The intricate interplay between epigenetic events, alternative splicing and noncoding RNA deregulation in colorectal cancer

Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC

Cell Adhesion Molecules and Cancer

Theodor Boveri in 1914 recognized the significance of changes in the adhesion of tumor cells to the development of cancer. Cell adhesion is essential in all aspects of in verte-brate cells such as cell growth, cell migration and cell differentiation. The majority of adhesion molecules fall into one of four families: cadherins, integrins, immunoglobulin superfamily (IgSF) and selectins. The cadherins are a family of homophilic CAMs (cell adhesion moleculs), Ca2+ dependent. The most important members of cadherins are E-cadherins (epithelial), P-cadherins (placental) and N-cadherins (neural). Immunoglobu-lin superfamily CAMs (IgSF CAMs) are either homophilic or heterophilic and bind in-tegrins, growth factor receptors cadherins or different IgSF CAMs. The integrins are a family of heterophilic CAMs that bind IgSF CAMs or the extracellular matrix. The se-lectins are a family of heterophilic CAMs that bind fucosylated carbohydrates, e.g. mu-cins. They are calcium-dependent. The three family members are E-selectin (endothelial (, L-selectin (leukocyte) and P-selectin (platelet). Recent experimental results indicate that, as well as mediating intercellular and cell–matrix interactions, cell-adhesion mole-cules also directly modulate signal transduction. Changes in the expression or function of cell-adhesion molecules can therefore contribute to tumor progression via altering the adhesion status of the cell or affecting cell signaling. The ability to colonize a specific organ has been correlated with the preferential adhesion of the cancer cells to endotheli-al cells derived from the target organ. This review summarizes recent findings about role of adhesion molecules in the tumor progression

In vivo effects of allogeneic mesenchymal stem cells in a rat model of acute ischemic kidney injury

Objective(s): Renal ischemia-reperfusion injury (IRI) as a severe condition of acute kidney injury (AKI) is the most common clinical problem with high mortality rates of 35-60% deaths in hospital. Mesenchymal stem cells (MSC) due to unique regenerative characteristics are ideal candidates for the treatment of the ischemic injuries. This work is focused on the administration of MSC to IRI-induced AKI Wistar rats and evaluating their significance in AKI treatment. Material and Methods: Animals underwent surgical procedure and AKI was induced by 40 min bilateral renal pedicle clamping. Immediately after reperfusion, 2×106 rat bone marrow derived MSCs were injected via intra-parenchymal or intra-aortic route. Results: Animals subjected to AKI after days 1 and 3 showed significant increase in the serum creatinine and blood urea nitrogen (BUN) concentration along with a declined glomerular filtration rate (GFR) when compared with non-ischemic animals. On the other hand, treated animals showed a significant enhanced regeneration as compared to ischemic animals in both administration route groups. Conclusion: According to the results concluded from the renoprotective effects of MSC in IRI/AKI, MSCs could be considered as promising therapeutic approach for AKI in clinical applications

Toward community standards and software for whole-cell modeling

Whole-cell (WC) modeling is a promising tool for biological research, bioengineering, and medicine. However, substantial work remains to create accurate, comprehensive models of complex cells. Methods: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in SBML. Results: Our analysis revealed several challenges to representing WC models using the current standards. Conclusion: We, therefore, propose several new WC modeling standards, software, and databases. Significance:We anticipate that these new standards and software will enable more comprehensive models

RNA-Binding Proteins: Emerging Therapeutics for Vascular Dysfunction

Vascular diseases account for a significant number of deaths worldwide, with cardiovascular diseases remaining the leading cause of mortality. This ongoing, ever-increasing burden has made the need for an effective treatment strategy a global priority. Recent advances in regenerative medicine, largely the derivation and use of induced pluripotent stem cell (iPSC) technologies as disease models, have provided powerful tools to study the different cell types that comprise the vascular system, allowing for a greater understanding of the molecular mechanisms behind vascular health. iPSC disease models consequently offer an exciting strategy to deepen our understanding of disease as well as develop new therapeutic avenues with clinical translation. Both transcriptional and post-transcriptional mechanisms are widely accepted to have fundamental roles in orchestrating responses to vascular damage. Recently, iPSC technologies have increased our understanding of RNA-binding proteins (RBPs) in controlling gene expression and cellular functions, providing an insight into the onset and progression of vascular dysfunction. Revelations of such roles within vascular disease states have therefore allowed for a greater clarification of disease mechanisms, aiding the development of novel therapeutic interventions. Here, we discuss newly discovered roles of RBPs within the cardio-vasculature aided by iPSC technologies, as well as examine their therapeutic potential, with a particular focus on the Quaking family of isoforms

The RNA world in the 21st century-a systems approach to finding non-coding keys to clinical questions

There was evidence that RNAs are a functionally rich class of molecules not only since the arrival of the next-generation sequencing technology. Non-coding RNAs (ncRNA) could be the key to accelerated diagnosis and enhanced prediction of disease and therapy outcomes as well as the design of advanced therapeutic strategies to overcome yet unsatisfactory approaches. In this review, we discuss the state of the art in RNA systems biology with focus on the application in the systems biomedicine field. We propose guidelines for analysing the role of microRNAs and long non-coding RNAs in human pathologies. We introduce RNA expression profiling and network approaches for the identification of stable and effective RNomics-based biomarkers, providing insights into the role of ncRNAs in disease regulation. Towards this, we discuss ways to model the dynamics of gene regulatory networks and signalling pathways that involve ncRNAs. We also describe data resources and computational methods for finding putative mechanisms of action of ncRNAs. Finally, we discuss avenues for the computer-aided design of novel RNA-based therapeutics

Strategies to Improve Homing of Stem Cells to achieve better Efficacy in Stem Cell Therapy

Stem/progenitor cell based therapeutic approach in our daily routine clinical practice, has been elusive dream in medical sciences and improvement of stem cell homing as one of major challenges in cell therapy programs, has been considered a promising milestone. It has been proved that stem/progenitor cells exhibit a homing response to injured tissues/organs, mediated by interactions of chemokine receptors expressed on the cells and chemokines secreted by the injured tissue. For improvement of directed homing of the cells, many techniques have been developed either to engineer stem/progenitor cells with higher amount of chemokine receptors (stem cell-based strategies) or to modulate the target tissues to release higher level of the corresponding chemokines (target tissue-based strategies). Treatment with chemical compounds, preconditioning of the cells with hypoxia, cytokine and growth factor priming of the cells, genetic modifications, coating of cell surface with antibodies, glycoengineering, coating of stem cells with homing ligands by streptavidin linkers are some of strategies to increase the ability of stem cells to respond to the migratory stimuli. On the other side to modulate target sites to be more attractive for stem cells, some strategies like direct injection of chemokines, direct transfection of the target tissue with chemokine encoding genes, injection of ectopic chemokine expressing cells, application of scaffolds, electrical fields and low level laser have been introduced. These extensive investigations have provided significant potentials to enhance targeted stem/progenitor cells homing. Meanwhile there are still some limitations to apply these findings in clinics. To overcome these limitations, further studies should be aimed, unveiling the molecular and cellular mechanisms underlying endogenous cell trafficking during physiological and pathological events like embryogenesis, inflammation, wound healing, or cancer metastasis. Keywords: Cell therapy, Homing, Stem cells