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Digoxin induces astrocyte activation into a human in vitro astrocyte model

ABSTRACT: In this study we have evaluated the effect of digoxin in human astrocytes. Our results have shown that non-cytotoxic concentration of digoxin is able to induce astrocytes activation, by affecting cytoskeleton proteins, increasing the expression of pro-inflammatory genes and altering energy metabolism pathways between other mechanisms.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Astrocyte

SUBMITTER: Tatjana Vujic

LAB HEAD: Jean-Charles Sanchez

PROVIDER: PXD029370 | Pride | 2023-03-11

REPOSITORIES: Pride

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			Action	DRS
	20200121_LU50HMC52_pl20001_TAV_POOL_A.raw	Raw
	20200121_LU50HMC52_pl20001_TAV_POOL_C.raw	Raw
	20200121_LU50HMC53_pl20001_TAV_CTRL_T_A.raw	Raw
	20200121_LU50HMC54_pl20001_TAV_TNFA_A.raw	Raw
	20200121_LU50HMC55_pl20001_TAV_CTRL_D_A.raw	Raw

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Publications

Digoxin Induces Human Astrocyte Reaction In Vitro.

Pamies David D Vujić Tatjana T Schvartz Domitille D Boccard Julien J Repond Cendrine C Nunes Carolina C Rudaz Serge S Sanchez Jean-Charles JC González-Ruiz Víctor V Zurich Marie-Gabrielle MG

Molecular neurobiology 20221012 1

Astrocyte reaction is a complex cellular process involving astrocytes in response to various types of CNS injury and a marker of neurotoxicity. It has been abundantly studied in rodents but relatively poorly in human cells due to limited access to the brain. Astrocytes play important roles in cerebral energy metabolism and are also key players in neuroinflammation. Astroglial metabolic and inflammatory changes have been reported with age, leading to the hypothesis that mitochondrial metabolism a ...[more]

PMID: 36223047

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Proteomics analysis unraveled paraquat-induced cholesterol biosynthesis dysregulation in human brain microvascular endothelial cells

Project description:Despite its banishment in several countries, Paraquat (PQ) is still one of the most commonly used herbicides in agriculture. This compound is known to induce damaging effects on human or animal brain cells such as glial cells or neurons through biological processes as redox by generation of Reactive Oxygen Species (ROS). This specific perturbation has already proven its association for increasing the risk of developing a long-term brain impairment in in vitro and in vivo studies using brain cells. However, there is few evidence of PQ effect on Human Brain Microvascular Endothelial Cells (HBMECs), a particular cell type acting as a macromolecule permeability regulator in the Blood-Brain Barrier (BBB). The present study aimed at unraveling biological mechanisms associated to the exposition of 1, 10 and 100 µM of PQ for 24h on HBMECs. High-throughput mass spectrometry-based proteomics using data-independent acquisition (DIA) was applied. Biological pathway enrichment and cellular assays such as mitochondrial respiration and cholesterol level of PQ-treated HBMECs were performed to verify proteomics results. Proteomic experiment reported a total of 3753 quantified proteins out of which 419 were significantly modulated by paraquat exposure. Biological pathway enrichment revealed that the modified proteins are involved in pathways such as the ubiquinone metabolism, a pathway directly linked to mitochondrial complex I proteins. This study also unveiled the modulation of the cholesterol metabolism. In conclusion, most of the highly differentially expressed proteins (DEPs) in PQ-treated HBMECs were associated to the ubiquinone metabolism pathway confirming the well know mechanism of PQ inducing oxidative stress and inhibit mitochondrial complex I activity. Additionally, this study also described the cholesterol biosynthesis modulation on primary human brain endothelial cells not yet described.

2022-02-17 | PXD026975 | Pride

Protein content of extracellular vesicles from human brain microvascular endothelial cells treated by paraquat

Project description:Since the last decade, the field of extracellular vesicles (EVs) has increasingly grown. These “intracellular messengers” became interesting as biomarker source in the SNC research, because of their content, which may reflect the physiological state of their donor cells in a context of an external stimuli. However, still little is known about EVs released from cell types constituting the blood-brain barrier (BBB), especially on the human brain microvascular endothelial cells (HBMECs). The current study aimed to isolate and characterize EVs from HBMECs and to analyze the EVs proteome modulation after an external stimulate such as the Paraquat (PQ), a neurotoxicant. Size distribution, quantity and presence of EV markers were assessed. Identification and quantification of EVs proteins was conducted by data-independent acquisition mass-spectrometry (DIA-MS). Signature pathway of PQ-treated EVs were analyzed by gene ontology terms and pathway enrichment. Results present evidence that PQ-treated HBMECs and EVs are sharing proteins belonging to the ubiquinone metabolism and to the transcription HIF-1 targets pathways with a highly significant p-values, suggesting that those pathways may be a potential EVs signature of the PQ-induced toxicity in the BBB.

2021-09-10 | PXD024691 | Pride

Cerebrospinal Fluid-Derived Microvesicles from Sleeping Sickness Patients Alter Protein Expression in Human Astrocytes

Project description:Human African trypanosomiasis (HAT) caused by the extracellular protozoon Trypanosoma brucei, is a neglected tropical disease affecting the poorest communities in sub-Saharan Africa. HAT progresses from a hemolymphatic first stage (S1) to a meningo-encephalitic late stage (S2) when parasites reach the central nervous system, although the existence of an intermediate stage (Int.) has also been proposed. The pathophysiological mechanisms associated with the development of S2 encephalopathy are yet to be fully elucidated. In the present study, we used data independent acquisition mass spectrometry (DIA-MS) to investigate the potential pathogenic effects of microvesicles (MVs) derived from HAT patients’ cerebrospinal fluid (CSF). To assess potential biological properties of these MVs, immortalized human astrocytes were exposed, in vitro, to MVs enriched from S1, Int. or S2 CSF. DIA-MS analyses showed that S2 MVs induced, compared to Int. or S1 MVs, a stronger proteome modulation in astrocytes that resembled the one produced by IFN-γ, a key molecule in HAT pathogenesis. Our results indicate that HAT S2 CSF harbors MVs potentially involved in the mechanisms of pathology associated with HAT late stage. Such vesicles might thus represent a new player to consider in future functional studies.

2019-10-28 | PXD014945 | Pride

DIA-MS proteomics of untreated and TAT-Cx43266-283-treated G166 GSCs

Project description:Glioblastoma (GBM) is the most frequent and aggressive primary brain cancer. Our studies have shown that the Src inhibitor, TAT-Cx43266-283, exerts antitumor effects in different preclinical models of GBM, including fresh specimens from GBM patients, and enhances survival in glioma-bearing mice. Because addressing TAT-Cx43266-283 mechanism of action is essential to translate these results to a clinical setting, in this study we carried out an unbiased proteomic approach in human glioblastoma stem cells (GSCs). Data-independent acquisition mass spectrometry proteomics allowed the identification and quantification of 6,561 proteins, of which 190 were modified by TAT-Cx43266-283. Our results are consistent with the inhibition of Src as the mechanism of action of TAT-Cx43266-283 and unveils additional crucial proteins. Altogether, this study expands the knowledge about the mechanism of action of TAT-Cx43266-283, providing a rationale for therapy combination and supporting its use in GBM clinical trials.

2024-06-22 | PXD045883 | Pride

Ferritinophagy is a Druggable Vulnerability of Quiescent Leukemic Stem Cells in Acute Myeloid Leukemia

Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.

2024-06-13 | PXD042796 | Pride

Laser microdissection and proteomic study of paraffin-embedded fetal and paediatric lung tissues.

Project description:The goal of this project was to understand if lasermicrodissected epithial portions of postanatal and fetal human lung tissue could be used for proteomics, and then, further confirmed by immunostaining. The proteomic data obtained from postanatal bronchi was compared to the one obtained from alveoli, with the same being applied to the fetal bronchi and canaliculi.

2023-08-14 | PXD040654 | Pride

Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Project description:Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

2023-05-17 | PXD041850 | Pride

Expression data from induced astrocytes , primary astrocyte and MEFs

Project description:MEFs treated by compounds for 25 days can be induced into astrocytes. In induced astrocytes, specific astrocytes-related sets of genes are up-regulated, but fibroblasts-related genes are down-regulated. The induced cells sorted for GFP-positive cells by flow cytometry and primary astrocytes and MEFs were parepared for RNA extraction and hybridization on Affymetrix microarrays. We sought to compare the induced astrocytes with primary astrocytes and MEFs.

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Astrocyte-encoded positional cues maintain sensorimotor circuit integrity

Project description:Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded Semaphorin3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a led to dysregulated α−motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α−but not of adjacent γ−motor neurons. Additionally, a subset of TrkA+ sensory afferents projected to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement. 12 total samples consisting of three biological replicates each of flow sorted postnatal day 7 dorsal spinal cord astrocytes, ventral spinal cord astrocytes, dorsal SC non astrocytes, and ventral SC non astrocytes

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