Editorial

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Open AccessEditorial

Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0

by Sergio Di Meo, Paola Venditti and Gaetana Napolitano

Int. J. Mol. Sci. 2022, 23(16), 9437; https://doi.org/10.3390/ijms23169437 - 21 Aug 2022

Cited by 3 | Viewed by 996

Abstract

Following the discovery of superoxide dismutase enzymes [...] Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

Research

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15 pages, 3279 KiB

Open AccessArticle

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines

by Jiaqi Zhu, Stefanie May, Claas Ulrich, Eggert Stockfleth and Jürgen Eberle

Int. J. Mol. Sci. 2021, 22(7), 3622; https://doi.org/10.3390/ijms22073622 - 31 Mar 2021

Cited by 10 | Viewed by 2067

Abstract

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained [...] Read more.

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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18 pages, 3083 KiB

Open AccessArticle

Modulation of VEGF Expression and Oxidative Stress Response by Iodine Deficiency in Irradiated Cancerous and Non-Cancerous Breast Cells

by Jessica Vanderstraeten, Bjorn Baselet, Jasmine Buset, Naziha Ben Said, Christine de Ville de Goyet, Marie-Christine Many, Anne-Catherine Gérard and Hanane Derradji

Int. J. Mol. Sci. 2020, 21(11), 3963; https://doi.org/10.3390/ijms21113963 - 31 May 2020

Cited by 3 | Viewed by 2139

Abstract

Breast cancer remains a major concern and its physiopathology is influenced by iodine deficiency (ID) and radiation exposure. Since radiation and ID can separately induce oxidative stress (OS) and microvascular responses in breast, their combination could additively increase these responses. Therefore, ID was [...] Read more.

Breast cancer remains a major concern and its physiopathology is influenced by iodine deficiency (ID) and radiation exposure. Since radiation and ID can separately induce oxidative stress (OS) and microvascular responses in breast, their combination could additively increase these responses. Therefore, ID was induced in MCF7 and MCF12A breast cell lines by medium change. Cells were then X-irradiated with doses of 0.05, 0.1, or 3 Gy. In MCF12A cells, both ID and radiation (0.1 and 3 Gy) increased OS and vascular endothelial growth factor (VEGF) expression, with an additive effect when the highest dose was combined with ID. However, in MCF7 cells no additive effect was observed. VEGF mRNA up-regulation was reactive oxygen species (ROS)-dependent, involving radiation-induced mitochondrial ROS. Results on total VEGF mRNA hold true for the pro-angiogenic isoform VEGF165 mRNA, but the treatments did not modulate the anti-angiogenic isoform VEGF165b. Radiation-induced antioxidant response was differentially regulated upon ID in both cell lines. Thus, radiation response is modulated according to iodine status and cell type and can lead to additive effects on ROS and VEGF. As these are often involved in cancer initiation and progression, we believe that iodine status should be taken into account in radiation prevention policies. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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14 pages, 3206 KiB

Open AccessArticle

Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina

by Shou Oosuka, Teruyo Kida, Hidehiro Oku, Taeko Horie, Seita Morishita, Masanori Fukumoto, Takaki Sato and Tsunehiko Ikeda

Int. J. Mol. Sci. 2020, 21(7), 2324; https://doi.org/10.3390/ijms21072324 - 27 Mar 2020

Cited by 24 | Viewed by 4118

Abstract

Purpose: To investigate the effect of a selective aquaporin 4 (AQP4) inhibitor, 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), on the expression of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) production, as well as on the retinal edema in diabetic retina. Methods: Intravitreal injections of [...] Read more.

Purpose: To investigate the effect of a selective aquaporin 4 (AQP4) inhibitor, 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), on the expression of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) production, as well as on the retinal edema in diabetic retina. Methods: Intravitreal injections of bevacizumab, TGN-020, or phosphate-buffered saline (PBS) were performed on streptozotocin-induced diabetic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. Protein levels of VEGF from collected retinas were determined by Western blot analysis. In addition, retinal vascular leakage of Evans Blue was observed in the flat-mounted retina from the diabetic rats in the presence or absence of TGN-020. Volumetric changes of rat retinal Müller cells (TR-MUL5; transgenic rat Müller cells) and intracellular levels of ROS were determined using flow cytometry analysis of ethidium fluorescence in the presence or absence of TGN-020 or bevacizumab under physiological and high glucose conditions. Results: In the diabetic retina, the immunoreactivity and protein levels of VEGF were suppressed by TGN-020. AQP4 immunoreactivity was higher than in the control retinas and the expressions of AQP4 were co-localized with GFAP. Similarly to VEGF, AQP4 and GFAP were also suppressed by TGN-020. In the Evans Blue assay, TGN-020 decreased leakage in the diabetic retinas. In the cultured Müller cells, the increase in cell volumes and intracellular ROS production under high glucose condition were suppressed by exposure to TGN-020 as much as by exposure to bevacizumab. Conclusion: TGN-020 may have an inhibitory effect on diabetic retinal edema. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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Review

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18 pages, 1991 KiB

Open AccessReview

Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia

by Silvia Trombetti, Elena Cesaro, Rosa Catapano, Raffaele Sessa, Alessandra Lo Bianco, Paola Izzo and Michela Grosso

Int. J. Mol. Sci. 2021, 22(5), 2470; https://doi.org/10.3390/ijms22052470 - 28 Feb 2021

Cited by 37 | Viewed by 4820

Abstract

Myeloid leukemic cells are intrinsically under oxidative stress due to impaired reactive oxygen species (ROS) homeostasis, a common signature of several hematological malignancies. The present review focuses on the molecular mechanisms of aberrant ROS production in myeloid leukemia cells as well as on [...] Read more.

Myeloid leukemic cells are intrinsically under oxidative stress due to impaired reactive oxygen species (ROS) homeostasis, a common signature of several hematological malignancies. The present review focuses on the molecular mechanisms of aberrant ROS production in myeloid leukemia cells as well as on the redox-dependent signaling pathways involved in the leukemogenic process. Finally, the relevance of new chemotherapy options that specifically exert their pharmacological activity by altering the cellular redox imbalance will be discussed as an effective strategy to eradicate chemoresistant cells. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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26 pages, 1122 KiB

Open AccessReview

Modulatory Effect of Myokines on Reactive Oxygen Species in Ischemia/Reperfusion

by Márton Richárd Szabó, Márton Pipicz, Tamás Csont and Csaba Csonka

Int. J. Mol. Sci. 2020, 21(24), 9382; https://doi.org/10.3390/ijms21249382 - 09 Dec 2020

Cited by 28 | Viewed by 5109

Abstract

There is a growing body of evidence showing the importance of physical activity against acute ischemic events in various organs. Ischemia/reperfusion injury (I/R) is characterized by tissue damage as a result of restriction and subsequent restoration of blood supply to an organ. Oxidative [...] Read more.

There is a growing body of evidence showing the importance of physical activity against acute ischemic events in various organs. Ischemia/reperfusion injury (I/R) is characterized by tissue damage as a result of restriction and subsequent restoration of blood supply to an organ. Oxidative stress due to increased reactive oxygen species formation and/or insufficient antioxidant defense is considered to play an important role in I/R. Physical activity not only decreases the general risk factors for ischemia but also confers direct anti-ischemic protection via myokine production. Myokines are skeletal muscle-derived cytokines, representing multifunctional communication channels between the contracting skeletal muscle and other organs through an endocrine manner. In this review, we discuss the most prominent members of the myokines (i.e., brain-derived neurotrophic factor (BDNF), cathepsin B, decorin, fibroblast growth factors-2 and -21, follistatin, follistatin-like, insulin-like growth factor-1; interleukin-6, interleukin-7, interleukin-15, irisin, leukemia inhibitory factor, meteorin-like, myonectin, musclin, myostatin, and osteoglycin) with a particular interest in their potential influence on reactive oxygen and nitrogen species formation or antioxidant capacity. A better understanding of the mechanism of action of myokines and particularly their participation in the regulation of oxidative stress may widen their possible therapeutic use and, thereby, may support the fight against I/R. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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14 pages, 743 KiB

Open AccessReview

Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders

by Luca Pangrazzi, Luigi Balasco and Yuri Bozzi

Int. J. Mol. Sci. 2020, 21(9), 3293; https://doi.org/10.3390/ijms21093293 - 06 May 2020

Cited by 104 | Viewed by 7701

Abstract

Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research [...] Read more.

Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research in the ASD field has focused on the characterization of pathways involved in neural development and synaptic plasticity, which support the pathogenesis of this group of diseases. More recently, immune system dysfunctions have been observed in ASD. In addition, high levels of reactive oxygen species (ROS), which cause oxidative stress, are present in ASD patients. In this review, we will describe the major alterations in the expression of genes coding for enzymes involved in the ROS scavenging system, in both ASD patients and ASD mouse models. In addition, we will discuss, in the context of the most recent literature, the possibility that oxidative stress, inflammation and immune system dysfunction may be connected to, and altogether support, the pathogenesis and/or severity of ASD. Finally, we will discuss the possibility of novel treatments aimed at counteracting the interplay between ROS and inflammation in people with ASD. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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25 pages, 1202 KiB

Open AccessReview

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

by Arnab Ghosh and Natalia Shcherbik

Int. J. Mol. Sci. 2020, 21(8), 2661; https://doi.org/10.3390/ijms21082661 - 11 Apr 2020

Cited by 39 | Viewed by 4495

Abstract

Cardiovascular diseases (CVDs) are a group of disorders that affect the heart and blood vessels. Due to their multifactorial nature and wide variation, CVDs are the leading cause of death worldwide. Understanding the molecular alterations leading to the development of heart and vessel [...] Read more.

Cardiovascular diseases (CVDs) are a group of disorders that affect the heart and blood vessels. Due to their multifactorial nature and wide variation, CVDs are the leading cause of death worldwide. Understanding the molecular alterations leading to the development of heart and vessel pathologies is crucial for successfully treating and preventing CVDs. One of the causative factors of CVD etiology and progression is acute oxidative stress, a toxic condition characterized by elevated intracellular levels of reactive oxygen species (ROS). Left unabated, ROS can damage virtually any cellular component and affect essential biological processes, including protein synthesis. Defective or insufficient protein translation results in production of faulty protein products and disturbances of protein homeostasis, thus promoting pathologies. The relationships between translational dysregulation, ROS, and cardiovascular disorders will be examined in this review. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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38 pages, 1108 KiB

Open AccessReview

The Role of Reactive Oxygen Species in the Life Cycle of the Mitochondrion

by Paola Venditti and Sergio Di Meo

Int. J. Mol. Sci. 2020, 21(6), 2173; https://doi.org/10.3390/ijms21062173 - 21 Mar 2020

Cited by 71 | Viewed by 5551

Abstract

Currently, it is known that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the [...] Read more.

Currently, it is known that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. It is also known that mitochondria, because of their capacity to produce free radicals, play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including the stimulation of permeability transition pore opening. This process leads to mitoptosis and mitophagy, two sequential processes that are a universal route of elimination of dysfunctional mitochondria and is essential to protect cells from the harm due to mitochondrial disordered metabolism. To date, there is significant evidence not only that the above processes are induced by enhanced reactive oxygen species (ROS) production, but also that such production is involved in the other phases of the mitochondrial life cycle. Accumulating evidence also suggests that these effects are mediated through the regulation of the expression and the activity of proteins that are engaged in processes such as genesis, fission, fusion, and removal of mitochondria. This review provides an account of the developments of the knowledge on the dynamics of the mitochondrial population, examining the mechanisms governing their genesis, life, and death, and elucidating the role played by free radicals in such processes. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment 2.0)

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