The Length and Flexibility of the 2-Substituent of 9-Ethyladenine Derivatives Modulate Affinity and Selectivity for the Human A2A Adenosine Receptor

The A2A adenosine receptor (A2A AR) is a key target for the development of pharmacological tools for the treatment of central nervous system disorders. Previous works have demonstrated that the insertion of substituents at various positions on adenine leads to A2A AR antagonists with affinity in the micromolar to nanomolar range. In this work, a series of 9-ethyladenine derivatives bearing phenylalkylamino, phenylakyloxy or phenylakylthio groups of different lengths at the 2-position were synthesised and tested against the human adenosine receptors. The derivatives showed sub-micromolar affinity for these membrane proteins. The further introduction of a bromine atom at the 8-position has the effect of improving the affinity and selectivity for all ARs and led to compounds that are able bind to the A2A AR subtype at low nanomolar levels. Functional studies confirmed that the new adenine derivatives behave as A2A AR antagonists with half-maximal inhibitory concentration values in the nanomolar range. Molecular modelling studies provide a description of the possible binding mode of these compounds at the A2A AR and an interpretation of the affinity data at this AR subtype

Characterization of biocompatible scaffolds manufactured by fused filament fabrication of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate

We characterize poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH) scaffolds for tissue repair and regeneration, manufactured by three-dimensional fused filament fabrication (FFF). PHBH belongs to the class of polyhydroxyalkanoates with interesting biodegradable and biocompatible capabilities, especially attractive for tissue engineering. Equally, FFF stands as a promising manufacturing technology for the production of custom-designed scaffolds. We address thermal, rheological and cytotoxicity properties of PHBH, placing special emphasis on the mechanical response of the printed material in a wide deformation range. Indeed, effective mechanical properties are assessed in both the linear and nonlinear regime. To warrant uniqueness of the material parameters, these are measured directly through digital image correlation, both in tension and compression, while experimental data fitting of finite-element analyses is only adopted for the determination of the second invariant coefficient in the nonlinear regime. Mechanical data are clearly porosity dependent, and they are given for both the cubic and the honeycomb infill pattern. Local strain spikes due to the presence of defects are observed and measured: those falling in the range 70\u2013100% lead to macro-crack development and, ultimately, to failure. Results suggest the significant potential attached to FFF printing of PHBH for customizable medical devices which are biocompatible and mechanically resilient

Performance of concrete reinforced with synthetic fibres obtained from recycling end-of-life sport pitches

Micro-plastics pollution has risen at an alarming pace over the last decades and it is now recognised as a leading environmental emergency. Indeed, only a very small fraction of annual plastic production is successfully reused, while the vast majority is either disposed of (mainly through incineration or landfilling) or dispersed into the environment. In this paper, polyolefins synthetic fibres, obtained from processing disposed artificial turf pitches aimed at paving sport facilities, are studied. Focus is set on assessing their potential for the Fibre Reinforced Concrete (FRC) technology. Mechanical performance is discussed at two fibre volume fractions, namely 3% and 5% vol., alongside environmental impact. The former is assessed in bending and reveals a significant enhancement of the post-crack energy dissipation capability, whose extent is compatible with what is usually obtained by the adoption of virgin fibres. This is especially significant in consideration of the light processing operated on the waste material. Indeed, life cycle assessment is adopted to evaluate the environmental impact of fibre reuse against fibre manufacturing from either virgin materials or plastic waste. It clearly appears that fibre reuse brings a double environmental benefit: on the one side, it decreases the need for new plastics and, on the other, it reduces plastic waste, whose traditional disposal technique, through incineration, entails a considerable footprint

Miscela per massetti alleggeriti contenente aggregati inerti generati dal recupero di campi sportivi

La presente invenzione si riferisce ad una miscela per massetti alleggeriti per la realizzazione di sottofondi non strutturali, sia per nuove costruzioni che per opere di restauro. Tale miscela è caratterizzata da una elevata capacità isolante termica, presentando infatti un basso coefficiente di conducibilità termica e una elevata permeabilità al vapore d’acqua. Sono note miscele per massetti realizzate con inerti naturali o sintetici, vergini o da riciclo. Tuttavia, tali miscele note presentano il problema di non consentire il re-impiego di materiale di recupero di natura polimerica ed elastomerica derivante dallo smaltimento di sottofondi in erba sintetica ad uso sportivo. Allo stato attuale, i suddetti materiali a fine vita, essendo di difficile reimpiego, sono destinati alla termovalorizzazione o al conferimento in discarica. Scopo della presente invenzione è quello di risolvere i suddetti problemi della tecnica anteriore fornendo una miscela per massetti alleggeriti che consenta di recuperare scarti plastici ed elastomerici, nonché sabbia minerale e macrofibre poliolefiniche, da fonti come i sottofondi in erba sintetica ad uso sportivo che, ad oggi, non trovano reimpiego alternativo a fine vita, evitandone il conferimento in discarica o alla valorizzazione termica. Un altro scopo della presente invenzione è quello di evitare trattamenti del rifiuto a monte dell’incorporazione nel premiscelato. Il materiale di riciclo, infatti, essendo di per sé inerte, viene esclusivamente recuperato e parzialmente suddiviso tramite semplice setacciamento, non necessitando di ulteriori trattamenti chimici più complessi e dispendiosi

The G Protein-Coupled Receptor GPR17: Overview and Update

The GPR17 receptor is a G protein-coupled receptor (GPCR) that seems to respond to two unrelated families of endogenous ligands: nucleotide sugars (UDP, UDP-galactose, and UDP-glucose) and cysteinyl leukotrienes (LTD4 , LTC4 , and LTE4 ), with significant affinity at micromolar and nanomolar concentrations, respectively. This receptor has a broad distribution at the level of the central nervous system (CNS) and is found in neurons and in a subset of oligodendrocyte precursor cells (OPCs). Unfortunately, disparate results emerging from different laboratories have resulted in a lack of clarity with regard to the role of GPR17-targeting ligands in OPC differentiation and in myelination. GPR17 is also highly expressed in organs typically undergoing ischemic damage and has various roles in specific phases of adaptations that follow a stroke. Under such conditions, GPR17 plays a crucial role; in fact, its inhibition decreases the progression of ischemic damage. This review summarizes some important features of this receptor that could be a novel therapeutic target for the treatment of demyelinating diseases and for repairing traumatic injury

Cytotoxic effects of ivermectin on Giardia lamblia: induction of apoptosis and cell cycle arrest

Introduction: Giardia lamblia is a flagellated protozoan parasite causing giardiasis, a common intestinal infection characterized by diarrhea, abdominal cramps, and nausea. Treatments employed to combat this parasitic infection have remained unchanged for the past 40 years, leading to the emergence of resistant strains and prompting the search for new therapeutic agents.Methods: This study investigated the cytotoxic effects of ivermectin (IVM) on G. lamblia trophozoites. We conducted dose-response experiments to assess IVM-induced cytotoxicity. We utilized various biochemical and ultrastructural analyses to explore the underlying mechanisms of cell death, including reactive oxygen species (ROS) production, DNA fragmentation, cell cycle arrest, and apoptosis markers.Results: Our findings demonstrate that IVM induces dose-dependent cytotoxicity and triggers cell death pathways. We found that IVM treatment generates elevated levels of reactive oxygen species (ROS), DNA fragmentation, and arrests of trophozoites in the cell cycle’s S phase. Additionally, ultrastructural analysis reveals morphological alterations consistent with apoptosis, such as cytoplasmic vacuolization, chromatin condensation, and tubulin distribution.Discussion: The insights gained from this study may contribute to developing new therapeutic strategies against giardiasis, addressing the challenge posed by drug-resistant strains.Fil: Barzola, Florencia Nicole. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Laiolo, Jerónimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Cotelo, Camilo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Joray, Mariana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Volpini, Ximena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Rivero, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Ropolo, Andrea Silvana. Universidad Nacional de Río Cuarto. Instituto para el Desarrollo Agroindustrial y de la Salud. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto para el Desarrollo Agroindustrial y de la Salud; ArgentinaFil: Touz, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Feliziani, Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

Adenosine receptors as neuroinflammation modulators: role of A1 agonists and A2A antagonists

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A1AR and A2AAR. Evidence suggests that A1AR activation produces a neuroprotective effect and A2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2'-dCCPA (2-chloro-N6-cyclopentyl-2'-deoxyadenosine) (C1 KiA1AR = 550 nM, KiA2AAR = 24,800 nM, and KiA3AR = 5560 nM, α = 0.70, EC50A1AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 KiA2AAR = 0.75 nM; KiA1AR = 17 nM and KiA3AR = 227 nM, IC50A2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1β, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy.This research was funded by Cofinanziamento Assegno di Ricerca Volpini-Marucci, n° FPI400037 and by Fundação para a Ciência e a Tecnologia (PTDC/BIM-MEC/47778/2014). This work was supported by the University of Camerino (Fondo di ricerca di Ateneo) and by a grant from the Ministry of Research (PRIN N° 2015E8EMCM_008, 2015).info:eu-repo/semantics/publishedVersio

Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta

: Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1-32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13-32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor-kinase interactions

Can digital technologies be useful for weight loss in individuals with overweight or obesity. A systematic review

Digital technologies have greatly developed and impacted several aspects of life, including health and lifestyle. Activity tracking, mobile applications, and devices may also provide messages and goals to motivate adopting healthy behaviors, namely physical activity and dietary changes. This review aimed to assess the effectiveness of digital resources in supporting behavior changes, and thus influencing weight loss, in people with overweight or obesity. A systematic review was conducted according to the PRISMA guidelines. The protocol was registered in PROSPERO (CRD42023403364). Randomized Controlled Trials published from the database’s inception to 8 November 2023 and focused on digital-based technologies aimed at increasing physical activity for the purpose of weight loss, with or without changes in diet, were considered eligible. In total, 1762 studies were retrieved and 31 met the inclusion criteria. Although they differed in the type of technology used and in their design, two-thirds of the studies reported significantly greater weight loss among electronic device users than controls. Many of these studies reported tailored or specialist-guided interventions. The use of digital technologies may be useful to support weight-loss interventions for people with overweight or obesity. Personalized feedback can increase the effectiveness of new technologies in motivating behavior changes