Oxidative Stress and Autophagy in Cardiac Disease, Neurological Disorders, Aging and Cancer

Autophagy is a catalytic process of the bulk degradation of long-lived cellular components, ultimately resulting in lysosomal digestion within mature cytoplasmic compartments known as autophagolysosomes. Autophagy serves many functions in the cell, including maintaining cellular homeostasis, a means of cell survival during stress (e.g., nutrient deprivation or starvation) or conversely as a mechanism for cell death. Increased reactive oxygen species (ROS) production and the resulting oxidative cell stress that occurs in many disease states has been shown to induce autophagy. The following review focuses on the roles that autophagy plays in response to the ROS generated in several diseases.

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Drug-Induced Oxidative Stress and Toxicity

Journal of Toxicology ◽

10.1155/2012/645460 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 269

Author(s):

Damian G. Deavall ◽

Elizabeth A. Martin ◽

Judith M. Horner ◽

Ruth Roberts

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Oxygen Radicals ◽

Oxygen Species ◽

Cardiac Damage ◽

Drug Induced ◽

Cellular Targets ◽

Disease States ◽

Normal Metabolism ◽

Cellular Components

Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

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Intracellular Sources of ROS/H2O2 in Health and Neurodegeneration: Spotlight on Endoplasmic Reticulum

Cells ◽

10.3390/cells10020233 ◽

2021 ◽

Vol 10 (2) ◽

pp. 233

Author(s):

Tasuku Konno ◽

Eduardo Pinho Melo ◽

Joseph E. Chambers ◽

Edward Avezov

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Hydrogen Peroxide ◽

Endoplasmic Reticulum ◽

Neurodegenerative Diseases ◽

Antioxidative Enzymes ◽

Redox Reactions ◽

Ros Production ◽

Oxygen Species ◽

Specific Target

Reactive oxygen species (ROS) are produced continuously throughout the cell as products of various redox reactions. Yet these products function as important signal messengers, acting through oxidation of specific target factors. Whilst excess ROS production has the potential to induce oxidative stress, physiological roles of ROS are supported by a spatiotemporal equilibrium between ROS producers and scavengers such as antioxidative enzymes. In the endoplasmic reticulum (ER), hydrogen peroxide (H2O2), a non-radical ROS, is produced through the process of oxidative folding. Utilisation and dysregulation of H2O2, in particular that generated in the ER, affects not only cellular homeostasis but also the longevity of organisms. ROS dysregulation has been implicated in various pathologies including dementia and other neurodegenerative diseases, sanctioning a field of research that strives to better understand cell-intrinsic ROS production. Here we review the organelle-specific ROS-generating and consuming pathways, providing evidence that the ER is a major contributing source of potentially pathologic ROS.

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Hyperglycemia Induces Generation of Reactive Oxygen Species and Accelerates Apoptotic Cell Death in Salivary Gland Cells

Pathobiology ◽

10.1159/000512639 ◽

2021 ◽

pp. 1-8

Author(s):

Naoyuki Matsumoto ◽

Daisuke Omagari ◽

Ryoko Ushikoshi-Nakayama ◽

Tomoe Yamazaki ◽

Hiroko Inoue ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Salivary Gland ◽

Tissue Injury ◽

Ros Production ◽

Oxygen Species ◽

Saliva Secretion ◽

Salivary Gland Tissue ◽

Gland Tissue

Introduction: Type-2 diabetes mellitus (T2DM) is associated with several systemic vascular symptoms and xerostomia. It is considered that hyperglycemia-induced polyuria and dehydration cause decreased body-water volume, leading to decreased saliva secretion and, ultimately, xerostomia. In T2DM, increased production of reactive oxygen species (ROS) causes tissue damage to vascular endothelial cells as well as epithelial tissue, including pancreas and cornea. Hence, a similar phenomenon may occur in other tissues and glands in a hyperglycemic environment. Methods: Salivary gland tissue injury was examined, using T2DM model mouse (db/db). Transferase‐mediated dUTP nick‐end labeling (TUNEL) was conducted to evaluate tissue injury. The levels of malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine, Bax/Bcl-2 ratio were measured as indicator of oxidative stress. Moreover, in vitro ROS production and cell injury was evaluated by mouse salivary gland-derived normal cells under high-glucose condition culture. Results: In vivo and in vitro analysis showed a higher percentage of TUNEL-positive cells and higher levels of MDA and 8-hydroxy-2′-deoxyguanosine in salivary gland tissue of db/db mice. This suggests damage of saliva secretion-associated lipids and DNA by hyperglycemic-induced oxidative stress. To analyze the mechanism by which hyperglycemia promotes ROS production, mouse salivary gland-derived cells were isolated. The cell culture with high-glucose medium enhanced ROS production and promotes apoptotic and necrotic cell death. Conclusion: These findings suggest a novel mechanism whereby hyperglycemic-induced ROS production promotes salivary gland injury, resulting in hyposalivation.

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The essential iron-sulfur protein Rli1 is an important target accounting for inhibition of cell growth by reactive oxygen species

Molecular Biology of the Cell ◽

10.1091/mbc.e12-05-0413 ◽

2012 ◽

Vol 23 (18) ◽

pp. 3582-3590 ◽

Cited By ~ 49

Author(s):

Alawiah Alhebshi ◽

Theodora C. Sideri ◽

Sara L. Holland ◽

Simon V. Avery

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Ribosomal Subunit ◽

Reactive Oxygen ◽

Oxygen Species ◽

Sulfur Protein ◽

Iron Sulfur Protein ◽

Cellular Components

Oxidative stress mediated by reactive oxygen species (ROS) is linked to degenerative conditions in humans and damage to an array of cellular components. However, it is unclear which molecular target(s) may be the primary “Achilles’ heel” of organisms, accounting for the inhibitory action of ROS. Rli1p (ABCE1) is an essential and highly conserved protein of eukaryotes and archaea that requires notoriously ROS-labile cofactors (Fe-S clusters) for its functions in protein synthesis. In this study, we tested the hypothesis that ROS toxicity is caused by Rli1p dysfunction. In addition to being essential, Rli1p activity (in nuclear ribosomal-subunit export) was shown to be impaired by mild oxidative stress in yeast. Furthermore, prooxidant resistance was decreased by RLI1 repression and increased by RLI1 overexpression. This Rlip1 dependency was abolished during anaerobicity and accentuated in cells expressing a FeS cluster–defective Rli1p construct. The protein's FeS clusters appeared ROS labile during in vitro incubations, but less so in vivo. Instead, it was primarily55FeS-cluster supply to Rli1p that was defective in prooxidant-exposed cells. The data indicate that, owing to its essential nature but dependency on ROS-labile FeS clusters, Rli1p function is a primary target of ROS action. Such insight could help inform new approaches for combating oxidative stress–related disease.

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The Characterization of TA-289, a Novel Antifungal from Fusarium sp.

10.26686/wgtn.16992670 ◽

2021 ◽

Author(s):

◽

Natelle C H Quek

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Cell Cycle ◽

Cell Death ◽

Reactive Oxygen ◽

Chemical Diversity ◽

Mitochondrial Morphology ◽

Ros Production ◽

Oxygen Species ◽

Wild Type

Natural products offer vast structural and chemical diversity highly sought after in drug discovery research. Saccharomyces cerevisiae makes an ideal model eukaryotic organism for drug mode-of-action studies owing to ease of growth, sophistication of genetic tools and overall homology to higher eukaryotes. Equisetin and a closely related novel natural product, TA-289, are cytotoxic to fermenting yeast, but seemingly less so when yeast actively respire. Cell cycle analyses by flow cytometry revealed a cell cycle block at S-G2/M phase caused by TA-289; previously described oxidative stress-inducing compounds causing cell cycle delay led to further investigation in the involvement of equisetin and TA-289 in mitochondrial-mediated generation of reactive oxygen species. Chemical genomic profiling involving genome-wide scans of yeast deletion mutant strains for TA-289 sensitivity revealed sensitization of genes involved in the mitochondria, DNA damage repair and oxidative stress responses, consistent with a possible mechanism-of-action at the mitochondrion. Flow cytometric detection of reactive oxygen species (ROS) generation caused by TA-289 suggests that the compound may induce cell death via ROS production. The generation of a mutant strain resistant to TA-289 also displayed resistance to a known oxidant, H2O2, at concentrations that were cytotoxic to wild-type cells. The resistant mutant displayed a higher basal level of ROS production compared to the wild-type parent, indicating that the resistance mutation led to an up-regulation of antioxidant capacity which provides cell survival in the presence of TA-289. Yeast mitochondrial morphology was visualized by confocal light microscopy, where it was observed that cells treated with TA-289 displayed abnormal mitochondria phenotypes, further indicating that the compound is acting primarily at the mitochondrion. Similar effects observed with equisetin treatment suggest that both compounds share the same mechanism, eliciting cell death via ROS production in the mitochondrial respiratory chain.

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Comparative Reactive Oxygen Species (ROS) Content among Various Flavored Disposable Vape Bars, including Cool (Iced) Flavored Bars

Toxics ◽

10.3390/toxics9100235 ◽

2021 ◽

Vol 9 (10) ◽

pp. 235

Author(s):

Shaiesh Yogeswaran ◽

Thivanka Muthumalage ◽

Irfan Rahman

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Health Effects ◽

Reactive Oxygen ◽

Ros Production ◽

Oxygen Species ◽

Aerosol Generator ◽

Pulmonary Cells ◽

Single Puff ◽

Insight Into

Studies have shown that aerosols generated from flavored e-cigarettes contain Reactive Oxygen Species (ROS), promoting oxidative stress-induced damage within pulmonary cells. Our lab investigated the ROS content of e-cigarette vapor generated from disposable flavored e-cigarettes (vape bars) with and without nicotine. Specifically, we analyzed vape bars belonging to multiple flavor categories (Tobacco, Minty Fruit, Fruity, Minty/Cool (Iced), Desserts, and Drinks/Beverages) manufactured by various vendors and of different nicotine concentrations (0–6.8%). Aerosols from these vape bars were generated via a single puff aerosol generator; these aerosols were then individually bubbled through a fluorogenic solution to semi-quantify ROS generated by these bars in H2O2 equivalents. We compared the ROS levels generated by each vape bar as an indirect determinant of their potential to induce oxidative stress. Our results showed that ROS concentration (μM) within aerosols produced from these vape bars varied significantly among different flavored vape bars and identically flavored vape bars with varying nicotine concentrations. Furthermore, our results suggest that flavoring chemicals and nicotine play a differential role in generating ROS production in vape bar aerosols. Our study provides insight into the differential health effects of flavored vape bars, in particular cool (iced) flavors, and the need for their regulation.

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Modulators of Oxidative Stress: Chemical and Pharmacological Aspects

Antioxidants ◽

10.3390/antiox9080657 ◽

2020 ◽

Vol 9 (8) ◽

pp. 657 ◽

Cited By ~ 2

Author(s):

Luciano Saso ◽

Hande Gürer-Orhan ◽

Višnja Stepanić

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Ros Production ◽

Oxygen Species ◽

Antioxidant Proteins

Oxidative stress is represented as an imbalance between reactive oxygen species (ROS) production and the response of antioxidant proteins [...]

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The Mitochondria: A Target of Polyphenols in the Treatment of Diabetic Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms21144962 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4962 ◽

Cited By ~ 3

Author(s):

Humna Bhagani ◽

Suzanne A. Nasser ◽

Ali Dakroub ◽

Ahmed F. El-Yazbi ◽

Assaad A. Eid ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Glucose Metabolism ◽

Protective Effect ◽

Diabetic Cardiomyopathy ◽

Mitochondrial Biogenesis ◽

Ventricular Dysfunction ◽

Therapeutic Targets ◽

Ros Production ◽

Oxygen Species

Diabetic cardiomyopathy (DCM) is a constellation of symptoms consisting of ventricular dysfunction and cardiomyocyte disarray in the presence of diabetes. The exact cause of this type of cardiomyopathy is still unknown; however, several processes involving the mitochondria, such as lipid and glucose metabolism, reactive oxygen species (ROS) production, apoptosis, autophagy and mitochondrial biogenesis have been implicated. In addition, polyphenols have been shown to improve the progression of diabetes. In this review, we discuss some of the mechanisms by which polyphenols, particularly resveratrol, play a role in slowing the progression of DCM. The most important intermediates by which polyphenols exert their protective effect include Bcl-2, UCP2, SIRT-1, AMPK and JNK1. Bcl-2 acts to attenuate apoptosis, UCP2 decreases oxidative stress, SIRT-1 increases mitochondrial biogenesis and decreases oxidative stress, AMPK increases autophagy, and JNK1 decreases apoptosis and increases autophagy. Our dissection of these molecular players aims to provide potential therapeutic targets for the treatment of DCM.

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Survival Signaling by C-RAF: Mitochondrial Reactive Oxygen Species and Ca2+ Are Critical Targets

Molecular and Cellular Biology ◽

10.1128/mcb.00683-07 ◽

2008 ◽

Vol 28 (7) ◽

pp. 2304-2313 ◽

Cited By ~ 31

Author(s):

Andrey V. Kuznetsov ◽

Julija Smigelskaite ◽

Christine Doblander ◽

Manickam Janakiraman ◽

Martin Hermann ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Cell Death ◽

Reactive Oxygen ◽

Ros Production ◽

Oxygen Species ◽

Mitochondrial Reactive Oxygen Species ◽

Mitochondrial Ros ◽

Survival Signaling ◽

First Time

ABSTRACT Survival signaling by RAF occurs through largely unknown mechanisms. Here we provide evidence for the first time that RAF controls cell survival by maintaining permissive levels of mitochondrial reactive oxygen species (ROS) and Ca2+. Interleukin-3 (IL-3) withdrawal from 32D cells resulted in ROS production, which was suppressed by activated C-RAF. Oncogenic C-RAF decreased the percentage of apoptotic cells following treatment with staurosporine or the oxidative stress-inducing agent tert-butyl hydroperoxide. However, it was also the case that in parental 32D cells growing in the presence of IL-3, inhibition of RAF signaling resulted in elevated mitochondrial ROS and Ca2+ levels. Cell death is preceded by a ROS-dependent increase in mitochondrial Ca2+, which was absent from cells expressing transforming C-RAF. Prevention of mitochondrial Ca2+ overload after IL-3 deprivation increased cell viability. MEK was essential for the mitochondrial effects of RAF. In summary, our data show that survival control by C-RAF involves controlling ROS production, which otherwise perturbs mitochondrial Ca2+ homeostasis.

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Apigenin induces oxidative stress in mouse Sertoli TM4 cells

Veterinary World ◽

10.14202/vetworld.2021.3132-3137 ◽

2021 ◽

pp. 3132-3137

Author(s):

Sathaporn Jittapalapong ◽

Thapanee Poompoung ◽

Samak Sutjarit

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Lactate Dehydrogenase ◽

Cell Viability ◽

Sertoli Cells ◽

Environmental Toxicants ◽

Ros Production ◽

Oxygen Species ◽

Estrogenic Compound ◽

Ldh Activity

Background and Aim: Apigenin (API) is an estrogenic compound found in many plants. Sertoli cells reside in the testis and are a key target of environmental toxicants. This study aimed to examine the cytotoxicity, especially oxidative stress of API in mouse Sertoli TM4 cells. Materials and Methods: Mouse Sertoli TM4 cells were treated with 50 and 100 μM API for 48 h. Cell viability, lactate dehydrogenase (LDH) activities, glutathione reductase (GR) activities, production of reactive oxygen species (ROS), and malondialdehyde (MDA) levels were evaluated using various assays. Results: Treatment with API at both 50 and 100 μM decreased viability and GR activity but increased LDH activity, ROS production, and MDA levels in mouse Sertoli TM4 cells. Conclusion: Exposure to API induced oxidative stress in mouse Sertoli TM4 cells.

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