👤 Eva Hernando

Alzheimer's disease (AD) is a neurodegenerative disorder (NDD) associated with the accumulation of beta-amyloid plaques (βA), oxidative stress, and a decrease in cholinergic activity among other pathologies. Given the limitations of current treatments, multitarget strategies present a promising alternative. In this study we prioritized six AD-related protein targets: acetylcholinesterase (AChE), beta-secretase 1 (BACE-1), cannabinoid receptor type 2 (CB2), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidase A (MAO-A), and the neuronal acetylcholine receptor subunit alpha-7 (nAChR7). Ligand- and structure-based virtual screening methods were applied to identify potential multitarget directed ligands (MTDLs), reducing an initial database of 14 million compounds to 21 early stage candidate MTDLs, that were tested experimentally against AChE, BACE-1, GSK-3β, MAO-A, nAChR7, and the additional targets BChE and MAO-B; however, CB2 could not be experimentally assessed. Among the tested molecules, PJ17 exhibited a dual-target profile with submicromolar activity against AChE and GSK-3β, while PJ11 showed notable MAO-B inhibition. Molecular dynamics simulations revealed key common interactions between PJ17 and those targets providing insights into its potential for further hit-to-lead optimization. In addition, PJ17 showed a safe profile in cellular primary culture suggesting its use as a template to design multitarget drugs against AD. Show less

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM. Show less