| 1. |
- Pinheiro, Tiago, et al.
(author)
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A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth
- 2017
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In: Biochemical and Biophysical Research Communications - BBRC. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0006-291X .- 1090-2104. ; 494:3-4, s. 477-483
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Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) is regarded as the most common malignant brain tumor but treatment options are limited. Thus, there is an unmet clinical need for compounds and corresponding targets that could inhibit GBM growth. We screened a library of 80 dopaminergic ligands with the aim of identifying compounds capable of inhibiting GBM cell line proliferation and survival. Out of 45 active compounds, 8 were further validated. We found that the dopamine receptor D2 antagonist trifluoperazine 2HC1 inhibits growth and proliferation of GBM cells in a dose dependent manner. Trifluoperazine's inhibition of GBM cells is cell line dependent and correlates with variations in dopamine receptor expression profile. We conclude that components of the dopamine receptor signaling pathways are potential targets for pharmacological interventions of GBM growth. (C) 2017 Elsevier Inc. All rights reserved.
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| 2. |
- Pinheiro, Tiago, et al.
(author)
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Reprint of : A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth
- 2018
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 499:2, s. 136-142
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Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) is regarded as the most common malignant brain tumor but treatment options are limited. Thus, there is an unmet clinical need for compounds and corresponding targets that could inhibit GBM growth. We screened a library of 80 dopaminergic ligands with the aim of identifying compounds capable of inhibiting GBM cell line proliferation and survival. Out of 45 active compounds, 8 were further validated. We found that the dopamine receptor D2 antagonist trifluoperazine 2HCl inhibits growth and proliferation of GBM cells in a dose dependent manner. Trifluoperazine’s inhibition of GBM cells is cell line dependent and correlates with variations in dopamine receptor expression profile. We conclude that components of the dopamine receptor signaling pathways are potential targets for pharmacological interventions of GBM growth.
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| 3. |
- Rraklli, Vilma
(author)
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Transcriptional regulation of neuronal differentiation in the developing CNS
- 2017
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Doctoral thesis (other academic/artistic)abstract
- The central nervous system (CNS) is responsible for our intellectual and cognitive functions and it comprises the brain and spinal cord. Generation of the CNS occurs during embryonic development from the neural tube that initially consist of a pool of immature progenitors that will give rise to all the neurons in the brain and spinal cord. CNS development is a highly coordinated process and any defect has a high risk of generating malformations and/or sensory, motor and cognitive impairments. The large number and variety of neurons that form the CNS mirrors the complexity and multitude of functions of the system itself. Despite that they are all generated from the same pool of immature progenitors, neurons greatly differ from each other in morphology, function and in gene expression. During development, generation of newborn neurons requires immature progenitor cells to undergo sequential fate restriction from a pluripotent stem cell to neural progenitor and finally to a differentiated neuron. The journey from a progenitor cell to a mature neuron with specific functions occurs in different developmental stages that involve interpretation of environmental cues, cell cycle exit, downregulation of progenitor markers, migration, expression of neuronal genes and repression of genes of other lineages. During these processes, the morphological metamorphosis of a cell is matched by changes in gene expression. Consequently, neuronal differentiation of a cell leads to a final epigenetic and transcriptional landscape quite distinct from the one of the cell of origin. During neuronal differentiation transcriptional regulation plays fundamental role in each step of the process from neural fate determination to neuronal specification. At a molecular level, neuronal differentiation is coordinated by transcription factors involved in all steps, such as cell cycle exit, loss of progenitor properties, restriction of other lineages, migration and acquisition of neuronal features. Despite the progress made in the field, a lot remains to be clarified about regulation of gene expression and regulation of transcriptional activity. The papers presented in this thesis aim to shed some light regarding the role of specific transcriptional factors at different stages of neuronal differentiation. Paper I investigates the role of chromatin remodeler CHD5 during neurogenesis, focusing on two specific aspects of terminal neuronal differentiation: induction of neuronal features and repression of other lineages determinants. Our data, in vitro and in vivo, suggest that CHD5 has a dual role during neuronal differentiation: it facilitates the activation of neuronal genes and it synergizes with Polycomb group proteins to facilitate repression of alternative lineages determinant. Paper II focuses on the role of ZAC1 transcription factor during neurogenesis and the importance of controlling its expression levels. Our data shows that elevated levels of ZAC1 transcription factor promote cell cycle exit, block neuronal specification and induce non-neuronal lineage determinants. Paper III investigates how changes in the surrounding environment, such as heat shock induced stress, affect transcriptional regulation, through the NOTCH pathway. Our in vitro and in vivo data show that stress induces sumoylation of NOTCH and its accumulation in the nucleus which results in repression of Notch target gene (Hes1, Hes5).
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| 4. |
- Shen, Xianli, et al.
(author)
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Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype
- 2016
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In: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:11, s. 1282-1290
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Journal article (peer-reviewed)abstract
- Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.
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| 5. |
- Södersten, Erik, et al.
(author)
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A comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- The brain is composed of hundreds of different neuronal subtypes, which largely retain their identity throughout the lifespan of the organism. The mechanisms governing this stability are not fully understood, partly due to the diversity and limited size of clinically relevant neuronal populations, which constitute a technical challenge for analysis. Here, using a strategy that allows for ChIP-seq combined with RNA-seq in small neuronal populations in vivo, we present a comparative analysis of permissive and repressive histone modifications in adult midbrain dopaminergic neurons, raphe nuclei serotonergic neurons, and embryonic neural progenitors. Furthermore, we utilize the map generated by our analysis to show that the transcriptional response of midbrain dopaminergic neurons following 6-OHDA or methamphetamine injection is characterized by increased expression of genes with promoters dually marked by H3K4me3/H3K27me3. Our study provides an in vivo genome-wide analysis of permissive/repressive histone modifications coupled to gene expression in these rare neuronal subtypes.
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