Tissue-Specific Target Analysis of Disease-Associated MicroRNAs in Human Signaling Pathways

MicroRNAs are a large class of post-transcriptional regulators that bind to the 3′ untranslated region of messenger RNAs. They play a critical role in many cellular processes and have been linked to the control of signal transduction pathways. Recent studies indicate that microRNAs can function as tumor suppressors or even as oncogenes when aberrantly expressed. For more general insights of disease-associated microRNAs, we analyzed their impact on human signaling pathways from two perspectives. On a global scale, we found a core set of signaling pathways with enriched tissue-specific microRNA targets across diseases. The function of these pathways reflects the affinity of microRNAs to regulate cellular processes associated with apoptosis, proliferation or development. Comparing cancer and non-cancer related microRNAs, we found no significant differences between both groups. To unveil the interaction and regulation of microRNAs on signaling pathways locally, we analyzed the cellular location and process type of disease-associated microRNA targets and proteins. While disease-associated proteins are highly enriched in extracellular components of the pathway, microRNA targets are preferentially located in the nucleus. Moreover, targets of disease-associated microRNAs preferentially exhibit an inhibitory effect within the pathways in contrast to disease proteins. Our analysis provides systematic insights into the interaction of disease-associated microRNAs and signaling pathways and uncovers differences in cellular locations and process types of microRNA targets and disease-associated proteins

Lens stem cells may reside outside the lens capsule: an hypothesis

In this paper, we consider the ocular lens in the context of contemporary developments in biological ideas. We attempt to reconcile lens biology with stem cell concepts and a dearth of lens tumors

Fetal and Maternal Brain and Plasma Levels of Cocaine and Benzoylecgonine Following Chronic Subcutaneous Administration of Cocaine During Gestation in Rats

The distribution of cocaine and the cocaine metabolite benzoylecgonine (BE) in brain and plasma of Sprague-Dawley rat dams and their near-term fetuses was assessed 0.5 and 2 h post-injection on gestational day 20 following chronic daily subcutaneous injections of 10, 20, or 40 mg/kg/3 ml cocaine hydrochloride beginning on gestational day 8. Plasma concentrations of cocaine reached in the dams were found to be in the range of, or to exceed, those reported in human cocaine users. Dose-related increases in plasma and brain levels of cocaine in the dams and the fetuses were observed, particularly at 2 h post-injection. Fetal concentrations of cocaine in brain and plasma were approximately 2–3-fold less than those of the dams, suggesting that the placenta may somewhat restrict cocaine entry into fetal circulation. Brain/plasma cocaine ratios, however, were generally equivalent in the dams and fetuses, suggesting that once cocaine enters the circulation, its affinity for brain tissue is similar in the fetus and dam. Whereas plasma levels of BE, like cocaine levels per se, were greater in the dams than fetuses, BE concentrations in fetal brain were greater than those observed in maternal brain. These high levels of BE may contribute to the production of neurobehavioral alterations in cocaine-exposed offspring, given that this active cocaine metabolite has been shown to form molecular complexes with calcium ions (Misra and Mule 1975), thereby having the potential to influence a multiplicity of calcium-regulated developmental events. Taken together, the results of the present study suggest that the subcutaneous route may prove to be an appropriate means in rats for administering cocaine prenatally in investigations designed to assess potential neurobehavioral ramifications of gestational cocaine exposure