Concurrent Proinflammatory and Apoptotic Activity of a Helicobacter pylori Protein (HP986) Points to Its Role in Chronic Persistence

Helicobacter pylori induces cytokine mediated changes in gastroduodenal pathophysiology, wherein, the activated macrophages at the sub-mucosal space play a central role in mounting innate immune response against the antigens. The bacterium gains niche through persistent inflammation and local immune-suppression causing peptic ulcer disease or chronic gastritis; the latter being a significant risk factor for the development of gastric adenocarcinoma. What favors persistence of H. pylori in the gastric niches is not clearly understood. We report detailed characterization of a functionally unknown gene (HP986), which was detected in patient isolates associated with peptic ulcer and gastric carcinoma. Expression and purification of recombinant HP986 (rHP986) revealed a novel, ∼29 kDa protein in biologically active form which associates with significant levels of humoral immune responses in diseased individuals (p<0.001). Also, it induced significant levels of TNF-α and Interleukin-8 in cultured human macrophages concurrent to the translocation of nuclear transcription factor-κB (NF-κB). Further, the rHP986 induced apoptosis of cultured macrophages through a Fas mediated pathway. Dissection of the underlying signaling mechanism revealed that rHP986 induces both TNFR1 and Fas expression to lead to apoptosis. We further demonstrated interaction of HP986 with TNFR1 through computational and experimental approaches. Independent proinflammatory and apoptotic responses triggered by rHP986 as shown in this study point to its role, possibly as a survival strategy to gain niche through inflammation and to counter the activated macrophages to avoid clearance

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Troglitazone. Is it all over?

In January 1997 a drug from a new pharmacological class, the thiazolidinediones, became available: troglitazone. Troglitazone indirectly enhances peripheral insulin sensitivity. In this way it lowers the levels of both glucose and insulin. Troglitazone also has a lowering effect on the levels of triglycerides. In clinical trials only mild side effects had been observed. Therefore, troglitazone seemed a promising drug. Recently, however, it became clear that troglitazone could cause liver dysfunction in some patients. Although this side effect is reversible in most cases, six deaths have been described due to liver damage. Troglitazone was to be introduced in Europe in 1998 but registration procedures and clinical trials have been stopped because of its side effects on the liver. In the United States and Japan troglitazone is still being used, albeit with extra precautions. Troglitazone is a valuable addition to the arsenal of antidiabetic drugs for type 2 diabetes. It can be particularly useful, both as an additive and as a replacement, in patients for whom metformin is not suitable because of contraindications or side effects. The risk of severe liver dysfunction is a reason to reserve troglitazone as a second-line drug. (C) 1999 Published by Elsevier Science B.V. All rights reserved