Flavia Giordano

University of Naples Federico II

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Ferdinando Fiorino

University of Naples Federico II

Beatrice Severino

University of Naples Federico II

Angela Corvino

University of Naples Federico II

Elisa Magli

University of Naples Federico II

Francesco Frecentese

University of Naples Federico II

Giuseppe Caliendo

University of Naples Federico II

Irene Saccone

University of Naples Federico II

Vincenzo Santagada

University of Naples Federico II

Elisa Perissutti

University of Naples Federico II

Gilberto De Nucci

Universidade Estadual de Campinas (UNICAMP)

Cooperative Institutions

University of Naples Federico II

Heidelberg University

University Hospital Heidelberg

Federico II University Hospital

University Medical Centre Mannheim

Universidade Estadual de Campinas (UNICAMP)

University of Salzburg

Istituto di Farmacologia Traslazionale

Medical University of Lublin

University of Mannheim

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A novel FRET peptide assay reveals efficient Helicobacter pylori HtrA inhibition through zinc and copper binding

Scientific Reports (2020)

Sabine Bernegger Cyrill Brunner Matej Vizovišek Marko Fonović Gaetano Cuciniello

Abstract Helicobacter pylori ( H. pylori ) secretes the chaperone and serine protease high temperature requirement A (HtrA) that cleaves gastric epithelial cell surface proteins to disrupt the epithelial integrity and barrier function. First inhibitory lead structures have demonstrated the essential role of HtrA in H. pylori physiology and pathogenesis. Comprehensive drug discovery techniques allowing high-throughput screening are now required to develop effective compounds. Here, we designed a novel fluorescence resonance energy transfer (FRET) peptide derived from a gel-based label-free proteomic approach (direct in-gel profiling of protease specificity) as a valuable substrate for H. pylori HtrA. Since serine proteases are often sensitive to metal ions, we investigated the influence of different divalent ions on the activity of HtrA. We identified Zn ++ and Cu ++ ions as inhibitors of H. pylori HtrA activity, as monitored by in vitro cleavage experiments using casein or E-cadherin as substrates and in the FRET peptide assay. Putative binding sites for Zn ++ and Cu ++ were then analyzed in thermal shift and microscale thermophoresis assays. The findings of this study will contribute to the development of novel metal ion-dependent protease inhibitors, which might help to fight bacterial infections.

Microscale Thermophoresis

10.1038/s41598-020-67578-2

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Citations (25)

Anxiolytic‐like effects of the new arylpiperazine derivatives containing isonicotinic and picolinic nuclei: behavioral and biochemical studies

Fundamental and Clinical Pharmacology (2018)

Ewa Kędzierska Ferdinando Fiorino Ewa Gibuła‐Tarłowska Angela Corvino Flavia Giordano

Abstract Anxiety disorder is a great challenge for modern psychopharmacology. Although a variety of single drugs are used in the treatment of anxiety, it is important to search for new therapeutics with faster onset of action, fewer side effects, and higher efficacy. In this work, we studied the possible anxiolytic action mechanism of two new arylpiperazine derivatives: compounds 4p N ‐(3‐(4‐(piperonyl)piperazin‐1‐yl)propyl)isonicotinamide and 3o N ‐(2‐(4‐(pyrimidin‐2‐yl)piperazin‐1‐yl)ethyl)picolinamide, focusing on their effects on the GABAergic and 5‐HT systems. The elevated plus‐maze test (EPM) was used for measuring anxiety. Additionally, in order to elucidate whether the new compounds have impact on the central redox balance, we conducted biochemical studies. In doing so, the relative activity of the enzymes responsible for glutathione metabolism – glutathione peroxidase and reductase (GPx and GR) – was measured. The results of the presented studies confirmed the anxiolytic effects of the new compounds 4p (60 mg/kg) and 3o (7.5 mg/kg), and suggested in the mechanism of their action, direct 5‐HT 1A receptors’ participation and indirect involvement of the GABAergic system. Furthermore, the compounds exerted significant agonistic effect with buspirone (BUS, the 5‐HT 1A partial agonist, 1 mg/kg i.p.) and diazepam (DZ, the classic benzodiazepine anxiolytic, 0.25 mg/kg s.c.), while WAY 100635 ( N ‐{2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl] ethyl}‐ N ‐(2‐pyridyl) cyclohexanecarboxamide, a selective 5‐HT 1A antagonist, 0.1 mg/kg s.c.), but not flumazenil (a GABA A ‐BDZ receptor complex antagonist, 10 mg/kg i.p.) was able to reverse their anxiolytic effects in EPM. A concomitant decrease in GPx by the compound 4p (and to a lesser degree, by compound 3o ) further seemed to confirm their anxiolytic and antioxidant activity.

Isonicotinic acid

Picolinic acid

10.1111/fcp.12443

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Synthesis and Pharmacological Screening of Pyridopyrimidines as Effective Anti‐Diarrheal Agents through the Suppression of Cyclic Nucleotide Accumulation

ChemistryOpen (2019)

Tiago Zaminelli Elisa Magli Francesco Frecentese Caroline Honaiser Lescano Rafael Campos

Abstract The increased levels of cyclic nucleotides (cGMP and cAMP) in enterocytes trigger intracellular mechanisms of ion and fluid secretion into the lumen, causing secretory diarrhea. Twelve novel pyridopyrimidines derived from 5‐(3,5‐bistrifluoromethylphenyl)‐1,3‐dimethyl‐5,11‐dihydro‐1H‐indeno[2,1 : 5,6]pyrido[2,3‐d]pyrimidine‐2,4,6‐trione (FPIPP) were synthesized and evaluated on intracellular cyclic nucleotide accumulation. All compounds had no effect on either cyclic nucleotide basal levels or on pre‐contracted aortic rings. The metabolic activity and viability in T84 cells, assessed by MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide) and the LDH (lactate dehydrogenase) assays, respectively, were not affected by incubation with the compounds (50 μM). Compound VI almost abolished cGMP accumulation (94 % inhibition) induced by STa toxin in T834 cells and significantly reduced (69 %) forskolin‐induced cAMP accumulation in Jurkat cells. Compound VI was active in an in vivo model for diarrhea in rabbits. These results prompted us to perform a microscopic histopathological analysis of intestinal tissues, showing that only compound VI preserves the intestine without significant pathological changes and with a decreased inflammatory pattern in comparison to FPIPP. In vitro stability test revealed that compound VI is resistant to oxidation promoted by atmospheric oxygen.

10.1002/open.201900060

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Citations (1)

Radiosensitization of Tumor Cells by Intracellular Delivery of Doxorubicin Using Novel Iron Oxide-based Nanoconstructs

International Journal of Radiation Oncology*Biology*Physics (2019)

Roxana Cristina Popescu Diana Savu I. A. Dorobantu Bogdan Ştefan Vasile Hiltraud Hosser

HeLa

Clonogenic assay

MTT assay

Iron oxide nanoparticles

10.1016/j.ijrobp.2019.06.1003

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Drawing with Oblique Coordinates: On a Single Case

Behavioural Neurology (2011)

Dario Grossi Gabriella Santangelo Giuseppe Carbone Flavia Giordano Valentina Gerarda Angelillo

We describe a patient with right hemisphere damage affected by mild left visuo-spatial neglect and constructional apraxia. During the rehabilitation, he failed to draw a draught-board using horizontal and vertical trajectories, but he performed it successfully using oblique trajectories. These observations suggested an impairment of vertical/horizontal spatial coordinates system. In copying tasks including figure elements in different orientations he drew more accurately components in oblique orientation, whereas failed to reproduce components in horizontal orientation. The patient performed visuospatial perceptual and perceptual-imaginative tasks successfully. From these findings, it is possible to suggest that the oblique coordinate system of reference operates independently of vertical and horizontal coordinate systems in building a complex figure and that, therefore, cardinal orientation do not constitute a reference norm to define oblique orientation, as previously suggested.

Horizontal and vertical

Frame of reference

Copying

10.1155/2011/783942

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Hybrids between H2S-donors and betamethasone 17-valerate or triamcinolone acetonide inhibit mast cell degranulation and promote hyperpolarization of bronchial smooth muscle cells

European Journal of Medicinal Chemistry (2021)

Flavia Giordano Angela Corvino Antonia Scognamiglio Valentina Citi Era Gorica

Hyperpolarization

10.1016/j.ejmech.2021.113517

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Citations (14)

Drawing with oblique coordinates: on a single case.

PubMed (2011)

Dario Grossi Gabriella Santangelo Giuseppe Carbone Flavia Giordano Valentina Gerarda Angelillo

Horizontal and vertical

Frame of reference

Copying

Horizontal axis

10.3233/ben-2011-0333

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The HIV-Derived Protein Vpr52-96 Has Antiglioma Activity In Vitro and In Vivo

International Journal of Radiation Oncology*Biology*Physics (2015)

Flavia Giordano Jens Kübler Stefanie Kirschner Laura Hartmann Grit Welzel

Clonogenic assay

Temozolomide

U87

10.1016/j.ijrobp.2015.07.336

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Citations (1)

PCB levels in adipose tissue of dogs from illegal dumping sites in Campania region (Italy)

Chemosphere (2019)

Maria Carmela Ferrante Paola Di Vaio Elisa Magli Francesco Frecentese Rosaria Meli

Dumping

Health hazard

10.1016/j.chemosphere.2019.125478

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Citations (9)

Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT1A) receptor antagonist radiotracers

EJNMMI Radiopharmacy and Chemistry (2020)

Vidya Narayanaswami Junchao Tong Ferdinando Fiorino Beatrice Severino Rosa Sparaco

Serotonin 1A (5-HT1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers.Syntheses of 1-3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT1A receptors. Binding of 1-3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α1-adrenergic receptors (4-6-fold less potent than that for 5-HT1A receptor). Radioligands [11C]1-3 were efficiently prepared by 11C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7-11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [11C]1 and [11C]2. In contrast, significant brain uptake of [11C]3 was observed with an early peak SUV of 4-5. However, [11C]3 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies.Despite efficient radiolabeling, results from PET imaging experiments limit the application of [11C]3 for in vivo quantification of 5-HT1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α1-adrenergic receptors.

Radioligand

Radiosynthesis

10.1186/s41181-020-00096-8

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Citations (6)