Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

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Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: Limitations, and current and future perspectives

Journal of Trace Elements in Medicine and Biology, Journal Year: 2021, Volume and Issue: 67, P. 126779 - 126779

Published: May 15, 2021

Alzheimer's disease (AD) is the most prevalent cause of cognitive impairment and dementia worldwide. The pathobiology has been studied in form several hypotheses, ranging from oxidative stress, amyloid-beta (Aβ) aggregation, accumulation tau forming neurofibrillary tangles (NFT) through metal dysregulation homeostasis, dysfunction cholinergic system, to inflammatory autophagic mechanism. However, none these hypotheses led confirmed diagnostics or approved cure for disease. This review aimed as a basic an encyclopedic short course into metals AD discusses advances chelation strategies developments adopted treatment Since there accumulating evidence role both biometal dyshomeostasis (iron (Fe), copper (Cu), zinc (Zn)) metal-amyloid interactions that lead pathogenesis AD, this focuses on unraveling therapeutic have considered disease, aiming sequester free protein-bound ions reducing cerebral burden. Promising compounds possessing chemically modified moieties evolving multi-target ligands used anti-AD drug candidates are also covered. Several multidirectional multifaceted studies therapeutics show need improved synthesis, screening, analysis be able effectively present chelating drugs. Most limitations their physicochemical properties; some enhance redistribution ions, while others indirectly activate signaling pathways AD. process vivo still needs established design potential bi-functionally well inhibit Aβ aggregation by competing with metal-induced damage neurotoxicity may signal bright end chelation-based

Language: Английский

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Biomedical applications of copper ionophores

Coordination Chemistry Reviews, Journal Year: 2020, Volume and Issue: 422, P. 213474 - 213474

Published: Aug. 1, 2020

Language: Английский

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Antimicrobial Peptides and Copper(II) Ions: Novel Therapeutic Opportunities

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2648 - 2712

Published: Feb. 1, 2021

The emergence of new pathogens and multidrug resistant bacteria is an important public health issue that requires the development novel classes antibiotics. Antimicrobial peptides (AMPs) are a promising platform with great potential for identification lead compounds can combat aforementioned due to their broad-spectrum antimicrobial activity relatively low rate resistance emergence. AMPs multicellular organisms made debut four decades ago thanks ingenious researchers who asked simple questions about bacterial infections insects. Questions such as "Do fruit flies ever get sick?", combined pioneering studies, have led understanding universal weapons immune system. This review focuses on subclass feature metal binding motif known amino terminal copper nickel (ATCUN) motif. One metal-based strategies hosts facing pathogen, it includes wielding inherent toxicity deliberately trafficking this ion into sites infection. sudden increase in concentration ions presence ATCUN-containing (ATCUN-AMPs) likely results synergistic interaction. Herein, we examine common structural features ATCUN-AMPs exist across species, highlight unique deserve additional attention. We also present current state knowledge molecular mechanisms behind methods available study class AMPs.

Language: Английский

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Copper-Targeting Approaches in Alzheimer’s Disease: How To Improve the Fallouts Obtained from in Vitro Studies

Inorganic Chemistry, Journal Year: 2019, Volume and Issue: 58(20), P. 13509 - 13527

Published: June 17, 2019

According to the amyloid cascade hypothesis, metal ions, mainly Cu and Zn bound amyloid-β (Aβ) peptides are implicated in Alzheimer's disease (AD), a widespread neurodegenerative disease. They indeed impact aggregation pathways of Aβ involved catalytic generation reactive oxygen species (ROS) that participate oxidative stress, while stress regarded as two key events AD etiology. ions due their redox ability have been considered be main potential therapeutic targets AD. A considerable number ligands developed order modulate toxicity associated with this context, via disruption Aβ-Cu interaction. Among them, small synthetic peptide scaffolds designed studied for remove from Aβ. Some those able prevent Cu(Aβ)-induced ROS production can modify vitro cellulo. Examples such gathered Viewpoint, function structures discussed respect properties against Cu(Aβ) deleterious fallouts. Nevertheless, beneficial activities most promising detected cellulo not transposed human yet. parameters might explain apparent contradiction concepts consider design "more" efficient thus reported discussed. En passant, Viewpoint sheds light on difficulties comparing results one study another hamper significant advances field.

Language: Английский

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Extracellular Cu2+ pools and their detection: From current knowledge to next-generation probes

Coordination Chemistry Reviews, Journal Year: 2021, Volume and Issue: 433, P. 213727 - 213727

Published: Feb. 8, 2021

Language: Английский

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Size-Dependent Bioactivity of Silver Nanoparticles: Antibacterial Properties, Influence on Copper Status in Mice, and Whole-Body Turnover

Nanotechnology Science and Applications, Journal Year: 2020, Volume and Issue: Volume 13, P. 137 - 157

Published: Dec. 1, 2020

The ability of silver nanoparticles (AgNPs) different sizes to influence copper metabolism in mice is assessed.AgNPs with diameters 10, 20, and 75 nm were fabricated through a chemical reduction nitrate characterized by UV/Vis spectrometry, transmission scanning electronic microscopy, laser diffractometry. To test their bioactivity, Escherichia coli cells, cultured A549 C57Bl/6 used. antibacterial activity AgNPs was determined inhibition colony-forming ability, cytotoxicity tested using the MTT (viability, %). Ceruloplasmin (Cp, major mammalian extracellular copper-containing protein) concentration enzymatic measured gel-assay analyses WB, respectively. In vitro binding serum proteins monitored spectroscopy. Metal concentrations atomic absorption spectrometry.The smallest displayed largest dose- time-dependent activity. All inhibited metabolic cells accordance dose time, but no correlation between nanoparticle size found. Nanosilver not uniformly distributed body intraperitoneally treated low AgNP concentrations. It predominantly accumulated liver. There, nanosilver included ceruloplasmin, Ag-ceruloplasmin oxidase level formed. Larger more effectively interfered mice. Large quickly induced drop blood practically zero, after cancellation treatment, rapidly restored. A fraction excreted bile Cp. bound alpha-2-macroglobulin vivo, did substitute for atoms Cp vitro.The data showed that even at concentrations, murine size-dependent manner. This property negatively correlated AgNPs.

Language: Английский

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Chemical background of silver nanoparticles interfering with mammalian copper metabolism

Journal of Hazardous Materials, Journal Year: 2023, Volume and Issue: 451, P. 131093 - 131093

Published: Feb. 26, 2023

Language: Английский

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The N-terminal 14-mer model peptide of human Ctr1 can collect Cu(ii) from albumin. Implications for copper uptake by Ctr1

Metallomics, Journal Year: 2018, Volume and Issue: 10(12), P. 1723 - 1727

Published: Jan. 1, 2018

The superior Cu(ii) affinity of human copper transporter 1 (hCtr1) drives acquisition from serum albumin (HSA).

Language: Английский

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The Sub‐picomolar Cu²⁺ Dissociation Constant of Human Serum Albumin

ChemBioChem, Journal Year: 2019, Volume and Issue: 21(3), P. 331 - 334

Published: July 12, 2019

The apparent affinity of human serum albumin (HSA) for divalent copper has long been the subject great interest, due to its presumed role as major Cu2+ -binding ligand in blood and cerebrospinal fluid. Using a combination electronic absorption, circular dichroism room-temperature electron paramagnetic resonance spectroscopies, together with potentiometric titrations, we competed tripeptide GGH against HSA reveal conditional binding constant log cKCuCu(HSA) =13.02±0.05 at pH 7.4. This rigorously determined value important implications understanding extracellular distribution copper.

Language: Английский

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