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Hu F.,Max Delbruck Center for Molecular Medicine | Ku M.-C.,Max Delbruck Center for Molecular Medicine | Markovic D.,Max Delbruck Center for Molecular Medicine | Dzaye O.D.,Max Delbruck Center for Molecular Medicine | And 4 more authors.
International Journal of Cancer | Year: 2014

The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix metalloprotease (MMP) 2, MMP9 and membrane-type 1 MMP. In this work we demonstrate that, MMP9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of MMP9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signaling pathway for the glioma induced upregulation of microglial MMP9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial MMP9. Moreover, glioma supernatant triggered an upregulation of Toll-like receptor 2 expression in microglia. Both, the upregulation of MMP9 and Toll-like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen-activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signaling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy. © 2014 UICC.

Boppana S.,Max Planck Institute for Experimental Medicine | Boppana S.,Rutgers University | Scheglov A.,Max Planck Institute for Experimental Medicine | Scheglov A.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry | And 3 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: Transcription factor Pax6 plays an essential role in the expression of other transcription factors, cell adhesion molecules and is crucial for neurogenesis in the developing forebrain. Analysis of gene expression profiles through microarray experiments in Pax6 mutants allowed us to focus on CRALBP, one of the many genes that were downregulated. Methods: We studied the expression of CRALBP in wt and Pax6-/- mutants through in situ hybridization and immunohistochemistry. ChIP assay and luciferase reporter assay were performed to show the regulatory role of Pax6 on CRALBP promoter. Results: RNA and protein expression data show that CRALBP expression was completely abolished in Pax6 mutants. In vivo binding assays and in vitro reporter assays indicate that Pax6 not only binds the promoter of CRALBP but also positively regulates protein expression. Conclusions: This work provides evidence supporting that CRALBP is a direct downstream target of Pax6. However, the role of CRALBP in the cortex is yet to be elucidated. General Significance: Pax6 is a marker expressed on neural stem cells and progenitor cells. Understanding Pax6-dependent gene regulatory mechanisms unravels signaling cascades that occur early during development. © 2011 Elsevier B.V. All Rights Reserved.

Savaskan N.E.,Institute of Cell Biology and Neurobiology | Eyupoglu I.Y.,Friedrich - Alexander - University, Erlangen - Nuremberg
Annals of Anatomy | Year: 2010

Several nutrient transporters impacting the glutathione/redox cycle regulation and cell proliferation have been identified in cancer, which render these transporters potential prime targets for cytotoxic anticancer therapy. One promising transporter is system Xc -, also known as xCT (SLC7a11), which is expressed in various cancers including primary malignant brain tumors (gliomas). An important biological feature of these transporters, and in particular of xCT is its specific modulation of the tumor microenvironment leading to growth advantage for cancer. Thus, tumor microenvironment shaping by xCT inhibition revealed a so far neglected hallmark of gliomas, i.e. tumor-induced neurotoxicity and its impact on the development of peritumoral brain swelling. This review here discusses available pharmacological tools for the tumor microenvironment normalization, in the context of perifocal edema and the Warburg effect and highlights the implications of such metabolic normalization approach in the design of new therapies. © 2010 Elsevier GmbH.

Pucci D.,University of Calabria | Bellini T.,University of Milan | Crispini A.,Consortium for Science and Technology of Materials | D'Agnano I.,Institute of Cell Biology and Neurobiology | And 5 more authors.
MedChemComm | Year: 2012

Two new heteroleptic pentacoordinated Zn(ii) complexes (1 and 2) containing 4,4′-disubstituted 2,2′-bipyridines as the main ligand and curcumin (curc) as an ancillary ligand have been synthesized, spectroscopically and structurally characterized, and tested in vitro towards different human cancer cell lines. While the nitrogen ligands are almost inactive, Zn(ii) curc derivatives 1 and 2 show promising and selective anticancer properties. In particular the curc Zn(ii) complex 1 shows the strongest growth inhibition in all cell lines, being even more effective than the pure curc in the LAN-5 neuroblastoma cell line. Furthermore, the curc moiety makes the complexes 1 and 2 fluorescent, a feature enabling investigation of their interaction with DNA through a new optical method previously tested with the reference fluorescent intercalator ethidium bromide. This analysis demonstrates that the interaction mode of curc, 1 and 2 with DNA in the double helix favors their alignment perpendicular to the DNA axis, suggesting a partial inter-base intercalation of these Zn(ii) complexes. © 2012 The Royal Society of Chemistry.

Neubert J.,Institute of Cell Biology and Neurobiology | Wagner S.,Charite - Medical University of Berlin | Kiwit J.,Clinic for Neurosurgery | Brauer A.U.,Institute of Cell Biology and Neurobiology | Glumm J.,Institute of Cell Biology and Neurobiology
International Journal of Nanomedicine | Year: 2015

The physicochemical properties of superparamagnetic iron oxide nanoparticles (SPIOs) enable their application in the diagnostics and therapy of central nervous system diseases. However, since crucial information regarding side effects of particle–cell interactions within the central nervous system is still lacking, we investigated the infuence of novel very small iron oxide particles or the clinically approved ferucarbotran or ferumoxytol on the vitality and morphology of brain cells. We exposed primary cell cultures of microglia and hippocampal neurons, as well as neuron–glia cocultures to varying concentrations of SPIOs for 6 and/or 24 hours, respectively. Here, we show that SPIO accumulation by microglia and subsequent morphological alterations strongly depend on the respective nanoparticle type. Microglial viability was severely compromised by high SPIO concentrations, except in the case of ferumoxytol. While ferumoxytol did not cause immediate microglial death, it induced severe morphological alterations and increased degeneration of primary neurons. Additionally, primary neurons clearly degenerated after very small iron oxide particle and ferucarbotran exposure. In neuron–glia cocultures, SPIOs rather stimulated the outgrowth of neuronal processes in a concentration- and particle-dependent manner. We conclude that the infuence of SPIOs on brain cells not only depends on the particle type but also on the physiological system they are applied to. © 2015, Neubert et al.

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