Tesi etd-06212020-213611
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Tipo di tesi
Dottorato
Autore
PEZZINI, ILARIA
URN
etd-06212020-213611
Titolo
Cerium oxide nanoparticles: a powerful nanotechnological tool in modulating reactive oxygen species detrimental effects.
Settore scientifico disciplinare
ING-IND/34
Corso di studi
Istituto di Biorobotica - BIOROBOTICS
Commissione
Presidente Prof. MICERA, SILVESTRO
Membro Prof. CIOFANI, GIANNI
Membro RICOTTI, LEONARDO
Membro Prof.ssa MENCIASSI, ARIANNA
Membro Prof. CIOFANI, GIANNI
Membro RICOTTI, LEONARDO
Membro Prof.ssa MENCIASSI, ARIANNA
Parole chiave
- mitochondrial metabolism
- nanoceria
- neurodegenerative diseases
- reactive oxygen species
Data inizio appello
30/09/2020;
Disponibilità
parziale
Riassunto analitico
The aim of this PhD Thesis has been the investigation of nanotechnological solutions for the treatment of physiological and clinical conditions where oxidative stress plays a key role both in pathogenesis and progression of symptomatology.
The first part of the thesis provides a conceptual framework that will give a basic understanding of the biological energetic pathways which are essential for the cellular physiological functions; the focus is on the role played by reactive oxygen species (ROS), which are generated through numerous metabolic pathways, both in physiological and pathological conditions.
The introduction also contains a basic understanding about the molecular mechanism of action of nanomaterials used for therapeutic purposes, with a focus on a nanotechnological solution capable of influencing the cellular redox homeostasis, supporting the cellular antioxidant defence system and reactivating the ROS signalling to perform normal cell functions: cerium oxide nanoparticles (nanoceria, NC). NC are an emerging powerful tool for the regulation of free radicals levels in the biological environment and thus could act as a therapeutic agent for the treatment of several clinical conditions which are unmet by current medical approaches. As a proof of concept, after a preliminary investigation on cytocompatibility, we tested NC in primary cultured skin fibroblasts derived from healthy individuals, evaluating the mitochondrial function both in basal conditions and after an oxidative insult. Our results demonstrated that NC act not only as cytoprotective agents, but also exploit a strong power as a proenergetic compounds.
In the second part of the thesis, the pathogenic role of ROS, together with the potential of NC treatment on the nervous system (NS) has been investigated. Growing evidence suggests that the impairment of mitochondrial metabolism could be involved in the pathogenesis of several neurodegenerative diseases (NDs); thus we investigated NC as a possible countermeasure for Hereditary Spastic Paraplegia Type 31 (SPG31), a disorder characterized by a length-dependent degeneration of upper motor neuron axons, due to a mutation in the receptor expression-enhancing protein 1 (REEP1) gene. We evaluated primary skin fibroblasts derived from two REEP1 mutated individuals, in order to screen the antioxidant pharmacological effect of NC in counteracting the generalized energetic imbalance seen in mutated cells.
Following this, we present preliminary results about an exploratory in vivo work on the evaluation of NC effects against injuries of the NS. Regenerative nerve interfaces have been long proposed as a feasible therapeutic option because of the capacity of injured axons to regrow spontaneously through an engineered device. Although the research areas of tissue engineering, nerve regeneration, and implantable neural-electronic interfaces, have been recently quickly developing, there is still the urgent need of merging all these fields, in order to create a high performance, mechanically compliant, scalable and biocompatible neural interface to tackle the new challenges of bioelectronic medicine. One of the main hurdles toward this is the long term usability of intra neural implants, which is hampered by the progressive development of a fibrotic capsule around the device: thus, the effect of a cerium oxide coating on a neuroelectrodes-compliant material has been investigated, in order to try to counteract the inflammatory response activation and the glial scar formation at the site of the implant.
As a conclusive part, we show the results collected during two international research programs, namely “PLANOX” and “NANOROS”, which represent an excellent integration to the two previously discussed research lines. During the first one, which was part of European Space Agency (ESA) “Spin Your Thesis (SYT)” programme, we assessed the capability of nanoceria to protect a living organism, the planarian Dugesia japonica, from the oxidative stress induced by exposure to simulated hypergravity.
Conversely, during the NANOROS programme, which was part of the Italian Space Agency (ASI) Biomission "Vita”, we studied NC effectiveness aboard the International Space Station (ISS), in microgravity conditions. In particular, we examined the NC capacity in counteracting the skeletal muscle alterations and functional deficiencies caused by the oxidative stress arising from long-term exposure to extreme conditions, that significantly limit astronauts’ stay in space and exploration.
This work highlights the link between the etiopathogenesis of clinical conditions in which oxidative stress plays a pivotal role and cellular energetic dysfunction due to ROS accumulation, underlining their interconnection. In this context, the exploitation of nanoceria as a possible countermeasure against ROS deleterious effects, demonstrates not only the cytoprotective and antioxidant effects, but also the action as a pro energetic actor.
The first part of the thesis provides a conceptual framework that will give a basic understanding of the biological energetic pathways which are essential for the cellular physiological functions; the focus is on the role played by reactive oxygen species (ROS), which are generated through numerous metabolic pathways, both in physiological and pathological conditions.
The introduction also contains a basic understanding about the molecular mechanism of action of nanomaterials used for therapeutic purposes, with a focus on a nanotechnological solution capable of influencing the cellular redox homeostasis, supporting the cellular antioxidant defence system and reactivating the ROS signalling to perform normal cell functions: cerium oxide nanoparticles (nanoceria, NC). NC are an emerging powerful tool for the regulation of free radicals levels in the biological environment and thus could act as a therapeutic agent for the treatment of several clinical conditions which are unmet by current medical approaches. As a proof of concept, after a preliminary investigation on cytocompatibility, we tested NC in primary cultured skin fibroblasts derived from healthy individuals, evaluating the mitochondrial function both in basal conditions and after an oxidative insult. Our results demonstrated that NC act not only as cytoprotective agents, but also exploit a strong power as a proenergetic compounds.
In the second part of the thesis, the pathogenic role of ROS, together with the potential of NC treatment on the nervous system (NS) has been investigated. Growing evidence suggests that the impairment of mitochondrial metabolism could be involved in the pathogenesis of several neurodegenerative diseases (NDs); thus we investigated NC as a possible countermeasure for Hereditary Spastic Paraplegia Type 31 (SPG31), a disorder characterized by a length-dependent degeneration of upper motor neuron axons, due to a mutation in the receptor expression-enhancing protein 1 (REEP1) gene. We evaluated primary skin fibroblasts derived from two REEP1 mutated individuals, in order to screen the antioxidant pharmacological effect of NC in counteracting the generalized energetic imbalance seen in mutated cells.
Following this, we present preliminary results about an exploratory in vivo work on the evaluation of NC effects against injuries of the NS. Regenerative nerve interfaces have been long proposed as a feasible therapeutic option because of the capacity of injured axons to regrow spontaneously through an engineered device. Although the research areas of tissue engineering, nerve regeneration, and implantable neural-electronic interfaces, have been recently quickly developing, there is still the urgent need of merging all these fields, in order to create a high performance, mechanically compliant, scalable and biocompatible neural interface to tackle the new challenges of bioelectronic medicine. One of the main hurdles toward this is the long term usability of intra neural implants, which is hampered by the progressive development of a fibrotic capsule around the device: thus, the effect of a cerium oxide coating on a neuroelectrodes-compliant material has been investigated, in order to try to counteract the inflammatory response activation and the glial scar formation at the site of the implant.
As a conclusive part, we show the results collected during two international research programs, namely “PLANOX” and “NANOROS”, which represent an excellent integration to the two previously discussed research lines. During the first one, which was part of European Space Agency (ESA) “Spin Your Thesis (SYT)” programme, we assessed the capability of nanoceria to protect a living organism, the planarian Dugesia japonica, from the oxidative stress induced by exposure to simulated hypergravity.
Conversely, during the NANOROS programme, which was part of the Italian Space Agency (ASI) Biomission "Vita”, we studied NC effectiveness aboard the International Space Station (ISS), in microgravity conditions. In particular, we examined the NC capacity in counteracting the skeletal muscle alterations and functional deficiencies caused by the oxidative stress arising from long-term exposure to extreme conditions, that significantly limit astronauts’ stay in space and exploration.
This work highlights the link between the etiopathogenesis of clinical conditions in which oxidative stress plays a pivotal role and cellular energetic dysfunction due to ROS accumulation, underlining their interconnection. In this context, the exploitation of nanoceria as a possible countermeasure against ROS deleterious effects, demonstrates not only the cytoprotective and antioxidant effects, but also the action as a pro energetic actor.
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