Search

Adenosine deaminase acting on RNA (ADAR) 1 binds and edits double-stranded (ds) RNA secondary structures found mainly within untranslated regions of many transcripts. In the current research, our aim was to study the role of ADAR1 in liver homeostasis. As previous studies show a conserved immunoregulatory function for ADAR1 in mammalians, we focused on its role in preventing chronic hepatic inflammation and the associated activation of hepatic stellate cells to produce extracellular matrix and promote fibrosis. We show that hepatocytes specific ADAR1 knock out (KO) mice display massive liver damage with multifocal inflammation and fibrogenesis. The bioinformatics analysis of the microarray gene-expression datasets of ADAR1 KO livers reveled a type-I interferons signature and an enrichment for immune response genes compared to control littermate livers. Furthermore, we found that in vitro silencing of ADAR1 expression in HepG2 cells leads to enhanced transcription of NFκB target genes, foremost of the pro-inflammatory cytokines IL6 and IL8. We also discovered immune cell-independent paracrine signaling among ADAR1-depleted HepG2 cells and hepatic stellate cells, leading to the activation of the latter cell type to adopt a profibrogenic phenotype. This paracrine communication dependent mainly on the production and secretion of the cytokine IL6 induced by ADAR1 silencing in hepatocytes. Thus, our findings shed a new light on the vital regulatory role of ADAR1 in hepatic immune homeostasis, chiefly its inhibitory function on the crosstalk between the NFκB and type-I interferons signaling cascades, restraining the development of liver inflammation and fibrosis.

Variation in the prevalence of various types of gastric polyps worldwide may reflect different etiologies. Here, the authors report the dynamic changes in histological distribution of gastric polyps over time and by ethnicity for individuals who underwent gastroscopies between 1994 and 2009 at two hospitals in Jerusalem, Israel. During this time period, the proportion of patients receiving proton pump inhibitors (PPIs) increased while the proportion of patients infected with Helicobacter pylori (H. pylori) decreased.Pathological reports of biopsies from 50,071 consecutive gastroscopies were reviewed.Gastric polyps were detected in 727 individuals. The yearly prevalence of gastric polyps was ≤ 1% between 1994 and 2001 and ≥ 2% from 2004 to 2009, of which overall 66% were hyperplastic polyps and 23% fundic gland polyps (FGPs). FGPs were diagnosed exclusively in the Jewish population. From 2001 to 2004, an increase in the absolute number of newly discovered hyperplastic and FGPs per year was observed. However from 2005, a divergent trend of changes was observed: While the proportion of patients with hyperplastic polyps dropped from 0.72 during the 2001-2004 period to 0.62 during the 2005-2009 period (p = 0.02), the proportion of patients with FGPs at these time periods increased from 0.16 to 0.33 (p = 0.0001).The yearly prevalence of gastric polyps in Jerusalem has recently doubled. This occurred mainly due to the increasing prevalence of FGPs. The changing epidemiology of gastric polyps is probably related to the interaction between genetic factors and fluctuating environmental factors like H. pylori infection rates and exposure to PPIs.

Mast cells have been implicated in chronic inflammatory conditions resulting in fibrosis, such as Crohn disease. However, a link between inflammation, fibrosis and mast cells has not been demonstrated in human or animal intestinal diseases. This work was undertaken to analyze whether mast cells play a role in inflammation and fibrosis in the TNBS-induced rat colitis.Rats were rectally instilled 2,4,6,-trinitrobenzene sulfonic acid in ethanol, and immediately or 4 days later injected daily i.p. with nedocromil sodium, a mast cell stabilizer, compound 48/80, a mast cell activator, or saline. Rats were sacrificed 5 days post-TNBS, or on day 21. Intestinal inflammation and fibrosis were assessed by gross and histopathological evaluation. Colonic mast cell numbers (toluidine blue) and collagen (type I mRNA expression) were evaluated. Mast cell sonicate was added to rat colon fibroblasts. Fibroblast proliferation (3H-thymidine), collagen synthesis (3H-proline) and contractile activity (tridimensional collagen lattice contraction) were then assessed.Nedocromil reduced inflammation and fibrosis possibly by decreasing mast cell numbers and activation and consequent collagen production. Compound 48/80 slightly enhanced the severity of the disease by activating mast cells. Mast cells increased fibroblast proliferation, collagen production and contractile activity.Mast cells are involved in the gastrointestinal tract inflammation and fibrosis of the TNBS-colitis rats.

Doxorubicin (DOX) has been encapsulated with high efficiency in the water phase of small-sized lipid vesicles. Plasma-induced drug leakage from these vesicles is minimal when hydrogenated phosphatidylcholine is present as the main component. A prolonged circulation time of liposome-encapsulated DOX is observed in animal models when a small fraction of polyethyleneglycol-derivatized phospholipid (PEG) is present in the liposome bilayer. Using these PEG-coated liposomes, we found that the concentration of DOX in tumor implants of the mouse M-109 carcinoma is significantly enhanced by liposome delivery. The antitumor activity of liposome-encapsulated DOX in a lung metastases model of the M-109 carcinoma is superior to that of free DOX. The minimal lethal dose of DOX to tumor-free mice was substantially increased by encapsulation in PEG-coated liposomes, indicating that toxicity is reduced. We also found that the vesicant of DOX after intradermal injection is prevented by liposome encapsulation. These...

We describe a 69-year-old woman with basal cell carcinoma, and chronic lymphocytic leukemia who developed Merkel cell tumor. This latter malignancy first appeared as enlarged lymph nodes in the axilla and elbow regions and responded initially to radiotherapy. Later, the patient developed obstructive jaundice which was due to pancreatic metastases of the Merkel cell tumor, documented by post-mortem examination. To our knowledge, this is the first description of a Merkel cell tumor causing obstructive jaundice, in a patient with chronic lymphocytic leukemia.