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"Agostini, Francesco"
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Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges
Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.
Journal Article
Sarcopenic Dysphagia, Malnutrition, and Oral Frailty in Elderly: A Comprehensive Review
Frailty is a highly prevalent condition in the elderly that has been increasingly considered as a crucial public health issue, due to the strict correlation with a higher risk of fragility fractures, hospitalization, and mortality. Among the age-related diseases, sarcopenia and dysphagia are two common pathological conditions in frail older people and could coexist leading to dehydration and malnutrition in these subjects. “Sarcopenic dysphagia” is a complex condition characterized by deglutition impairment due to the loss of mass and strength of swallowing muscles and might be also related to poor oral health status. Moreover, the aging process is strictly related to poor oral health status due to direct impairment of the immune system and wound healing and physical and cognitive impairment might indirectly influence older people’s ability to carry out adequate oral hygiene. Therefore, poor oral health might affect nutrient intake, leading to malnutrition and, consequently, to frailty. In this scenario, sarcopenia, dysphagia, and oral health are closely linked sharing common pathophysiological pathways, disabling sequelae, and frailty. Thus, the aim of the present comprehensive review is to describe the correlation among sarcopenic dysphagia, malnutrition, and oral frailty, characterizing their phenotypically overlapping features, to propose a comprehensive and effective management of elderly frail subjects.
Journal Article
Linking ROS Levels to Autophagy: The Key Role of AMPK
Oxygen reactive species (ROS) are a group of molecules generated from the incomplete reduction of oxygen. Due to their high reactivity, ROS can interact with and influence the function of multiple targets, which include DNA, lipids, and proteins. Among the proteins affected by ROS, AMP-activated protein kinase (AMPK) is considered a major sensor of the intracellular energetic status and a crucial hub involved in the regulation of key cellular processes, like autophagy and lysosomal function. Thanks to these features, AMPK has been recently demonstrated to be able to perceive signals related to the variation of mitochondrial dynamics and to transduce them to the lysosomes, influencing the autophagic flux. Since ROS production is largely dependent on mitochondrial activity, through the modulation of AMPK these molecules may represent important signaling agents which participate in the crosstalk between mitochondria and lysosomes, allowing the coordination of these organelles’ functions. In this review, we will describe the mechanisms through which ROS activate AMPK and the signaling pathways that allow this protein to affect the autophagic process. The picture that emerges from the literature is that AMPK regulation is highly tissue-specific and that different pools of AMPK can be localized at specific intracellular compartments, thus differentially responding to altered ROS levels. For this reason, future studies will be highly advisable to discriminate the specific contribution of the activation of different AMPK subpopulations to the autophagic pathway.
Journal Article
In Ovarian Cancer Multicellular Spheroids, Platelet Releasate Promotes Growth, Expansion of ALDH+ and CD133+ Cancer Stem Cells, and Protection against the Cytotoxic Effects of Cisplatin, Carboplatin and Paclitaxel
A high platelet count is associated with a poor prognosis in ovarian cancer (OvCa). Despite good clinical responses with platinating agents in combination with taxanes, numerous OvCa patients relapse due to chemotherapy resistance. Here, we report that treatment of OvCa cells A2780, OVCAR5 and MDAH with releasate from activated platelets (PR) promoted multicellular tumor spheroid (MCTS) formation. These OvCa-MCTSs had increased percentages of CD133+ and aldehyde dehydrogenase (ALDH)+ cells, bona fide markers of OvCa cancer stem cells (CSCs). PR increased OVCAR5- and MDAH-MCTS viability and decreased the cytotoxic and pro-apoptotic effects of paclitaxel, cisplatin and carboplatin. PR increased the volume of spontaneously formed OVCAR8-MCTSs and counteracted their size reduction due to cisplatin, carboplatin and paclitaxel treatment. PR promoted the survival of ALDH+ and CD133+ OvCa cells during cisplatin, carboplatin and paclitaxel treatment. In conclusion, molecules and growth factors released by activated platelets (EGF, PDGF, TGF-β, IGF and CCL5) may protect tumor cells from chemotherapy by promoting the expansion of ALDH+ and CD133+ OvCa-CSCs, favoring drug resistance and tumor relapse.
Journal Article
Supervised and unsupervised learning to classify scoliosis and healthy subjects based on non-invasive rasterstereography analysis
The aim of our study was to classify scoliosis compared to to healthy patients using non-invasive surface acquisition via Video-raster-stereography, without prior knowledge of radiographic data. Data acquisitions were made using Rasterstereography; unsupervised learning was adopted for clustering and supervised learning was used for prediction model Support Vector Machine and Deep Network architectures were compared. A M -fold cross validation procedure was performed to evaluate the results. The accuracy and balanced accuracy of the best supervised model were close to 85%. Classification rates by class were measured using the confusion matrix, giving a low percentage of unclassified patients. Rasterstereography has turned out to be a good tool to distinguish subject with scoliosis from healthy patients limiting the exposure to unnecessary radiations.
Journal Article
Carbon Sequestration by Perennial Energy Crops: Is the Jury Still Out?
Soil organic carbon (SOC) changes associated with land conversion to energy crops are central to the debate on bioenergy and their potential carbon neutrality. Here, the experimental evidence on SOC under perennial energy crops (PECs) is synthesised to parameterise a whole systems model and to identify uncertainties and knowledge gaps determining PECs being a sink or source of greenhouse gas (GHG). For Miscanthus and willow (Salix spp.) and their analogues (switchgrass, poplar), we examine carbon (C) allocation to above- and belowground residue inputs, turnover rates and retention in the soil. A meta-analysis showed that studies on dry matter partitioning and C inputs to soils are plentiful, whilst data on turnover are rare and rely on few isotopic C tracer studies. Comprehensive studies on SOC dynamics and GHG emissions under PECs are limited and subsoil processes and C losses through leaching remain unknown. Data showed dynamic changes of gross C inputs and SOC stocks depending on stand age. C inputs and turnover can now be specifically parameterised in whole PEC system models, whilst dependencies on soil texture, moisture and temperature remain empirical. In conclusion, the annual net SOC storage change exceeds the minimum mitigation requirement (0.25 Mg C ha⁻¹ year⁻¹) under herbaceous and woody perennials by far (1.14 to 1.88 and 0.63 to 0.72 Mg C ha⁻¹ year⁻¹, respectively). However, long-term time series of field data are needed to verify sustainable SOC enrichment, as the physical and chemical stabilities of SOC pools remain uncertain, although they are essential in defining the sustainability of C sequestration (half-life >25 years).
Journal Article
α-Synuclein Toxicity in Drosophila melanogaster Is Enhanced by the Presence of Iron: Implications for Parkinson’s Disease
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the preferential loss of dopaminergic neurons and by the accumulation of intracellular inclusions mainly composed of α-synuclein (α-Syn). While the etiopathogenesis of the disorder is still elusive, recent experimental evidence supports the involvement of ferroptosis, an iron-dependent cell death pathway, in the pathogenesis of PD. In the present work, using different ferroptosis inducers and inhibitors, we evaluated, in vivo, the involvement of iron in the α-Syn-mediated toxicity. Using a Drosophila melanogaster model of PD based on the selective over-expression of α-Syn within dopaminergic neurons, we demonstrated that the over-expression of α-Syn promotes the accumulation of protein aggregates, which is accompanied by dopaminergic neurodegeneration, locomotor impairment, and lifespan reduction. These pathological phenotypes were further exacerbated by reduced intracellular levels of glutathione or increased concentrations of iron. Coherently, both the use of an iron chelator and the presence of the antioxidant compound N-acetylcysteine exerted protective effects. Overall, our results support the involvement of ferroptosis in the α-Syn-mediated toxicity.
Journal Article
Oxygen–Ozone Therapy in the Rehabilitation Field:State of the Art on Mechanisms of Action, Safety andEffectiveness in Patients with Musculoskeletal Disorders
In recent years, the interest in oxygen–ozone (O2O3) therapy application has considerably increased in the field of rehabilitation. Despite its widespread use in common clinical practice, the biochemical effects of O2O3 are still far from being understood, although its chemical properties seem to play a pivotal role in exerting its positive effects on different pathological conditions. Indeed, the effectiveness of O2O3 therapy might be partly due to the moderate oxidative stress produced by O3 interactions with biological components. O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune over-activation, and most musculoskeletal disorders share these pathophysiological processes. The present comprehensive review depicts the state-of-the-art on the mechanisms of action, safety and effectiveness of O2O3 therapy in the complex scenario of the management of musculoskeletal disorders. Taken together, our findings suggest that O2O3 therapy seems to reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis, as reported by several studies in the literature. However, to date, further studies are warranted to clearly investigate the therapeutic effects of this promising therapy on other musculoskeletal disorders in the field of rehabilitation.
Journal Article
Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?
Iron is an essential metal ion implicated in several cellular processes. However, the reactive nature of iron renders this metal ion potentially dangerous for cells, and its levels need to be tightly controlled. Alterations in the intracellular concentration of iron are associated with different neuropathological conditions, including neurodegeneration with brain iron accumulation (NBIA). As the name suggests, NBIA encompasses a class of rare and still poorly investigated neurodegenerative disorders characterized by an abnormal accumulation of iron in the brain. NBIA is mostly a genetic pathology, and to date, 10 genes have been linked to familial forms of NBIA. In the present review, after the description of the principal mechanisms implicated in iron homeostasis, we summarize the research data concerning the pathological mechanisms underlying the genetic forms of NBIA and discuss the potential involvement of iron in such processes. The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology. The onset of these pathologies is rather caused by a combination of processes involving the interplay between lipid metabolism, mitochondrial functions, and autophagic activity, eventually leading to iron dyshomeostasis.
Journal Article