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Antioxidants and Oxidative Stress in the Development of Diseases and Therapy

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 16364

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Prof. Dr. Binghua Jiang

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Academy of Medical Science, School of Basic Medical Science, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, 450008, China
Interests: cancer development; cancer therapeutic resistance; carcinogenesis; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Canhua Huang

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1. School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
2. West China School of Basic Medical Sciences and Forensic Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Interests: redox regulation in tumorigenesis; the mechanism of virus-induced tumorigenesis
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Oxidative stress is the imbalance of reactive oxygen species (ROS) and endogenous antioxidants, and is the driving cause of many human diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, immune-system disorders, and musculoskeletal diseases. The dramatically increased human lifespan leads to the increased prevalence of these oxidative-stress-related diseases, which may be prevented and treated in order to reduce an economic and psychological burden for patients, their families and society that is currently showing a progressive increase. Healthy aging is crucial and needs to be highlighted as it affects the quality of lifespan. Recent evidence shows that antioxidants and small molecules for inhibiting ROS have therapeutic potential in preclinical studies and clinical trials. A better understanding of mechanisms of ROS production and antioxidant action is important for disease prevention and treatment in the future.

Oxidative stress induces cell proliferation, cellular senescence, and/or cell death through multiple mechanisms, including mitochondrial dysfunction, mitophagy impairment, apoptosis, protein modification, non-coding RNA dysregulation, and other epigenetic regulations. In the past few years, translational research has been extensively carried to elucidate the molecular mechanisms of oxidative stress and to find new chemicals or naturally derived compounds and antioxidants for the treatment of these oxidative-stress-related diseases.

This Special Issue will focus on the molecular mechanisms of oxidative stress in causing major human diseases, as well as the therapeutic and nutraceutical effects and molecular mechanisms of antioxidants, both naturally and synthetically derived, on oxidative-stress-induced diseases. It is our hope that this Special Issue will review molecular mechanisms of oxidative stress and redox signaling in disease development, and that it will advance our understanding of translational and clinical studies using antioxidants to foster new strategies for disease prevention.

Prof. Dr. Binghua Jiang
Prof. Dr. Canhua Huang
Guest Editors

Manuscript Submission Information

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Keywords

human disease
cancer
neurodegenerative diseases
age-related diseases
antioxidants
oxidative stress
reactive oxygen species
cell senescence
non-coding RNAs
epigenetic regulations

Published Papers (8 papers)

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Research

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20 pages, 7105 KiB

Open AccessArticle

Glutathione Induces Keap1 S-Glutathionylation and Mitigates Oscillating Glucose-Induced β-Cell Dysfunction by Activating Nrf2

by Xiufang Chen, Qian Zhou, Huamin Chen, Juan Bai, Ruike An, Keyi Zhang, Xinyue Zhang, Hui An, Jitai Zhang, Yongyu Wang and Ming Li

Antioxidants 2024, 13(4), 400; https://doi.org/10.3390/antiox13040400 - 27 Mar 2024

Viewed by 528

Abstract

Glutathione (GSH), a robust endogenous antioxidant, actively participates in the modulation of the redox status of cysteine residues in proteins. Previous studies have indicated that GSH can prevent β-cell failure and prediabetes caused by chronic oscillating glucose (OsG) administration. However, the precise mechanism underlying the protective effect is not well understood. Our current research reveals that GSH is capable of reversing the reduction in Nrf2 levels, as well as downstream genes Grx1 and HO-1, in the islet β-cells of rats induced by chronic OsG. In vitro experiments have further demonstrated that GSH can prevent β-cell dedifferentiation, apoptosis, and impaired insulin secretion caused by OsG. Additionally, GSH facilitates the translocation of Nrf2 into the nucleus, resulting in an upregulation of Nrf2-targeted genes such as GCLC, Grx1, HO-1, and NQO1. Notably, when the Nrf2 inhibitor ML385 is employed, the effects of GSH on OsG-treated β-cells are abrogated. Moreover, GSH enhances the S-glutathionylation of Keap1 at Cys273 and Cys288, but not Cys151, in OsG-treated β-cells, leading to the dissociation of Nrf2 from Keap1 and facilitating Nrf2 nuclear translocation. In conclusion, the protective role of GSH against OsG-induced β-cell failure can be partially attributed to its capacity to enhance Keap1 S-glutathionylation, thereby activating the Nrf2 signaling pathway. These findings provide novel insights into the prevention and treatment of β-cell failure in the context of prediabetes/diabetes, highlighting the potential of GSH. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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26 pages, 10797 KiB

Open AccessArticle

Development of New Resolvin D1 Analogues for Osteoarthritis Therapy: Acellular and Computational Approaches to Study Their Antioxidant Activities

by Zahra Kariminezhad, Mahdi Rahimi, Julio Fernandes, René Maltais, Jean-Yves Sancéau, Donald Poirier, Hassan Fahmi and Mohamed Benderdour

Antioxidants 2024, 13(4), 386; https://doi.org/10.3390/antiox13040386 - 22 Mar 2024

Viewed by 822

Abstract

In osteoarthritis (OA), oxidative stress plays a crucial role in maintaining and sustaining cartilage degradation. Current OA management requires a combination of pharmaceutical and non-pharmacological strategies, including intraarticular injections of hyaluronic acid (HA). However, several lines of evidence reported that HA oxidation by reactive oxygen species (ROS) is linked with HA cleavage and fragmentation, resulting in reduced HA viscosity. Resolvin D1 (RvD1) is a lipid mediator that is biosynthesized from omega-3 polyunsaturated fatty acids and is a good candidate with the potential to regulate a panoply of biological processes, including tissue repair, inflammation, oxidative stress, and cell death in OA. Herein, newly designed and synthesized imidazole-derived RvD1 analogues were introduced to compare their potential antioxidant properties with commercially available RvD1. Their antioxidant capacities were investigated by several in vitro chemical assays including oxygen radical absorbance capacity, 2,2-diphenyl-1-picrylhydrazyl radical scavenging, ferric ion reducing antioxidant power, hydroxyl radical scavenging, and HA fragmentation assay. All results proved that imidazole-derived RvD1 analogues showed excellent antioxidant performance compared to RvD1 due to their structural modifications. Interestingly, they scavenged the formed reactive oxygen species (ROS) and protected HA from degradation, as verified by agarose gel electrophoresis and gel permission chromatography. A computational study using Gaussian 09 with DFT calculations and a B3LYP/6-31 G (d, p) basis set was also employed to study the relationship between the antioxidant properties and chemical structures as well as calculation of the molecular structures, frontier orbital energy, molecular electrostatic potential, and bond length. The results showed that the antioxidant activity of our analogues was higher than that of RvD1. In conclusion, the findings suggest that imidazole-derived RvD1 analogues can be good candidates as antioxidant molecules for the treatment of oxidative stress-related diseases like OA. Therefore, they can prolong the longevity of HA in the knee and thus may improve the mobility of the articulation. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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16 pages, 5286 KiB

Open AccessArticle

Superoxide-Mediated Upregulation of MMP9 Participates in BMPR2 Destabilization and Pulmonary Hypertension Development

by Norah Alruwaili, Sharath Kandhi, Ghezal Froogh, Melissa R. Kelly, Dong Sun and Michael S. Wolin

Antioxidants 2023, 12(11), 1961; https://doi.org/10.3390/antiox12111961 - 02 Nov 2023

Viewed by 902

Abstract

Background and Aims: we previously reported in studies on organoid-cultured bovine pulmonary arteries that pulmonary hypertension (PH) conditions of exposure to hypoxia or endothelin-1 caused a loss of a cartilage oligomeric matrix protein (COMP) stabilization of bone morphogenetic protein receptor-2 (BMPR2) function, a known key process contributing to pulmonary hypertension development. Based on subsequent findings, these conditions were associated with an extracellular superoxide-mediated increase in matrix metalloproteinase 9 (MMP-9) expression. We investigated if this contributed to PH development using mice deficient in MMP9. Results: wild-type (WT) mice exposed to Sugen/Hypoxia (SuHx) to induce PH had increased levels of MMP9 in their lungs. Hemodynamic measures from MMP9 knockout mice (MMP9 KO) indicated they had attenuated PH parameters compared to WT mice based on an ECHO assessment of pulmonary artery pressure, right ventricular systolic pressure, and Fulton index hypertrophy measurements. In vitro vascular reactivity studies showed impaired endothelium-dependent and endothelium-independent NO-associated vasodilatory responses in the pulmonary arteries of SuHx mice and decreased lung levels of COMP and BMPR2 expression. These changes were attenuated in MMP9 KO mice potentially through preserving COMP-dependent stabilization of BMPR2. Innovation: this study supports a new function of superoxide in increasing MMP9 and the associated impairment of BMPR2 in promoting PH development which could be a target for future therapies. Conclusion: superoxide, through promoting increases in MMP9, mediates BMPR2 depletion and its consequent control of vascular function in response to PH mediators and the SuHx mouse model of PH. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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17 pages, 3415 KiB

Open AccessArticle

Integrated Multi-Omics Analysis for Inferring Molecular Players in Inclusion Body Myositis

by Judith Cantó-Santos, Laura Valls-Roca, Ester Tobías, Clara Oliva, Francesc Josep García-García, Mariona Guitart-Mampel, Félix Andújar-Sánchez, Anna Esteve-Codina, Beatriz Martín-Mur, Joan Padrosa, Raquel Aránega, Pedro J. Moreno-Lozano, José César Milisenda, Rafael Artuch, Josep M. Grau-Junyent and Glòria Garrabou

Antioxidants 2023, 12(8), 1639; https://doi.org/10.3390/antiox12081639 - 19 Aug 2023

Cited by 1 | Viewed by 1153

Abstract

Inclusion body myositis (IBM) is an acquired inflammatory myopathy affecting proximal and distal muscles that leads to weakness in patients over 50. It is diagnosed based on clinical and histological findings in muscle related to inflammation, degeneration, and mitochondria. In relation to IBM, a shortage of validated disease models and a lack of biomarkers and effective treatments constitute an unmet medical need. To overcome these hurdles, we performed an omics analysis of multiple samples from IBM patients (saliva, fibroblasts, urine, plasma, and muscle) to gain insight into the pathophysiology of IBM. Degeneration was evident due to the presence of amyloid β peptide 1–42 (Aβ1–42) in the saliva of the analyzed IBM patients. The presence of metabolic disarrangements in IBM was indicated by an imbalanced organic acid profile in fibroblasts and urine. Specifically, abnormal levels of L-pyroglutamic and orotic acid were supported by the abnormal expression of related metabolites in plasma and urine (glutathione and pyrimidines) and the aberrant expression of upstream gene regulators (L2HGDH, IDH2, OPLAH, and ASL) in muscle. Combined levels of L-pyroglutamic and orotic acid displayed an outstanding biomarker signature in urine with 100% sensitivity and specificity. The confirmation of systemic metabolic disarrangements in IBM and the identification of novel biomarkers reported herein unveil novel insights that require validation in larger cohorts. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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14 pages, 2377 KiB

Open AccessArticle

CRISPR/Cas9-Based Screening of FDA-Approved Drugs for NRF2 Activation: A Novel Approach to Discover Therapeutics for Non-Alcoholic Fatty Liver Disease

by James Li, Sandra Arest, Bartlomiej Olszowy, John Gordon, Carlos A. Barrero and Oscar Perez-Leal

Antioxidants 2023, 12(7), 1363; https://doi.org/10.3390/antiox12071363 - 29 Jun 2023

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Abstract

With the rising prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) now affects 20–25% of the global population. NAFLD, a progressive condition associated with oxidative stress, can result in cirrhosis and liver cancer in 10% and 3% of patients suffering NAFLD, respectively. Therapeutic options are currently limited, emphasizing the need for novel treatments. In this study, we examined the potential of activating the transcription factor NRF2, a crucial player in combating oxidative stress, as an innovative approach to treating NAFLD. Utilizing a CRISPR/Cas9-engineered human HEK293T cell line, we were able to monitor the expression of heme oxygenase-1 (HMOX1), an NRF2 target, using a Nanoluc luciferase tag. Our model was validated using a known NRF2 activator, after which we screened 1200 FDA-approved drugs, unearthing six compounds (Disulfiram, Thiostrepton, Auranofin, Thimerosal, Halofantrine, and Vorinostat) that enhanced NRF2 activity and antioxidant response. These compounds demonstrated protective effects against oxidative stress induced by hydrogen peroxide and lipid droplets accumulation in vitro with hepatoma HUH-7 cells. Our study underscores the utility of CRISPR/Cas9 tagging with Nanoluc luciferase in identifying potential NRF2 activators, paving the way for potential NAFLD therapeutics. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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17 pages, 4782 KiB

Open AccessArticle

The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2

by Yoshiki Higa, Masahiro Hiasa, Hirofumi Tenshin, Emiko Nakaue, Mariko Tanaka, Sooha Kim, Motosumi Nakagawa, So Shimizu, Kotaro Tanimoto, Jumpei Teramachi, Takeshi Harada, Asuka Oda, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Hiroki Yamagami, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe Show full author list Hide full author list

Antioxidants 2023, 12(1), 133; https://doi.org/10.3390/antiox12010133 - 05 Jan 2023

Cited by 3 | Viewed by 2380

Abstract

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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Review

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38 pages, 2960 KiB

Open AccessReview

Role of Nanoparticle-Conjugates and Nanotheranostics in Abrogating Oxidative Stress and Ameliorating Neuroinflammation

by Tapan A. Patel, Bhavesh D. Kevadiya, Neha Bajwa, Preet Amol Singh, Hong Zheng, Annet Kirabo, Yu-Long Li and Kaushik P. Patel

Antioxidants 2023, 12(10), 1877; https://doi.org/10.3390/antiox12101877 - 18 Oct 2023

Viewed by 2821

Abstract

Oxidative stress is a deteriorating condition that arises due to an imbalance between the reactive oxygen species and the antioxidant system or defense of the body. The key reasons for the development of such conditions are malfunctioning of various cell organelles, such as mitochondria, endoplasmic reticulum, and Golgi complex, as well as physical and mental disturbances. The nervous system has a relatively high utilization of oxygen, thus making it particularly vulnerable to oxidative stress, which eventually leads to neuronal atrophy and death. This advances the development of neuroinflammation and neurodegeneration-associated disorders such as Alzheimer’s disease, Parkinson’s disease, epilepsy, dementia, and other memory disorders. It is imperative to treat such conditions as early as possible before they worsen and progress to irreversible damage. Oxidative damage can be negated by two mechanisms: improving the cellular defense system or providing exogenous antioxidants. Natural antioxidants can normally handle such oxidative stress, but they have limited efficacy. The valuable features of nanoparticles and/or nanomaterials, in combination with antioxidant features, offer innovative nanotheranostic tools as potential therapeutic modalities. Hence, this review aims to represent novel therapeutic approaches like utilizing nanoparticles with antioxidant properties and nanotheranostics as delivery systems for potential therapeutic applications in various neuroinflammation- and neurodegeneration-associated disease conditions. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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27 pages, 1424 KiB

Open AccessReview

Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases

by Daniela Mokra, Juraj Mokry, Romana Barosova and Juliana Hanusrichterova

Antioxidants 2023, 12(9), 1713; https://doi.org/10.3390/antiox12091713 - 02 Sep 2023

Cited by 3 | Viewed by 4754

Abstract

N-acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols of cystic fibrosis. NAC is also administered as an antidote in acetaminophen (paracetamol) overdosing. Thanks to its wide antioxidative and anti-inflammatory effects, NAC may also be of benefit in other chronic inflammatory and fibrotizing respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or lung silicosis. In addition, NAC exerts low toxicity and rare adverse effects even in combination with other treatments, and it is cheap and easily accessible. This article brings a review of information on the mechanisms of inflammation and oxidative stress in selected chronic respiratory diseases and discusses the use of NAC in these disorders. Full article

(This article belongs to the Special Issue Antioxidants and Oxidative Stress in the Development of Diseases and Therapy)

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