Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the cause and progression of this disorder are not completely understood. While the main hallmark of AD is the deposition of amyloid plaques consisting of the β-amyloid (Aβ) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen species (ROS), and oxidative stress. Thus, bifunctional metal chelators that can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF) – a natural biflavonoid compound, exhibits good metal-chelating properties, especially for chelating Cu2+ with very high affinity (pCu7.4 = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity (Ki = 287 ± 20 nM) – as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques ex vivo in the brain sections of transgenic AD mice – as confirmed via immunostaining with an Ab antibody. The effect of AMF on Aβ42 aggregation and disaggregation of Aβ42 fibrils was also investigated, to reveal that AMF can control the formation of neurotoxic soluble Aβ42 oligomers, both in absence and presence of metal ions, and as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu2+ and significantly diminish the Cu2+-ascorbate redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity, can also bind Cu2+ and mediate its deleterious redox properties, and thus AMF has the potential to be a lead compound for further therapeutic agent development for AD.

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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

10.26434/chemrxiv.12445505.v1 ◽

2020 ◽

Author(s):

Liang Sun ◽

Anuj K. Sharma ◽

Byung-Hee Han ◽

Liviu M. Mirica

Keyword(s):

Reactive Oxygen Species ◽

Metal Ions ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

Amyloid Plaques ◽

Transition Metal Ions ◽

Oxygen Species ◽

High Affinity ◽

Amyloid Aβ ◽

Β Amyloid

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How to express the antioxidant properties of substances properly?

Chemical Papers ◽

10.1007/s11696-021-01799-1 ◽

2021 ◽

Author(s):

Małgorzata Olszowy-Tomczyk

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Literature Review ◽

Antioxidant Activities ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

The Body ◽

Universal Method ◽

Oxygen Species ◽

Good Tool

AbstractOxidative stress, associated with an imbalance between the oxidants (reactive oxygen species) and the antioxidants in the body, contributes to the development of many diseases. The body’s fight against reactive oxygen species is supported by antioxidants. Nowadays, there are too many analytical methods, but there is no one universal technique for assessing antioxidant properties. Moreover, the applied different ways of expressing the results lead to their incompatibility and unreasonable interpretation. The paper is a literature review concerning the most frequent ways of antioxidant activities expression and for an easy and universal method of the obtained results discussion. This paper is an attempt to point out their disadvantages and advantages. The manuscript can support the searching interpretation of the obtained results which will be a good tool for the development of a number of fields, especially medicine what can help in the future detection and treatment of many serious diseases. Graphic abstract

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Novel Antioxidant Properties of Doxycycline

International Journal of Molecular Sciences ◽

10.3390/ijms19124078 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4078 ◽

Cited By ~ 9

Author(s):

Dahn Clemens ◽

Michael Duryee ◽

Cleofes Sarmiento ◽

Andrew Chiou ◽

Jacob McGowan ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Hydrogen Peroxide ◽

Chronic Inflammation ◽

Antioxidant Properties ◽

Antibacterial Properties ◽

Reactive Oxygen ◽

Protein Adducts ◽

Oxygen Species ◽

Free System

Doxycycline (DOX), a derivative of tetracycline, is a broad-spectrum antibiotic that exhibits a number of therapeutic activities in addition to its antibacterial properties. For example, DOX has been used in the management of a number of diseases characterized by chronic inflammation. One potential mechanism by which DOX inhibits the progression of these diseases is by reducing oxidative stress, thereby inhibiting subsequent lipid peroxidation and inflammatory responses. Herein, we tested the hypothesis that DOX directly scavenges reactive oxygen species (ROS) and inhibits the formation of redox-mediated malondialdehyde-acetaldehyde (MAA) protein adducts. Using a cell-free system, we demonstrated that DOX scavenged reactive oxygen species (ROS) produced during the formation of MAA-adducts and inhibits the formation of MAA-protein adducts. To determine whether DOX scavenges specific ROS, we examined the ability of DOX to directly scavenge superoxide and hydrogen peroxide. Using electron paramagnetic resonance (EPR) spectroscopy, we found that DOX directly scavenged superoxide, but not hydrogen peroxide. Additionally, we found that DOX inhibits MAA-induced activation of Nrf2, a redox-sensitive transcription factor. Together, these findings demonstrate the under-recognized direct antioxidant property of DOX that may help to explain its therapeutic potential in the treatment of conditions characterized by chronic inflammation and increased oxidative stress.

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Reactive Oxygen Species Activity and Antioxidant Properties ofFusariumInfected Bananas

Journal of Phytopathology ◽

10.1111/jph.12552 ◽

2017 ◽

Vol 165 (4) ◽

pp. 213-222 ◽

Cited By ~ 5

Author(s):

Kelvin Kiran Anthony ◽

Dominic Soloman George ◽

Hasvinder Kaur Baldev Singh ◽

Shi Ming Fung ◽

Vicknesha Santhirasegaram ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

Oxygen Species ◽

Species Activity

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Influence of Acetylcholinesterase Inhibitors Used in Alzheimer’s Disease Treatment on the Activity of Antioxidant Enzymes and the Concentration of Glutathione in THP-1 Macrophages under Fluoride-Induced Oxidative Stress

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16010010 ◽

2018 ◽

Vol 16 (1) ◽

pp. 10 ◽

Cited By ~ 3

Author(s):

Marta Goschorska ◽

Izabela Gutowska ◽

Irena Baranowska-Bosiacka ◽

Katarzyna Piotrowska ◽

Emilia Metryka ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Reactive Oxygen Species ◽

Alzheimer's Disease ◽

Antioxidant Enzymes ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

Acetylcholinesterase Inhibitors ◽

Oxygen Species ◽

Ache Inhibitors

It has been reported that donepezil and rivastigmine, the acetylcholinesterase (AchE) inhibitors commonly used in the treatment of Alzheimer’s disease (AD), do not only inhibit AChE but also have antioxidant properties. As oxidative stress is involved in AD pathogenesis, in our study we attempted to examine the influence of donepezil and rivastigmine on the activity of antioxidant enzymes and glutathione concentration in macrophages—an important source of reactive oxygen species and crucial for oxidative stress progression. The macrophages were exposed to sodium fluoride induced oxidative stress. The antioxidant enzymes activity and concentration of glutathione were measured spectrophotometrically. The generation of reactive oxygen species was visualized by confocal microscopy. The results of our study showed that donepezil and rivastigmine had a stimulating effect on catalase activity. However, when exposed to fluoride-induced oxidative stress, the drugs reduced the activity of some antioxidant enzymes (Cat, SOD, GR). These observations suggest that the fluoride-induced oxidative stress may suppress the antioxidant action of AChE inhibitors. Our results may have significance in the clinical practice of treatment of AD and other dementia diseases.

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Recent advances in semiconducting polymer dots as optical probes for biosensing

Biomaterials Science ◽

10.1039/d0bm01038c ◽

2021 ◽

Author(s):

Ye Yuan ◽

Weiying Hou ◽

Weiping Qin ◽

Changfeng Wu

Keyword(s):

Reactive Oxygen Species ◽

Metal Ions ◽

Reactive Oxygen ◽

Oxygen Species ◽

Optical Probes ◽

Semiconducting Polymer ◽

Ph Values ◽

Recent Advances ◽

Polymer Dots ◽

Semiconducting Polymer Dots

This review mainly summarized the recent results that used bright polymer dots (Pdots) for the detection of different analytes such as reactive oxygen species (ROS), metal ions, pH values, and a variety of biomolecules.

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Effect of reactive oxygen species on NH 4 + permeation in Xenopus laevis oocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00410.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. C1445-C1453 ◽

Cited By ~ 19

Author(s):

Marc Cougnon ◽

Samia Benammou ◽

Franck Brouillard ◽

Philippe Hulin ◽

Gabrielle Planelles

Keyword(s):

Reactive Oxygen Species ◽

Xenopus Laevis ◽

Reactive Oxygen ◽

Membrane Conductance ◽

Xenopus Laevis Oocytes ◽

Oxygen Species ◽

Cation Conductance ◽

Β Amyloid ◽

Oocyte Membrane ◽

Ros Scavengers

To investigate the effects of reactive oxygen species (ROS) on NH[Formula: see text]permeation in Xenopus laevis oocytes, we used intracellular double-barreled microelectrodes to monitor the changes in membrane potential ( V m) and intracellular pH (pHi) induced by a 20 mM NH4Cl-containing solution. Under control conditions, NH4Cl exposure induced a large membrane depolarization (to V m = 4.0 ± 1.5 mV; n = 21) and intracellular acidification [reaching a change in pHi(ΔpHi) of 0.59 ± 0.06 pH units in 12 min]; the initial rate of cell acidification (dpHi/d t) was 0.06 ± 0.01 pH units/min. Incubation of the oocytes in the presence of H2O2 or β-amyloid protein had no marked effect on the NH4Cl-induced ΔpHi. By contrast, in the presence of photoactivated rose bengal (RB), tert-butyl-hydroxyperoxide ( t-BHP), or xanthine/xanthine oxidase (X/XO), the same experimental maneuver induced significantly greater ΔpHi and dpHi/d t. These increases in ΔpHiand dpHi/d t were prevented by the ROS scavengers histidine and desferrioxamine, suggesting involvement of the reactive species 1ΔgO2 and ·OH. Using the voltage-clamp technique to identify the mechanism underlying the ROS-measured effects, we found that RB induced a large increase in the oocyte membrane conductance ( G m). This RB-induced G m increase was prevented by 1 mM diphenylamine-2-carboxylate (DPC) and by a low Na+concentration in the bath. We conclude that RB, t-BHP, and X/XO enhance NH[Formula: see text] influx into the oocyte via activation of a DPC-sensitive nonselective cation conductance pathway.

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Implication of the small GTPase Rac1 in the generation of reactive oxygen species in response to β-amyloid in C6 astroglioma cells

Biochemical Journal ◽

10.1042/bj20020453 ◽

2002 ◽

Vol 366 (3) ◽

pp. 937-943 ◽

Cited By ~ 26

Author(s):

Mina LEE ◽

Hye-Jin YOU ◽

Sung-Hoon CHO ◽

Chang-Hoon WOO ◽

Min-Hyuk YOO ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Leukotriene B4 ◽

Small Gtpase ◽

Cell Surface Receptor ◽

Oxygen Species ◽

Exogenous Application ◽

Essential Components ◽

Β Amyloid ◽

Astroglioma Cells

Exogenous application of β-amyloid (Aβ25—35, a fragment of Aβ1—42) significantly elevated levels of reactive oxygen species (ROS) in C6 astroglioma cells, as measured by confocal microscopic analysis of H2O2-sensitive 2′,7′-dichlorofluorescin fluorescence. Subsequent characterization of the signalling pathway revealed that expression of RacN17, a dominant-negative Rac1 mutant, completely blocked Aβ25—35-induced generation of ROS, which is indicative of the crucial role played by Rac GTPase in this process. To better understand the downstream mediators affected by Rac, we assessed the degree to which inhibition of cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO) contributed to the response and found that inhibition of either enzyme completely blocked Aβ25—35-induced ROS generation, indicating its dependence on arachidonic acid synthesis and metabolism to leukotrienes (e.g. leukotriene B4). Consistent with those findings, Aβ25—35 Rac-dependently stimulated translocation of 5-LO to the nuclear envelope and increased intracellular levels of leukotriene B4, while exogenous application of leukotriene B4 increased intracellular H2O2 via BLT, its cell-surface receptor. In addition to the aforementioned downstream mediators, inhibition of phosphoinositide 3-kinase (PI 3-kinase), an enzyme situated upstream of Rac, also completely blocked Aβ25—35-induced H2O2 generation. Our findings thus demonstrate that PI 3-kinase, Rac, cPLA2 and 5-LO are all essential components of the β-amyloid signaling cascade leading to generation of ROS.

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Reactive Oxygen Species and RBC Membrane Integrity in Peroxyredoxin II Deficient Mice.

Blood ◽

10.1182/blood.v104.11.54.54 ◽

2004 ◽

Vol 104 (11) ◽

pp. 54-54

Author(s):

Amrita Bhagat ◽

Renee Emerson ◽

Kitty DeJong ◽

Frans A. Kuypers

Keyword(s):

Reactive Oxygen Species ◽

Antioxidant Properties ◽

Flow Cytometric Analysis ◽

Membrane Integrity ◽

Reactive Oxygen ◽

Extinction Time ◽

Oxygen Species ◽

Rbc Membrane ◽

Small Proteins ◽

Phospholipid Scrambling

Abstract Red blood cells (RBCs) contain a complex set of enzymes and non-enzymatic scavengers as defense against reactive oxygen species (ROS). Peroxiredoxin II (PrxII), a member of a family of small proteins with strong antioxidant properties, is highly abundant in RBCs. PrxII is likely to play an essential role in ROS protection, as RBCs generate high levels of ROS due to their role in oxygen transport and the presence of redox active hemoglobin. Phosphatidylserine (PS) asymmetry in RBCs is maintained by the active transport of PS from outer to inner monolayer by the oxidant sensitive aminophospholipid translocase or flipase. PS exposure is found in RBCs where phospholipid scrambling is activated and the flipase is inhibited. In PrxII−/− mice, PrxII is absent from the RBC. These mice are anemic (Hct 41% vs. 46% in wild type mice (WT)), with increased reticulocyte count (4.7% vs. 2.0 % in WT), and a morphologically diverse RBC population. RBC indices after isovolumetric sphering showed a similar MCH (14.3 vs. 14.2), slightly increased MCV (49.2 fl vs. 45.5 fl) and slightly decreased MCHC (30.1 vs. 32.1) in PrxII−/− mice as compared to WT. In flow cytometric analysis, two distinct populations of RBC are found with either slight or significantly increased autofluorescence in the fluorescein channel (excitation 488 nm, emission 515 nm), indicative of oxidant damage. These two populations of low (LF) and high (HF) fluorescent cells comprise 70–80% and 20–30% of the total RBC population respectively. RBC from PrxII−/− and WT mice were biotinylated using EZ-Link Sulfo-NHS-Biotin (Pierce) allowing turnover studies of the LF and HF population. At set time points, the number of biotinylated cells was determined in small blood samples by flow cytometry using fluorescently labeled streptavidin. The data were mathematically fitted to 100–100*[1−(1/T)*t]exp(−kt), where t is the time point, T is the extinction time, and k the exponential rate of RBC removal. The data in the WT showed a linear removal rate (k=0), and a T of 40 days (R2=0.99). In PrxII−/−, an overall faster disappearance of biotinylated cells was noted, and the number of surviving (biotinylated) cells in the population followed an exponential pattern, consistent with random removal (k=0.08, R2= 0.98). At 20 days, 50% of biotinylated RBC were present in WT, but only 18% were found in PrxII−/− mice. In the non-biotinylated RBC, HF cells started to appear at day 13, indicating that autofluorescence is acquired in time. Using the fluorescent ROS membrane probe C11-BODIPY, our data indicate a higher level of ROS in the HF population. The HF population exhibited a lower flipase activity and increased phospholipid scrambling, as measured by labeling with annexin V. Together, our data indicate the importance of PrxII in the maintenance of RBC membrane integrity and suggest that oxidant induced PS exposure is in part responsible for shortened RBC survival in these mice. These findings indicate a role for oxidation in the exposure of PS on the RBC surface, which may clarify mechanisms in oxidant induced membrane alterations in hemoglobinopathies.

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