2024

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24 pages, 5420 KiB

Open AccessArticle

Gadolinium-Based Magnetic Resonance Theranostic Agent with Gallic Acid as an Anti-Neuroinflammatory and Antioxidant Agent

by Bokyung Sung, Dongwook Hwang, Ahrum Baek, Byeongwoo Yang, Sangyun Lee, Jangwoo Park, Eunji Kim, Minsup Kim, Eunshil Lee and Yongmin Chang

Antioxidants 2024, 13(2), 204; https://doi.org/10.3390/antiox13020204 - 05 Feb 2024

Viewed by 813

Abstract

Studies in the field have actively pursued the incorporation of diverse biological functionalities into gadolinium-based contrast agents, aiming at the amalgamation of MRI imaging and therapeutic capabilities. In this research, we present the development of Gd-Ga, an anti-neuroinflammatory MR contrast agent strategically designed [...] Read more.

Studies in the field have actively pursued the incorporation of diverse biological functionalities into gadolinium-based contrast agents, aiming at the amalgamation of MRI imaging and therapeutic capabilities. In this research, we present the development of Gd-Ga, an anti-neuroinflammatory MR contrast agent strategically designed to target inflammatory mediators for comprehensive imaging diagnosis and targeted lesion treatment. Gd-Ga is a gadolinium complex composed of 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) conjugated with gallic acid (3,4,5-trihydroxybenzoic acid). Upon intravenous administration in LPS-induced mouse models, Gd-Ga demonstrated a remarkable three-fold increase in signal-to-noise (SNR) variation compared to Gd-DOTA, particularly evident in both the cortex and hippocampus 30 min post-MR monitoring. In-depth investigations, both in vitro and in vivo, into the anti-neuroinflammatory properties of Gd-Ga revealed significantly reduced protein expression levels of pro-inflammatory mediators compared to the LPS group. The alignment between in silico predictions and phantom studies indicates that Gd-Ga acts as an anti-neuroinflammatory agent by directly binding to MD2. Additionally, the robust antioxidant activity of Gd-Ga was confirmed by its effective scavenging of NO and ROS. Our collective findings emphasize the immense potential of this theranostic complex, where a polyphenol serves as an anti-inflammatory drug, presenting an exceptionally efficient platform for the diagnosis and treatment of neuroinflammation. Full article

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2023

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16 pages, 2363 KiB

Open AccessFeature PaperArticle

A Peptoid-Chelator Selective to Cu²⁺ That Can Extract Copper from Metallothionein-2 and Lead to the Production of ROS

by Anastasia Esther Behar and Galia Maayan

Antioxidants 2023, 12(12), 2031; https://doi.org/10.3390/antiox12122031 - 22 Nov 2023

Viewed by 997

Abstract

Copper is an essential metal ion that is involved in critical cellular processes, but which can also exhibit toxic effects through its ability to catalyze reactive oxygen species (ROS) formation. Dysregulation of copper homeostasis has been implicated in the progression of several diseases, [...] Read more.

Copper is an essential metal ion that is involved in critical cellular processes, but which can also exhibit toxic effects through its ability to catalyze reactive oxygen species (ROS) formation. Dysregulation of copper homeostasis has been implicated in the progression of several diseases, including cancer. A novel therapeutic approach, extensively studied in recent years, is to capitalize on the increased copper uptake and dependency exhibited by cancer cells and to promote copper-associated ROS production within the tumor microenvironment, leading to the apoptosis of cancer cells. Such an effect can be achieved by selectively chelating copper from copper-bearing metalloproteins in cancer cells, thereby forming a copper–chelator complex that produces ROS and, through this, induces oxidative stress and initiates apoptosis. Herein, we describe a peptoid chelator, TB, that is highly suitable to carry this task. Peptoids are N-substituted glycine oligomers that can be efficiently synthesized on a solid support and are also biocompatible; thus, they are considered promising drug candidates. We show, by rigorous spectroscopic techniques, that TB is not only selective for Cu(II) ions, but can also effectively extract copper from metallothionein-2, and the formed complex CuTB can promote ROS production. Our findings present a promising first example for the future development of peptoid-based chelators for applications in anti-cancer chelation therapy, highlighting the potential for the prospect of peptoid chelators as therapeutics. Full article

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14 pages, 1365 KiB

Open AccessArticle

Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency

by Monica Gomaraschi, Marta Turri, Arianna Strazzella, Marie Lhomme, Chiara Pavanello, Wilfried Le Goff, Anatol Kontush, Laura Calabresi and Alice Ossoli

Antioxidants 2023, 12(8), 1498; https://doi.org/10.3390/antiox12081498 - 27 Jul 2023

Viewed by 1416

Abstract

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the LCAT gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and [...] Read more.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the LCAT gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells. Full article

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12 pages, 534 KiB

Open AccessReview

Oxidative and Glycation Damage to Mitochondrial DNA and Plastid DNA during Plant Development

by Diwaker Tripathi, Delene J. Oldenburg and Arnold J. Bendich

Antioxidants 2023, 12(4), 891; https://doi.org/10.3390/antiox12040891 - 06 Apr 2023

Cited by 3 | Viewed by 1529

Abstract

Oxidative damage to plant proteins, lipids, and DNA caused by reactive oxygen species (ROS) has long been studied. The damaging effects of reactive carbonyl groups (glycation damage) to plant proteins and lipids have also been extensively studied, but only recently has glycation damage [...] Read more.

Oxidative damage to plant proteins, lipids, and DNA caused by reactive oxygen species (ROS) has long been studied. The damaging effects of reactive carbonyl groups (glycation damage) to plant proteins and lipids have also been extensively studied, but only recently has glycation damage to the DNA in plant mitochondria and plastids been reported. Here, we review data on organellar DNA maintenance after damage from ROS and glycation. Our focus is maize, where tissues representing the entire range of leaf development are readily obtained, from slow-growing cells in the basal meristem, containing immature organelles with pristine DNA, to fast-growing leaf cells, containing mature organelles with highly-fragmented DNA. The relative contributions to DNA damage from oxidation and glycation are not known. However, the changing patterns of damage and damage-defense during leaf development indicate tight coordination of responses to oxidation and glycation events. Future efforts should be directed at the mechanism by which this coordination is achieved. Full article

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23 pages, 5407 KiB

Open AccessArticle

Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives

by Aurore Tourville, Sarah Viguier, Florencia González-Lizárraga, Rodrigo Hernán Tomas-Grau, Paola Ramirez, Jean-Michel Brunel, Mauricio Dos Santos Pereira, Elaine Del-Bel, Rosana Chehin, Laurent Ferrié, Rita Raisman-Vozari, Bruno Figadère and Patrick Pierre Michel

Antioxidants 2023, 12(3), 575; https://doi.org/10.3390/antiox12030575 - 24 Feb 2023

Cited by 5 | Viewed by 2580

Abstract

Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson’s disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare [...] Read more.

Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson’s disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare the rescue effect of DOX to that of other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced antibiotic activity. For that, we used cultures of mouse midbrain dopamine (DA) neurons and experimental conditions that model iron-mediated oxidative damage, a key mechanism in PD pathobiology. We found that DOX and the other TC antibiotic, demeclocycline (DMC), provided sustained protection to DA neurons enduring iron-mediated insults, whereas chlortetracycline and non-TC class antibiotics did not. Most interestingly, non-antibiotic derivatives of DOX and DMC, i.e., DDOX and DDMC, respectively, were also robustly protective for DA neurons. Interestingly, DOX, DDOX, DMC, and DDMC remained protective for DA neurons until advanced stages of neurodegeneration, and the rescue effects of TCs were observable regardless of the degree of maturity of midbrain cultures. Live imaging studies with the fluorogenic probes DHR-123 and TMRM revealed that protective TCs operated by preventing intracellular oxidative stress and mitochondrial membrane depolarization, i.e., cellular perturbations occurring in this model system as the ultimate consequence of ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults were generated acutely, DOX, DDOX, DMC, and DDMC were no longer neuroprotective, suggesting that these compounds are mostly effective when neuronal damage is chronic and of low-intensity. Overall, our data suggest that TC derivatives, particularly those lacking antibiotic activity, might be of potential therapeutic utility to combat low-level oxidative insults that develop chronically in the course of PD neurodegeneration. Full article

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2022

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9 pages, 1150 KiB

Open AccessArticle

A Caveat When Using Alkyl Halides as Tagging Agents to Detect/Quantify Reactive Sulfur Species

by Xiaohua Wu, Yuping Xin, Qingda Wang, Yongzhen Xia, Luying Xun and Huaiwei Liu

Antioxidants 2022, 11(8), 1583; https://doi.org/10.3390/antiox11081583 - 16 Aug 2022

Viewed by 1558

Abstract

Using alkyl halides to tag reactive sulfur species (RSSs) (H₂S, per/polysulfide, and protein-SSH) is an extensively applied approach. The underlying supposition is that, as with thiols, RSS reacts with alkyl halides via a nucleophilic substitution reaction. We found that this supposition [...] Read more.

Using alkyl halides to tag reactive sulfur species (RSSs) (H₂S, per/polysulfide, and protein-SSH) is an extensively applied approach. The underlying supposition is that, as with thiols, RSS reacts with alkyl halides via a nucleophilic substitution reaction. We found that this supposition is facing a challenge. RSS also initiates a reductive dehalogenation reaction, which generates the reduced unloaded tag and oxidized RSS. Therefore, RSS content in bio-samples might be underestimated, and its species might not be precisely determined when using alkyl halide agents for its analysis. To calculate to the extent of this underestimation, further studies are still required. Full article

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2021

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18 pages, 2442 KiB

Open AccessArticle

Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia

by Zhengqi Wang, Tian Mi, Heath L. Bradley, Jonathan Metts, Himalee Sabnis, Wandi Zhu, Jack Arbiser and Kevin D. Bunting

Antioxidants 2021, 10(6), 956; https://doi.org/10.3390/antiox10060956 - 15 Jun 2021

Cited by 6 | Viewed by 2525

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has [...] Read more.

Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD⁺ cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses. Full article

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20 pages, 2695 KiB

Open AccessArticle

Frataxins Emerge as New Players of the Intracellular Antioxidant Machinery

by Ana Belén Uceda, Josefa Donoso, Juan Frau, Bartolomé Vilanova and Miquel Adrover

Antioxidants 2021, 10(2), 315; https://doi.org/10.3390/antiox10020315 - 20 Feb 2021

Cited by 5 | Viewed by 2443

Abstract

Frataxin is a mitochondrial protein which deficiency causes Friedreich’s ataxia, a cardio-neurodegenerative disease. The lack of frataxin induces the dysregulation of mitochondrial iron homeostasis and oxidative stress, which finally causes the neuronal death. The mechanism through which frataxin regulates the oxidative stress balance [...] Read more.

Frataxin is a mitochondrial protein which deficiency causes Friedreich’s ataxia, a cardio-neurodegenerative disease. The lack of frataxin induces the dysregulation of mitochondrial iron homeostasis and oxidative stress, which finally causes the neuronal death. The mechanism through which frataxin regulates the oxidative stress balance is rather complex and poorly understood. While the absence of human (Hfra) and yeast (Yfh1) frataxins turn out cells sensitive to oxidative stress, this does not occur when the frataxin gene is knocked-out in E. coli. To better understand the biological roles of Hfra and Yfh1 as endogenous antioxidants, we have studied their ability to inhibit the formation of reactive oxygen species (ROS) from Cu²⁺- and Fe³⁺-catalyzed degradation of ascorbic acid. Both proteins drastically reduce the formation of ROS, and during this process they are not oxidized. In addition, we have also demonstrated that merely the presence of Yfh1 or Hfra is enough to protect a highly oxidation-prone protein such as α-synuclein. This unspecific intervention (without a direct binding) suggests that frataxins could act as a shield to prevent the oxidation of a broad set of intracellular proteins, and reinforces that idea that frataxin can be used to prevent neurological pathologies linked to an enhanced oxidative stress. Full article

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2020

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16 pages, 19065 KiB

Open AccessArticle

Spontaneous Formation of Melanin from Dopamine in the Presence of Iron

by David M. Hedges, Jordan T. Yorgason, Andrew W. Perez, Nathan D. Schilaty, Benjamin M. Williams, Richard K. Watt and Scott C. Steffensen

Antioxidants 2020, 9(12), 1285; https://doi.org/10.3390/antiox9121285 - 16 Dec 2020

Cited by 9 | Viewed by 4117

Abstract

Parkinson’s disease is associated with degeneration of neuromelanin (NM)-containing substantia nigra dopamine (DA) neurons and subsequent decreases in striatal DA transmission. Dopamine spontaneously forms a melanin through a process called melanogenesis. The present study examines conditions that promote/prevent DA melanogenesis. The kinetics, intermediates, [...] Read more.

Parkinson’s disease is associated with degeneration of neuromelanin (NM)-containing substantia nigra dopamine (DA) neurons and subsequent decreases in striatal DA transmission. Dopamine spontaneously forms a melanin through a process called melanogenesis. The present study examines conditions that promote/prevent DA melanogenesis. The kinetics, intermediates, and products of DA conversion to melanin in vitro, and DA melanogenesis under varying levels of Fe³⁺, pro-oxidants, and antioxidants were examined. The rate of melanogenesis for DA was substantially greater than related catecholamines norepinephrine and epinephrine and their precursor amino acids tyrosine and l-Dopa as measured by UV-IR spectrophotometry. Dopamine melanogenesis was concentration dependent on the pro-oxidant species and Fe³⁺. Melanogenesis was enhanced by the pro-oxidant hydrogen peroxide (EC₅₀ = 500 μM) and decreased by the antioxidants ascorbate (IC₅₀ = 10 μM) and glutathione (GSH; IC₅₀ = 5 μM). Spectrophotometric results were corroborated by tuning a fast-scan cyclic voltammetry system to monitor DA melanogenesis. Evoked DA release in striatal brain slices resulted in NM formation that was prevented by GSH. These findings suggest that DA melanogenesis occurs spontaneously under physiologically-relevant conditions of oxidative stress and that NM may act as a marker of past exposure to oxidative stress. Full article

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16 pages, 2338 KiB

Open AccessArticle

Antioxidants as Molecular Probes: Structurally Novel Dihydro-m-Terphenyls as Turn-On Fluorescence Chemodosimeters for Biologically Relevant Oxidants

by Víctor González-Ruiz, Jegathalaprathaban Rajesh, Ana I. Olives, Damiano Rocchi, Jorge Gómez-Carpintero, Juan F. González, Vellaisamy Sridharan, M. Antonia Martín and J. Carlos Menéndez

Antioxidants 2020, 9(7), 605; https://doi.org/10.3390/antiox9070605 - 10 Jul 2020

Cited by 3 | Viewed by 3480

Abstract

One interesting aspect of antioxidant organic molecules is their use as probes for the detection and quantitation of biologically relevant reactive oxidant species (ROS). In this context, a small library of dihydroterphenyl derivatives has been synthesised and studied as fluorescent chemodosimeters for detecting [...] Read more.

One interesting aspect of antioxidant organic molecules is their use as probes for the detection and quantitation of biologically relevant reactive oxidant species (ROS). In this context, a small library of dihydroterphenyl derivatives has been synthesised and studied as fluorescent chemodosimeters for detecting reactive oxygen species and hypochlorite. The fluorescence quantum yields of these molecules are negligible, while the corresponding aromatized compounds formed upon oxidation show moderate to high native fluorescence, depending on their structures. The fluorescence signal is quickly developed in the presence of trace amounts of the probe and the analytes in acetonitrile media at room temperature, with good analytical figures. ROS detection in aqueous media required incubation at 37 °C in the presence of horseradish peroxidase, and was applied to glucose quantitation by coupling glucose oxidation by O₂ to fluorescence detection of H₂O₂. The mild reaction conditions and sensitive fluorescent response lead us to propose dihydroterphenyls with an embedded anthranilate moiety as chemosensors/chemodosimeters for ROS detection. Full article

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23 pages, 9017 KiB

Open AccessArticle

Allies or Enemies: The Role of Reactive Oxygen Species in Developmental Processes of Black Cottonwood (Populus trichocarpa)

by Katarzyna Marzec-Schmidt, Natalia Wojciechowska, Klaudia Nemeczek, Agnieszka Ludwików, Joanna Mucha and Agnieszka Bagniewska-Zadworna

Antioxidants 2020, 9(3), 199; https://doi.org/10.3390/antiox9030199 - 27 Feb 2020

Cited by 4 | Viewed by 3476

Abstract

In contrast to aboveground organs (stems and leaves), developmental events and their regulation in underground organs, such as pioneer and fine roots, are quite poorly understood. The objective of the current study was to achieve a better understanding of the physiological and molecular [...] Read more.

In contrast to aboveground organs (stems and leaves), developmental events and their regulation in underground organs, such as pioneer and fine roots, are quite poorly understood. The objective of the current study was to achieve a better understanding of the physiological and molecular role of reactive oxygen species (ROS) and ROS-related enzymes in the process of stem and pioneer root development in black cottonwood (Populus trichocarpa), as well as in the senescence of leaves and fine roots. Results of a transcriptomic analysis revealed that primary/secondary growth and senescence are accompanied by substantial changes in the expression of genes related to oxidative stress metabolism. We observed that some mechanisms common for above- and under-ground organs, e.g., the expression of superoxide dismutase (SOD) genes and SOD activity, declined during stems’ and pioneer roots’ development. Moreover, the localization of hydrogen peroxide (H₂O₂) and superoxide (O₂•^–) in the primary and secondary xylem of stems and pioneer roots confirms their involvement in xylem cell wall lignification and the induction of programmed cell death (PCD). H₂O₂ and O₂•^– in senescing fine roots were present in the same locations as demonstrated previously for ATG8 (AuTophaGy-related) proteins, implying their participation in cell degradation during senescence, while O₂•^– in older leaves was also localized similarly to ATG8 in chloroplasts, suggesting their role in chlorophagy. ROS and ROS-related enzymes play an integral role in the lignification of xylem cell walls in Populus trichocarpa, as well as the induction of PCD during xylogenesis and senescence. Full article

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13 pages, 3599 KiB

Open AccessArticle

Reactive Sulfur Species Interact with Other Signal Molecules in Root Nodule Symbiosis in Lotus japonicus

by Mitsutaka Fukudome, Hazuki Shimada, Nahoko Uchi, Ken-ichi Osuki, Haruka Ishizaki, Ei-ichi Murakami, Masayoshi Kawaguchi and Toshiki Uchiumi

Antioxidants 2020, 9(2), 145; https://doi.org/10.3390/antiox9020145 - 07 Feb 2020

Cited by 13 | Viewed by 3566

Abstract

Reactive sulfur species (RSS) function as strong antioxidants and are involved in various biological responses in animals and bacteria. Few studies; however, have examined RSS in plants. In the present study, we clarified that RSS are involved in root nodule symbiosis in the [...] Read more.

Reactive sulfur species (RSS) function as strong antioxidants and are involved in various biological responses in animals and bacteria. Few studies; however, have examined RSS in plants. In the present study, we clarified that RSS are involved in root nodule symbiosis in the model legume Lotus japonicus. Polysulfides, a type of RSS, were detected in the roots by using a sulfane sulfur-specific fluorescent probe, SSP4. Supplying the sulfane sulfur donor Na₂S₃ to the roots increased the amounts of both polysulfides and hydrogen sulfide (H₂S) in the roots and simultaneously decreased the amounts of nitric oxide (NO) and reactive oxygen species (ROS). RSS were also detected in infection threads in the root hairs and in infected cells of nodules. Supplying the sulfane sulfur donor significantly increased the numbers of infection threads and nodules. When nodules were immersed in the sulfane sulfur donor, their nitrogenase activity was significantly reduced, without significant changes in the amounts of NO, ROS, and H₂S. These results suggest that polysulfides interact with signal molecules such as NO, ROS, and H₂S in root nodule symbiosis in L. japonicus. SSP4 and Na₂S₃ are useful tools for study of RSS in plants. Full article

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