Cinzia Volonté - Academia.edu (original) (raw)

Papers by Cinzia Volonté

Lancet Neurology, May 1, 2022

Journal of Biological Chemistry, Oct 1, 1992

More than 600 different neurological diseases affect the human population. Some of these are gene... more More than 600 different neurological diseases affect the human population. Some of these are genetic and can emerge even before birth, and some are caused by defects, infections, trauma, degeneration, inflammation, and cancer. However, they all share disabilities caused by damage to the nervous system. In the last decades, the burden of almost all neurological disorders has increased in terms of absolute incidence, prevalence, and mortality, largely due to the population's growth and aging. This represents a dangerous trend and should become our priority for the future. But what new goals are we going to set and reach now, and how will we exploit thought-provoking technological skills for making these goals feasible? Machine learning can be at the root of the problem. Indeed, most recently, there has been a push towards medical data analysis by machine learning, and a great improvement in the training capabilities particularly of artificial deep neural networks (DNNs) inspired by the biological neural networks characterizing the human brain. This has generated competitive results for applications such as biomolecular target and protein structure prediction, structure-based rational drug design, and repurposing, all exerting a major impact on neuroscience and human well-being. By approaching early risks for diseases, non-invasive diagnosis, personalized treatment assessment, drug discovery, and automated science, the machine learning arena has thus the potential of becoming the new frontier for empowering neuroscience research and clinical practice in the years ahead.

Springer eBooks, 1986

It is a well-established and widely recognized notion that tumor cells have a particularly active... more It is a well-established and widely recognized notion that tumor cells have a particularly active glycolysis (Warburg 1967). This phenomenon is generally known as Warburg effect, in recognition of the scientist who first identified this process and described it in many papers: “Oxygen gas, the donor of energy in plants and animals, is dethroned in cancer cells and replaced by an energy-yielding reaction of the lowest living forms, namely a fermentation of glucose”.

The Society for Neuroscience Abstracts, May 3, 1991

Neurotherapeutics, May 13, 2021

The continuous adherence to the conventional "one target, one drug" paradigm has failed... more The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.

Neuropharmacology, Dec 1, 2022

Frontiers in Pharmacology, Feb 19, 2021

Huntington's disease (HD) is a life-threatening neurodegenerative disorder. Altered levels and fu... more Huntington's disease (HD) is a life-threatening neurodegenerative disorder. Altered levels and functions of the purinergic ionotropic P2X7 receptors (P2X7Rs) have been found in animal and cellular models of HD, suggesting their possible role in the pathogenesis of the disease; accordingly, the therapeutic potential of P2X7R antagonists in HD has been proposed. Here we further investigated the effects of P2X7R ligands in in vitro and ex vivo HD experimental models. In ST14A/Q120 rat striatal cells, we found a reduction of P2X7R expression; however, the P2X7R agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′triphosphate (BzATP) induced cellular death, and this effect was fully reversed by the antagonist periodate-oxidized adenosine 5′-triphosphate (OxATP). Moreover, in corticostriatal slices from symptomatic R6/2 mice, BzATP reduced the synaptic transmission to a larger extent than in wild-type (WT) mice. Such an effect was accompanied by a concomitant increase of the paired-pulse ratio, suggesting a presynaptic inhibitory action. This was confirmed to be the case, since while the effects of BzATP were unaffected by the P2X7R antagonist OxATP, they were blocked by the adenosine A 1 receptor (A 1 R) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), suggesting possible BzATP hydrolysis to 2′(3′)-O-(4-benzoylbenzoyl) adenosine (Bz-adenosine) and consequent activation of A 1 Rs as a mechanism. Taken together, these data point out that 1) P2X7R expression and activity are confirmed to be altered in the presence of HD mutation; 2) in some experimental settings, such an abnormal functioning can be ascribed to presynaptic A 1 Rs activation.

Frontiers Media SA eBooks, 2020

Neural Regeneration Research, 2023

Journal of Biological Chemistry, Jul 1, 1990

Journal of Cellular Physiology

The insulin signaling pathway controls cell growth and metabolism, thus its deregulation is assoc... more The insulin signaling pathway controls cell growth and metabolism, thus its deregulation is associated with both cancer and diabetes. Phosphatidylinositol 3‐kinase (PI3K) contributes to the cascade of phosphorylation events occurring in the insulin pathway by activating the protein kinase B (PKB/AKT), which phosphorylates several substrates, including those involved in glucose uptake and storage. PI3K inactivating mutations are associated with insulin resistance while activating mutations are identified in human cancers. Here we show that RNAi‐induced depletion of the Drosophila PI3K catalytic subunit (Dp110) results in diabetic phenotypes such as hyperglycemia, body size reduction, and decreased glycogen content. Interestingly, we found that hyperglycemia produces chromosome aberrations (CABs) triggered by the accumulation of advanced glycation end‐products and reactive oxygen species. Rearing PI3KRNAi flies in a medium supplemented with pyridoxal 5′‐phosphate (PLP; the catalytical...

International Journal of Molecular Sciences, 2021

S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pa... more S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pattern molecule. A direct correlation between the increased amount of S100B and inflammatory processes has been demonstrated, and in particular, the inhibitor of S100B activity pentamidine has been shown to ameliorate clinical scores and neuropathologic-biomolecular parameters in the relapsing-remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This study investigates the effect of arundic acid (AA), a known inhibitor of astrocytic S100B synthesis, in the chronic experimental autoimmune encephalomyelitis, which is another mouse model of multiple sclerosis usually studied. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the spinal cord, we observed that the AA-treated group showed lower severity compared to the vehicle-treated mice, particularly in the early phase of disease onset. We also observed a signific...

British Journal of Pharmacology, 2021

Background and PurposeAmyotrophic lateral sclerosis (ALS), a neurodegenerative disease characteri... more Background and PurposeAmyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi‐target drug used to treatment of coronary artery disease, trimetazidine, in SOD1G93Amice.Experimental ApproachAs a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti‐inflammatory and antioxidant effect. We orally treated SOD1G93Amice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg−1, from disease onset. We assessed the impact of trimetaz...

Ageing Research Reviews, 2020

Decisione di contrattare semplificata: Spese servizio di open access per l'articolo scientifico d... more Decisione di contrattare semplificata: Spese servizio di open access per l'articolo scientifico dal titolo "Omics-based exploration and functional validation of neurotrophic factors and histamine as therapeutic targets in als" sottomesso alla rivista scientifica "Ageing Research Reviews" per il tramite della casa editrice Elsevier Ltd-Progetto "Diagnosi precoce di alcune malattie lisosomiali" collegato alla Convenzione tra Sanofi e IRIB-CUP: B61G18000290005 IL RESPONSABILE VISTA la Legge 241/1990 e s.m.i. recante "Nuove norme in materia di procedimento amministrativo e di diritto di accesso ai documenti amministrativi" ;

Cellular and Molecular Life Sciences, 2021

Amyotrophic lateral sclerosis (ALS) is a rare, devastating disease, causing movement impairment, ... more Amyotrophic lateral sclerosis (ALS) is a rare, devastating disease, causing movement impairment, respiratory failure and ultimate death. A plethora of genetic, cellular and molecular mechanisms are involved in ALS signature, although the initiating causes and progressive pathological events are far from being understood. Drosophila research has produced seminal discoveries for more than a century and has been successfully used in the past 25 years to untangle the process of ALS pathogenesis, and recognize potential markers and novel strategies for therapeutic solutions. This review will provide an updated view of several ALS modifiers validated in C9ORF72, SOD1, FUS, TDP-43 and Ataxin-2 Drosophila models. We will discuss basic and preclinical findings, illustrating recent developments and novel breakthroughs, also depicting unsettled challenges and limitations in the Drosophila-ALS field. We intend to stimulate a renewed debate on Drosophila as a screening route to identify more successful disease modifiers and neuroprotective agents.

Frontiers in Endocrinology, 2020

Whole-body energy metabolism entails the highly regulated balance between food intake, nutrient b... more Whole-body energy metabolism entails the highly regulated balance between food intake, nutrient breakdown, energy generation (ATP), and energy storage for the preservation of vital functions and body mass. Purinergic signaling has attracted increasing attention in the regulatory mechanisms not only for the reverse processes of white adipose tissue lipogenesis and lipolysis, but also for brown adipocyte-dependent thermogenesis and leptin production. This regulatory role has remarkable implications in the handling of body's energy expenditure and energy reservoir. Hence, selected purinergic receptors can play a relevant function in lipid metabolism, endocrine activity, glucose uptake, ATP-dependent increased expression of uncoupling protein 1, and browning of adipose tissue. Indeed, purinergic P2 receptors regulate adipogenesis and lipid metabolism and are involved in adipogenic differentiation. In particular, the ionotropic ATP-activated P2X7 subtype is involved in fat distribution, as well as in the modulation of inflammatory pathways in white adipose tissue. Within this context, very recent evidence has established a direct function of P2X7 in energy metabolism. Specifically, either genetic deletion (P2X7 knockout mice) or subchronic pharmacological inhibition of the receptor produces a decrease of whole-body energy expenditure and, concurrently, an increase of carbohydrate oxidation. As further evidence, lipid accumulation, increased fat mass distribution, and weight gain are reported in P2X7-depleted mice. Conversely, the stimulation of P2X7 enhances energy expenditure. Altogether, this knowledge supports the role of P2X7 signaling in the fight against obesity and insulin resistance, as well as in the promotion of adaptive thermogenesis.

Seminars in Cell & Developmental Biology, 2019

• Microglia involvement is a prominent feature and crucial mechanism of ALS. • Modulation of neur... more • Microglia involvement is a prominent feature and crucial mechanism of ALS. • Modulation of neurotransmitter expression confers a pathological signature to ALS microglia. • ATP receptors are strongly involved in the microglia-mediated mechanisms of ALS. • Glutamate signaling acquires a pathogenic role in ALS microglia. • Histamine receptors activation drives an anti-inflammatory phenotype in ALS microglia.

Cell Death & Differentiation, 2016

Understanding the means by which microglia self-regulate the neuroinflammatory response helps mod... more Understanding the means by which microglia self-regulate the neuroinflammatory response helps modulating their reaction during neurodegeneration. In amyotrophic lateral sclerosis (ALS), classical NF-κB pathway is related to persistent microglia activation and motor neuron injury; however, mechanisms of negative control of NF-κB activity remain unexplored. One of the major players in the termination of classical NF-κB pathway is the ubiquitin-editing enzyme A20, which has recognized anti-inflammatory functions. Lately, microRNAs are emerging as potent fine-tuners of neuroinflammation and reported to be regulated in ALS, for instance, by purinergic P2X7 receptor activation. In this work, we uncover an interplay between miR-125b and A20 protein in the modulation of classical NF-κB signaling in microglia. In particular, we establish the existence of a pathological circuit in which termination of A20 function by miR-125b strengthens and prolongs the noxious P2X7 receptor-dependent activation of NF-κB in microglia, with deleterious consequences on motor neurons. We prove that, by restoring A20 levels, miR-125b inhibition then sustains motor neuron survival. These results introduce miR-125b as a key mediator of microglia dynamics in ALS.