The spatial and temporal coordination of each element is a pivotal characteristic of systems, and the central nervous system (CNS) is not an exception. Glial elements and the vascular interface have been considered more recently, together... more
The spatial and temporal coordination of each element is a pivotal characteristic of systems, and the central nervous system (CNS) is not an exception. Glial elements and the vascular interface have been considered more recently, together with the extracellular matrix and the immune system. However, the knowledge of the single-element configuration is not sufficient to predict physiological or pathological long-lasting changes. Ionic currents, complex molecular cascades, genomic rearrangement, and the regional energy demand can be different even in neighboring cells of the same phenotype, and their differential expression could explain the region-specific progression of the most studied neurodegenerative diseases. We here reviewed the main nodes and edges of the system, which could be studied to develop a comprehensive knowledge of CNS plasticity from the neurovascular unit to the synaptic cleft. The future goal is to redefine the modeling of synaptic plasticity and achieve a better...
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Additional file 4.
Additional file 1. Supplementary Materials.
Datasets: communities, networks, enrichments (ZIP available at https://dx.doi.org/10.6084/m9.figshare.2070124 ).
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Pathology Specific Processes. (PDF 66 kb)
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Common Processes. (PDF 66 kb)
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Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an... more
Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
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Background Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting... more
Background Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. Methods We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. Results We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among...
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Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the... more
Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to neuronal loss through post-ischemic and reperfusion injuries, as well as coagulatory and inflammatory processes. The ictal core is produced in a few minutes by the high metabolic demand of the central nervous system. Uncontrolled or prolonged inflammatory response is characterized by leukocyte infiltration of the injured site that is limited by astroglial reaction. The metabolic failure reshapes the NECM through matrix metalloproteinases (MMPs) and novel deposition of structural proteins continues within months of the acute event. These maladaptive reparative processes are responsible for the neurological clinical phenotype. In this review, we aim to provide a systems biology approach to stroke pathoph...
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The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric... more
The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, p...
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Neuroinflammation, a hallmark of chronic neurodegenerative disorders, is characterized by sustained glial activation and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause... more
Neuroinflammation, a hallmark of chronic neurodegenerative disorders, is characterized by sustained glial activation and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause oxidative stress and limit functional repair of brain parenchyma. Dietary antioxidants may protect against neurodegenerative diseases by counteracting chronic neuroinflammation and reducing oxidative stress. Here, we describe the effects of a number of natural antioxidants (polyphenols, carotenoids, and thiolic molecules) in rescuing astrocytic function and neuronal viability following glial activation by reducing astrocyte proliferation and restoring astrocytic and neuronal survival and basal levels of reactive oxygen species (ROS). All antioxidant molecules are also effective under conditions of oxidative stress and glutamate toxicity, two maladaptive components of neuroinflammatory processes. Moreover, it is remarkable that their antioxidant and an...
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The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson’s disease (PD). How this molecular networking achieves its various functionalities and... more
The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson’s disease (PD). How this molecular networking achieves its various functionalities and how processes operating at the seconds-minutes time scale cause a disease at a time scale of multiple decennia is enigmatic.By computational analysis, we here disentangle the reactive oxygen species (ROS) regulatory network into a hierarchy of subnetworks that each correspond to a different functionality. The detailed dynamic model of ROS management obtained integrates these functionalities and fitsin vitrodata sets from two different laboratories.The model shows effective ROS-management for a century, followed by a sudden system’s collapse due to the loss of p62 protein. PD related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the system’s collapse. Variousin-silicointerventions (e.g. addition of antioxidants or caffein...
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Research Interests: Endocrinology, Chemistry, Medicine, Gene expression, In Situ Hybridization, and 15 moreHippocampus, Dexamethasone, Internal Medicine, Cerebral Cortex, Aldosterone, Animals, Corticosterone, Fibroblast Growth Factor, Dentate Gyrus, Adrenocorticotropic Hormone, Nerve Growth Factor, Brain Chemistry, Glucocorticoids, Medical and Health Sciences, and Basic Fibroblast Growth Factor
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Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role... more
Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate tha...
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HSPA8/hsc70 (70-kDa heat shock cognate) chaperone protein exerts multiple protective roles. Beside its ability to confer to the cells a generic resistance against several metabolic stresses, it is also involved in at least two critical... more
HSPA8/hsc70 (70-kDa heat shock cognate) chaperone protein exerts multiple protective roles. Beside its ability to confer to the cells a generic resistance against several metabolic stresses, it is also involved in at least two critical processes whose activity is essential in preventing Parkinson's disease (PD) pathology. Actually, hsc70 protein acts as the main carrier of chaperone-mediated autophagy (CMA), a selective catabolic pathway for alpha-synuclein, the main pathogenic protein that accumulates in degenerating dopaminergic neurons in PD. Furthermore, hsc70 efficiently fragments alpha-synuclein fibrils in vitro and promotes depolymerization into non-toxic alpha-synuclein monomers. Considering that the mitochondrial complex I inhibitor rotenone, used to generate PD animal models, induces alpha-synuclein aggregation, this study was designed in order to verify whether rotenone exposure leads to hsc70 alteration possibly contributing to alpha-synuclein aggregation. To this ai...
Research Interests: Biology, Medicine, Alpha Synuclein, Neurotoxicology, Insecticides, and 14 moreHumans, Cerebral Cortex, Reactive Oxygen Species, Mice, Animals, Neurons, Neuroblastoma, Hydrogen Peroxide, Time Factors, Transfection, Neurosciences, Gene Expression Regulation, Rotenone, and Pharmacology and pharmaceutical sciences
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Recent advances in large datasets analysis offer new insights to modern biology allowing system-level investigation of pathologies. Here we describe a novel computational method that exploits the ever-growing amount of "omics"... more
Recent advances in large datasets analysis offer new insights to modern biology allowing system-level investigation of pathologies. Here we describe a novel computational method that exploits the ever-growing amount of "omics" data to shed light on Alzheimer's and Parkinson's diseases. Neurological disorders exhibit a huge number of molecular alterations due to a complex interplay between genetic and environmental factors. Classical reductionist approaches are focused on a few elements, providing a narrow overview of the etiopathogenic complexity of multifactorial diseases. On the other hand, high-throughput technologies allow the evaluation of many components of biological systems and their behaviors. Analysis of Parkinson's Disease (PD) and Alzheimer's Disease (AD) from a network perspective can highlight proteins or pathways common but differently represented that can be discriminating between the two pathological conditions, thus highlight similarities ...
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Microglia-induced maladaptive plasticity is being recognized as a major cause of deleterious self-sustaining pathological processes that occur in neurodegenerative and neuroinflammatory diseases. Microglia, the primary homeostatic... more
Microglia-induced maladaptive plasticity is being recognized as a major cause of deleterious self-sustaining pathological processes that occur in neurodegenerative and neuroinflammatory diseases. Microglia, the primary homeostatic guardian of the central nervous system, exert critical functions both during development, in neural circuit reshaping, and during adult life, in the brain physiological and pathological surveillance. This delicate critical role can be disrupted by neural, but also peripheral, noxious stimuli that can prime microglia to become overreactive to a second noxious stimulus or worsen underlying pathological processes. Among regulators of microglia, neuropeptides can play a major role. Their receptors are widely expressed in microglial cells and neuropeptide challenge can potently influence microglial activityin vitro. More relevantly, this regulator activity has been assessed alsoin vivo, in experimental models of brain diseases. Neuropeptide action in the centra...
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Dietary antioxidants may be useful in counteracting the chronic inflammatory status in neurodegenerative diseases by reducing oxidative stress due to accumulation of reactive oxygen species (ROS). In this study, we newly described the... more
Dietary antioxidants may be useful in counteracting the chronic inflammatory status in neurodegenerative diseases by reducing oxidative stress due to accumulation of reactive oxygen species (ROS). In this study, we newly described the efficacy of a number of dietary antioxidants (polyphenols, carotenoids, thiolic compounds, and oligoelements) on viability of neuronal PC12 cells following Nerve Growth Factor (NGF) deprivation, a model of age-related decrease of neurotrophic support that triggers neuronal loss. Neuroprotection by antioxidants during NGF deprivation for 24 h was largely dependent on their concentrations: all dietary antioxidants were able to efficiently support cell viability by reducing ROS levels and restoring mitochondrial function, while preserving the neuronal morphology. Moreover, ROS reduction and neuroprotection during NGF withdrawal were also achieved with defined cocktails of 3–6 different antioxidants at concentrations 5–60 times lower than those used in sin...
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Research Interests: Biomarkers, Biology, Medicine, Immunity, Cellular and Molecular Neurobiology, and 15 moreAnimals, Microglia, Male, Neuronal Plasticity, Astrocytes, Membrane transport proteins, Nerve Growth Factor, Calcium Binding Proteins, Neurosciences, Glutamic Acid, Glutamate decarboxylase, Biochemistry and cell biology, Peripheral nerve injuries, Gliosis, and lumbar vertebrae
Stimulation of β-adrenergic receptors (BAR) by clenbuterol (CLE) increases nerve growth factor (NGF) biosynthesis in the rat cerebral cortex but not in other regions of the brain. We have explored the transcription mechanisms that may... more
Stimulation of β-adrenergic receptors (BAR) by clenbuterol (CLE) increases nerve growth factor (NGF) biosynthesis in the rat cerebral cortex but not in other regions of the brain. We have explored the transcription mechanisms that may account for the cortex-specific activation of the NGF gene. Although the NGF promoter contains an AP-1 element, AP-1-binding activity in the cerebral cortex was not induced by CLE, suggesting that other transcription factors govern the brain area-specific induction of NGF. Because BAR activation increases cAMP levels, we examined the role of CCAAT/enhancer-binding proteins (C/EBP), some of which are known to be cAMP-inducible. In C6–2B glioma cells, whose NGF expression is induced by BAR agonists, ( i ) CLE increased C/EBPδ-binding activity, ( ii ) NGF mRNA levels were increased by overexpressing C/EBPδ, and ( iii ) C/EBPδ increased the activity of an NGF promoter–reporter construct. Moreover, DNase footprinting and deletion analyses identified a C/EBP...
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Research Interests: Pain, Immunohistochemistry, Medicine, Neuropathic pain, Animals, and 15 moreMale, Astrocyte, Central Nervous System, Rats, Biological markers, Rat Model, Nerve Growth Factor, Neurosciences, Biochemistry and cell biology, Dorsal Horn, Myelin Sheath, Gliosis, Cell count, Pharmacology and pharmaceutical sciences, and Expression pattern
Recombinant human nerve growth factor (rhNGF) is regarded as the most promising therapy for neurodegeneration of the central and peripheral nervous systems as well as for several other pathological conditions involving the immune system.... more
Recombinant human nerve growth factor (rhNGF) is regarded as the most promising therapy for neurodegeneration of the central and peripheral nervous systems as well as for several other pathological conditions involving the immune system. However, rhNGF is not commercially available as a drug. In this work, we provide data about the production on a laboratory scale of large amounts of a rhNGF that was shown to possess in vivo biochemical, morphological, and pharmacological effects that are comparable with the murine NGF (mNGF), with no apparent side effects, such as allodynia. Our rhNGF was produced by using conventional recombinant DNA technologies combined with a biotechnological approach for high-density culture of mammalian cells, which yielded a production of approximately 21.5 +/- 2.9 mg/liter recombinant protein. The rhNGF-producing cells were thoroughly characterized, and the purified rhNGF was shown to possess a specific activity comparable with that of the 2.5S mNGF by mean...
Research Interests: Multidisciplinary, Cell Differentiation, Humans, Mice, Animals, and 15 morePeripheral Nervous System, Phosphorylation, Immune system, Specific Activity, Chickens, HeLa cells, Bioreactors, High Density Concrete, Side Effect, In Vitro Studies, Biological activity, Nerve Growth Factor, Recombinant Protein, Recombinant Proteins, and Cell Survival
... This review aims to give an overview of the essential molecular pathways underlyingneuroapoptosis and the complex intracellular and inter-cellular cross-talks which involve a large number of metabolic and signaling cascades that may... more
... This review aims to give an overview of the essential molecular pathways underlyingneuroapoptosis and the complex intracellular and inter-cellular cross-talks which involve a large number of metabolic and signaling cascades that may also act synergistically during brain ...
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Research Interests: Multidisciplinary, Cell Differentiation, Humans, Mice, Animals, and 15 morePeripheral Nervous System, Phosphorylation, Immune system, Specific Activity, Chickens, HeLa cells, Bioreactors, High Density Concrete, Side Effect, In Vitro Studies, Biological activity, Nerve Growth Factor, Recombinant Protein, Recombinant Proteins, and Cell Survival
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The presence of functional receptors for calcitonin gene-related peptide (CGRP) in the brain of adult rats and on nerve cell cultures was investigated. Neuronal and glial cultures were obtained from mesencephalons of embryos at... more
The presence of functional receptors for calcitonin gene-related peptide (CGRP) in the brain of adult rats and on nerve cell cultures was investigated. Neuronal and glial cultures were obtained from mesencephalons of embryos at gestational day 16. The response to CGRP was tested by measuring the adenylyl cyclase (AC) activity on isolated membranes. CGRP binding in adult rat brains was ineffective in activating AC, whereas a dose-dependent stimulation of AC activity was induced by the peptide both in neuronal and glial cultures. This effect was more pronounced in the glial cells where high affinity binding sites for CGRP were detected. The presence of functional CGRP receptors in embryonic mesencephalic cells, suggests a role for CGRP in the development of rat mesencephalon.
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Research Interests: Neurobiology Of Disease, Neurobiology, Peripheral Nerve Injury, Glutamate, Animals, and 17 moreSpinal Cord, Male, Astrocyte, Astrocytes, Structural Change, Clinical Sciences, Rats, Homeostasis, SYNAPSES, Neurodegenerative Disease, Sciatic Nerve, Neural pathways, Nerve Growth Factor, Neurosciences, Glutamate Transporter, Nerve Injury, and Gliosis
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Regulation of the cytosolic free Ca2+ concentration by nerve growth factor was investigated in C6-2B glioma cells newly expressing the high affinity nerve growth factor receptor trkA, using Fura-2 fluorescence ratio imaging. In these... more
Regulation of the cytosolic free Ca2+ concentration by nerve growth factor was investigated in C6-2B glioma cells newly expressing the high affinity nerve growth factor receptor trkA, using Fura-2 fluorescence ratio imaging. In these cells, nerve growth factor (50 ng/ml) evoked a novel approximately 3-fold increase in cytosolic free Ca2+ concentration, while no measurable Ca2+ response was observed in wild type or mock-transfected cells lacking a functional trkA receptor. K-252a, a tyrosine kinase inhibitor which prevents nerve growth factor-mediated responses in C6-2B cells expressing trkA, also blocked the rise in cytosolic free Ca2+ concentration by nerve growth factor. Moreover, basic fibroblast growth factor, which in these cells elicits biochemical changes similar to nerve growth factor, failed to affect cytosolic free Ca2+ concentration, further supporting the specificity of nerve growth factor/trkA receptor in mediating a Ca2+ response. While insensitive to chelation of extracellular Ca2+, the response was abolished following depletion of Ca2+ stores or blockade of intracellular Ca2+ release, providing strong evidence that intracellular Ca2+ is the main source for nerve growth factor-evoked cytosolic free Ca2+ concentration increase. Nerve growth factor increased the cytosolic free Ca2+ concentration also in NIH3T3 cells overexpressing trkA but devoid of p75 nerve growth factor receptor. Our data suggest that trkA but not p75 is required for nerve growth factor-evoked Ca2+ signaling.