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Therapeutic Strategies and Targets for Reactive Oxygen Species Related Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 18874

Special Issue Editors

Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
Interests: nanomedicine; tumor-targeting; EPR effect; carbon monoxide; inflammation; reactive oxygen species
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Guest Editor
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan
Interests: Oxidative stress; redox signaling; Nitric oxide persulfide and sulfur metabolism; inflammation; infectious diseases

Special Issue Information

Dear Colleagues,

Oxidative stress, and namely over-production of ROS, involves in the initiation and progression of many diseases and disorders, including cardiovascular diseases, inflammation, ischemia–reperfusion (I/R) injury, viral pathogenesis, drug-induced tissue injury, hypertension, formation of drug resistant mutant, as well as cancer. Thus, it is essential to counterbalance ROS and to treat such ROS-related diseases by inhibiting ROS production. This aim could be achieved by focusing on the antioxidative defence systems including superoxide dismutase (SOD), catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1), as well as using antioxidants ascorbate, tocopherol, glutathione, and more recently discovered persulfides/polysulfides (RSS). On the contrary, due to their highly cytotoxic nature, ROS can also be used to kill cancer cells if their generation can be selectively modulated in cancer. Generation of ROS is the major anticancer mechanism of many anticancer drugs such as doxorubicin, camptothecin, cisplatin, etc. Targeted delivery ROS to a tumor is a promising anticancer approach. This Special Issue focuses on the therapeutic strategies and potential target molecules for the treatment of ROS-related diseases.

Dr. Jun Fang
Prof. Dr. Tomohiro Sawa
Guest Editors

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Published Papers (7 papers)

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Research

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18 pages, 3390 KiB  
Article
Different Molecular Forms of TFF3 in the Human Respiratory Tract: Heterodimerization with IgG Fc Binding Protein (FCGBP) and Proteolytic Cleavage in Bronchial Secretions
by Jens Weste, Till Houben, Sönke Harder, Hartmut Schlüter, Eva Lücke, Jens Schreiber and Werner Hoffmann
Int. J. Mol. Sci. 2022, 23(23), 15359; https://doi.org/10.3390/ijms232315359 - 6 Dec 2022
Cited by 4 | Viewed by 1933
Abstract
The polypeptide TFF3 belongs to the trefoil factor family (TFF) of lectins. TFF3 is typically secreted from mucous epithelia together with mucins. Both intestinal and salivary TFF3 mainly exist as disulfide-linked heterodimers with IgG Fc binding protein (FCGBP). Here, we investigated bronchial tissue [...] Read more.
The polypeptide TFF3 belongs to the trefoil factor family (TFF) of lectins. TFF3 is typically secreted from mucous epithelia together with mucins. Both intestinal and salivary TFF3 mainly exist as disulfide-linked heterodimers with IgG Fc binding protein (FCGBP). Here, we investigated bronchial tissue specimens, bronchial secretions, and bronchoalveolar lavage (BAL) fluid from patients with a chronic obstructive pulmonary disease (COPD) background by fast protein liquid chromatography and proteomics. For the first time, we identified different molecular forms of TFF3 in the lung. The high-molecular mass form represents TFF3-FCGBP oligomers, whereas the low-molecular mass forms are homodimeric and monomeric TFF3 with possibly anti-apoptotic activities. In addition, disulfide-linked TFF3 heterodimers with an Mr of about 60k and 30k were detected in both bronchial secretions and BAL fluid. In these liquids, TFF3 is partly N-terminally truncated probably by neutrophil elastase cleavage. TFF3-FCGBP is likely involved in the mucosal innate immune defense against microbial infections. We discuss a hypothetical model how TFF3 might control FCGBP oligomerization. Furthermore, we did not find indications for interactions of TFF3-FCGBP with DMBT1gp340 or the mucin MUC5AC, glycoproteins involved in mucosal innate immunity. Surprisingly, bronchial MUC5AC appeared to be degraded when compared with gastric MUC5AC. Full article
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21 pages, 8543 KiB  
Article
1,3-Benzodioxole Derivatives Improve the Anti-Tumor Efficiency of Arsenicals
by Xue-Min Shi, Wen-Yan She, Ting-Ting Liu, Lian-Xun Gao, Yu-Jiao Liu and Yi Liu
Int. J. Mol. Sci. 2022, 23(13), 6930; https://doi.org/10.3390/ijms23136930 - 22 Jun 2022
Cited by 1 | Viewed by 1827
Abstract
Arsenicals have been widely used in the treatment of cancers such as leukemia and other tumors. However, their side effects limit their clinical application. Stiripentol, a second-line adjunctive treatment for epilepsy with a good safety profile, inhibits microsomal cytochrome-P450-family enzymes to extend the [...] Read more.
Arsenicals have been widely used in the treatment of cancers such as leukemia and other tumors. However, their side effects limit their clinical application. Stiripentol, a second-line adjunctive treatment for epilepsy with a good safety profile, inhibits microsomal cytochrome-P450-family enzymes to extend the retention time of co-administration. Inspired by the metabolism of stiripentol, the 1,3-benzodioxole responsible for the inhibition and its metabolic derivatives were conjugated with arsenical precursors. The fabricated arsenicals were eliminated much slower in mice and maintained an efficient concentration in the blood for a longer time than that of the arsenical precursors. They also performed better in anti-proliferation by inhibiting the thioredoxin system to induce oxidative stress, and concomitantly to initiate apoptosis in vitro and in vivo. The fabricated arsenicals reversed the hemogram of tumor-bearing mice to normal and eliminated the tumor without causing damage to any organs, exhibiting a good design strategy and pre-clinical application for leukemia and other tumors. Full article
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25 pages, 7064 KiB  
Article
Regenerative Effects of Hypoxia Primed Flowable Placental Formulation in Muscle and Dermal Injury
by Sandeep Dhall, Min Sung Park, Chaoyang Li and Malathi Sathyamoorthy
Int. J. Mol. Sci. 2021, 22(13), 7151; https://doi.org/10.3390/ijms22137151 - 1 Jul 2021
Viewed by 2427
Abstract
The placental tissue, due to its angiogenic, anti-inflammatory, antioxidative, antimicrobial, and anti-fibrotic properties, has become a compelling source towards a solution for several indications in regenerative medicine. However, methods to enhance and capture the therapeutic properties with formulations that can further the applications [...] Read more.
The placental tissue, due to its angiogenic, anti-inflammatory, antioxidative, antimicrobial, and anti-fibrotic properties, has become a compelling source towards a solution for several indications in regenerative medicine. However, methods to enhance and capture the therapeutic properties with formulations that can further the applications of viable placental tissue have not been explored. In this study, we investigated the regenerative effects of a hypoxia primed flowable placental formulation (FPF), composed of amnion/chorion and umbilical tissue, in two in vivo injury models. Laser Doppler data from rodent ischemia hindlimbs treated with FPF revealed significant tissue perfusion improvements compared to control ischemic hindlimbs. To further corroborate FPF’s effects, we used a rodent ischemic bipedicle skin flap wound model. FPF treatment significantly increased the rate of wound closure and the quality of wound healing. FPF-treated wounds displayed reduced inflammation and an increase in angiogenesis. Furthermore, quantitative PCR and next-generation sequencing analysis confirmed these changes in the FPF-treated group at both the gene and transcriptional level. The observed modulation in miRNAs was associated with angiogenesis, regulation of inflammatory microenvironment, cell migration and apoptosis, reactive oxygen species generation, and restoring epithelial barrier function, all processes involved in impaired tissue healing. Taken together, these data validate the tissue regenerative properties of the flowable placental formulation configuration tested. Full article
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17 pages, 2228 KiB  
Article
Comprehensive Comparison of Amnion Stromal Cells and Chorion Stromal Cells by RNA-Seq
by Brielle Jones, Chaoyang Li, Min Sung Park, Anne Lerch, Vimal Jacob, Nicholas Johnson, Jin-Qiang Kuang, Sandeep Dhall and Malathi Sathyamoorthy
Int. J. Mol. Sci. 2021, 22(4), 1901; https://doi.org/10.3390/ijms22041901 - 14 Feb 2021
Cited by 4 | Viewed by 1882
Abstract
Mesenchymal stromal cells derived from the fetal placenta, composed of an amnion membrane, chorion membrane, and umbilical cord, have emerged as promising sources for regenerative medicine. Here, we used next-generation sequencing technology to comprehensively compare amniotic stromal cells (ASCs) with chorionic stromal cells [...] Read more.
Mesenchymal stromal cells derived from the fetal placenta, composed of an amnion membrane, chorion membrane, and umbilical cord, have emerged as promising sources for regenerative medicine. Here, we used next-generation sequencing technology to comprehensively compare amniotic stromal cells (ASCs) with chorionic stromal cells (CSCs) at the molecular and signaling levels. Principal component analysis showed a clear dichotomy of gene expression profiles between ASCs and CSCs. Unsupervised hierarchical clustering confirmed that the biological repeats of ASCs and CSCs were able to respectively group together. Supervised analysis identified differentially expressed genes, such as LMO3, HOXA11, and HOXA13, and differentially expressed isoforms, such as CXCL6 and HGF. Gene Ontology (GO) analysis showed that the GO terms of the extracellular matrix, angiogenesis, and cell adhesion were significantly enriched in CSCs. We further explored the factors associated with inflammation and angiogenesis using a multiplex assay. In comparison with ASCs, CSCs secreted higher levels of angiogenic factors, including angiogenin, VEGFA, HGF, and bFGF. The results of a tube formation assay proved that CSCs exhibited a strong angiogenic function. However, ASCs secreted two-fold more of an anti-inflammatory factor, TSG-6, than CSCs. In conclusion, our study demonstrated the differential gene expression patterns between ASCs and CSCs. CSCs have superior angiogenic potential, whereas ASCs exhibit increased anti-inflammatory properties. Full article
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Review

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18 pages, 870 KiB  
Review
Antioxidant Therapeutic Strategies in Neurodegenerative Diseases
by Constanza Morén, Ruth Mary deSouza, Darly Milena Giraldo and Christopher Uff
Int. J. Mol. Sci. 2022, 23(16), 9328; https://doi.org/10.3390/ijms23169328 - 19 Aug 2022
Cited by 30 | Viewed by 3440
Abstract
The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using [...] Read more.
The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using antioxidant molecules towards redox equilibrium have been widely used for the treatment of several brain pathologies. Globally, polyphenols, carotenes and vitamins are among the most typical exogenous antioxidant agents that have been tested in neurodegeneration as adjunctive therapies. However, other types of antioxidants, including hormones, such as the widely used melatonin, are also considered neuroprotective agents and have been used in different neurodegenerative contexts. This review highlights the most relevant mitochondrial antioxidant targets in the main neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease and also in the less represented amyotrophic lateral sclerosis, as well as traumatic brain injury, while summarizing the latest randomized placebo-controlled trials. Full article
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15 pages, 1547 KiB  
Review
Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives
by Yesi Choi, Lisa Rekers, Ying Dong, Lena Holzfurtner, Maurizio J. Goetz, Tayyab Shahzad, Klaus-Peter Zimmer, Judith Behnke, Jonas Behnke, Saverio Bellusci and Harald Ehrhardt
Int. J. Mol. Sci. 2021, 22(20), 11006; https://doi.org/10.3390/ijms222011006 - 12 Oct 2021
Cited by 11 | Viewed by 3877
Abstract
In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm delivery and extrauterine exposure to high fractions of oxygen are among the key events [...] Read more.
In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm delivery and extrauterine exposure to high fractions of oxygen are among the key events leading to bronchopulmonary dysplasia (BPD). Reactive oxygen species (ROS) production constitutes the initial driver of pulmonary inflammation and cell death, altered gene expression, and vasoconstriction, leading to the distortion of further lung development. From preclinical studies mainly performed on rodents over the past two decades, the deleterious effects of oxygen toxicity and the injurious insults and downstream cascades arising from ROS production are well recognized. This article provides a concise overview of disease drivers and different therapeutic approaches that have been successfully tested within experimental models. Despite current studies, clinical researchers are still faced with an unmet clinical need, and many of these strategies have not proven to be equally effective in clinical trials. In light of this challenge, adapting experimental models to the complexity of the clinical situation and pursuing new directions constitute appropriate actions to overcome this dilemma. Our review intends to stimulate research activities towards the understanding of an important issue of immature lung injury. Full article
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17 pages, 330 KiB  
Review
Oxygen Toxicity to the Immature Lung—Part II: The Unmet Clinical Need for Causal Therapy
by Judith Behnke, Constanze M. Dippel, Yesi Choi, Lisa Rekers, Annesuse Schmidt, Tina Lauer, Ying Dong, Jonas Behnke, Klaus-Peter Zimmer, Saverio Bellusci and Harald Ehrhardt
Int. J. Mol. Sci. 2021, 22(19), 10694; https://doi.org/10.3390/ijms221910694 - 2 Oct 2021
Cited by 7 | Viewed by 2572
Abstract
Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden [...] Read more.
Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures. Full article
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