scholarly journals A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications

2021 ◽  
Vol 22 (6) ◽  
pp. 3015
Author(s):  
Sara La Manna ◽  
Daniele Florio ◽  
Ilaria Iacobucci ◽  
Fabiana Napolitano ◽  
Ilaria De Benedictis ◽  
...  
Keyword(s):  
Neuroblastoma Cells ◽  
Platinum Complexes ◽  
Cd Spectroscopy ◽  
Amyloid Peptide ◽  
Ligand Field ◽  
Ionization Mass ◽  
Amyloid Aggregation ◽  
Binding Assays ◽  
Self Recognition ◽  
Dose Dependent

Herein the effects of three platinum complexes, namely (SP-4-2)-(2,2′-bipyridine)dichloridoplatinum(II), Pt-bpy, (SP-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (SP-4-2)-chlorido(2,2′:6′,2′′-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ21–40) were investigated. Thioflavin T (ThT) binding assays revealed the ability of Pt(II) compounds to repress amyloid aggregation in a dose-dependent way, whereas the ability of Aβ21–40 peptide to interfere with ligand field of metal complexes was analyzed through UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. Spectroscopic data provided micromolar EC50 values and allowed to assess that the observed inhibition of amyloid aggregation is due to the formation of adducts between Aβ21–40 peptide and complexes upon the release of labile ligands as chloride and that they can explore different modes of coordination toward Aβ21–40 with respect to the entire Aβ1–40 polypeptide. In addition, conformational studies through circular dichroism (CD) spectroscopy suggested that Pt-terpy induces soluble β-structures of monomeric Aβ21–40, thus limiting self-recognition. Noticeably, Pt-terpy demonstrated the ability to reduce the cytotoxicity of amyloid peptide in human SH-SY5Y neuroblastoma cells. Presented data corroborate the hypothesis to enlarge the application field of already known metal-based agents to neurodegenerative diseases, as potential neurodrugs.

scholarly journals Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

2020 ◽  
Vol 13 (8) ◽  
pp. 171 ◽  
Author(s):  
Daniele Florio ◽  
Maria Cuomo ◽  
Ilaria Iacobucci ◽  
Giarita Ferraro ◽  
Ahmed M. Mansour ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Effective Concentration ◽  
Mass Spectrometry Data ◽  
Ionization Mass ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Binding Assays ◽  
Before And After ◽  
Half Maximal Effective Concentration ◽  
Micromolar Range

Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents.

scholarly journals Platinum(II) O,S Complexes Inhibit the Aggregation of Amyloid Model Systems

2019 ◽  
Vol 20 (4) ◽  
pp. 829 ◽  
Author(s):  
Daniele Florio ◽  
Anna Maria Malfitano ◽  
Sarah Di Somma ◽  
Carolin Mügge ◽  
Wolfgang Weigand ◽  
...  
Keyword(s):  
Neuroblastoma Cells ◽  
Model Systems ◽  
Aggregation Process ◽  
Bidentate Ligands ◽  
Yeast Prion ◽  
Amyloid Aggregation ◽  
Binding Assays ◽  
Cinnamic Acid Derivatives ◽  
Ic50 Values ◽  
Micromolar Range

Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC50 values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on β-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.

scholarly journals A Reversible Shift of Driver Dependence from EGFR to Notch1 in Non-Small Cell Lung Cancer as a Cause of Resistance to Tyrosine Kinase Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2022
Author(s):  
Francesca Iommelli ◽  
Viviana De Rosa ◽  
Cristina Terlizzi ◽  
Rosa Fonti ◽  
Rosa Camerlingo ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Parental Cell ◽  
Egfr Inhibitors ◽  
Simultaneous Increase ◽  
Adherent Cells ◽  
Binding Assays ◽  
Mesenchymal Transition ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to Notch1, and thus causing resistance to EGFR inhibitors. Adherent cells (parental) and tumor spheres (TS) from NSCLC H1975 cells and patient-derived CD133-positive cells were tested for EGFR and Notch1 signaling cascade. The Notch1-dependent modulation of EGFR, NCID, Hes1, p53, and Sp1 were then analyzed in parental cells by binding assays with a Notch1 agonist, DLL4. TS were more resistant than parental cells to EGFR inhibitors. A strong upregulation of Notch1 and a concomitant downregulation of EGFR were observed in TS compared to parental cells. Parental cell exposure to DLL4 showed a dose-dependent decrease of EGFR and a simultaneous increase of NCID, Hes1, p53, and Sp1, along with the dislocation of Sp1 from the EGFR promoter. Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors.

scholarly journals DNA repair and cholesterol-mediated drug efflux induce dose-dependent chemoresistance in nutrient-deprived neuroblastoma cells

iScience ◽  
2021 ◽  
Vol 24 (4) ◽  
pp. 102325
Author(s):  
Soo Yeon Chae ◽  
Dowoon Nam ◽  
Do Young Hyeon ◽  
Areum Hong ◽  
Timothy Dain Lee ◽  
...  
Keyword(s):  
Dna Repair ◽  
Neuroblastoma Cells ◽  
Drug Efflux ◽  
Dose Dependent

scholarly journals μ-opioids activate phospholipase C in SH-SY5Y human neuroblastoma cells via calcium-channel opening

1995 ◽  
Vol 305 (2) ◽  
pp. 577-581 ◽  
Author(s):  
D Smart ◽  
G Smith ◽  
D G Lambert
Keyword(s):  
Phospholipase C ◽  
Opioid Receptor ◽  
Neuroblastoma Cells ◽  
Receptor Occupancy ◽  
Mu Opioid Receptor ◽  
Human Neuroblastoma ◽  
Mu Opioid ◽  
Inositol 1,4,5 Trisphosphate ◽  
Dependent Inhibition ◽  
Dose Dependent

We have recently reported that, in SH-SY5Y cells, mu-opioid receptor occupancy activates phospholipase C via a pertussis toxin-sensitive G-protein. In the present study we have further characterized the mechanisms involved in this process. Fentanyl (0.1 microM) caused a monophasic increase in inositol 1,4,5-trisphosphate mass formation, with a peak (20.5 +/- 3.6 pmol/mg of protein) at 15 s. Incubation in Ca(2+)-free buffer abolished this response, while Ca2+ replacement 1 min later restored the stimulation of inositol 1,4,5-trisphosphate formation (20.1 +/- 0.6 pmol/mg of protein). In addition, nifedipine (1 nM-0.1 mM), an L-type Ca(2+)-channel antagonist, caused a dose-dependent inhibition of inositol 1,4,5-trisphosphate formation, with an IC50 of 60.3 +/- 1.1 nM. Elevation of endogenous beta/gamma subunits by selective activation of delta-opioid and alpha 2 adrenoceptors failed to stimulate phospholipase C. Fentanyl also caused a dose-dependent (EC50 of 16.2 +/- 1.0 nM), additive enhancement of carbachol-induced inositol 1,4,5-trisphosphate formation. In summary, we have demonstrated that in SH-SY5Y cells activation of the mu-opioid receptor allows Ca2+ influx to activate phospholipase C. However, the possible role of this mechanism in the process of analgesia remains to be elucidated.

Identification of Mentha piperita L. and Ricinus communis L. polyphe-nols by HPLC-DAD-ESI-MS and evaluation of their insecticidal properties against Aphis spiraecola P

2017 ◽  
Vol 7 (1) ◽  
pp. 28-34
Author(s):  
Malika Malika Boualem ◽  
Meriem Mokhtar ◽  
Farida Saiah ◽  
Fouzia Benourad ◽  
Radia Bouhadiba ◽  
...  
Keyword(s):  
Ricinus Communis ◽  
Syringic Acid ◽  
Mentha Piperita ◽  
Ionization Mass ◽  
Coumaric Acid ◽  
Esi Ms ◽  
Aphis Spiraecola ◽  
Ricinus Communis L ◽  
Array Detection ◽  
Dose Dependent

Aphids infest most crops, and are considered as one of the most destructive groups of insects in temperate regions. The purpose of this study was to identify the polyphenols of castor (Ricinus communis L.) and mint (Mentha piperita L.) with liquid chromatography coupled to diode array detection and electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS), and evaluate their insecticidal properties against Aphis spiraecola P. A total of 10 compounds were identified in castor mainly phenolic acids (gallic acid, protocatechuic acid, syringic acid, chlorogenic acid, gentisic acid and p-coumaric acid). On the other hands, flavonoids (catechin, naringin, diosmin, rutin, diosmetin, luteolin, neohesperidin, naringenin and apigenin) were the major polyphe-nols in mint representing 10 compounds out of 14. In the test of insecticidal activity, four concentrations were tested (5, 10, 20 and 40%). Both plants had a good inhibitory activity especially mint. The effect was dose dependent and the highest mortality was obtained with the maximum used concentration (40%). After the first day, a percentage of 44 and 76% of mortality was recorded in the presence of just 5% of castor and mint which increased to reach 100% after 7 days.

scholarly journals Reaction with Proteins of a Five-Coordinate Platinum(II) Compound

2019 ◽  
Vol 20 (3) ◽  
pp. 520 ◽  
Author(s):  
Giarita Ferraro ◽  
Tiziano Marzo ◽  
Maria Cucciolito ◽  
Francesco Ruffo ◽  
Luigi Messori ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Platinum Complexes ◽  
Rnase A ◽  
Side Chain ◽  
Planar Geometry ◽  
Ionization Mass ◽  
X Ray ◽  
X Ray Crystallography ◽  
Egg White Lysozyme ◽  
Square Planar

Stable five-coordinate Pt(II) complexes have been highlighted as a promising and original platform for the development of new cytotoxic drugs. Their interaction with proteins has been scarcely studied. Here, the reactivity of the five-coordinate Pt(II) compound [Pt(I)(Me) (dmphen)(olefin)] (Me = methyl, dmphen = 2,9-dimethyl-1,10-phenanthroline, olefin = dimethylfumarate) with the model proteins hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) has been investigated by X-ray crystallography and electrospray ionization mass spectrometry. The X-ray structures of the adducts of RNase A and HEWL with [Pt(I)(Me)(dmphen)(olefin)] are not of very high quality, but overall data indicate that, upon reaction with RNase A, the compound coordinates the side chain of His105 upon releasing the iodide ligand, but retains the pentacoordination. On the contrary, upon reaction with HEWL, the trigonal bi-pyramidal Pt geometry is lost, the iodide and the olefin ligands are released, and the metal center coordinates the side chain of His15 probably adopting a nearly square-planar geometry. This work underlines the importance of the combined use of crystallographic and mass spectrometry techniques to characterize, in detail, the protein–metallodrug recognition process. Our findings also suggest that five-coordinate Pt(II) complexes can act either retaining their uncommon structure or functioning as prodrugs, i.e., releasing square-planar platinum complexes as bioactive species.

Sign in / Sign up

Export Citation Format

Share Document