Proteomic and transcriptomic analysis of heart failure due to volume overload in a rat aorto-caval fistula model provides support for new potential therapeutic targets - monoamine oxidase A and transglutaminase 2

<p>Abstract</p> <p>Background</p> <p>Chronic hemodynamic overloading leads to heart failure (HF) due to incompletely understood mechanisms. To gain deeper insight into the molecular pathophysiology of volume overload-induced HF and to identify potential markers and targets for novel therapies, we performed proteomic and mRNA expression analysis comparing myocardium from Wistar rats with HF induced by a chronic aorto-caval fistula (ACF) and sham-operated rats harvested at the advanced, decompensated stage of HF.</p> <p>Methods</p> <p>We analyzed control and failing myocardium employing iTRAQ labeling, two-dimensional peptide separation combining peptide IEF and nano-HPLC with MALDI-MS/MS. For the transcriptomic analysis we employed Illumina RatRef-12v1 Expression BeadChip.</p> <p>Results</p> <p>In the proteomic analysis we identified 2030 myocardial proteins, of which 66 proteins were differentially expressed. The mRNA expression analysis identified 851 differentially expressed mRNAs.</p> <p>Conclusions</p> <p>The differentially expressed proteins confirm a switch in the substrate preference from fatty acids to other sources in the failing heart. Failing hearts showed downregulation of the major calcium transporters SERCA2 and ryanodine receptor 2 and altered expression of creatine kinases. Decreased expression of two NADPH producing proteins suggests a decreased redox reserve. Overexpression of annexins supports their possible potential as HF biomarkers. Most importantly, among the most up-regulated proteins in ACF hearts were monoamine oxidase A and transglutaminase 2 that are both potential attractive targets of low molecular weight inhibitors in future HF therapy.</p

Quinone reductase acts as a redox switch of the 20 S yeast proteasome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102111/1/embr2008218.pd

Burnout nos estudantes do ensino superior

Os estudantes fazem parte de uma organização de educação onde desempenham um determinado papel, realizam tarefas que exigem esforço, possuem metas a cumprir e seu desempenho é constantemente avaliado pelos seus professores, os quais exercem uma função muito semelhante à de uma chefia num contexto de trabalho. O burnout académico é definido como exaustão cognitiva e emocional devido às exigências académicas, a sentimentos de incapacidade e ineficácia e uma atitude cínica em relação aos estudos, aos professores e colegas.info:eu-repo/semantics/publishedVersio

Detailed Functional and Proteomic Characterization of Fludarabine Resistance in Mantle Cell Lymphoma Cells

<div><p>Mantle cell lymphoma (MCL) is a chronically relapsing aggressive type of B-cell non-Hodgkin lymphoma considered incurable by currently used treatment approaches. Fludarabine is a purine analog clinically still widely used in the therapy of relapsed MCL. Molecular mechanisms of fludarabine resistance have not, however, been studied in the setting of MCL so far. We therefore derived fludarabine-resistant MCL cells (Mino/FR) and performed their detailed functional and proteomic characterization compared to the original fludarabine sensitive cells (Mino). We demonstrated that Mino/FR were highly cross-resistant to other antinucleosides (cytarabine, cladribine, gemcitabine) and to an inhibitor of Bruton tyrosine kinase (BTK) ibrutinib. Sensitivity to other types of anti-lymphoma agents was altered only mildly (methotrexate, doxorubicin, bortezomib) or remained unaffacted (cisplatin, bendamustine). The detailed proteomic analysis of Mino/FR compared to Mino cells unveiled over 300 differentially expressed proteins. Mino/FR were characterized by the marked downregulation of deoxycytidine kinase (dCK) and BTK (thus explaining the observed crossresistance to antinucleosides and ibrutinib), but also by the upregulation of several enzymes of de novo nucleotide synthesis, as well as the up-regulation of the numerous proteins of DNA repair and replication. The significant upregulation of the key antiapoptotic protein Bcl-2 in Mino/FR cells was associated with the markedly increased sensitivity of the fludarabine-resistant MCL cells to Bcl-2-specific inhibitor ABT199 compared to fludarabine-sensitive cells. Our data thus demonstrate that a detailed molecular analysis of drug-resistant tumor cells can indeed open a way to personalized therapy of resistant malignancies.</p></div

Differentially expressed proteins in Mino/FR cells identified by the proteomic analysis.

<p>Differentially expressed proteins with fold-change >1.5 are listed. Gene names are shown, proteins with fold-change >3 fold are present in bold letters).</p

Decreased levels of total BTK and its activated p-BTKY²³³ form in Mino/FR cells.

<p>Relative expression of total and phosphorylated (active) p-BTK233 was determined by Western blotting using specific antibodies in Mino and Mino/FR cells. GAPDH was used as the loading control.</p