The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure‐Based Virtual Screening to In Vivo Biological Activity

A mismatch between β‐oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3‐(2,2,2‐ trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP‐derived carnitine‐lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Two analogues of the MS3 aptamer, which was previously shown to have an exquisite capability to selectively bind and modulate the activity of mutant huntingtin (mHTT), have been here designed and evaluated in their physicochemical and biological properties. Featured by a distinctive propensity to form complex G-quadruplex structures, including large multimeric aggregates, the original 36-mer MS3 has been truncated to give a 33-mer (here named MS3-33) and a 17-mer (here named MS3-17). A combined use of different techniques (UV, CD, DSC, gel electrophoresis) allowed a detailed physicochemical characterization of these novel G-quadruplex-forming aptamers, tested in vitro on SH-SY5Y cells and in vivo on a Drosophila Huntington’s disease model, in which these shorter MS3-derived oligonucleotides proved to have improved bioactivity in comparison with the parent aptamer

Fighting the Huntington's Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization, In Vitro and In Vivo Studies

A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established Drosophila melanogaster model for Huntington's disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer

The CNR activities for NBFC Spoke 7 “Biodiversity and society: communication, education and social impact”

Promoting a more responsible behaviour and enhancing a more sustainable management of biodiversity

An integrated multimedia scientific communication for increasing awareness and sustainably manage biodiversity

CNR participates in the activities of Spoke 7 “Biodiversity and society: communication, education and social impact” through the Department of Earth System Sciences and Environmental Technologies, the Institute for the study of Anthropogenic impacts and Sustainability in the marine environment, the Institute of Environmental Geology and Geoengineering, the Institute for electromagnetic sensing of the environment, the research Institute for Terrestrial Ecosystems, the Institute of Marine Sciences. Thanks to the interdisciplinary experience of the researchers and technologists involved (biologists, geologists, communicators, naturalists, etc.) and through an integrated multimedia scientific communication, researchers aim to reach wider audiences to promote a more responsible behavior and a more sustainable management of biodiversity. To reach a larger portion of public opinion and new audiences, especially those stakeholders which have never been exposed to scientific content related to biodiversity (from industry to young children), researchers used new languages, formats and methods of communication in order to make the central messages of the NBFC truly visible, popular and shared. Through the launch of pilot projects, researchers combined scientific storytelling on biodiversity with comics, gamification activities, exhibition and dissemination events. As part of public engagement activities, citizen science projects, field trips as well as new educational paths, training activities and open labs for schools aimed at marine sciences, coastal biodiversity, geodiversity and paleo-biodiversity were carried out. Through the use of specific tools, such as “Contratti di Fiume”, and methods of awareness-raising, education and involvement of public administrations, an attempt was made to make biodiversity protection actions more effective

The Emerging Role of Macrophages in Chronic Obstructive Pulmonary Disease: The Potential Impact of Oxidative Stress and Extracellular Vesicle on Macrophage Polarization and Function

Chronic obstructive pulmonary disease (COPD) is one of the most common airway diseases, and it is considered a major global health problem. Macrophages are the most representative immune cells in the respiratory tract, given their role in surveying airways, removing cellular debris, immune surveillance, and resolving inflammation. Macrophages exert their functions by adopting phenotypical changes based on the stimuli they receive from the surrounding tissue. This plasticity is described as M1/M2 macrophage polarization, which consists of a strictly coordinated process leading to a difference in the expression of surface markers, the production of specific factors, and the execution of biological activities. This review focuses on the role played by macrophages in COPD and their implication in inflammatory and oxidative stress processes. Particular attention is on macrophage polarization, given macrophage plasticity is a key feature in COPD. We also discuss the regulatory influence of extracellular vesicles (EVs) in cell-to-cell communications. EV composition and cargo may influence many COPD-related aspects, including inflammation, tissue remodeling, and macrophage dysfunctions. These findings could be useful for better addressing the role of macrophages in the complex pathogenesis and outcomes of COPD

The Emerging Role of Macrophages in Chronic Obstructive Pulmonary Disease: The Potential Impact of Oxidative Stress and Extracellular Vesicle on Macrophage Polarization and Function

Chronic obstructive pulmonary disease (COPD) is one of the most common airway diseases, and it is considered a major global health problem. Macrophages are the most representative immune cells in the respiratory tract, given their role in surveying airways, removing cellular debris, immune surveillance, and resolving inflammation. Macrophages exert their functions by adopting phenotypical changes based on the stimuli they receive from the surrounding tissue. This plasticity is described as M1/M2 macrophage polarization, which consists of a strictly coordinated process leading to a difference in the expression of surface markers, the production of specific factors, and the execution of biological activities. This review focuses on the role played by macrophages in COPD and their implication in inflammatory and oxidative stress processes. Particular attention is on macrophage polarization, given macrophage plasticity is a key feature in COPD. We also discuss the regulatory influence of extracellular vesicles (EVs) in cell-to-cell communications. EV composition and cargo may influence many COPD-related aspects, including inflammation, tissue remodeling, and macrophage dysfunctions. These findings could be useful for better addressing the role of macrophages in the complex pathogenesis and outcomes of COPD.</jats:p