Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec

Santander, Spain

Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec

Santander, Spain
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Lantero A.,University of Cantabria | Lantero A.,Institute Formacion E Investigacion Marques Of Valdecilla | Tramullas M.,University of Cantabria | Tramullas M.,Institute Formacion E Investigacion Marques Of Valdecilla | And 12 more authors.
Journal of Neuroscience | Year: 2014

Transforming growth factor-β1 (TGF-β1) protects against neuroinflammatory events underlying neuropathic pain. TGF-β signaling enhancement is a phenotypic characteristic of mice lacking the TGF-β pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects of BAMBI deficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-β1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of μ- and δ-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of μ-opioid receptors was reduced. By this time, BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced in BAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-β1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-β1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-β signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions. © 2014 the authors.

Linge R.,University of Cantabria | Linge R.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | Linge R.,Institute Salud Carlos III | Pazos A.,University of Cantabria | And 5 more authors.
Behavioural Brain Research | Year: 2013

Social isolation in rodents may interfere in their behavioural responses on paradigms used to test anxiety- and depressive-like states. Herein we study the influence of social isolation upon the behavioural responses of olfactory bulbectomized mice (OBX). In the open-field test (OFT), social isolation enhanced OBX-induced hyperactivity and exploratory behaviour. However, OBX-induced anxiety in the OFT (central activity) was less apparent after isolation, due to the increased level of anxiety showed by the sham-isolated counterparts. In the novelty-suppressed feeding (NSF), isolation derived in an increased latency to feeding of both OBX and sham mice. The isolation did not affect the response of OBX mice and sham mice in the forced-swimming test (FST). Interestingly, OBX animals exhibited an increased immobility time during the FST, though a dramatic decrease in the climbing scores. Finally, OBX-induced anhedonia in the sucrose intake test was not affected by housing conditions. Our findings demonstrate that social isolation influences the performance of OBX mice in some behavioural paradigms, thus facilitating the characterization of depressive-like states, and by contrast, hindering anxiety-related behaviours. This fact should be taken into account in order to minimize economical and time-consuming efforts when assessing potential antidepressant and anxiolytic drugs. © 2013 Elsevier B.V.

Calvo F.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | Calvo F.,Cancer Research UK Research Institute | Sanz-Moreno V.,Cancer Research UK Research Institute | Sanz-Moreno V.,King's College London | And 5 more authors.
Nature Cell Biology | Year: 2011

Individual tumour cells move in three-dimensional environments with either a rounded or an elongated mesenchymalmorphology. These two modes of movement are tightly regulated by Rho family GTPases: elongated movement requires activation of Rac1, whereas rounded/amoeboid movement engages specific Cdc42 and Rho signalling pathways. In siRNA screens targeting the genes encoding guanine nucleotide exchange factors (GEFs), we found that the Ras GEF RasGRF2 regulates conversion between elongated- and rounded-type movement. RasGRF2 suppresses rounded movement by inhibiting the activation of Cdc42 independently of its capacity to activate Ras. RasGRF2 and RasGRF1 directly bind to Cdc42, outcompeting Cdc42 GEFs, thereby preventing Cdc42 activation. By this mechanism, RasGRFs regulate other Cdc42-mediated cellular processes such as the formation of actin spikes, transformation and invasion in vitro and in vivo. These results demonstrate a role for RasGRF GEFs as negative regulators of Cdc42 activation. © 2011 Macmillan Publishers Limited. All rights reserved.

Albajar M.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | Albajar M.,Hospital Universitario Marques Of Valdecilla Ifimav | Gomez-Casares M.T.,University of Las Palmas de Gran Canaria | Llorca J.,University of Cantabria | And 11 more authors.
Molecular Cancer Research | Year: 2011

Untreated chronic myeloid leukemia (CML) progresses from chronic phase to blastic crisis (BC). Increased genomic instability, deregulated proliferation, and loss of differentiation appear associated to BC, but the molecular alterations underlying the progression of CML are poorly characterized. MYC oncogene is frequently deregulated in human cancer, often associated with tumor progression. Genomic instability and induction of aberrant DNA replication are described as effects of MYC. In this report, we studied MYC activities in CML cell lines with conditional MYC expression with and without exposure to imatinib, the front-line drug in CML therapy. In cells with conditional MYC expression, MYC did not rescue the proliferation arrest mediated by imatinib but provoked aberrant DNA synthesis and accumulation of cells with 4C content. We studied MYC mRNA expression in 66 CML patients at different phases of the disease, and we found that MYC expression was higher in CML patients at diagnosis than control bone marrows or in patients responding to imatinib. Further, high MYC levels at diagnosis correlated with a poor response to imatinib. MYC expression did not directly correlate with BCR-ABL levels in patients treated with imatinib. Overall our study suggests that, as in other tumor models, MYC-induced aberrant DNA synthesis in CML cells is consistent with MYC overexpression in untreated CML patients and nonresponding patients and supports a role for MYC in CML progression, possibly through promotion of genomic instability. ©2011 AACR.

Sanchez-Juan P.,University of Cantabria | Bishop M.T.,University of Edinburgh | Aulchenko Y.S.,Erasmus Medical Center | Brandel J.-P.,Groupe Hospitalier Pitie Salpetriere | And 18 more authors.
Neurobiology of Aging | Year: 2012

The aim of our study was to discover genomic variations related to variant Creutzfeldt-Jakob disease (vCJD) susceptibility. A genome-wide association analysis with most vCJD samples available in the world was performed. A series of 93 vCJD UK patients and 1504 UK controls were included in the discovery stage. Our best findings were replicated in an independent population of 22 UK and 20 French vCJD cases. Post hoc analysis to assess our main results included 5711 French controls, 445 Dutch controls, and 446 sporadic Creutzfeldt-Jakob disease (CJD) cases. We found 2 genome wide significant variants tagging PRNP: rs6107516 (p = 2.6 × 10-18) and rs2065706 (p = 8.8 × 10-14). Two other single nucleotide polymorphisms (SNPs) (rs4921542 and rs7565981) were successfully replicated in independent samples and reached genome-wide significance after pooling discovery and replication populations. Rs4921542 (p = 1.6 × 10-8) is an intronic variant in the myotubularin related protein 7 gene (MTMR7), which is specifically expressed in the central nervous system (CNS) and dephosphorylates phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate. Rs7565981 (p = 4.2 × 10-8) is in an intergenic region upstream of the neuronal PAS (per-ARNT-sim) domain-containing protein 2 gene (NPAS2), a regulatory gene belonging to a family of transcription factors that has been implicated in memory, seasonal affective disorder, and the molecular clock in the mammalian forebrain. A proxy of rs7565981 (rs17024792; r2 = 1.0) has been found to regulate the phospholipase C-delta-3 gene (PLCD3) in trans. This enzyme catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate. Our study reveals 2 new genome-wide significant markers for vCJD outside PRNP and provides evidence supporting a role of the phosphatidylinositol pathway in vCJD susceptibility. © 2012 Elsevier Inc.

Campo Esquisabel A.B.,Hospital Sierrallana | Campo Esquisabel A.B.,Hospital Universitario Marques Of Valdecilla | Rodriguez M.C.,Hospital Universitario Marques Of Valdecilla | Rodriguez M.C.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | And 3 more authors.
Clinical Microbiology and Infection | Year: 2011

The MIC of cefepime determined with the MicroScan WalkAway system was ≥2 times higher than that of ceftazidime for 105 clinical isolates of Pseudomonas aeruginosa. This phenotype was confirmed by reference microdilution in 68 (64.8%) isolates, corresponding to 48 different rep-PCR patterns. The PSE-1 blactamase was identified in only 13.2% isolates, while oxacillinases were not identified in any of the 68 isolates. The level of expression of mexB, mexD and mexY was determined by real-time RT-PCR in eight clinical isolates representative of the different clones and patterns of susceptibility to cefepime and ceftazidime and in strain PAO1. All clinical strains overexpressed the mexY gene (18.3- to 152.7-fold in comparison with PAO1), although there was not a linear relationship between MIC of cefepime and level of mexY expression. Five of these strains contained mutations in the regulatory gene mexZ. mexD and mexB were also overexpressed in three and two isolates, respectively. Different mutations were observed in the regulatory genes nalD, mexR, nfxB and nalC. In conclusion, we have documented in our institution a polyclonal spread of P. aeruginosa with higher MICs of cefepime than of ceftazidime, related to overexpression of MexXY-OprM, coincident in some isolates with the production of PSE-1, MexCD-OprJ or MexAB-OprM. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

PubMed | University College Dublin and Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec
Type: Journal Article | Journal: Molecular & cellular oncology | Year: 2016

Current antitumor therapies targeting the RAS-ERK pathway have been mostly aimed at inhibiting the activity of the kinases that populate the route. A small-molecule inhibitor of ERK dimerization effectively prevents the progression of tumors harboring oncogenic RAS and BRAF, demonstrating that targeting regulatory protein-protein interactions can be a valid strategy for treating RAS-ERK pathway-driven neoplasia.

PubMed | Centro Atlantico del Medicamento CEAMED, Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec, España University, University of Las Palmas de Gran Canaria and Instituto Canario Of Investigacion Sobre El Cancer Icic
Type: | Journal: Oncotarget | Year: 2016

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 0.5 M) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker H2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies.

Ocampo-Sosa A.A.,Hospital Universitario Marques Of Valdecilla Ifimav | Cabot G.,Hospital Universitario Son Espases | Rodriguez C.,Hospital Universitario Marques Of Valdecilla Ifimav | Roman E.,Hospital Universitario Marques Of Valdecilla Ifimav | And 12 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

We investigated the presence of OprD mutations in 60 strains of metallo-β-lactamase-negative Pseudomonas aeruginosa intermediately susceptible (IS [n = 12]; MIC = 8 μg/ml) or susceptible (S [n = 48]; MICs ≤ 1 to 4 μg/ml) to imipenem and/or meropenem that were isolated from patients with bacteremia in order to evaluate their impact on carbapenem susceptibility profiles. The presence of mutations in oprD was detected by sequencing analysis. OprD expression was assessed by both outer membrane protein (OMP) analysis and real-time PCR (RT-PCR). Fourteen (23%) isolates had an OprD identical to that of PAO1, and OprD modifications were detected in 46 isolates (77%). Isolates were classified as OprD "full-length types" (T1 [n = 40, including both wild-type OprD and variants showing several polymorphisms]) and OprD "deficient types" (T2 [n = 3 for OprD frameshift mutations] and T3 [n = 17 for premature stop codons in oprD]). RT-PCR showed that 5 OprD type T1 isolates presented reduced transcription of oprD (0.1- to 0.4-fold compared to PAO1), while oprD levels increased more than 2-fold over that seen with PAO1 in 4 OprD type T1 isolates. A total of 50% of the isolates belonging to OprD "deficient types" were susceptible to both carbapenems, and 40% were susceptible to meropenem and intermediately susceptible to imipenem. Only one isolate (5%) within this group was intermediately susceptible to both carbapenems, and one (5%) was susceptible to imipenem and intermediately susceptible to meropenem. We concluded that OprD inactivating mutations in clinical isolates of P. aeruginosa are not restricted only to carbapenem-resistant isolates but are also found in isolates with imipenem or meropenem MICs of only 0.06 to 4 μg/ml. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Fernandez-Lopez R.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | del Campo I.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | Revilla C.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | Cuevas A.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec | de la Cruz F.,Institute Biomedicina Y Biotecnologia Of Cantabria Ibbtec
PLoS Genetics | Year: 2014

Horizontal gene transfer (HGT) is a major force driving bacterial evolution. Because of their ability to cross inter-species barriers, bacterial plasmids are essential agents for HGT. This ability, however, poses specific requisites on plasmid physiology, in particular the need to overcome a multilevel selection process with opposing demands. We analyzed the transcriptional network of plasmid R388, one of the most promiscuous plasmids in Proteobacteria. Transcriptional analysis by fluorescence expression profiling and quantitative PCR revealed a regulatory network controlled by six transcriptional repressors. The regulatory network relied on strong promoters, which were tightly repressed in negative feedback loops. Computational simulations and theoretical analysis indicated that this architecture would show a transcriptional burst after plasmid conjugation, linking the magnitude of the feedback gain with the intensity of the transcriptional burst. Experimental analysis showed that transcriptional overshooting occurred when the plasmid invaded a new population of susceptible cells. We propose that transcriptional overshooting allows genome rebooting after horizontal gene transfer, and might have an adaptive role in overcoming the opposing demands of multilevel selection. © 2014 Fernandez-Lopez et al.

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