Highly potent and selective aryl-1,2,3-triazolyl benzylpiperidine inhibitors toward butyrylcholinesterase in Alzheimer's disease.

Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported.

Cytogenetic instability in childhood acute lymphoblastic leukemia survivors.

Contemporary anticancer therapies have largely improved the outcome for children with cancer, especially for Acute Lymphoblastic Leukemia (ALL). Actually, between 78% and 85% of patients achieve complete remission and are alive after 5 years of therapy completion. However, as cure rates increase, new concerns about the late effects of genotoxic treatment emerge, being the risk of developing secondary neoplasias, the most serious life-threatening rising problem. In the present paper, we describe and review the cytogenetic findings in peripheral lymphocytes from ALL survivors, and discuss aspects associated to the occurrence of increased chromosome rearrangements in this growing cohort.

Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients.

Alzheimer's disease (AD) is an age-related neurodegenerative pathology associated with accumulation of DNA damage. Inflammation and cell cycle alterations seem to be implicated in the pathogenesis of AD, although the molecular mechanisms have not been thoroughly elucidated to date. The aim of the present study was to evaluate whether peripheral blood mononuclear cells (PBMCs) of AD patients display alterations in gene expression profiles, focusing on finding markers that might improve the diagnosis of AD. Blood samples were collected from 22 AD patients and 13 healthy individuals to perform genome-wide mRNA expression. We found 593 differentially expressed genes in AD compared to controls, from which 428 were upregulated, and 165 were downregulated. By performing a gene set enrichment analysis, we observed pathways involved in inflammation, DNA damage response, cell cycle, and neuronal processes. Moreover, functional annotation analyses indicated that differentially expressed genes are strongly related to pathways associated with the cell cycle and the immune system. The results were compared with those of an independent study on hippocampus samples, and a number of genes in common between both studies were identified as potential peripheral biomarkers for AD, including DUSP1, FOS, SLC7A2, RGS1, GFAP, CCL2, ANGPTL4, and SSPN. Taken together, our results demonstrate that PBMCs of AD patients do present alterations in gene expression profiles, and these results are comparable to those previously reported in the literature for AD neurons, supporting the hypothesis that blood peripheral mononuclear cells express molecular changes that occur in the neurons of AD patients.