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The development of an oesophageal adenocarcinoma arising in Barrett's mucosa is associated with a multistep process of genetic lesions that may be triggered by persistent oxidative damage. The glutathione peroxidase isoforms pGPx and GI-GPx, which were identified recently in the mucosa of the esophagus, may play a role as defense factors to prevent such oxidative injury. To determine alterations of the expression of pGPx and GI-GPx in Barrett's mucosa as compared to primary and regenerative squamous epithelium. Biopsy samples of oesophageal mucosa of patients with Barrett's esophagus (n = 12), patients with squamous restoration after thermal ablation (n = 10), and healthy controls (n = 5) were analyzed for pGPx and GI-GPx mRNA expression by Northern blot and for glutathione peroxidase activity by enzymatic assay. Squamous regeneration was induced by argon plasma coagulation (APC) combined with proton pump inhibitor therapy. In Barrett's epithelium mRNA levels of pGPx (the secreted isoform) were significantly reduced and of GI-GPx (the intracellular isoform) significantly increased as compared to normal squamous mucosa. In squamous mucosa that had regenerated after APC, no significant differences compared to the expression pattern of primary squamous mucosa were found. Compared to squamous mucosa, Barrett's metaplasia shows a different mRNA expression of pGPx and GI-GPx that may be associated with increased susceptibility to oxidative damage.

Tolerance of interferon-α therapy for hepatitis C is often poor and medication is expensive. Compliance with diagnostic procedures and, even more important, with medical treatment is obviously critical to minimize the rate of dropouts and to maximize cost efficiency. Moreover, a good concordance with scheduled follow-ups is important for early recognition and treatment of interferon-associated side effects. Therefore, we investigated psychiatric symptoms, interpersonal problems, different modes of acquisition, and sociodemographic factors in HCV-infected patients as possible predictor variables of good versus poor compliance. In a longitudinal study, 74 patients with chronic hepatitis C (CHC) who fulfilled the criteria for treatment with interferon (IFN)-α-2b with or without ribavirin were investigated prospectively to identify those at risk for poor compliance during IFN medication. To assess predictive factors, we used both IIP-C (Inventory of Interpersonal Problems) and SCL-90-R (Symptom Check List 90 Items Revised) as psychometric instruments. Sociodemographic and somatic variables as well as compliance during IFN therapy were also evaluated. Poor compliance before or during medication was demonstrated by 23% (N = 17) of HCV patients. Sociodemographic factors and mode of acquisition, particularly former intravenous drug (IVD) abuse were not significantly linked with compliance. Logistic regression analysis demonstrated that the subgroup of patients with compliance problems was best identified by both pretherapeutic psychiatric symptoms and interpersonal problems. Predictive value was best and significant for anger-hostility (P = 0.009), intrusive (P = 0.014), depression (P = 0.015), and phobic anxiety (P = 0.049). Adopting this statistical prediction model, sensitivity was 47.1%, but specificity reached 98.3%. In total, 86.5% of cases were classified correctly. In situations of unclear indication for IFN therapy, psychological variables assessment of before the beginning of treatment may represent an additional decision-making factor.

There is experimental and epidemiological evidence for an association between low selenium levels and gastrointestinal cancer incidence, prevalence, and mortality. To identify targets for selenium supplementation in the human digestive tract, we examined mRNA expression of various selenocysteine-containing proteins in normal mucosa biopsy specimens. Tissue samples from the esophagus and from different sites of the stomach, small bowel, and colon were obtained during endoscopies of the upper and lower gastrointestinal tract. Northern blot analyses revealed a lack of cytosolic glutathione peroxidase mRNA but a differential mRNA expression pattern of gastrointestinal and plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase. Glutathione peroxidase and thioredoxin reductase activities were detected in the mucosa of all biopsies, but the differential pattern did not reflect the differential mRNA steady-state levels. In addition to gastrointestinal glutathione peroxidase, which was found to play a role in colon cancer resistance, we identified further gastrointestinal selenoproteins, which may be involved in gastrointestinal cell defense and cell differentiation.

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor regulating genes involved in adipogenesis, glucose homeostasis and cell differentiation. Moreover, PPARgamma has been demonstrated to control proliferation and apoptosis in various cancer cells. We investigated the biological effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's adenocarcinoma cells in vitro and in vivo.PPARgamma mRNA and protein were overexpressed in endoscopic biopsies of Barrett's epithelium and the human Barrett's adenocarcinoma cancer cell line OE33 as compared to normal esophagus and stomach and the esophageal squamous epithelium cancer cell line Kyse-180. PPARgamma activation by pioglitazone in OE33 cells in vitro led to reduced cell growth by induction of apoptosis. Effects of systemic PPARgamma activation by the thiazolidinedione pioglitazone on tumor cell proliferation and apoptosis were then assessed in vivo in nude mice bearing transplantable Barrett's adenocarcinomas derived from OE33 cells. Unexpectedly, enhanced growth of OE33 derived transplantable adenocarcinomas was observed in Balb/c nu/nu mice upon systemic pioglitazone treatment due to increased cell proliferation.These results indicate that PPARgamma is involved in the molecular pathogenesis of Barrett's adenocarcinoma formation and growth. However, activation of PPARgamma exerts differential effects on growth of Barrett's adenocarcinoma cells in vitro and in vivo emphasizing the importance of additional cell context specific factors and systemic metabolic status for the modulation of PPARgamma action in vivo.

Basis Selenium is an essential trace element, which is incorporated as selenocysteine (secys) into specific proteins in a regulated fashion. In the presence of a hairpin loop structure within the 3' untranslated region of the mRNA the opal stop codon UGA is coding for selenocysteine. Selenoprotein functions are dependent on secys incorporation. Members of the family of deiodinases as well as the family of glutathione peroxidases, selenoprotein P and thioredoxin reductase are selenoproteins. Discussion Bone, the intestine and the thyroid rely on antioxidant systems against potential cell and DNA damage through endogenous and environmental peroxides and reactive oxygen species (ROS) potentially promoting inflammation and tumorigenesis. Optimized cell defense through antioxidant selenoproteins requires optimal selenium supplementation of the organism. We have analyzed the expression of selenoproteins in these tissues, thus providing molecular tools to further elucidate optimal selenium supply on a cellular level. Conclusion Clinical intervention studies that focus on the development of disease must confirm the relevance of optimized selenium supply for the pathogenesis, prevention and therapy of metabolic bone disease as well as chronic (autoimmune) inflammation and tumorigenesis in the thyroid and intestine.

Four selenocysteine-containing proteins (gastrointestinal glutathione peroxidase, plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase-alpha) are expressed in the colonic mucosa. Because of their antioxidant functions, a protective role in colon carcinogenesis is discussed. The aim of this study was to elucidate an involvement of gastrointestinal selenoproteins during the adenoma-carcinoma sequence. Matched pairs of biopsies of colorectal adenomas and adjacent normal mucosa from 11 patients were analyzed for mRNA expression, protein expression, or enzyme activity of selenoproteins by Northern blot, Western blot, or enzymatic tests. All adenomas revealed a marked reduction of selenoprotein P and a variable increase of gastrointestinal glutathione peroxidase mRNA compared with adjacent tissue. Thioredoxin reductase-alpha and plasma glutathione peroxidase mRNA expression were not altered in adenomas. The Northern blot results were confirmed by Western blot analysis or enzyme activity measurement, respectively. We conclude that gastrointestinal glutathione peroxidase and selenoprotein P play a complementary role in the antioxidative cell defense along the adenoma-carcinoma sequence. It remains to be shown whether upregulation of gastrointestinal glutathione peroxidase in adenomas represents a compensatory mechanism to reduce susceptibility for oxidative damage resulting from the loss of selenoprotein P.

The trace element selenium is discussed as a chemopreventive agent in colorectal carcinogenesis. Selenocysteine-containing proteins, so-called selenoproteins, represent potential molecular targets for nutritive selenium supplementation. Due to their antioxidative potential, the selenoproteins gastrointestinal glutathione peroxidase (GI-GPx) and selenoprotein P (SePP) are considered to provide protection against reactive oxygen species (ROS), thereby reducing DNA damage and preventing development of colon cancer. GI-GPx and SePP are abundantly expressed in normal colon mucosa. Recently, we demonstrated both reduced SePP expression and increased GI-GPx expression in colorectal adenomas. In this study, we investigated the expression of SePP and GI-GPx in colorectal cancers compared with corresponding normal mucosa. Further, the occurrence of genetic alterations within the SePP and GI-GPx genes was analyzed. We observed a significant reduction or loss of SePP mRNA expression in colon cancers, whereas GI-GPx mRNA and protein expression varied between different tumor samples. In addition, we identified novel polymorphisms within the SePP and GI-GPx genes with so far unknown relevance for protein function. Our results argue against a general decrease of selenoprotein expression in colorectal carcinogenesis but imply specific differential regulation of expression of individual selenoproteins.

Selenoproteins such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR), and selenoprotein P (SePP) contain molecular selenium in form of selenocysteines within their active center. They are involved in the defense of reactive oxygen species, which otherwise may cause DNA damage and alterations of protein function. Selenium intake has been linked to colon carcinogenesis in epidemiological and interventional studies. In a double-blinded, placebo-controlled trial, we demonstrate that carriers of colon adenomas present with low basal serum levels of selenium and plasma glutathione peroxidase (pGPx) activity before treatment, but both parameters can be normalized by interventional selenium supplementation. GPx activity in colon mucosa was enhanced in the verum group, albeit this had only borderline significance. No change of activity was observed for mucosal TrxR activity on selenium supplementation. In summary, our results confirm the existence of low selenium levels in patients prone to colon adenomas and show that by selenium supplementation this can be normalized. If prospective trials confirm that selenium supplementation reduces colon cancer incidence rates, it may be concluded that selenium supplementation should be recommended for patients at risk.