ASACO: Automatic and Serial Analysis of CO-expression to discover gene modifiers with potential use in drug repurposing.

Massive gene expression analyses are widely used to find differentially expressed genes under specific conditions. The results of these experiments are often available in public databases that are undergoing a growth similar to that of molecular sequence databases in the past. This now allows novel secondary computational tools to emerge that use such information to gain new knowledge. If several genes have a similar expression profile across heterogeneous transcriptomics experiments, they could be functionally related. These associations are usually useful for the annotation of uncharacterized genes. In addition, the search for genes with opposite expression profiles is useful for finding negative regulators and proposing inhibitory compounds in drug repurposing projects. Here we present a new web application, Automatic and Serial Analysis of CO-expression (ASACO), which has the potential to discover positive and negative correlator genes to a given query gene, based on thousands of public transcriptomics experiments. In addition, examples of use are presented, comparing with previous contrasted knowledge. The results obtained propose ASACO as a useful tool to improve knowledge about genes associated with human diseases and noncoding genes. ASACO is available at http://www.bioinfocabd.upo.es/asaco/.

Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer's disease.

Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2', 2'-difluoro 2'deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aß1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment.