A5065244580- Treatment of Major Depression
- Sirtuins and Resveratrol in Medicine
- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- ATP Synthase and ATPases Research
- RNA Interference and Gene Delivery
- Psychedelics and Drug Studies
- Neurotransmitter Receptor Influence on Behavior
- Phytochemicals and Antioxidant Activities
- Adipose Tissue and Metabolism
- Toxin Mechanisms and Immunotoxins
- Nanoparticle-Based Drug Delivery
- Pharmacological Receptor Mechanisms and Effects
- Bioactive natural compounds
- Botulinum Toxin and Related Neurological Disorders
- Biochemical effects in animals
- Diet and metabolism studies
- Calcium signaling and nucleotide metabolism
- Cardiac electrophysiology and arrhythmias
- Bipolar Disorder and Treatment
- Synthesis and biological activity
- Venomous Animal Envenomation and Studies
- Chemokine receptors and signaling
- Advanced biosensing and bioanalysis techniques
University of Padua
2016-2025
Pharmac
2024
University of Milan
2022
University of Modena and Reggio Emilia
2022
Bambino Gesù Children's Hospital
2022
Neuroscience Education Institute
2021
University of Genoa
2021
University of Regensburg
2017
Neuroscience Institute
2012-2015
Objective: The purpose of this study was to examine the effects REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed benefit from one three standard antidepressant treatments their current episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising arms, conducted assess safety, tolerability, pharmacokinetics, and efficacy two dosages (25 mg or 50 orally once...
Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. Methods:In this phase 3, double-blind, placebo-controlled trial, outpatients MDD (DSM-5) were randomized daily oral (75 mg on day 1, followed by 25 days 2 through 28) or placebo between December 2020 2022.The primary efficacy measure was change from baseline (CFB) 28 the Montgomery-Asberg Depression Rating Scale (MADRS)...
Background: Esmethadone is a novel N-methyl-D-aspartate receptor (NMDAR) uncompetitive antagonist in development as adjunctive treatment for major depressive disorder (MDD). Methods: This 12-month, open-label study evaluated the safety and efficacy of esmethadone patients with MDD meeting DSM-5 criteria who completed 1 3 double-blind studies (rollover) no prior participation (de novo). Safety was assessed from adverse events, laboratory parameters, vital signs, electrocardiogram,...
Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the of cancers. is modulated by different factors, but whether mitochondrial energetic state unknown. Here, we show that sublethal concentrations compounds decrease ATP production specifically downregulate Wnt/β-catenin in vitro colon cancer cells and vivo zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient generated model lead to reduced signaling. We identify...
Ought to their bioinert properties and facile synthesis, poly[(oligoethylene glycol)methacrylate]s (POEGMAs) have been raised as attractive alternatives poly(ethylene glycols) (PEGs) in an array of (bio)material applications, especially when they are applied polymer brush coatings. However, commercially available OEG-methacrylate (macro)monomers feature a broad distribution OEG lengths, thus generating structurally polydisperse POEGMAs polymerized through reversible deactivation radical...
The pharmacological exploitation of resveratrol is hindered by rapid phase-II conjugative metabolism in enterocytes and hepatocytes. One approach to the solution this problem relies on prodrugs. We report synthesis characterization as well assessment vivo absorption a set prodrugs which OH groups are engaged formal (−OCH2OR) or more labile acetal (−OCH(CH3)OR) linkages. As carrier group (R) prodrug, we have used short ethyleneglycol oligomers (OEG) capped terminal methoxy group:...
Ca2+ transport across the inner membrane of mitochondria (IMM) is major importance for their functions in bioenergetics, cell death and signalling. It therefore tightly regulated. has been recently proposed that LETM1 an IMM protein with a crucial role mitochondrial K+/H+ exchange volume homeostasis also acts as Ca2+/H+ exchanger. Here we show first time lowering gene expression by shRNA hampers Na+/H+ exchange. Decreased activity resulted matrix K+ accumulation these mitochondria....
Scope Pterostilbene (Pt) is emerging as an important health‐promoting natural compound. Pharmacokinetic studies so far have focused on plasma levels, while Pt distribution in tissues most relevant for biological action. This study determined tissue of and its major metabolite, pterostilbene‐4′‐sulfate (Pt‐S), rats after oral administration. Methods results Upon intravenous (iv) administration (88 μmol/kg), was cleared from blood with a half‐life 1.8 ± 0.3 h. Oral (same dose) resulted...
Abstract Ca 2+ handling by mitochondria is crucial for cell life and the direct measure of mitochondrial concentration in living cells pivotal interest. Genetically‐encoded indicators greatly facilitated this task, however they require demanding delivery procedures. On other hand, existing mitochondria‐targeted synthetic are plagued several drawbacks, example, non‐specific localization, leakage, toxicity. Here we report synthesis characterization a new fluorescent sensor, named mt‐fura‐2,...
Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to neurons, the contribution of types ALS phenotypes is understudied. G4C2 repeat expansion C9ORF72 most common genetic cause along with frontotemporal dementia (C9-ALS/FTD), increasing evidence supporting repeat-encoded poly(GR) disease pathogenesis. Here, we show Drosophila muscle that enters mitochondria interacts components Mitochondrial Contact Site Cristae...
Ion channels are emerging as promising oncological targets. The potassium Kv1.3 and IKCa highly expressed in the plasma membrane mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition mitoKv1.3 by PAPTP was shown kill ex vivo primary CLL while targeting with TRAM-34 decreased cell proliferation.Here we evaluated effect above drugs cells from ibrutinib-resistant patients combination Venetoclax, two used clinical practice. effects...
Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization uncompetitive may improve our understanding function physiology pathology. REL-1017 (esmethadone-HCl), a novel blocker Phase 3 trials the treatment MDD, was characterized together with...
Abstract Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, current understanding early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic knock-in mice patient-derived biopsies, we show SBMA presymptomatic stage develop respiratory defect matching defective expression genes involved excitation-contraction coupling (ECC),...
Abstract MitoK ATP is a channel of the inner mitochondrial membrane that controls K + influx according to availability. Recently, genes encoding pore-forming (MITOK) and regulatory ATP-sensitive (MITOSUR) subunits mitoK were identified, allowing genetic manipulation channel. Here, we analyzed role in determining skeletal muscle structure activity. Mitok −/− muscles characterized by cristae remodeling defective oxidative metabolism, with consequent impairment exercise performance altered...
Mitochondria-targeted compounds are needed to act on a variety of processes that take place in these subcellular organelles and have great pathophysiological relevance. In particular, redox-active molecules capable homing mitochondria provide tool intervene major cellular source reactive oxygen species the they induce, notably mitochondrial permeability transition cell death. We linked 3-OH quercetin (3,3',4',5,7-pentahydroxy flavone), model polyphenol, triphenylphosphonium moiety,...
The regioselective synthesis of several quercetin (3,3’,4’,5,7-pentahydroxy flavone) tetraesters bearing a single free OH on 5-C was achieved in good yield by proper choice reaction conditions using common esterification procedures. Tetracetylated with the 7-C selectively obtained instead via imidazole-promoted deacylation corresponding pentaester. Unambiguous structural characterization two isomeric tetraacetyl derivatives combined HSQC and HMBC 2D-NMR analysis. These molecules can be used...
Resveratrol derivatives bearing an O-linked mitochondria-targeting 4-triphenylphosphoniumbutyl group at either position 3 or 4' are prooxidant and cytotoxic for cultured cells, selectively killing fast-growing cells when supplied in the low μM range. is essentially without effect under these experimental conditions, while cytotoxicity of mitochondriotropic increases if they methylated on remaining hydroxyls. Experiments with Bax(-/-)/Bak(-/-) a pan-caspase inhibitor show that cell death...
Background/Aims: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number newly diagnosed patients with central nervous system (CNS) cancers in United States and Europe. Major features GBM include invasive growth as well resistance to treatment. Kv1.3, potassium channel shaker family, expressed inner mitochondrial membrane many cancer cells. Inhibition Kv1.3 was shown induce apoptosis several tumor cells at doses that were not lethal normal Methods: We...
Botulinum and tetanus neurotoxins are the most toxic substances known form growing family of clostridial neurotoxins. They composed a metalloprotease light chain (L), linked via disulfide bond to heavy (H). H mediates binding nerve terminals membrane translocation L into cytosol where their substrates, three SNARE proteins, localised. is accompanied by unfolding, it has be reduced reacquire native fold exert its neurotoxicity. The Thioredoxin reductase-Thioredoxin system responsible for...