University of Leuven Medical School

Brussels, Belgium

University of Leuven Medical School

Brussels, Belgium
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Dadhich R.K.,University of Granada | Dadhich R.K.,University of Leuven Medical School | Barrionuevo F.J.,University of Granada | Real F.M.,University of Granada | And 5 more authors.
Biology of Reproduction | Year: 2013

In males of seasonally breeding species, testes undergo a severe involution at the end of the breeding season, with a major volume decrease due to massive germ-cell depletion associated with photoperiod-dependent reduced levels of testosterone and gonadotropins. Although it has been repeatedly suggested that apoptosis is the principal effector of testicular regression in vertebrates, recent studies do not support this hypothesis in some mammals. The purpose of our work is to discover alternative mechanisms of testis regression in these species. In this paper, we have performed a morphological, hormonal, ultrastructural, molecular, and functional study of the mechanism of testicular regression and the role that cell junctions play in the cell-content dynamics of the testis of the Iberian mole, Talpa occidentalis, throughout the seasonal breeding cycle. Desquamation of live, nonapoptotic germ cells has been identified here as a new mechanism for seasonal testis involution in mammals, indicating that testis regression is regulated by modulating the expression and distribution of the cell-adhesion molecules in the seminiferous epithelium. During this process, which is mediated by low intratesticular testosterone levels, Sertoli cells lose their nursing and supporting function, as well as the impermeability of the blood-testis barrier. Our results contradict the current paradigm that apoptosis is the major testis regression effector in vertebrates, as it is clearly not true in all mammals. The new testis regression mechanism described here for the mole could then be generalized to other mammalian species. Available data from some previously studied mammals should be reevaluated.


PubMed | University of Malaga, University of Navarra and University of Leuven Medical School
Type: | Journal: Scientific reports | Year: 2017

This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p<0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p<0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p<0.01) and serum (p<0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p<0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p<0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF.


Jinnah H.A.,Emory University | Sabina R.L.,Oakland University | Van Den Berghe G.,University of Leuven Medical School
Handbook of Clinical Neurology | Year: 2013

The purines are a group of molecules used by all cells for many vital biochemical processes including energy-requiring enzymatic reactions, cofactor-requiring reactions, synthesis of DNA or RNA, signaling pathways within and between cells, and other processes. Defects in some of the enzymes of purine metabolism are known to be associated with specific clinical disorders, and neurological problems may be a presenting sign or the predominant clinical problem for several of them. This chapter describes three disorders for which the clinical features and metabolic basis are well characterized. Deficiency of adenylosuccinate-lyase (ADSL) causes psychomotor retardation, epilepsy, and autistic features. Lesch-Nyhan disease is caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and is characterized by hyperuricemia, motor and cognitive disability, and self-injurious behavior. Deficiency of myoadenylate deaminase (mAMPD) is associated with myopathic features. In addition to these disorders, several other disorders are briefly summarized. These include defects of phosphoribosylpyrophosphate synthase, adenosine deaminase (ADA), purine nucleoside phosphorylase (PND), deoxyguanosine kinase (dGK), or IMP dehydrogenase (IMPDH). Each of these disorders provides an unusual window on the unique importance of purine metabolism for function of different parts of the nervous system. © 2013 Elsevier B.V.


Maritzen T.,Charité - Medical University of Berlin | Schmidt M.R.,Charité - Medical University of Berlin | Kukhtina V.,Charité - Medical University of Berlin | Higman V.A.,Leibniz Institute for Molecular Pharmacology | And 6 more authors.
Journal of Biological Chemistry | Year: 2010

Membrane traffic between the trans-Golgi network (TGN) and endosomes is mediated in part by the assembly of clathrin-AP-1 adaptor complex-coated vesicles. This process involves multiple accessory proteins that directly bind to the ear domain of AP-1γ via degenerate peptide motifs that conform to the consensus sequence ∅G(P/D/E)(∅/L/M) (with ∅ being a large hydrophobic amino acid). Recently, γ-BAR (hereafter referred to as Gadkin for reasons explained below) has been identified as a novel AP-1 recruitment factor involved in AP-1-dependent endosomal trafficking of lysosomal enzymes. How precisely Gadkin interacts with membranes and with AP-1γ has remained unclear. Here we show that Gadkin is an S-palmitoylated peripheral membrane protein that lacks stable tertiary structure. S-Palmitoylation is required for the recruitment of Gadkin to TGN/endosomal membranes but not for binding to AP-1. Furthermore, we identify a novel subtype of AP-1-binding motif within Gadkin that specifically associates with the γ1-adaptin ear domain. Mutational inactivation of this novel type of motif, either alone or in combination with three more conventional AP-1γ binding peptides, causes Gadkin to mislocalize to the plasma membrane and interferes with its ability to render AP-1 brefeldin A-resistant, indicating its physiological importance. Our studies thus unravel the molecular basis for Gadkin-mediated AP-1 recruitment to TGN/endosomal membranes and identify a novel subtype of the AP-1-binding motif. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Tran H.T.,Vlaams Institute for Biotechnology | Tran H.T.,Ghent University | Sekkali B.,Vlaams Institute for Biotechnology | Sekkali B.,Ghent University | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

The formation of primitive (embryonic) blood in vertebrates is mediated by spatio-temporally restricted signaling between different tissue layers. In Xenopus, in which primitive blood originates in the ventral blood island, this involves the secretion of bone morphogenetic protein (BMP) ligands by the ectoderm that signal to the underlying mesoderm during gastrulation. Using novel transgenic reporter lines, we report that the canonical Wnt/β-catenin pathway is also activated in the blood islands in Xenopus. Furthermore, Wnt-reporter activity was also detected in the blood islands of the mouse yolk sac. By using morpholino-mediated depletion in Xenopus, we identified Wnt4 as the ligand that is expressed in the mesoderm of the ventral blood island and is essential for the expression of hematopoietic and erythroid marker genes. Injection of an inducible Wnt-interfering construct further showed that, during gastrulation, Wnt/β-catenin signaling is required both in the mesoderm and in the overlying ectoderm for the formation of the ventral blood island. Using recombination assays with embryonic explants, we document that ectodermal BMP4 expression is dependent on Wnt4 signals from the mesoderm. Our results thus reveal a unique role for Wnt4-mediated canonical signaling in the formation and maintenance of the ventral blood island in Xenopus.


Rath G.,University of Leuven Medical School | Saliez J.,University of Leuven Medical School | Behets G.,University of Leuven Medical School | Romero-Perez M.,University of Leuven Medical School | And 6 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

Objective-We investigated the impact of hypoxia-reoxygenation on endothelial relaxation and aimed to clarify the role of transient receptor potential cation channels V4 (TRPV4) and gap junctions in the protective effect associated with hypoxic preconditioning on the vascular function. Methods and Results-By mimicking ischemia-reperfusion in C57BL/6 male mice in vivo, we documented a reduced NO-mediated relaxation and an increased endothelium-derived hyperpolarization (EDH[F])-mediated relaxation. Hypoxic preconditioning, however, restored NO relaxation and further improved the EDH(F) response. We also examined specifically 2 major effectors of the EDH(F) pathway, transient receptor potential cation channels V4 and connexins. We found that in endothelial cells, expression and activity of transient receptor potential cation channels V4 were increased by hypoxic stimuli independently of preconditioning which was interestingly associated with an increase of structural caveolar component caveolin-1 at membrane locations. Gap junctions, however, seemed to directly support EDH(F)-driven preconditioning as connexin 40 and connexin 43 expression increased and as in vivo carbenoxolone treatment completely inhibited the EDH(F) pathway and significantly reduced the protection afforded by preconditioning for the concomitant NO-mediated relaxation. Conclusion-Our work provides evidence on how transient receptor potential cation channels V4 and connexins might participate in preserving vasorelaxation under hypoxia and restoring the NO-mediated pathway in hypoxic preconditioning conditions pointing out caveolae as a common signaling location. © 2012 American Heart Association, Inc.


Jossin Y.,Fred Hutchinson Cancer Research Center | Jossin Y.,University of Leuven Medical School
Small GTPases | Year: 2011

Neuronal migration is essential for the development of the cerebral cortex. Mutations leading to defective migration are associated with numerous brain pathologies. An important challenge in the field is to understand the intrinsic and extrinsic mechanisms that regulate neuronal migration during normal development and in disease. Many small GTPases are expressed in the central nervous system during embryonic development. Recent findings have shown that Rap1 and its downstream partners Ral, Rac and Cdc42 are involved in themaintenance of N-Cadherin at the plasma membrane which is necessary for the correct polarization of migrating neurons. The activation of Rap1 is triggered by Reelin, an extracellular protein known for its role in the organization of the cortex into layers of neurons. In the absence of Reelin, neurons exhibit a broader and irregular pattern of positioning. The prevailing model suggests that Reelin signals to neurons during the last step of their migration, a notion that is inconsistent with new data describing an effect of Reelin on early steps of migration. In regard to these recent findings I suggest a revised model, which I call the "polarity model," that further refines our understanding of the developmental function played by Reelin and its downstream small GTPases. © 2011 Landes Bioscience.


Porporato P.E.,University of Leuven Medical School | Dhup S.,University of Leuven Medical School | Dadhich R.K.,University of Leuven Medical School | Copetti T.,University of Leuven Medical School | Sonveaux P.,University of Leuven Medical School
Frontiers in Pharmacology | Year: 2011

Cancer is a metabolic disease and the solution of two metabolic equations: to produce energy with limited resources and to fulfill the biosynthetic needs of proliferating cells. Both equations are solved when glycolysis is uncoupled from oxidative phosphorylation in the tricarboxylic acid cycle, a process known as the glycolytic switch. This review addresses in a comprehensive manner the main molecular events accounting for high-rate glycolysis in cancer. It starts from modulation of the Pasteur Effect allowing short-term adaptation to hypoxia, highlights the key role exerted by the hypoxia-inducible transcription factor HIF-1 in long-term adaptation to hypoxia, and summarizes the current knowledge concerning the necessary involvement of aerobic glycolysis (theWarburg effect) in cancer cell proliferation. Based on the many observations positioning glycolysis as a central player in malignancy, the most advanced anticancer treatments targeting tumor glycolysis are briefly reviewed. © 2011 Porporato, Dhup, Dadhich, Copetti and Sonveaux.


Glineur D.,University of Leuven Medical School | Boodhwani M.,University of Leuven Medical School | Poncelet A.,University of Leuven Medical School | De Kerchove L.,University of Leuven Medical School | And 6 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2010

Background: Composite Y-grafts, using the left internal thoracic artery as the inflow, allow a more efficient use of conduits without the need to touch a diseased ascending aorta. Among other conduits, the saphenous vein graft may be an alternative to the radial artery in elderly patients. Patients and Methods: We evaluated the hemodynamic characteristics of 17 composite Y-grafts made with the left internal thoracic artery anastomosed to the left anterior descending coronary artery in all cases and with either the free right internal thoracic artery (RITA group, n = 10) or a saphenous vein graft (SVG group, n = 7) implanted proximally to the left internal thoracic artery and distally to the circumflex territory 6 months after the operation. Results: At baseline, the pressure gradient measured with a 0.014-inch pressure wire was minimal between the aorta and the internal thoracic artery stem (2 ± 1 mm Hg), the internal thoracic artery and left anterior descending (4 ± 2 mm Hg), the internal thoracic artery and left circumflex (3 ± 1 mm Hg), and the saphenous vein graft and left circumflex (2 ± 2 mm Hg). During hyperemia induced by adenosine, the pressure gradient increased significantly to 6 ± 2 mm Hg in the internal thoracic artery stem, 9 ± 4 mm Hg in the internal thoracic artery and left anterior descending artery, 9 ± 3 mm Hg in the internal thoracic artery and left circumflex, and 7 ± 4 mm Hg in the saphenous vein graft and left circumflex. Fractional flow reserve was 0.94 ± 0.02 in internal thoracic artery stem, 0.90 ± 0.04 mm Hg in the internal thoracic artery and left anterior descending, 0.91 ± 0.03 mm Hg in the internal thoracic artery and left circumflex, and 0.92 ± 0.06 mm Hg in the saphenous vein graft and left circumflex. No difference between the two types of composite Y-grafts was observed for pressure gradients or fractional flow reserve measured in internal thoracic artery stem or in distal branches. Conclusions: Composite Y-grafts with saphenous vein or right internal thoracic arteries allow similar and adequate reperfusion of the left system with minimal resistance to maximal flow and an even distribution of flow in both distal branches. © 2010 by The American Association for Thoracic Surgery.


Boidot R.,Center Georges Francois Leclerc | Boidot R.,University of Leuven Medical School | Vegran F.,Center Georges Francois Leclerc | Vegran F.,University of Leuven Medical School | And 6 more authors.
Oncogene | Year: 2010

Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas. © 2010 Macmillan Publishers Limited All rights reserved.

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