Biocruces Health Research Institute

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Biocruces Health Research Institute

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Andia I.,BioCruces Health Research Institute | Abate M.,University of Chieti Pescara
International Journal of Clinical Rheumatology | Year: 2012

Tendinopathy and osteoarthritis are common chronic musculoskeletal conditions that are associated with frequent pain and reduced function. With the advent of autologous platelet-rich plasma (PRP), new opportunities are available to elucidate potential healing mechanisms and elaborate safe injection therapies. PRP therapy involves the use of autologous activated platelets retained in fibrin matrices as a source of growth factors and cytokines that are active in healing mechanisms, such as inflammation, angiogenesis, cell migration and proliferation. Here we provide an overview of the main components of PRP products relevant to the mechanism of action in tendinopathy and osteoarthritis, and emphasize the importance of identifying and exploiting principal molecular components in PRP for therapeutic benefit. We review the clinical applications of PRP in osteoarthritis and tendinopathy and discuss the current existing challenges. © 2012 Future Medicine Ltd.


Andia I.,Cruces University Hospital | Latorre P.M.,BioCruces Health Research Institute | Gomez M.C.,BioCruces Health Research Institute | Burgos-Alonso N.,BioCruces Health Research Institute | And 2 more authors.
British Medical Bulletin | Year: 2014

Background Platelet-rich plasma (PRP) seeks to meet the multifaceted demand of degenerated tendons providing several molecules capable of boosting healing. Areas timely for developing research PRP is used for managing tendinopathy, but its efficacy is controversial. Sources of data Electronic databases were searched for clinical studies assessing PRP efficacy. Methodological quality was evaluated using the methods described in the Cochrane Handbook for systematic reviews. Areas of agreement Thirteen prospective controlled studies, comprising 886 patients and diverse tendons were included; 53.8% of studies used identical PRP protocol. Areas of controversy Sources of heterogeneity included different comparators, outcome scores, follow-up periods and diverse injection protocols, but not PRP formulation per se. Growing points Pooling pain outcomes over time and across different tendons showed that L-PRP injections ameliorated pain in the intermediate-long term compared with control interventions, weighted mean difference (95% CI): 3 months, -0.61 (-0.97, -0.25); 1 year, -1.56 (-2.27, -0.83). However, these findings cannot be applied to the management of individual patients given low power and precision. Research Further studies circumventing heterogeneity are needed to reach firm conclusions. Available evidence can help to overcome hurdles to future clinical research and bring forward PRP therapies. © The Author 2014.


Muguruza C.,University of the Basque Country | Miranda-Azpiazu P.,University of the Basque Country | Diez-Alarcia R.,University of the Basque Country | Morentin B.,Basque Institute of Legal Medicine | And 5 more authors.
Neuropharmacology | Year: 2014

Several studies have demonstrated alterations in serotonin 5-HT2A (5-HT2AR) and glutamate metabotropic mGlu2 (mGlu2R) receptors in depression, but never in the same sample population. Recently it has been shown that both receptors form a functional receptor heterocomplex that is altered in schizophrenia. The present study evaluates the gene expression and protein density of 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder (n = 14) compared with control subjects (n = 14) in a paired design. No significant differences between subjects with depression and controls in the relative mRNA levels of the genes HTR2A, GRM2 and GRM3 were observed. The 5-HT2AR density evaluated by [3H]ketanserin binding was significantly lower in antidepressant-treated subjects (Bmax = 313 ± 17 fmol/mg protein; p < 0.05) compared to controls (Bmax = 360 ± 12 fmol/mg protein) but not in antidepressant-free subjects (Bmax = 394 ± 16 fmol/mg protein; p > 0.05). In rats, chronic treatment with citalopram (10 mg/kg/day) and mirtazapine (5 mg/kg/day) decreased mRNA expression and 5-HT2AR density whereas reboxetine (20 mg/kg/day) modified only mRNA expression. The mGlu2/3R density evaluated by [3H]LY341495 binding was not significantly different between depression and control subjects. The present results demonstrate no changes in expression and density of both 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder under basal conditions. However, antidepressant treatment induces a decrease in 5-HT2AR density. This finding suggests that 5-HT2AR down-regulation may be a mechanism for antidepressant effect. © 2014 Elsevier Ltd. All rights reserved.


Pulido R.,BioCruces Health Research Institute | Pulido R.,Ikerbasque
Methods | Year: 2015

The PTEN gene is a tumor suppressor gene frequently mutated in human tumors, which encodes a ubiquitous protein whose major activity is to act as a lipid phosphatase that counteracts the action of the oncogenic PI3K. In addition, PTEN displays protein phosphatase- and catalytically-independent activities. The physiologic control of PTEN function, and its inactivation in cancer and other human diseases, including some neurodevelopmental disorders, is upon the action of multiple regulatory mechanisms. This provides a wide spectrum of potential therapeutic approaches to reconstitute PTEN activity. By contrast, inhibition of PTEN function may be beneficial in a different group of human diseases, such as type 2 diabetes or neuroregeneration-related pathologies. This makes PTEN a functionally dual yin-yang protein with high potential in the clinics. Here, a brief overview on PTEN and its relation with human disease is presented. © 2015 Elsevier Inc.


Marroqui L.,Free University of Colombia | Santin I.,Free University of Colombia | Santin I.,BioCruces Health Research Institute | Dos Santos R.S.,Free University of Colombia | And 3 more authors.
Diabetes | Year: 2014

Type 1 diabetes is a chronic autoimmune disease characterized by specific destruction of pancreatic β-cells by the immune system. Linkage and genome-wide association studies have identified more than 50 loci across the human genome associated with risk of type 1 diabetes. Recently, basic leucine zipper transcription factor 2 (BACH2) has been associated with genetic risk to develop type 1 diabetes, in an effect ascribed to the immune system. We evaluated whether BACH2 may also play a role in immune-mediated pancreatic β-cell apoptosis. BACH2 inhibition exacerbated cytokine-induced β-cell apoptosis in human and rodent β-cells by the mitochondrial pathway of cell death, whereas BACH2 overexpression had protective effects. BACH2 silencing and exposure to proinflammatory cytokines increased phosphorylation of the proapoptotic protein JNK1 by upregulation of mitogen-activated protein kinase kinase 7 (MKK7) and downregulation of PTPN2. JNK1 increased phosphorylation of the proapoptotic protein BIM, and both JNK1 and BIM knockdown protected β-cells against cytokine-induced apoptosis in BACH2-silenced cells. The present findings suggest that the type 1 diabetes candidate gene BACH2 regulates proinflammatory cytokine-induced apoptotic pathways in pancreatic β-cells by crosstalk with another candidate gene, PTPN2, and activation of JNK1 and BIM. This clarifies an unexpected and relevant mechanism by which BACH2 may contribute to diabetes. © 2014 by the American Diabetes Association.


Arechavala-Gomeza V.,BioCruces Health Research institute | Khoo B.,University College London | Aartsma-Rus A.,Leiden University
Application of Clinical Genetics | Year: 2014

Antisense-mediated splicing modulation is a tool that can be exploited in several ways to provide a potential therapy for rare genetic diseases. This approach is currently being tested in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy. The present review outlines the versatility of the approach to correct cryptic splicing, modulate alternative splicing, restore the open reading frame, and induce protein knockdown, providing examples of each. Finally, we outline a possible path forward toward the clinical application of this approach for a wide variety of inherited rare diseases. © 2014 Arechavala-Gomeza et al.


Alonso A.,University of Valladolid | Pulido R.,Biocruces Health Research Institute | Pulido R.,Ikerbasque
FEBS Journal | Year: 2016

Tyr phosphatases are, by definition, enzymes that dephosphorylate phospho-Tyr (pTyr) from proteins. This activity is found in several structurally diverse protein families, including the protein Tyr phosphatase (PTP), arsenate reductase, rhodanese, haloacid dehalogenase (HAD) and His phosphatase (HP) families. Most of these families include members with substrate specificity for non-pTyr substrates, such as phospho-Ser/phospho-Thr, phosphoinositides, phosphorylated carbohydrates, mRNAs, or inorganic moieties. A Cys is essential for catalysis in PTPs, rhodanese and arsenate reductase enzymes, whereas this work is performed by an Asp in HAD phosphatases and by a His in HPs, via a catalytic mechanism shared by all of the different families. The category that contains most Tyr phosphatases is the PTP family, which, although it received its name from this activity, includes Ser, Thr, inositide, carbohydrate and RNA phosphatases, as well as some inactive pseudophosphatase proteins. Here, we propose an extended collection of human Tyr phosphatases, which we call the extended human PTPome. The addition of new members (SACs, paladin, INPP4s, TMEM55s, SSU72, and acid phosphatases) to the currently categorized PTP group of enzymes means that the extended human PTPome contains up to 125 proteins, of which ~ 40 are selective for pTyr. We set criteria to ascribe proteins to the extended PTPome, and summarize the more important features of the new PTPome members in the context of their phosphatase activity and their relationship with human disease. Dephosphorylation of phospho-Tyr from proteins is exerted by several protein families, including Cys-, Asp-, and His-based PTPs, and several PTPs display substrate specificity towards non-phospho-Tyr substrates, such as phospho-Ser/Thr or phospho-inositides, among others. Here, we define criteria to ascribe proteins to the Tyr phosphatase family (extended PTPome), present an open list of PTPome members, and summarize their more important features and their relation with human disease. © 2015 FEBS.


Zenarruzabeitia O.,BioCruces Health Research Institute | Vitalle J.,BioCruces Health Research Institute | Eguizabal C.,Cell Therapy and Stem Cell Group | Simhadri V.R.,Review Centre | And 2 more authors.
Journal of Immunology | Year: 2015

The CD300a inhibitory receptor belongs to the CD300 family of cell surface molecules that regulate a diverse array of immune cell processes. The inhibitory signal of CD300a depends on the phosphorylation of tyrosine residues embedded in ITIMs of the cytoplasmic tail. CD300a is broadly expressed on myeloid and lymphoid cells, and its expression is differentially regulated depending on the cell type. The finding that CD300a recognizes phosphatidylserine and phosphatidylethanolamine, two aminophospholipids exposed on the outer leaflet of dead and activated cells, has shed new light on its role in the modulation of immune functions and in its participation in the host response to several diseases states, such as infectious diseases, cancer, allergy, and chronic inflammatory diseases. This review summarizes the literature on CD300a expression, regulation, signaling pathways, and ligand interaction, as well as its role in fine tuning immune cell functions and its clinical relevance. Copyright © 2015 by The American Association of Immunologists, Inc.


Hendriks W.J.A.J.,Radboud University Nijmegen | Pulido R.,BioCruces Health Research Institute | Pulido R.,Ikerbasque
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism to steer normal development and physiological functioning of multicellular organisms. Phosphotyrosine dephosphorylation is exerted by members of the super-family of protein tyrosine phosphatase (PTP) enzymes and many play such essential roles that a wide variety of hereditary disorders and disease susceptibilities in man are caused by PTP alleles. More than two decades of PTP research has resulted in a collection of PTP genetic variants with corresponding consequences at the molecular, cellular and physiological level. Here we present a comprehensive overview of these PTP gene variants that have been linked to disease states in man. Although the findings have direct bearing for disease diagnostics and for research on disease etiology, more work is necessary to translate this into therapies that alleviate the burden of these hereditary disorders and disease susceptibilities in man. © 2013 The Authors.


Pulido R.,BioCruces Health Research Institute | Pulido R.,Ikerbasque | Stoker A.W.,University College London | Hendriks W.J.A.J.,Radboud University Nijmegen
Human Molecular Genetics | Year: 2013

Protein tyrosine phosphatases (PTPs) constitute a family of key homeostatic regulators, with wide implications on physiology and disease. Recent findings have unveiled that the biological activity of PTPs goes beyond the dephosphorylation of phospho-proteins to shut down protein tyrosine kinase-driven signaling cascades. Substrates dephosphorylated by clinically relevant PTPs extend to phospholipids and phosphorylated carbohydrates as well. In addition, non-catalytic functions are also used by PTPs to regulate essential cellular functions. Consequently, PTPs have emerged as novel potential therapeutic targets for human diseases, including cancer predispositions, myopathies and neuropathies. In this review, we highlight recent advances on the multifaceted role of lipid-phosphatase PTPs in human pathology, with an emphasis on hereditary diseases. The involved PTP regulatory networks and PTP modulatory strategies with potential therapeutic application are discussed. © The Author 2013. Published by Oxford University Press. All rights reserved.

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