Postnatal inflammation following intrauterine inflammation exacerbates the development of atherosclerosis in ApoE mice.

Atherosclerosis is a chronic inflammatory disease that has its origins in early life. Postnatal inflammation exacerbates atherosclerosis, but the possible effect of intrauterine inflammation is largely unexplored. Exposure to inflammation is common, especially in infants born preterm, who have increased cardiovascular risk in adulthood.

Overexpression of IL-11 promotes premalignant gastric epithelial hyperplasia in isolation from germline gp130-JAK-STAT driver mutations.

Expression of the cytokine IL-11 is elevated in human Helicobacter pylori infection and progressively increases with worsening gastric pathology. Additionally, IL-11 is required for tumor development in STAT3-dependent murine models of gastric cancer (GC) and, when administered acutely, causes resolving atrophic gastritis. However, it is unclear whether locally elevated IL-11 ligand expression can, in isolation from oncogenic gp130-JAK-STAT pathway mutations, initiate GC pathogenesis.

Altered gp130 signalling ameliorates experimental colitis via myeloid cell-specific STAT3 activation and myeloid-derived suppressor cells.

STAT3 regulates the expansion of myeloid-derived suppressor cells (MDSCs) during inflammation, infection and cancer. Hyperactivation of STAT3 in gp130(757F/F) mice is associated with protection from experimental colitis. This study determined mechanisms for this protection and compared this to mice with myeloid-specific STAT3-deficiency (LysMcre/STAT3(flox); gp130(757F/F) LysMcre/STAT3(flox)).

Enteric Neural Cells From Hirschsprung Disease Patients Form Ganglia in Autologous Aneuronal Colon.

Background & Aims: Hirschsprung disease (HSCR) is caused by failure of cells derived from the neural crest (NC) to colonize the distal bowel in early embryogenesis, resulting in absence of the enteric nervous system (ENS) and failure of intestinal transit postnatally. Treatment is by distal bowel resection, but neural cell replacement may be an alternative. We tested whether aneuronal (aganglionic) colon tissue from patients may be colonized by autologous ENS-derived cells.

STAT3: a critical component in the response to Helicobacter pylori infection.

STAT3 imparts a profound influence on both the epithelial and immune components of the gastric mucosa, and through regulation of key intracellular signal transduction events, is well placed to control inflammatory and oncogenic outcomes in the context of Helicobacter (H.) pylori infection. Here we review the roles of STAT3 in the host immune response to H.

Perinatal inflammation: a common factor in the early origins of cardiovascular disease?

Cardiovascular disease continues to be the leading cause of global morbidity and mortality. Traditional risk factors account for only part of the attributable risk. The origins of atherosclerosis are in early life, a potential albeit largely unrecognized window of opportunity for early detection and treatment of subclinical cardiovascular disease.

The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome.

Objectives: The mucin MUC1, best known for providing an epithelial barrier, is an important protective host factor in both humans and mice during Helicobacter pylori pathogenesis. This study aimed to identify the long-term consequences of MUC1 deficiency on H. pylori pathogenesis and the mechanism by which MUC1 protects against H.

Why are enteric ganglia so small? Role of differential adhesion of enteric neurons and enteric neural crest cells.

The avian enteric nervous system (ENS) consists of a vast number of unusually small ganglia compared to other peripheral ganglia. Each ENS ganglion at mid-gestation has a core of neurons and a shell of mesenchymal precursor/glia-like enteric neural crest (ENC) cells. To study ENS cell ganglionation we isolated midgut ENS cells by HNK-1 fluorescence-activated cell sorting (FACS) from E5 and E8 quail embryos, and from E9 chick embryos.

IL33 Is a Stomach Alarmin That Initiates a Skewed Th2 Response to Injury and Infection.

Background & Aims: Interleukin (IL)33 is a recently described alarmin that is highly expressed in the gastric mucosa and potently activates Th2 immunity. It may play a pivotal role during infection. Here, we delineate the role of IL33 in the normal gastric mucosa and in response to gastropathy.

IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment.

IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1β, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis.

TFF2 deficiency exacerbates weight loss and alters immune cell and cytokine profiles in DSS colitis, and this cannot be rescued by wild-type bone marrow.

The trefoil factor TFF2 is a member of a tripartite family of small proteins that is produced by the stomach and the colon. Recombinant TFF2, when applied intrarectally in a rodent model of hapten colitis, hastens mucosal healing and reduces inflammatory indexes. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel.

Linking immunity, epigenetics, and cancer in inflammatory bowel disease.

Most of what is known about the pathogenesis of inflammatory bowel disease (IBD) pertains to complex interplay between host genetics, immunity, and environmental factors. Epigenetic modifications play pivotal roles in intestinal immunity and mucosal homeostasis as well as mediating gene-environment interactions. In this article, we provide a historical account of epigenetic research either directly related or pertinent to the pathogenesis and management of IBD.

Gastrokines: stomach-specific proteins with putative homeostatic and tumor suppressor roles.

During the past decade, a new family of stomach-specific proteins has been recognized. Known as "gastrokines" (GKNs), these secreted proteins are products of gastric mucus-producing cell lineages. GKNs are highly conserved in physical structure, and emerging data point to convergent functions in the modulation of gastric mucosal homeostasis and inflammation.

Targeting STAT3 in gastric cancer.

Introduction: STAT3 is a key transcription factor for many regulatory factors that modulate gene transcription. Particularly important are cytokines and growth factors that maintain homeostasis by regulating immunocytes, stromal and epithelial cells. Dysregulation of STAT3 by constitutive activation plays an important role in the initiation of inflammation and cellular transformation in numerous cancers, especially of epithelial origin.

Helicobacter pylori CagA triggers expression of the bactericidal lectin REG3γ via gastric STAT3 activation.

Background: Most of what is known about the Helicobacter pylori (H. pylori) cytotoxin, CagA, pertains to a much-vaunted role as a determinant of gastric inflammation and cancer. Little attention has been devoted to potential roles of CagA in the majority of H.

IL-11 is a parietal cell cytokine that induces atrophic gastritis.

Background And Aims: IL-is important in gastric damage, mucosal repair and gastric cancer progression. We analysed IL-11 expression in H.pylori infected mouse stomach, the site of gastric IL-11 expression in mice and humans, and the effect of exogenous IL-11 on gastric mucosal homeostasis.

A novel TFF2 splice variant (∆EX2TFF2) correlates with longer overall survival time in cholangiocarcinoma.

Trefoil factor 2 (TFF2) is a member of trefoil factor family found to be overexpressed in many cancers including cholangiocarcinoma (CCA). The majority of studies have focused on wild-type TFF2 (wtTFF2) expression, but information regarding alternative splicing variants of TFF2 mRNA has not been reported. In this study, we aimed to identify and quantify a novel TFF2 splice variant in cholangiocarcinoma (CCA).

Trefoil factors: tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma.

Aim: To investigate trefoil factor (TFF) gene copy number, mRNA and protein expression as potential biomarkers in cholangiocarcinoma (CCA).

Methods: TFF mRNA levels, gene copy number and protein expression were determined respectively by quantitative reverse transcription polymerase chain reaction (PCR), quantitative PCR and immunohistochemistry in bile duct epithelium biopsies collected from individuals with CCA, precancerous bile duct dysplasia and from disease-free controls. The functional impact of recombinant human (rh)TFF2 peptide treatment on proliferation and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling was assessed in the CCA cell line, KMBC, by viable cell counting and immunoblotting, respectively.