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Rodriguez M.I.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Majuelos-Melguizo J.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Marti Martin-Consuegra J.M.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Ruiz de Almodovar M.,University of Granada | And 2 more authors.
Medicinal Research Reviews | Year: 2015

Poly (ADP-ribose) polymerase (PARP) inhibitors are particularly efficient against tumors with defects in the homologous recombination repair pathway. Nonetheless poly(ADP-ribosylation) (PARylation) modulates prometastasic activities and adaptation of tumor to a hostile microenvironment. Modulation of metastasis-promoting traits is possible through the alteration of key transcription factors involved in the regulation of the hypoxic response, the recruitment of new vessels (or angiogenesis), and the stimulation of epithelial to mesenchymal transition (EMT). In this review, we summarized some of the findings that focalize on PARP-1's action on tumor aggressiveness, suggesting new therapeutic opportunities against an assembly of tumors not necessarily bearing DNA repair defects. Metastasis accounts for the vast majority of mortality derived from solid cancer. PARP-1 is an active player in tumor adaptation to metastasis and PARP inhibitors, recognized as promising therapeutic agents against homologous recombination deficient tumors, has novel properties responsible for the antimetastatic actions in different tumor settings. © 2015 Wiley Periodicals, Inc.

Bossini-Castillo L.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Simeon C.P.,Servicio de Medicina Interna | Beretta L.,systemIC | Broen J.,University Utrecht | And 22 more authors.
Arthritis Research and Therapy | Year: 2012

Introduction: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort.Methods: The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay.Results: Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients.Conclusions: Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients. © 2012 Bossini-Castillo et al.; licensee BioMed Central Ltd.

Delgado-Garcia M.,Hospital Universitario Virgen Macarena | Matesanz F.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Fedetz M.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | And 16 more authors.
Multiple Sclerosis | Year: 2015

Background: Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS). Objectives: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters. Methods: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients. Results: We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E- 07, Beta = 0.207). zFurthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06). Conclusions: Our results suggest that the polymorphism of the IGHC locus could be altering the swiching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses. © The Author(s), 2015.

Matesanz F.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN
European Journal of Human Genetics | Year: 2016

Genome-wide association studies (GWAS) in migraine are providing the molecular basis of this heterogeneous disease, but the understanding of its aetiology is still incomplete. Although some biomarkers have currently been accepted for migraine, large amount of studies for identifying new ones is needed. The migraine-associated variant rs12355831:A>G (P=2 × 10-6), described in a GWAS of the International Headache Genetic Consortium, is localized in a non-coding sequence with unknown function. We sought to identify the causal variant and the genetic mechanism involved in the migraine risk. To this end, we integrated data of RNA sequences from the Genetic European Variation in Health and Disease (GEUVADIS) and genotypes from 1000 GENOMES of 344 lymphoblastoid cell lines (LCLs), to determine the expression quantitative trait loci (eQTLs) in the region. We found that the migraine-associated variant belongs to a linkage disequilibrium block associated with the expression of an acyl-coenzyme A synthetase 5 (ACSL5) transcript lacking exon 20 (ACSL5-Δ20). We showed by exon-skipping assay a direct causality of rs2256368-G in the exon 20 skipping of approximately 20 to 40% of ACSL5 RNA molecules. In conclusion, we identified the functional variant (rs2256368:A>G) affecting ACSL5 exon 20 skipping, as a causal factor linked to the migraine-associated rs12355831:A>G, suggesting that the activation of long-chain fatty acids by the spliced ACSL5-Δ20 molecules, a mitochondrial located enzyme, is involved in migraine pathology.European Journal of Human Genetics advance online publication, 18 May 2016; doi:10.1038/ejhg.2016.54. © 2016 Macmillan Publishers Limited

Martinez-Garcia M.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Campos-Salinas J.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Cabello-Donayre M.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Pineda-Molina E.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | And 6 more authors.
Parasites and Vectors | Year: 2016

Background: Mitochondria play essential biological functions including the synthesis and trafficking of porphyrins and iron/sulfur clusters (ISC), processes that in mammals involve the mitochondrial ATP-Binding Cassette (ABC) transporters ABCB6 and ABCB7, respectively. The mitochondrion of pathogenic protozoan parasites such as Leishmania is a promising goal for new therapeutic approaches. Leishmania infects human macrophages producing the neglected tropical disease known as leishmaniasis. Like most trypanosomatid parasites, Leishmania is auxotrophous for heme and must acquire porphyrins from the host. Methods: LmABCB3, a new Leishmania major protein with significant sequence similarity to human ABCB6/ABCB7, was identified and characterized using bioinformatic tools. Fluorescent microscopy was used to determine its cellular localization, and its level of expression was modulated by molecular genetic techniques. Intracellular in vitro assays were used to demonstrate its role in amastigotes replication, and an in vivo mouse model was used to analyze its role in virulence. Functional characterization of LmABCB3 was carried out in Leishmania promastigotes and Saccharomyces cerevisiae. Structural analysis of LmABCB3 was performed using molecular modeling software. Results: LmABCB3 is an atypical ABC half-transporter that has a unique N-terminal extension not found in any other known ABC protein. This extension is required to target LmABCB3 to the mitochondrion and includes a potential metal-binding domain. We have shown that LmABCB3 interacts with porphyrins and is required for the mitochondrial synthesis of heme from a host precursor. We also present data supporting a role for LmABCB3 in the biogenesis of cytosolic ISC, essential cofactors for cell viability in all three kingdoms of life. LmABCB3 fully complemented the severe growth defect shown in yeast lacking ATM1, an orthologue of human ABCB7 involved in exporting from the mitochondria a gluthatione-containing compound required for the generation of cytosolic ISC. Indeed, docking analyzes performed with a LmABCB3 structural model using trypanothione, the main thiol in this parasite, as a ligand showed how both, LmABCB3 and yeast ATM1, contain a similar thiol-binding pocket. Additionally, we show solid evidence suggesting that LmABCB3 is an essential gene as dominant negative inhibition of LmABCB3 is lethal for the parasite. Moreover, the abrogation of only one allele of the gene did not impede promastigote growth in axenic culture but prevented the replication of intracellular amastigotes and the virulence of the parasites in a mouse model of cutaneous leishmaniasis. Conclusions: Altogether our results present the previously undescribed LmABCB3 as an unusual mitochondrial ABC transporter essential for Leishmania survival through its role in the generation of heme and cytosolic ISC. Hence, LmABCB3 could represent a novel target to combat leishmaniasis. © 2016 Martínez-García et al.

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