1,720,998 research outputs found
mGlu5 receptor negative allosteric modulation reduces the aberrant cellular reactivity and neurotoxicity of iNPCs-derived human astrocytes differentiated from ALS patients
No full textBACKGROUND. Amyotrophic Lateral Sclerosis (ALS) is a multifactorial and non-cell-autonomous neurodegenerative disease, characterized by brainstem and spinal cord motor neuron (MN) death. The etiopathological mechanisms are numerous and among them, glutamate excitotoxicity plays a major role. The metabotropic glutamate receptor type 5 (mGluR5) fine modulates glutamate neurotransmission other than astrocyte reactivity, and this mechanism can be exploited as potential target to counteract MN loss in ALS. We provided in-vitro and in-vivo evidence showing that genetic ablation or the pharmacological modulation of mGluR5, by the selective negative allosteric modulator CTEP, positively affects the reactive phenotype and neurotoxicity of ALS astrocytes and significantly improved the life span and disease progression in SOD1G93A ALS mice.
Here we investigated in-vitro the impact of mGluR5 modulation by CTEP on human i-Astrocytes differentiated from inducible neural progenitor cells (iNPCs) obtained from skin fibroblasts of ALS patients and healthy donors. With this aim, we monitored the cellular phenotype of i-Astrocytes when exposed to 100nM CTEP by exploiting molecular biology and immunohistochemical studies. We monitored the intracellular calcium level by live imaging and fluorometric detection, moreover we quantified the secretion of neurotoxic factors by ELISA assay. The accumulation of reactive oxygen species, as well as oxidative stress markers have been investigated by immunohistochemical and biochemical studies, moreover we measured the activity of antioxidant response enzymes. As an indirect, but very important readout, we finally investigated the neurotoxicity of the astrocyte conditioned medium on human-derived motor neurons differentiated from iPSCs of healthy donors and ALS patients.
RESULTS. In-vitro pharmacological modulation with CTEP did not alter the mGluR5 total expression in i-Astrocytes. RT-qPCR analyses, western blot and immunohistochemical experiments showed that 5 days in-vitro exposure to 100nM CTEP reduced the over-expression of astrogliosis (GFAP, S100β, C3) and neuroinflammation (NLRP3) markers (p<0.05; two-way ANOVA) in i-Astrocytes from ALS-patients vs. untreated or control cells. CTEP treatment was also able to restore oxidative stress conditions by promoting Nrf2 nuclear translocation, enhancement of the antioxidant enzymes activity (glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, catalase), and consequent reduction of ROS and direct oxidative stress markers (p<0.001; two-way ANOVA) in ALS i-Astrocytes. Acute CTEP in-vitro treatment significantly reduces the intracellular calcium mobilization upon mGlu5 receptor activation, in ALS and control i-Astrocytes. On the other hand, the reduced astrocyte reactivity by CTEP treatment translates into a beneficial effect towards iPSCs-derived MNs exposed to the conditioned medium collected from i-Astrocytes.
CONCLUSIONS. We here show that the in-vitro pharmacological allosteric blockade of the mGluR5 by CTEP positively affects the reactive phenotype of human-derived i-Astrocytes differentiated form from C9orf72 and SOD1A4V ALS patients, mainly by ameliorating the general oxidative stress response and reducing the release of toxic factors. These data extend our previous results in SOD1G93A in-vitro and in-vivo models, thus further encouraging a translational application of mGluR5 modulators in clinical trials
Eco-innovation and competitiveness in industrial clusters
No full textThe article aims to investigate the presence of a correlation between eco-innovation and competitiveness within districts. The case analyzed in this article is based on a study concerning a sample of 54 Italian industrial clusters entitled "Eco-Districts" that has compiled a list of the most eco-efficient districts at the national level. After selecting two districts operating in the same productive field, this study assesses the economic performance of the last three years through the analysis of trends in four indicators: number of enterprises, employment, production and export.
The results show that only in some cases there is a connection between eco innovation and competitiveness
The link between environmental and economic performance: evidence from some eco-innovative industrial clusters
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Exploring the alignment and misalignment in the transition to a circular economy within private companies and public organizations
Full text linkThe paper explores the alignment and misalignment of objectives within private companies and public organizations in their approach to the circular economy. While many studies have investigated the alignment within
single actor types, this research reveals the dynamics of alignment when private companies and public organizations engage. Drawing upon qualitative research protocol, our study employs a circular economy financing initiative implemented in Italy as the empirical foundation for investigating these dynamics. The results highlight
the positive repercussions when private companies and public organizations achieve perfect alignment, which triggers internal transformations within both entities. However, perfect alignment is seldom achieved. Our findings thus contribute to the literature by proposing actor misalignment as a potential barrier to the circular
economy. This paper provides both theoretical and managerial insights into alignment dynamics within the context of the circular economy and offers a perspective on how these dynamics might evolve over time in multistakeholder circular economy initiatives
Cluster approach and eco-innovation in four industrial clusters of Tuscany region (Italy)
No full text"Uno studio sui Soggetti Gestori delle APEA italiane: profili giuridici, funzioni, rapporti con le imprese" in “Eco-aree produttive. Guida all’eco-innovazione, alle politiche per la sostenibilità e ai progetti operativi nelle Aree Produttive Ecologicamente Attrezzate (APEA)”
No full textPerceptions on LCA implementation: evidence from a survey on adopters and nonadopters in Italy
No full textIsomorphic or dissimilar implementation among environmental management scheme adopters? Empirical evidence from the European context
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