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The A2B adenosine receptor (A2BR) mediates biological responses to extracellular adenosine in a wide variety of cell types. Adenosine deaminase (ADA) can degrade adenosine and bind extracellularly to adenosine receptors. Adenosine modulates chloride secretion in gastric glands and gastric mucosa parietal cells. A close functional link between surface A2BR and ADA has been found on cells of the immune system, but whether this occurs in the gastrointestinal tract is unknown. The goal of this study was to determine whether A2BR and ADA are coexpressed at the plasma membrane of the acid-secreting gastric mucosa parietal cells. We used isolated gastric parietal cells after purification by centrifugal elutriation. The membrane fraction was obtained by sucrose gradient centrifugation. A2BR mRNA expression was analyzed by RT-PCR. The surface expression of A2BR and ADA proteins was evaluated by Western blotting, flow cytometry and confocal microscopy. Our findings demonstrate that A2BR and ADA are expressed in cell membranes isolated from gastric parietal cells. They show a high degree of colocalization that is particularly evident in the surface of contact between parietal cells. The confocal microscopy data together with flow cytometry analysis suggest a tight association between A2BR and ADA that might be specifically linked to glandular secretory function.

Context SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Adenosine modulates different functional activities in many cells of the gastrointestinal tract; some of them are believed to be mediated by interaction with its four G protein-coupled receptors. The renewed interest in the adenosine A2B receptor (A2BR) subtype can be traced by studies in which the introduction of new genetic and chemical tools has widened the pharmacological and structural knowledge of this receptor as well as its potential therapeutic use in cancer and inflammation- or hypoxia-related pathologies. In the acid-secreting parietal cells of the gastric mucosa, the use of various radioligands for adenosine receptors suggested the presence of the A2 adenosine receptor subtype(s) on the cell surface. Recently, we confirmed A2BR expression in native, nontransformed parietal cells at rest by using flow cytometry and confocal microscopy. In this study, we show that A2BR is functional in primary rabbit gastric parietal cells, as indicated by the fact that agonist binding to A2BR increased adenylate cyclase activity and acid production. In addition, both acid production and radioligand binding of adenosine analogs to isolated cell membranes were potently blocked by selective A2BR antagonists, whereas ligands for A1, A2A, and A3 adenosine receptors failed to abolish activation. We conclude that rabbit gastric parietal cells possess functional A2BR proteins that are coupled to Gs and stimulate HCl production upon activation. Whether adenosine- and A2BR-mediated functional responses play a role in human gastric pathophysiology is yet to be elucidated.

E-SAR-94010 (LipoEsar) is a natural product extracted from the marine species S. pilchardus, by means of non-denaturing biotechnological procedures. The main chemical ingredient of LipoEsar is a lipoprotein (60-80%) whose micelle structure probably mimics that of physiological lipoproteins involved in lipid metabolism. In preclinical studies LipoEsar has shown to be effective in (a) reducing blood cholesterol (Cho), triglyceride (TG), uric acid (UA), and glucose (Glu) levels, as well as liver alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity; (b) enhancing immunological function by regulating both lymphocyte and microglia activity; (c) inducing antioxidant effects mediated by superoxide dismutase activity; and (d) improving cognitive function.Clinical studies have revealed that LipoEsar reduces blood total cholesterol (T-Cho) (20-30%), Glu (5-10%), UA (10-15%), TG (30-50%), ALT and AST, after 1-3 months of treatment at a daily dose of 250-500 mg (t.i.d.). The effect on T-Cho is the result of decreasing LDL-Cho levels and increasing HDL-Cho levels in parallel with an improvement in hepatic protection reflected by reduction in ALT, AST, and GGT activity. Most of these therapeutic effects on the regulation of lipid metabolism tend to show an age-dependent pattern and are also associated with specific genomic profiles in the population. In addition, LipoEsar diminishes the size of xanthelasma plaques by 30-60% after 6-9 months of treatment. Similar effects can be observed on atheromatous plaques on the aortic wall of patients with familial and sporadic hypercholesterolemia.LipoEsar is the first marine biotechnological product with lipoprotein structure displaying hypolipemic activity in blood and tissues acting as a potential neuroprotectant in cerebrovascular disorders and arteriosclerosis.Preliminary studies indicate that the biological activity of LipoEsar is genotype-dependent. Since genetic defects in the APOE gene result in familial dysbetalipoproteinemia or type III hyperlipoproteinemia (HLP-III) with increased plasma Cho and TG as a consequence of impaired clearance of chylomicron and VLDL remnants, in the present paper we have investigated the influence of different APOE genotypes on the therapeutic response of LipoEsar in patients with chronic dyslipemia. The study has been performed in 419 patients (age: 55.24 ± 17.71 years; range: 9-96 years) of both sexes (females: N = 212; age: 57.04 ± 17.68 years; range: 15-96 years; males: N = 207; age: 53.38 ± 17.58