Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases

Background: Prostaglandin (PG) E₂ plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE₂ catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE₂ content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE₂ in human CRC cells in vitro. Methods: Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE₂ levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β. Results: PGE₂ levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE₂. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.Conclusions: There is significant intra-tumoral heterogeneity in PGE₂ content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE₂ metabolism should be targeted for novel treatment of advanced CRC

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms

Young women with diabetes: using internet communication to create stability during life transitions

Aims and objectives. The aim of the current study was to explore and describe the strategies young women with Type 1 diabetes used to manage transitions in their lives. This paper will describe one aspect of the findings of how women with Type 1 diabetes used the Internet to interact with other people with diabetes and create stability in their lives.Background. Individuals living with diabetes develop a range of different strategies to create stability in their lives and enhance their well-being. Changing social and emotional conditions during life transitions have a major impact on diabetes management. Although the literature indicates that strategies enabling the individuals to cope with transitions are important, they remain under-researched.Design. Using grounded theory, interviews were conducted with 20 women with Type 1 diabetes. Constant comparative data analysis was used to analyse the data and develop an understanding of how young women with Type 1 diabetes used the Internet to create stability in their lives.Findings. The findings revealed that the women valued their autonomy and being in control of when and to whom they reveal their diabetic status, especially during life transitions and at times of uncertainty. However, during these times they also required health and social information and interacting with other people. One of the women\u27s main strategies in managing transitions was to use Internet chat lines as a way of obtaining information and communicating with others. This strategy gave women a sense of autonomy, enabled them to maintain their anonymity and interact with other people on their own terms.Conclusions. Having meaningful personal interactions, social support and being able to connect with others were fundamental to the women\u27s well being. Most importantly, preserving autonomy and anonymity during such interactions were integral to the way the women with Type 1 diabetes managed life transitions.Relevance to clinical practice. Health professionals need to explore and incorporate Internet communication process or anonymous help lines into their practice as a way to assist people manage their diabetes.<br /