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Paris J.L.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 | Paris J.L.,CIBER ISCIII | Torre P.D.L.,Institute Investigacion Hospital 12 Of Octubre I12 | Manzano M.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 | And 5 more authors.
Acta Biomaterialia | Year: 2016

The potential use of human Decidua-derived mesenchymal stem cells (DMSCs) as a platform to carry mesoporous silica nanoparticles in cancer therapy has been investigated. Two types of nanoparticles were evaluated. The nanoparticles showed negligible toxicity to the cells, a fast uptake and a long retention inside them. Nanoparticle location in the cell was studied by colocalization with the lysosomes. Moreover, the in vitro and in vivo migration of DMSCs towards tumors was not modified by the evaluated nanoparticles. Finally, DMSCs transporting doxorubicin-loaded nanoparticles were capable of inducing cancer cell death in vitro. Statement of Significance: The use of nanotechnology for anticancer drug delivery has recently attracted great interest. Nanoparticles such as mesoporous silica nanoparticles (MSNs) can reach tumors, either by passive targeting, through the enhanced permeability and retention (EPR) effect, or active targeting, through the functionalization of nanoparticle surface. However, nanotechnology has not yet achieved the expected results in improving drug targeting, highlighting the need for a better localization of the nanoparticles in the tumors. Human mesenchymal stem cells from the decidua of the human placenta (DMSCs) have been observed to migrate towards tumors in a preclinical model of breast cancer. Moreover, they have been shown to inhibit growth of primary tumors and development of new tumors. In this work, combining MSNs and DMSCs, we have studied for the first time whether placental stem cells could be employed as a platform to load nanoparticles and carry them towards tumors for future anticancer therapies. © 2016 Acta Materialia Inc.


Matesanz M.C.,Complutense University of Madrid | Feito M.J.,Complutense University of Madrid | Onaderra M.,Complutense University of Madrid | Ramirez-Santillan C.,Complutense University of Madrid | And 7 more authors.
Journal of Colloid and Interface Science | Year: 2014

Hypothesis: Synthetic hydroxyapatite (HA) and Si substituted hydroxyapatite (SiHA) are calcium phosphate ceramics currently used in the field of dentistry and orthopaedic surgery. The preparation of both biomaterials as polycrystalline solid pieces or grains formed by nanocrystallites has awakened a great interest to enhance the bioactive behavior due to the microstructural defects and the higher surface area. The study of the macrophage and lymphocyte behavior in contact with nanocrystalline HA and SiHA will allow to elucidate the immune response which conditions the success or rejection of these biomaterials. Experiments: HA and SiHA granules (with sizes of tens of microns) have been prepared by controlled aqueous precipitation avoiding subsequent high temperature sintering. HA and SiHA granules were constituted by crystallites smaller than 50. nm. The effects of both nanocrystalline materials on immune system have been evaluated with macrophages (main components of innate immune system) and T lymphocytes (specific cells of adaptive response) after short-term culture as in vitro models of the early immune response. Findings: Significant decreases of macrophage proliferation and phagocytic activity, increased production of inflammatory cytokines (IL-6, TNF-α) and T lymphocyte apoptosis, were induced by these nanocrystalline ceramics suggesting that, after in vivo implantation, they induce significant effects on immune responses, including an early activation of the innate immune system. © 2013 Elsevier Inc.


Martinez-Gras I.,Complutense University of Madrid | Martinez-Gras I.,Research Center Biomedica En Red Of Salud Mental Cibersam | Martinez-Gras I.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 | Perez-Nievas B.G.,Complutense University of Madrid | And 24 more authors.
Schizophrenia Research | Year: 2011

A number of findings suggest that inflammation plays a role in the pathophysiology of schizophrenia. Taking into account a physiological balance between pro- and anti-inflammatory mediators, we measured the plasma levels of cyclooxygenase-derived mediators and other key pro- and anti-inflammatory transcription factors in peripheral blood mononuclear cells (PBMC). Forty healthy subjects and 46 treated chronic schizophrenic patients with an acutely exacerbated condition who met DSM-IV criteria were included. COX by-products prostaglandin E2 (PGE2) and 15d-prostaglandin J2 (15d-PGJ2) plasma levels were measured by EIA. Peroxisome proliferator-activated receptor gamma (PPARγ) as well as nuclear factor kappaB (NFκB) activity in nuclear extracts from PBMC and expression of its inhibitory subunit IκBα in cytosolic extracts were determined using ELISA-based kits. Schizophrenic patients showed higher plasma levels of pro-inflammatory PGE2 than age-matched controls (p=0.043). On the contrary, levels of anti-inflammatory 15-d-PGJ2 were lower (p=0.004), correlating with a lower expression of its nuclear target, PPARγ in nuclear extracts from PBMC (p=0.001). Although no changes in NFκB activity were observed between patients and healthy controls, the expression of its inhibitory protein IκBα was lower in the patients compared to the controls (p=0.027). These findings suggest that schizophrenia is associated with a systemic imbalance in the plasma levels of pro-inflammatory/anti-inflammatory prostaglandins in favor of the former. Furthermore, the expression and activity of anti-inflammatory PPARα are diminished in PBMC, which indicates a state of inflammation and blunted anti-inflammatory counterbalancing mechanisms at systemic level in these patients. © 2011 Elsevier B.V.


Cruz-Bermudez A.,Autonomous University of Madrid | Cruz-Bermudez A.,Research Center Biomedica en Red en Enfermedades Raras | Cruz-Bermudez A.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 | Vallejo C.G.,Autonomous University of Madrid | And 13 more authors.
Oncotarget | Year: 2015

To understand how mitochondria are involved in malignant transformation we have generated a collection of transmitochondrial cybrid cell lines on the same nuclear background (143B) but with mutant mitochondrial DNA (mtDNA) variants with different degrees of pathogenicity. These include the severe mutation in the tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber's hereditary optic neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A) and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B ρ0 cells devoid of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial dysfunction do not produce tumors when injected in nude mice. By contrast cybrids containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending on OXPHOS dysfunction. The differences in tumorigenicity correlate with an enhanced resistance to apoptosis and high levels of NOX expression. However, the final capacity of the different cybrid cell lines to generate tumors is most likely a consequence of a complex array of pro-oncogenic and anti-oncogenic factors associated with mitochondrial dysfunction. Our results demonstrate the essential role of mtDNA in tumorigenesis and explain the numerous and varied mtDNA mutations found in human tumors, most of which give rise to mild mitochondrial dysfunction.


PubMed | Institute Investigacion Hospital 12 Of Octubre I12, Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 and CIBER ISCIII
Type: | Journal: Acta biomaterialia | Year: 2016

The potential use of human Decidua-derived mesenchymal stem cells (DMSCs) as a platform to carry mesoporous silica nanoparticles in cancer therapy has been investigated. Two types of nanoparticles were evaluated. The nanoparticles showed negligible toxicity to the cells, a fast uptake and a long retention inside them. Nanoparticle location in the cell was studied by colocalization with the lysosomes. Moreover, the in vitro and in vivo migration of DMSCs towards tumors was not modified by the evaluated nanoparticles. Finally, DMSCs transporting doxorubicin-loaded nanoparticles were capable of inducing cancer cell death in vitro.The use of nanotechnology for anticancer drug delivery has recently attracted great interest. Nanoparticles such as mesoporous silica nanoparticles (MSNs) can reach tumors, either by passive targeting, through the enhanced permeability and retention (EPR) effect, or active targeting, through the functionalization of nanoparticle surface. However, nanotechnology has not yet achieved the expected results in improving drug targeting, highlighting the need for a better localization of the nanoparticles in the tumors. Human mesenchymal stem cells from the decidua of the human placenta (DMSCs) have been observed to migrate towards tumors in a preclinical model of breast cancer. Moreover, they have been shown to inhibit growth of primary tumors and development of new tumors. In this work, combining MSNs and DMSCs, we have studied for the first time whether placental stem cells could be employed as a platform to load nanoparticles and carry them towards tumors for future anticancer therapies.


PubMed | Autonomous University of Madrid, University of Valladolid, Rey Juan Carlos University, Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 and Fundacion Jimenez Diaz University Hospital
Type: Journal Article | Journal: PloS one | Year: 2016

The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Lebers hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations.


PubMed | Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 and CIBER ISCIII
Type: Journal Article | Journal: International journal of pharmaceutics | Year: 2015

This work presents the tuning of drug-loaded scaffolds for bone regeneration as dual-drug delivery systems. Two therapeutic substances, zoledronic acid (anti-osteoporotic drug) and ibuprofen (anti-inflammatory drug) were successfully incorporated in a controlled manner into three dimensional designed porous scaffolds of apatite/agarose composite. A high-performance liquid chromatography method was optimized to separate and simultaneously quantify the two drugs released from the dual-drug codelivery system. The multifunctional porous scaffolds fabricated show a very rapid delivery of anti-inflammatory (interesting to reduce inflammation after implantation), whereas the anti-osteoporotic drug showed sustained release behaviour (important to promote bone regeneration). Since ibuprofen release was faster than desired, this drug was encapsulated in chitosan spheres which were then incorporated into the scaffolds, obtaining a release profile suitable for clinical application. The results obtained open the possibility to simultaneously incorporate two or more drugs to an osseous implant in a controlled way improving it for bone healing application.


Manzano R.,University of Zaragoza | Toivonen J.M.,University of Zaragoza | Olivan S.,University of Zaragoza | Calvo A.C.,University of Zaragoza | And 5 more authors.
Neurodegenerative Diseases | Year: 2011

Background: In the superoxide dismutase 1 (SOD1)-G93A mouse model of amyotrophic lateral sclerosis (ALS), skeletal muscle is a key target of mutant SOD1 toxicity. However, the expression of factors that control the regenerative potential of the muscle is unknown in this model. Objective: To characterize the expression of satellite cell marker Pax7 and myogenic regulatory factors (MRF) in skeletal muscle of SOD1-G93A mice at different stages of the disease. Methods: The expressions of Pax7, Myod1, Myf5 and myogenin (Myog) were determined by quantitative real-time PCR and by Western blotting from the grouped gastrocnemius, quadriceps and soleus muscles of SOD1-G93A mice at presymptomatic, symptomatic and terminal stages of the disease, and from surgically denervated wild-type gastrocnemius muscles. Results:Pax7 mRNA and MYF5 protein were upregulated in presymptomatic mice, coinciding with increased muscle damage marker Rrad and chemokine Ccl5. All MRF transcripts and most proteins (excluding MYOG) were increased, starting from 3 months of age, simultaneously with increased expression of denervation marker Chrna1. However, in the terminal stage, no protein increase was evident for Pax7 or any of the MRF despite the increased mRNA levels. The transcripts for chemokine Ccl2 and chemokine receptor Cxcr4 were increased starting from the onset of symptoms. Conclusions: The characterization of Pax7 and MRF in SOD1-G93A mice reveals a progressive induction of the myogenic program at the RNA level, but a blunted protein level response at late stages of the disease. Altered posttranscriptional and posttranslational mechanisms likely to operate, as well as the potential role of chemokine signaling in mutant SOD1 muscle, are discussed. Copyright © 2011 S. Karger AG.


Martinez-Carmona M.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 | Baeza A.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 | Rodriguez-Milla M.A.,Institute Salud Carlos III | Garcia-Castro J.,Institute Salud Carlos III | Vallet-Regi M.,Institute Investigacion Sanitaria Hospital 12 Of Octubre I12
Journal of Materials Chemistry B | Year: 2015

A novel phototriggered drug delivery nanocarrier, which exhibits very high tumor cytotoxicity against human tumoral cells, is presented. This device is based on mesoporous silica nanoparticles decorated with a biocompatible protein shell cleavable by light irradiation. The proteins that compose the protein shell (avidin, streptavidin and biotinylated transferrin) act as targeting and capping agents at the same time, avoiding the use of redundant systems. The light responsive behavior is provided by a biotinylated photocleavable cross-linker covalently grafted on the mesoporous surface, which suffers photocleavage by UV radiation (366 nm). Human tumoral cells incubated in the presence of a very low particle concentration enter into the apoptotic stage after a short irradiation time. Thus, the system described here could be applied to the treatment of exposed tumors that affect the skin, oesophagus, and stomach, among others, and are easily accessible for light irradiation. © The Royal Society of Chemistry 2015.

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