117 results on '"Wielockx, Ben"'
Search Results
2. Liquid chromatography-tandem mass spectrometry based quantification of arginine metabolites including polyamines in different sample matrices
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Langner, Mathias, Mateska, Ivona, Bechmann, Nicole, Wielockx, Ben, Chavakis, Triantafyllos, Alexaki, Vasileia Ismini, and Peitzsch, Mirko
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- 2022
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3. Dickkopf1 fuels inflammatory cytokine responses
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Jaschke, Nikolai P., Pählig, Sophie, Sinha, Anupam, Adolph, Timon E., Colunga, Maria Ledesma, Hofmann, Maura, Wang, Andrew, Thiele, Sylvia, Schwärzler, Julian, Kleymann, Alexander, Gentzel, Marc, Tilg, Herbert, Wielockx, Ben, Hofbauer, Lorenz C., Rauner, Martina, Göbel, Andy, and Rachner, Tilman D.
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- 2022
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4. Intertwined regulators: hypoxia pathway proteins, microRNAs, and phosphodiesterases in the control of steroidogenesis.
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Ariyeloye, Stephen, Kämmerer, Susanne, Klapproth, Erik, Wielockx, Ben, and El-Armouche, Ali
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HYPOXIA-inducible factors ,GENE expression ,REGULATOR genes ,IMMUNOLOGIC diseases ,TRANSCRIPTION factors - Abstract
Oxygen sensing is of paramount importance for maintaining cellular and systemic homeostasis. In response to diminished oxygen levels, the hypoxia-inducible factors (HIFs) orchestrate various biological processes. These pivotal transcription factors have been identified as key regulators of several biological events. Notably, extensive research from our group and others has demonstrated that HIF1α exerts an inverse regulatory effect on steroidogenesis, leading to the suppression of crucial steroidogenic enzyme expression and a subsequent decrease in steroid levels. These steroid hormones occupy pivotal roles in governing a myriad of physiological processes. Substantial or prolonged fluctuations in steroid levels carry detrimental consequences across multiple organ systems and underlie various pathological conditions, including metabolic and immune disorders. MicroRNAs serve as potent mediators of multifaceted gene regulatory mechanisms, acting as influential epigenetic regulators that modulate a broad spectrum of gene expressions. Concomitantly, phosphodiesterases (PDEs) play a crucial role in governing signal transduction. PDEs meticulously manage intracellular levels of both cAMP and cGMP, along with their respective signaling pathways and downstream targets. Intriguingly, an intricate interplay seems to exist between hypoxia signaling, microRNAs, and PDEs in the regulation of steroidogenesis. This review highlights recent advances in our understanding of the role of microRNAs during hypoxia-driven processes, including steroidogenesis, as well as the possibilities that exist in the application of HIF prolyl hydroxylase (PHD) inhibitors for the modulation of steroidogenesis. [ABSTRACT FROM AUTHOR]
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- 2024
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5. HIF1α is a direct regulator of steroidogenesis in the adrenal gland
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Watts, Deepika, Stein, Johanna, Meneses, Ana, Bechmann, Nicole, Neuwirth, Ales, Kaden, Denise, Krüger, Anja, Sinha, Anupam, Alexaki, Vasileia Ismini, Luis Gustavo Perez-Rivas, Kircher, Stefan, Martinez, Antoine, Theodoropoulou, Marily, Eisenhofer, Graeme, Peitzsch, Mirko, El-Armouche, Ali, Chavakis, Triantafyllos, and Wielockx, Ben
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- 2021
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6. From Vessels to Neurons—The Role of Hypoxia Pathway Proteins in Embryonic Neurogenesis.
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Stepien, Barbara K. and Wielockx, Ben
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NEURAL stem cells , *DEVELOPMENTAL neurobiology , *NEUROGENESIS , *HYPOXEMIA , *HYPOXIA-inducible factors , *CENTRAL nervous system , *FETAL development - Abstract
Embryonic neurogenesis can be defined as a period of prenatal development during which divisions of neural stem and progenitor cells give rise to neurons. In the central nervous system of most mammals, including humans, the majority of neocortical neurogenesis occurs before birth. It is a highly spatiotemporally organized process whose perturbations lead to cortical malformations and dysfunctions underlying neurological and psychiatric pathologies, and in which oxygen availability plays a critical role. In case of deprived oxygen conditions, known as hypoxia, the hypoxia-inducible factor (HIF) signaling pathway is activated, resulting in the selective expression of a group of genes that regulate homeostatic adaptations, including cell differentiation and survival, metabolism and angiogenesis. While a physiological degree of hypoxia is essential for proper brain development, imbalanced oxygen levels can adversely affect this process, as observed in common obstetrical pathologies such as prematurity. This review comprehensively explores and discusses the current body of knowledge regarding the role of hypoxia and the HIF pathway in embryonic neurogenesis of the mammalian cortex. Additionally, it highlights existing gaps in our understanding, presents unanswered questions, and provides avenues for future research. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss
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Rauner, Martina, Murray, Marta, Thiele, Sylvia, Watts, Deepika, Neumann, Drorit, Gabet, Yankel, Hofbauer, Lorenz C., and Wielockx, Ben
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- 2021
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8. Hematopoietic stem cell response to acute thrombocytopenia requires signaling through distinct receptor tyrosine kinases
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Ramasz, Beáta, Krüger, Anja, Reinhardt, Julia, Sinha, Anupam, Gerlach, Michael, Gerbaulet, Alexander, Reinhardt, Susanne, Dahl, Andreas, Chavakis, Triantafyllos, Wielockx, Ben, and Grinenko, Tatyana
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- 2019
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9. CD38 promotes hematopoietic stem cell dormancy.
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Ibneeva, Liliia, Singh, Sumeet Pal, Sinha, Anupam, Eski, Sema Elif, Wehner, Rebekka, Rupp, Luise, Kovtun, Iryna, Pérez-Valencia, Juan Alberto, Gerbaulet, Alexander, Reinhardt, Susanne, Wobus, Manja, von Bonin, Malte, Sancho, Jaime, Lund, Frances, Dahl, Andreas, Schmitz, Marc, Bornhäuser, Martin, Chavakis, Triantafyllos, Wielockx, Ben, and Grinenko, Tatyana
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HEMATOPOIETIC stem cells ,CD38 antigen ,ADENOSINE diphosphate ribose ,STEM cell transplantation ,TRANSCRIPTION factors - Abstract
A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs. The state of dormancy protects the HSC pool from exhaustion throughout life; however, excessive dormancy may prevent an efficient response to hematological stresses. Despite the significance of dHSCs, the mechanisms maintaining their dormancy remain elusive. Here, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. We demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing the release of Ca
2+ from the endoplasmic reticulum (ER). Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57Kip2 to drive HSC dormancy. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+ /c-Fos/p57Kip2 axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease. Dormant hematopoietic stem cells (dHSC) represent a stem cell reserve that is important for hematopoiesis throughout life. In this study, CD38 is identified as a surface marker and novel regulator of mouse HSCs that promotes their dormancy. Interestingly, while human HSCs lack CD38 expression, CD38 expression in neighboring cells similarly promotes human HSC quiescence. [ABSTRACT FROM AUTHOR]- Published
- 2024
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10. DEL-1 promotes macrophage efferocytosis and clearance of inflammation
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Kourtzelis, Ioannis, Li, Xiaofei, Mitroulis, Ioannis, Grosser, Daniel, Kajikawa, Tetsuhiro, Wang, Baomei, Grzybek, Michal, von Renesse, Janusz, Czogalla, Aleksander, Troullinaki, Maria, Ferreira, Anaisa, Doreth, Christian, Ruppova, Klara, Chen, Lan-Sun, Hosur, Kavita, Lim, Jong-Hyung, Chung, Kyoung-Jin, Grossklaus, Sylvia, Tausche, Anne Kathrin, Joosten, Leo A. B., Moutsopoulos, Niki M., Wielockx, Ben, Castrillo, Antonio, Korostoff, Jonathan M., Coskun, Ünal, Hajishengallis, George, and Chavakis, Triantafyllos
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- 2019
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11. Hyporesponsiveness of SPRET/Ei Mice to Lethal Shock Induced by Tumor Necrosis Factor and Implications for a TNF-Based Antitumor Therapy
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Staelens, Jan, Wielockx, Ben, Puimège, Leen, Van Roy, Frans, Guénet, Jean-Louis, and Libert, Claude
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- 2002
12. PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome.
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Vetrivel, Sharmilee, Tamburello, Mariangela, Oßwald, Andrea, Ru Zhang, Khan, Ali, Sara Jung, Baker, Jessica E., Rainey, William E., Nowak, Elisabeth, Altieri, Barbara, Detomas, Mario, Watts, Deepika, Williams, Tracy Ann, Wielockx, Ben, Beuschlein, Felix, Reincke, Martin, Sbiera, Silviu, and Riester, Anna
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CUSHING'S syndrome ,DRUG target ,PEROXISOME proliferator-activated receptors ,CORTISONE ,NUCLEOTIDE sequencing ,ADENOMATOUS polyps - Abstract
Background: We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing’s syndrome (CS) to define areas of dysregulated and druggable targets. Methodology: Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing’s disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1). Results: Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes – FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) – were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively. Outcome: This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
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Alissafi, Themis, Hatzioannou, Aikaterini, Mintzas, Konstantinos, Barouni, Roza Maria, Banos, Aggelos, Sormendi, Sundary, Polyzos, Alexandros, Xilouri, Maria, Wielockx, Ben, Gogas, Helen, and Verginis, Panayotis
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Cancer treatment -- Research ,Autophagy (Cytology) -- Health aspects ,Suppressor cells -- Physiological aspects -- Health aspects ,Immunologic research ,Immune response -- Health aspects ,Health care industry - Abstract
Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune responses. Notably, tumor- infiltrating autophagy-deficient monocytic MDSCs (M-MDSCs) demonstrated impaired suppressive activity in vitro and in vivo, whereas transcriptome analysis revealed substantial differences in genes related to lysosomal function. Accordingly, autophagy-deficient M- MDSCs exhibited impaired lysosomal degradation, thereby enhancing surface expression of MHC class II molecules, resulting in efficient activation of tumor-specific [CD4.sup.+] T cells. Finally, targeting of the membrane-associated RING-CH1 (MARCH1) E3 ubiquitin ligase that mediates the lysosomal degradation of MHC II in M-MDSCs attenuated their suppressive function, and resulted in markedly decreased tumor volume followed by development of a robust antitumor immunity. Collectively, these findings depict autophagy as a molecular target of MDSC-mediated suppression of antitumor immunity., Introduction The effectiveness of current cancer immunotherapies is critically dependent on the presence of activated effector T cells in the tumor microenvironment (TME), and preexisting T cell infiltration in solid [...]
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- 2018
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14. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche
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Mitroulis, Ioannis, Chen, Lan-Sun, Singh, Rashim Pal, Kourtzelis, Ioannis, Economopoulou, Matina, Kajikawa, Tetsuhiro, Troullinaki, Maria, Ziogas, Athanasios, Ruppova, Klara, Hosur, Kavita, Maekawa, Tomoki, Wang, Baomei, Subramanian, Pallavi, Tonn, Torsten, Verginis, Panayotis, von Bonin, Malte, Wobus, Manja, Bornhauser, Martin, Grinenko, Tatyana, Di Scala, Marianna, Hidalgo, Andres, Wielockx, Ben, Hajishengallis, George, and Chavakis, Triantafyllos
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Hematopoietic stem cells -- Health aspects ,Health care industry - Abstract
Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by [beta] integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis., Introduction Hematopoietic stem cells (HSC) lie at the core of the hematopoietic and immune systems and have a unique capacity for self-renewal and differentiation to multipotent and lineage-committed hematopoietic progenitors, [...]
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- 2017
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15. HIF-1α Promotes Glutamine-Mediated Redox Homeostasis and Glycogen-Dependent Bioenergetics to Support Postimplantation Bone Cell Survival
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Stegen, Steve, van Gastel, Nick, Eelen, Guy, Ghesquière, Bart, D’Anna, Flora, Thienpont, Bernard, Goveia, Jermaine, Torrekens, Sophie, Van Looveren, Riet, Luyten, Frank P., Maxwell, Patrick H., Wielockx, Ben, Lambrechts, Diether, Fendt, Sarah-Maria, Carmeliet, Peter, and Carmeliet, Geert
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- 2016
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16. HIF prolyl hydroxylase 2/3 deletion disrupts astrocytic integrity and exacerbates neuroinflammation.
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Rosiewicz, Kamil Sebastian, Muinjonov, Bakhrom, Kunz, Séverine, Radbruch, Helena, Chen, Jessy, Jüttner, René, Kerkering, Janis, Ucar, Julia, Crowley, Tadhg, Wielockx, Ben, Paul, Friedemann, Alisch, Marlen, and Siffrin, Volker
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- 2023
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17. Succinate mediates inflammation-induced adrenocortical dysfunction.
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Mateska, Ivona, Witt, Anke, Hagag, Eman, Sinha, Anupam, Yilmaz, Canelif, Thanou, Evangelia, Sun, Na, Kolliniati, Ourania, Patschin, Maria, Abdelmegeed, Heba, Henneicke, Holger, Kanczkowski, Waldemar, Wielockx, Ben, Tsatsanis, Christos, Dahl, Andreas, Walch, Axel Karl, Ka Wan Li, Peitzsch, Mirko, Chavakis, Triantafyllos, and Alexaki, Vasileia Ismini
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- 2023
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18. Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice
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Grinenko, Tatyana, Eugster, Anne, Thielecke, Lars, Ramasz, Beáta, Krüger, Anja, Dietz, Sevina, Glauche, Ingmar, Gerbaulet, Alexander, von Bonin, Malte, Basak, Onur, Clevers, Hans, Chavakis, Triantafyllos, and Wielockx, Ben
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- 2018
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19. HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress
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Singh, Rashim Pal, Franke, Kristin, Kalucka, Joanna, Mamlouk, Soulafa, Muschter, Antje, Gembarska, Agnieszka, Grinenko, Tatyana, Willam, Carsten, Naumann, Ronald, Anastassiadis, Konstantinos, Stewart, A. Francis, Bornstein, Stefan, Chavakis, Triantafyllos, Breier, Georg, Waskow, Claudia, and Wielockx, Ben
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- 2013
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20. Haematopoietic prolyl hydroxylase‐1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis
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Van Welden, Sophie, De Vos, Martine, Wielockx, Ben, Tavernier, Simon J, Dullaers, Melissa, Neyt, Sara, Descamps, Benedicte, Devisscher, Lindsey, Devriese, Sarah, Van den Bossche, Lien, Holvoet, Tom, Baeyens, Ann, Correale, Carmen, DʼAlessio, Silvia, Vanhove, Christian, De Vos, Filip, Verhasselt, Bruno, Breier, Georg, Lambrecht, Bart N, Janssens, Sophie, Carmeliet, Peter, Danese, Silvio, Elewaut, Dirk, Laukens, Debby, and Hindryckx, Pieter
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- 2017
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21. The impact of hepatocytespecific deletion of hypoxiainducible factors on the development of polymicrobial sepsis with focus on GR and PPARα function.
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Vanderhaeghen, Tineke, Timmermans, Steven, Eggermont, Melanie, Watts, Deepika, Vandewalle, Jolien, Wallaeys, Charlotte, Nuyttens, Louise, De Temmerman, Joyca, Hochepied, Tino, Dewaele, Sylviane, Berghe, Joke Vanden, Sanders, Niek, Wielockx, Ben, Beyaert, Rudi, and Libert, Claude
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KNOCKOUT mice ,SEPSIS ,WHITE adipose tissue ,PEROXISOME proliferator-activated receptors ,FREE fatty acids - Abstract
Introduction: Polymicrobial sepsis causes acute anorexia (loss of appetite), leading to lipolysis in white adipose tissue and proteolysis in muscle, and thus release of free fatty acids (FFAs), glycerol and gluconeogenic amino acids. Since hepatic peroxisome proliferator-activated receptor alpha (PPARa) and glucocorticoid receptor (GR) quickly lose function in sepsis, these metabolites accumulate (causing toxicity) and fail to yield energy-rich molecules such as ketone bodies (KBs) and glucose. The mechanism of PPARa and GR dysfunction is not known. Methods & results: We investigated the hypothesis that hypoxia and/or activation of hypoxia inducible factors (HIFs) might play a role in these issues with PPARa and GR. After cecal ligation and puncture (CLP) in mice, leading to lethal polymicrobial sepsis, bulk liver RNA sequencing illustrated the induction of the genes encoding HIF1α and HIF2α, and an enrichment of HIF-dependent gene signatures. Therefore, we generated hepatocyte-specific knock-out mice for HIF1α, HIF2α or both, and a new HRE-luciferase reporter mouse line. After CLP, these HRE-luciferase reporter mice show signals in several tissues, including the liver. Hydrodynamic injection of an HRE-luciferase reporter plasmid also led to (liver-specific) signals in hypoxia and CLP. Despite these encouraging data, however, hepatocyte-specific HIF1α and/or HIF2α knock-out mice suggest that survival after CLP was not dependent on the hepatocytespecific presence of HIF proteins, which was supported by measuring blood levels of glucose, FFAs, and KBs. The HIF proteins were also irrelevant in the CLPinduced glucocorticoid resistance, but we found indications that the absence of HIF1α in hepatocytes causes less inactivation of PPARa transcriptional function. Conclusion: We conclude that HIF1α and HIF2α are activated in hepatocytes in sepsis, but their contribution to the mechanisms leading to lethality are minimal. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Hypoxia signaling pathway: A central mediator in endocrine tumors.
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Watts, Deepika, Jaykar, Mangesh T., Bechmann, Nicole, and Wielockx, Ben
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CELLULAR signal transduction ,HYPOXEMIA ,PARAGANGLIOMA ,OXYGEN detectors ,ADRENAL tumors ,ADRENAL glands ,ENDOCRINE system - Abstract
Adequate oxygen levels are essential for the functioning and maintenance of biological processes in virtually every cell, albeit based on specific need. Thus, any change in oxygen pressure leads to modulated activation of the hypoxia pathway, which affects numerous physiological and pathological processes, including hematopoiesis, inflammation, and tumor development. The Hypoxia Inducible Factors (HIFs) are essential transcription factors and the driving force of the hypoxia pathway; whereas, their inhibitors, HIF prolyl hydroxylase domain (PHDs) proteins are the true oxygen sensors that critically regulate this response. Recently, we and others have described the central role of the PHD/HIF axis in various compartments of the adrenal gland and its potential influence in associated tumors, including pheochromocytomas and paragangliomas. Here, we provide an overview of the most recent findings on the hypoxia signaling pathway in vivo, including its role in the endocrine system, especially in adrenal tumors. [ABSTRACT FROM AUTHOR]
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- 2023
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23. Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice.
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Awida, Zamzam, Hiram-Bab, Sahar, Bachar, Almog, Saed, Hussam, Zyc, Dan, Gorodov, Anton, Ben-Califa, Nathalie, Omari, Sewar, Omar, Jana, Younis, Liana, Iden, Jennifer Ana, Graniewitz Visacovsky, Liad, Gluzman, Ida, Liron, Tamar, Raphael-Mizrahi, Bitya, Kolomansky, Albert, Rauner, Martina, Wielockx, Ben, Gabet, Yankel, and Neumann, Drorit
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ERYTHROPOIETIN receptors ,ERYTHROPOIETIN ,OSTEOCLASTOGENESIS ,BONE growth ,B cells ,BONE marrow ,MONOCYTES ,MICE - Abstract
Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating a contribution by EPOR on other cell lineages. This study was designed to define the role of monocyte EPOR in EPO-mediated bone loss, by using two mouse lines with conditional deletion of EPOR in the monocytic lineage. Low-dose EPO attenuated the reduction in bone volume (BV/TV) in Cx3cr1
Cre EPORf/f female mice (27.05%) compared to controls (39.26%), but the difference was not statistically significant. To validate these findings, we increased the EPO dose in LysMCre model mice, a model more commonly used to target preosteoclasts. There was a significant reduction in both the increase in the proportion of bone marrow preosteoclasts (CD115+ ) observed following high-dose EPO administration and the resulting bone loss in LysMCre EPORf/f female mice (44.46% reduction in BV/TV) as compared to controls (77.28%), without interference with the erythropoietic activity. Our data suggest that EPOR in the monocytic lineage is at least partially responsible for driving the effect of EPO on bone mass. [ABSTRACT FROM AUTHOR]- Published
- 2022
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24. A gene expression map of host immune response in human brucellosis.
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Mitroulis, Ioannis, Chrysanthopoulou, Akrivi, Divolis, Georgios, Ioannidis, Charalampos, Ntinopoulou, Maria, Tasis, Athanasios, Konstantinidis, Theocharis, Antoniadou, Christina, Soteriou, Natalia, Lallas, George, Mitka, Stella, Lesche, Mathias, Dahl, Andreas, Gembardt, Stephanie, Panopoulou, Maria, Sideras, Paschalis, Wielockx, Ben, Coskun, Ünal, Ritis, Konstantinos, and Skendros, Panagiotis
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BRUCELLA ,BRUCELLOSIS ,MONONUCLEAR leukocytes ,IMMUNE response ,GENE expression ,GENE mapping - Abstract
Brucellosis is a common zoonotic disease caused by intracellular pathogens of the genus Brucella. Brucella infects macrophages and evades clearance mechanisms, thus resulting in chronic parasitism. Herein, we studied the molecular changes that take place in human brucellosis both in vitro and ex vivo. RNA sequencing was performed in primary human macrophages (Mj) and polymorphonuclear neutrophils (PMNs) infected with a clinical strain of Brucella spp. We observed a downregulation in the expression of genes involved in host response, such as TNF signaling, IL-1b production, and phagosome formation in Mj, and phosphatidylinositol signaling and TNF signaling in PMNs, being in line with the ability of the pathogen to survive within phagocytes. Further transcriptomic analysis of isolated peripheral blood mononuclear cells (PBMCs) and PMNs from patients with acute brucellosis before treatment initiation and after successful treatment revealed a positive correlation of the molecular signature of active disease with pathways associated with response to interferons (IFN). We identified 24 common genes that were significantly altered in both PMNs and PBMCs, including genes involved in IFN signaling that were downregulated after treatment in both cell populations, and IL1R1 that was upregulated. The concentration of several inflammatory mediators was measured in the serum of these patients, and levels of IFN-g, IL-1b and IL-6 were found significantly increased before the treatment of acute brucellosis. An independent cohort of patients with chronic brucellosis also revealed increased levels of IFN-g during relapse compared to remissions. Taken together, this study provides for the first time an in-depth analysis of the transcriptomic alterations that take place in human phagocytes upon infection, and in peripheral blood immune populations during active disease. [ABSTRACT FROM AUTHOR]
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- 2022
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25. Characterization of Adrenal miRNA-Based Dysregulations in Cushing's Syndrome.
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Vetrivel, Sharmilee, Zhang, Ru, Engel, Mareen, Oßwald, Andrea, Watts, Deepika, Chen, Alon, Wielockx, Ben, Sbiera, Silviu, Reincke, Martin, and Riester, Anna
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CUSHING'S syndrome ,ADRENAL glands ,WNT genes ,WNT signal transduction ,NUCLEOTIDE sequencing ,ADRENOCORTICOTROPIC hormone - Abstract
MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing's syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing's disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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26. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development
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Mamlouk, Soulafa, Kalucka, Joanna, Singh, Rashim Pal, Franke, Kristin, Muschter, Antje, Langer, Anika, Jakob, Christiane, Gassmann, Max, Baretton, Gustavo B., and Wielockx, Ben
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- 2014
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27. Hypoxia-inducible factors as key regulators of tumor inflammation
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Mamlouk, Soulafa and Wielockx, Ben
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- 2013
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28. Neuron-Specific Prolyl-4-Hydroxylase Domain 2 Knockout Reduces Brain Injury After Transient Cerebral Ischemia
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Kunze, Reiner, Zhou, Wei, Veltkamp, Roland, Wielockx, Ben, Breier, Georg, and Marti, Hugo H.
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- 2012
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29. Inflammatory Modulation of Hematopoiesis: Linking Trained Immunity and Clonal Hematopoiesis with Chronic Disorders.
- Author
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Chavakis, Triantafyllos, Wielockx, Ben, and Hajishengallis, George
- Abstract
Inflammation-adapted hematopoietic stem and progenitor cells (HSPCs) have long been appreciated as key drivers of emergency myelopoiesis, thereby enabling the bone marrow to meet the elevated demand for myeloid cell generation under various stress conditions, such as systemic infection, inflammation, or myelosuppressive insults. In recent years, HSPC adaptations were associated with potential involvement in the induction of long-lived trained immunity and the emergence of clonal hematopoiesis of indeterminate potential (CHIP). Whereas trained immunity has context-dependent effects, protective in infections and tumors but potentially detrimental in chronic inflammatory diseases, CHIP increases the risk for hematological neoplastic disorders and cardiometabolic pathologies. This review focuses on the inflammatory regulation of HSPCs in the aforementioned processes and discusses how modulation of HSPC function could lead to novel therapeutic interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
30. Reprogramming of glucocorticoid receptor function by hypoxia.
- Author
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Vanderhaeghen, Tineke, Timmermans, Steven, Watts, Deepika, Paakinaho, Ville, Eggermont, Melanie, Vandewalle, Jolien, Wallaeys, Charlotte, Van Wyngene, Lise, Van Looveren, Kelly, Nuyttens, Louise, Dewaele, Sylviane, Vanden Berghe, Joke, Lemeire, Kelly, De Backer, Joey, Dirkx, Laura, Vanden Berghe, Wim, Caljon, Guy, Ghesquière, Bart, De Bosscher, Karolien, and Wielockx, Ben
- Abstract
Here, we investigate the impact of hypoxia on the hepatic response of glucocorticoid receptor (GR) to dexamethasone (DEX) in mice via RNA‐sequencing. Hypoxia causes three types of reprogramming of GR: (i) much weaker induction of classical GR‐responsive genes by DEX in hypoxia, (ii) a number of genes is induced by DEX specifically in hypoxia, and (iii) hypoxia induces a group of genes via activation of the hypothalamic–pituitary–adrenal (HPA) axis. Transcriptional profiles are reflected by changed GR DNA‐binding as measured by ChIP sequencing. The HPA axis is induced by hypothalamic HIF1α and HIF2α activation and leads to GR‐dependent lipolysis and ketogenesis. Acute inflammation, induced by lipopolysaccharide, is prevented by DEX in normoxia but not during hypoxia, and this is attributed to HPA axis activation by hypoxia. We unfold new physiological pathways that have consequences for patients suffering from GC resistance. Synopsis: This study investigates the impact of hypoxia on hepatic GR function and unfolds new physiological pathways that might have implications for patients suffering from GC resistance. Hypoxia stabilizes HIF1α and HIF2α at the hypothalamus and activates the HPA axis which leads to increased GR‐dependent lipolysis and ketogenesis.Hypoxia induces transcriptional reprogramming of the GR.In hypoxic conditions, DEX is no longer able to protect against acute inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
31. Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C
- Author
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Kuzmanov, Aleksandar, Wielockx, Ben, Rezaei, Maryam, Kettelhake, Antje, and Breier, Georg
- Published
- 2012
- Full Text
- View/download PDF
32. Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy
- Author
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Wielockx, Ben, Lannoy, Katrien, Shapiro, Steven D., Itoh, Takeshi, Itohara, Shigeyoshi, Vandekerckhove, Joel, and Libert, Claude
- Abstract
Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-[gamma] therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines., Author(s): Ben Wielockx [1]; Katrien Lannoy [1]; Steven D. Shapiro [2]; Takeshi Itoh [3]; Shigeyoshi Itohara [4]; Joel Vandekerckhove [5]; Claude Libert (corresponding author) [1] The abrupt or chronic loss [...]
- Published
- 2001
- Full Text
- View/download PDF
33. HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla.
- Author
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Watts, Deepika, Bechmann, Nicole, Meneses, Ana, Poutakidou, Ioanna K., Kaden, Denise, Conrad, Catleen, Krüger, Anja, Stein, Johanna, El-Armouche, Ali, Chavakis, Triantafyllos, Eisenhofer, Graeme, Peitzsch, Mirko, and Wielockx, Ben
- Subjects
ADRENALINE ,CHROMAFFIN cells ,ERYTHROPOIETIN receptors ,ADRENAL glands ,SMALL molecules ,POLYCYTHEMIA - Abstract
The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly understood. Here, we reveal that deficiency of HIF (hypoxia inducible factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Simultaneous loss of PHD2 in renal erythropoietin (EPO)-producing cells (REPCs) stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis), and systemic hypoglycemia, which is necessary and sufficient to enhance exocytosis of epinephrine from the adrenal medulla. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla regulates the synthesis of epinephrine, whereas in REPCs, it indirectly induces the release of this hormone. Our findings are also highly relevant to the testing of small molecule PHD inhibitors in phase III clinical trials for patients with renal anemia. Key messages: HIF2α and not HIF1α modulates PNMT during epinephrine synthesis in chromaffin cells. The PHD2-HIF2α-EPO axis induces erythrocytosis and hypoglycemia. Reduced systemic glucose facilitates exocytosis of epinephrine from adrenal gland. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
34. Adenoviral gene transfer of ABIN-1 protects mice from TNF/galactosamine-induced acute liver failure and lethality
- Author
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Wullaert, Andy, Wielockx, Ben, Van Huffel, Sofie, Bogaert, Veerle, De Geest, Bart, Papeleu, Peggy, Schotte, Peter, El Bakkouri, Karim, Heyninck, Karen, Libert, Claude, and Beyaert, Rudi
- Published
- 2005
- Full Text
- View/download PDF
35. Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation?
- Author
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Wielockx, Ben, Libert, Claude, and Wilson, Carole
- Published
- 2004
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- View/download PDF
36. Adrenal Hormone Interactions and Metabolism: A Single Sample Multi-Omics Approach.
- Author
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Bechmann, Nicole, Watts, Deepika, Steenblock, Charlotte, Wallace, Paal William, Schürmann, Annette, Bornstein, Stefan R., Wielockx, Ben, Eisenhofer, Graeme, and Peitzsch, Mirko
- Subjects
CHROMAFFIN cells ,ADRENAL glands ,MASS spectrometry ,HORMONES ,MACROMOLECULES - Abstract
The adrenal gland is important for many physiological and pathophysiological processes, but studies are often restricted by limited availability of sample material. Improved methods for sample preparation are needed to facilitate analyses of multiple classes of adrenal metabolites and macromolecules in a single sample. A procedure was developed for preparation of chromaffin cells, mouse adrenals, and human chromaffin tumors that allows for multi-omics analyses of different metabolites and preservation of native proteins. To evaluate the new procedure, aliquots of samples were also prepared using conventional procedures. Metabolites were analyzed by liquid-chromatography with mass spectrometry or electrochemical detection. Metabolite contents of chromaffin cells and tissues analyzed with the new procedure were similar or even higher than with conventional methods. Catecholamine contents were comparable between both procedures. The TCA cycle metabolites, cis -aconitate, isocitate, and α-ketoglutarate were detected at higher concentrations in cells, while in tumor tissue only isocitrate and potentially fumarate were measured at higher contents. In contrast, in a broad untargeted metabolomics approach, a methanol-based preparation procedure of adrenals led to a 1.3-fold higher number of detected metabolites. The established procedure also allows for simultaneous investigation of adrenal hormones and related enzyme activities as well as proteins within a single sample. This novel multi-omics approach not only minimizes the amount of sample required and overcomes problems associated with tissue heterogeneity, but also provides a more complete picture of adrenal function and intra-adrenal interactions than previously possible. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
37. HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas.
- Author
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Bechmann, Nicole, Moskopp, Mats Leif, Ullrich, Martin, Calsina, Bruna, Wallace, Pål William, Richter, Susan, Friedemann, Markus, Langton, Katharina, Fliedner, Stephanie M. J., Timmers, Henri J. L. M., Nölting, Svenja, Beuschlein, Felix, Fassnacht, Martin, Prejbisz, Aleksander, Pacak, Karel, Ghayee, Hans K., Bornstein, Stefan R., Dieterich, Peter, Pietzsch, Jens, and Wielockx, Ben
- Subjects
GENE expression profiling ,CYTOSKELETAL proteins ,FOCAL adhesions ,LIVER metastasis ,GAIN-of-function mutations ,DISEASE susceptibility - Abstract
Mutations that drive the stabilization of hypoxia inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2α in predisposition to metastatic disease remains unclear. To assess such a role we combined gene-manipulations in pheochromocytoma cell lines with retrospective analyses of patient data and gene expression profiling in tumor specimens. Among 425 patients with PPGLs identified with mutations in tumor-susceptibility genes, those with tumors due to activation of pseudohypoxic pathways had a higher frequency of metastatic disease than those with tumors due to activation of kinase-signaling pathways, even without inclusion of patients with mutations in SDHB (18.6% vs 4.3% in, P < 0.0001). Three out of nine (33%) patients with gain-of-function mutations in HIF2α had metastatic disease. In cell line studies, elevated expression of HIF2α enhanced cell proliferation and led to increased migration and invasion capacity. Moreover, HIF2α expression in HIF2α-deficient cells resulted in increased cell motility, diffuse cluster formation and emergence of pseudopodia indicating changes in cell adhesion and cytoskeletal remodeling. In a mouse liver metastasis model, Hif2a enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix-receptor interactions in HIF2α-mutated PPGLs. Our translational findings demonstrate that HIF2α supports pro-metastatic behavior in PPGLs, though other factors remain critical for subsequent transition to metastasis. We identified LAMB1 and COL4A2 as new potential therapeutic targets for HIF2α-driven PPGLs. Identified HIF2α downstream targets might open a new therapeutic window for aggressive HIF2α-expressing tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. The ACE-2 in COVID-19: Foe or Friend?
- Author
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Dalan, Rinkoo, Bornstein, Stefan R., El-Armouche, Ali, Rodionov, Roman N, Markov, Alexander, Wielockx, Ben, Beuschlein, Felix, and Boehm, Bernhard O.
- Subjects
ANGIOTENSIN converting enzyme ,COVID-19 ,METABOLIC disorders ,RESPIRATORY organs ,INSULIN resistance ,OLDER people - Abstract
COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT
1 R axis and ACE-2-Ang-(1–7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT1 R axis with a downregulation of ACE-2-Ang-(1–7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1–7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1–7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
39. Cancer Stem Cells in Pheochromocytoma and Paraganglioma.
- Author
-
Scriba, Laura D., Bornstein, Stefan R., Santambrogio, Alice, Mueller, Gregor, Huebner, Angela, Hauer, Julia, Schedl, Andreas, Wielockx, Ben, Eisenhofer, Graeme, Andoniadou, Cynthia L., and Steenblock, Charlotte
- Subjects
CANCER stem cells ,PARAGANGLIOMA ,STEM cell niches ,CELL tumors ,PHEOCHROMOCYTOMA ,CHROMAFFIN cells - Abstract
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated with high cardiovascular morbidity and variable risk of malignancy. The current therapy of choice is surgical resection. Nevertheless, PCCs/PGLs are associated with a lifelong risk of tumor persistence or recurrence. A high rate of germline or somatic mutations in numerous genes has been found in these tumors. For some, the tumorigenic processes are initiated during embryogenesis. Such tumors carry gene mutations leading to pseudohypoxic phenotypes and show more immature characteristics than other chromaffin cell tumors; they are also often multifocal or metastatic and occur at an early age, often during childhood. Cancer stem cells (CSCs) are cells with an inherent ability of self-renewal, de-differentiation, and capacity to initiate and maintain malignant tumor growth. Targeting CSCs to inhibit cancer progression has become an attractive anti-cancer therapeutic strategy. Despite progress for this strategy for solid tumors such as neuroblastoma, brain, breast, and colon cancers, no substantial advance has been made employing similar strategies in PCCs/PGLs. In the current review, we discuss findings related to the identification of normal chromaffin stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs in PCCs/PGLs. Additionally, we examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating especially recurrent and metastatic tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
40. THE ROLE OF COMPLEMENT ACTIVATION IN TUMOUR NECROSIS FACTOR-INDUCED LETHAL HEPATITIS
- Author
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Libert, Claude, Wielockx, Ben, Grijalba, Bernardo, Van Molle, Wim, Kremmer, Elisabeth, Colten, Harvey R, Fiers, Walter, and Brouckaert, Peter
- Published
- 1999
- Full Text
- View/download PDF
41. Hematopoietic hypoxia-inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis.
- Author
-
Korovina, Irina, Neuwirth, Ales, Sprott, David, Weber, Silvio, Pasha, Sheik Pran Babu Sardar, Gercken, Bettina, Breier, Georg, El-Armouche, Ali, Deussen, Andreas, Karl, Mike O., Wielockx, Ben, Chavakis, Triantafyllos, and Ameln, Anne Klotzsche-von
- Published
- 2019
- Full Text
- View/download PDF
42. Endothelial Cell-Specific Overexpression of Del-1 Drives Expansion of Haematopoietic Progenitor Cells in the Bone Marrow.
- Author
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Lan-Sun Chen, Kourtzelis, Ioannis, Singh, Rashim Pal, Grossklaus, Sylvia, Wielockx, Ben, Hajishengallis, George, Chavakis, Triantafyllos, and Mitroulis, Ioannis
- Published
- 2018
- Full Text
- View/download PDF
43. Interaction of endothelial cells with macrophages-linking molecular and metabolic signaling.
- Author
-
Kalucka, Joanna, Bierhansl, Laura, Wielockx, Ben, Carmeliet, Peter, and Eelen, Guy
- Subjects
ENDOTHELIAL cells ,MACROPHAGES ,CELL metabolism ,CELLULAR signal transduction ,NEOVASCULARIZATION - Abstract
Angiogenesis and inflammation go hand in hand in various (patho-)physiological conditions. Several studies have highlighted the interconnection between endothelial cells (ECs) and macrophages in these conditions at the level of growth factor and cytokine signaling, yet the importance of metabolism and metabolic signaling has been largely overlooked. Modulating macrophage and/or endothelial functions by interfering with metabolic pathways offers new perspectives for therapeutic strategies. In this review, we highlight the complexity of the interrelationship between the inflammatory response and angiogenesis. More in particular, the interaction between macrophages and ECs will be discussed with a special focus on how their metabolism can contribute to (patho-)physiological conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
44. PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages.
- Author
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Guentsch, Annemarie, Beneke, Angelika, Swain, Lija, Farhat, Katja, Nagarajan, Shunmugam, Wielockx, Ben, Raithatha, Kaamini, Dudek, Jan, Rehling, Peter, Zieseniss, Anke, Jatho, Aline, Mei Chong, Santos, Celio X. C., Shah, Ajay M., and Katschinski, Dörthe M.
- Subjects
MACROPHAGES ,PROLINE hydroxylase ,OXYGEN detectors ,METABOLISM ,NATURAL immunity - Abstract
The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1α (HIF-1α) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macrophage behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
45. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells.
- Author
-
Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz C, and Wielockx, Ben
- Abstract
ABSTRACT The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2-erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF-1α and HIF-2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO-producing cells, osteoblasts, and hematopoietic cells (CD68:cre-PHD2
f/f ) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast-specific (Osx:cre-PHD2f/f ) and osteoclast-specific PHD2 knock-out mice (Vav:cre- PHD2f/f ), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α-subunit of HIF-2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF-2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status. © 2016 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
46. Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen.
- Author
-
Siegert, Isabel, Schödel, Johannes, Nairz, Manfred, Schatz, Valentin, Dettmer, Katja, Dick, Christopher, Kalucka, Joanna, Franke, Kristin, Ehrenschwender, Martin, Schley, Gunnar, Beneke, Angelika, Sutter, Jörg, Moll, Matthias, Hellerbrand, Claus, Wielockx, Ben, Katschinski, Dörthe M., Lang, Roland, Galy, Bruno, Hentze, Matthias W., and Koivunen, Peppi
- Abstract
Summary Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron). [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
47. Erythropoietin directly stimulates osteoclast precursors and induces bone loss.
- Author
-
Hiram-Bab, Sahar, Liron, Tamar, Deshet-Unger, Naamit, Mittelman, Moshe, Gassmann, Max, Rauner, Martina, Franke, Kristin, Wielockx, Ben, Neumann, Drorit, and Gabet, Yankel
- Subjects
ERYTHROPOIETIN ,ERYTHROPOIESIS ,ERYTHROCYTES ,ANEMIA ,OSTEOCLASTS ,OSTEOBLASTS - Abstract
Erythropoietin (EPO) primarily regulates red blood cell formation, and EPO serum levels are increased on hypoxic stress (e.g., anemia and altitude). In addition to anemia, recent discoveries suggest new therapeutic indications for EPO, unrelated to erythropoiesis. We investigated the skeletal role of EPO using several models of overexpression (Tg6 mice) and EPO administration (intermittent/continuous, high/low doses) in adult C57Bl6 female mice. Using microcomputed tomography, histology, and serum markers, we found that EPO induced a 32%-61% trabecular bone loss caused by increased bone resorption (+60%-88% osteoclast number) and reduced bone formation rate (-19 to -74%; P < 0.05 throughout). EPO targeted the monocytic lineage by increasing the number of bonemonocytes/macrophages, preosteoclasts, and mature osteoclasts. In contrast to the attenuated bone formation in vivo, EPO treatment in vitro did not inhibit osteoblast differentiation and activity, suggesting an indirect effect of EPO on osteoblasts. However, EPO had a direct effect on preosteoclasts by stimulating osteoclastogenesis in isolated cultures (+60%) via the Jak2 and PI3K pathways. In summary, our findings demonstrate that EPO negatively regulates bone mass and thus bears significant clinical implications for the potential management of patients with endogenously or therapeutically elevated EPO levels. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
48. Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice.
- Author
-
Kalucka, Joanna, Ettinger, Andreas, Franke, Kristin, Mamlouk, Soulafa, Singh, Rashim Pal, Farhat, Katja, Muschter, Antje, Olbrich, Susanne, Breier, Georg, Katschinski, Dörthe M., Huttner, Wieland, Weidemann, Alexander, and Wielockx, Ben
- Subjects
WOUND healing ,HYPOXIA-inducible factors ,HYDROXIDES ,KERATINOCYTES ,EPITHELIAL cells ,OXYGEN detectors - Abstract
Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β
3 -integrin in the keratinocytes around the tip of the migrating tongue in an HIF 1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
49. Hypoxia-Mediated Regulation of Stem Cell Fate.
- Author
-
Pal Singh, Rashim, Franke, Kristin, and Wielockx, Ben
- Published
- 2012
- Full Text
- View/download PDF
50. HIF prolyl hydroxylase-2 inhibition diminishes tumor growth through matrix metalloproteinase-induced TGFβ activation.
- Author
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Ameln, Anne Klotzsche-von, Muschter, Antje, Heimesaat, Markus M., Breie, Georg, and Wielockx, Ben
- Published
- 2012
- Full Text
- View/download PDF
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