Low catalytic activity of the Cu( ii )-binding motif (Xxx-Zzz-His; ATCUN) in reactive oxygen species production and inhibition by the Cu( i )-chelator BCS

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Cisplatin Inhibits the Formation of a Reactive Intermediate during Copper-Catalyzed Oxidation of Amyloid β Peptide

Cisplatin was studied for its effect on the copper-catalyzed oxidation of amyloid β (Aβ) peptide. The interaction of cisplatin with Aβ1-16 in the presence of Cu^II was investigated using cyclic voltammetry and mass spectrometry. The positive shift in the <i>E</i>_1/2 value of Aβ1-16-Cu^II suggests that the interaction of cisplatin alters the copper-binding properties of Aβ1-16. The mass spectrometry data show complete inhibition of copper-catalyzed decarboxylation/deamination of the Asp1 residue of Aβ1-16, while there is a significant decrease in copper-catalyzed oxidation of Aβ1-16 in the presence of cisplatin. Overall, our results provide a novel mode by which cisplatin inhibits copper-catalyzed oxidation of Aβ. These findings may lead to the design of better platinum complexes to treat oxidative stress in Alzheimer’s disease and other related neurological disorders

From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

The micropipette manipulation technique is capable of making fundamental single particle measurements and analyses. This information is critical for establishing processing parameters in systems such as microfluidics and homogenization. To demonstrate what can be achieved at the single particle level, the micropipette technique was used to form and characterize the encapsulation of Ibuprofen (Ibp) into poly(lactic-co-glycolic acid) (PLGA) microspheres from dichloromethane (DCM) solutions, measuring the loading capacity and solubility limits of Ibp in typical PLGA microspheres. Formed in phosphate buffered saline (PBS), pH 7.4, Ibp/PLGA/DCM microdroplets were uniformly solidified into Ibp/PLGA microparticles up to drug loadings (DL) of 41%. However, at DL 50 wt% and above, microparticles showed a phase separated pattern. Working with single microparticles, we also estimated the dissolution time of pure Ibp microspheres in the buffer or in detergent micelle solutions, as a function of the microsphere size and compare that to calculated dissolution times using the Epstein-Plesset (EP) model. Single, pure Ibp microparticles precipitated as liquid phase microdroplets that then gradually dissolved into the surrounding PBS medium. Analyzing the dissolution profiles of Ibp over time, a diffusion coefficient of 5.5 ± 0.2 × 10−6 cm2/s was obtained by using the EP model, which was in excellent agreement with the literature. Finally, solubilization of Ibp into sodium dodecyl sulfate (SDS) micelles was directly visualized microscopically for the first time by the micropipette technique, showing that such micellization could increase the solubility of Ibp from 4 to 80 mM at 100 mM SDS. We also introduce a particular microfluidic device that has recently been used to make PLGA microspheres, showing the importance of optimizing the flow parameters. Using this device, perfectly smooth and size-homogeneous microparticles were formed for flow rates of 0.167 mL/h for the dispersed phase (Qd) and 1.67 mL/h for the water phase (Qc), i.e., a flow rate ratio Qd/Qc of 10, based on parameters such as interfacial tension, dissolution rates and final concentrations. Thus, using the micropipette technique to observe the formation, and quantify solvent dissolution, solidification or precipitation of an active pharmaceutical ingredient (API) or excipient for single and individual microparticles, represents a very useful tool for understanding microsphere-processes and hence can help to establish process conditions without resorting to expensive and material-consuming bulk particle runs

Fluorescent Copper Probe Inhibiting Aβ1–16-Copper(II)-Catalyzed Intracellular Reactive Oxygen Species Production

A variety of fluorescent probes are proposed to monitor the intracellular copper content. So far, none of the probes have been evaluated for their potential to inhibit copper-associated intracellular oxidative stress. Herein, we studied the ability of a fluorescent copper probe, OBEP-CS1, to inhibit intracellular oxidative stress associated with an amyloid β (Aβ) peptide–copper complex. The data showed that OBEP-CS1 completely inhibits the copper-catalyzed oxidation as well as decarboxylation/deamination of Aβ1–16. Moreover, the cell imaging experiments confirmed that OBEP-CS1 can inhibit Aβ-Cu^II-catalyzed reactive oxygen species production in SH-SY5Y cells. We also demonstrated that Aβ1–16 peptide can bind intracellular copper and thereby exert oxidative stress

Acetylcholinesterase and Aβ Aggregation Inhibition by Heterometallic Ruthenium(II)–Platinum(II) Polypyridyl Complexes

Two heteronuclear ruthenium­(II)–platinum­(II) complexes [Ru­(bpy)₂(BPIMBp)­PtCl₂]²⁺ (<b>3</b>) and [Ru­(phen)₂(BPIMBp)­PtCl₂]²⁺ (<b>4</b>), where bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, and BPIMBp = 1,4′-bis­[(2-pyridin-2-yl)-1H-imidazol-1-ylmethyl]-1,1′-biphenyl, have been designed and synthesized from their mononuclear precursors [Ru­(bpy)₂(BPIMBp)]²⁺ (<b>1)</b> and [Ru­(phen)₂(BPIMBp)]²⁺ (<b>2</b>) as multitarget molecules for Alzheimer’s disease (AD). The inclusion of the cis-PtCl₂ moiety facilitates the covalent interaction of Ru­(II) polypyridyl complexes with amyloid β (Aβ) peptide. These multifunctional complexes act as inhibitors of acetylcholinesterase (AChE), Aβ aggregation, and Cu-induced oxidative stress and protect neuronal cells against Aβ-toxicity. The study highlights the design of metal based anti-Alzheimer’s disease (AD) systems