Involvement of oxidative stress response genes in redox homeostasis, the level of reactive oxygen species, and ageing in

AbstractMAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.

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Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling

Blood ◽

10.1182/blood-2013-04-491944 ◽

2013 ◽

Vol 122 (19) ◽

pp. 3322-3330 ◽

Cited By ~ 93

Author(s):

Paul S. Hole ◽

Joanna Zabkiewicz ◽

Chinmay Munje ◽

Zarabeth Newton ◽

Lorna Pearn ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Stress Response ◽

Reactive Oxygen ◽

Oxidative Stress Response ◽

Antioxidant Defenses ◽

Stress Signaling ◽

Oxygen Species ◽

Key Points ◽

P38mapk Signaling

Key Points More than 60% of primary AML blasts constitutively produce high levels of NOX-derived reactive oxygen species (ROS), which drives AML proliferation. High ROS AMLs show depleted antioxidant defenses but evade the oxidative stress response through suppression of p38MAPK signaling.

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ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages

Journal of Biological Chemistry ◽

10.1074/jbc.m608083200 ◽

2006 ◽

Vol 282 (5) ◽

pp. 2871-2879 ◽

Cited By ~ 461

Author(s):

Cristiane M. Cruz ◽

Alessandra Rinna ◽

Henry Jay Forman ◽

Ana L. M. Ventura ◽

Pedro M. Persechini ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Stress Response ◽

Proinflammatory Cytokines ◽

Reactive Oxygen ◽

Oxidative Stress Response ◽

Oxygen Species

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Dengue Virus Targets Nrf2 for NS2B3-Mediated Degradation Leading to Enhanced Oxidative Stress and Viral Replication

Journal of Virology ◽

10.1128/jvi.01551-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Matteo Ferrari ◽

Alessandra Zevini ◽

Enrico Palermo ◽

Michela Muscolini ◽

Magdalini Alexandridi ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Dengue Virus ◽

Redox Homeostasis ◽

Reactive Oxygen ◽

Hemorrhagic Fever ◽

Denv Infection ◽

Progressive Increase ◽

Severe Dengue ◽

Oxygen Species

ABSTRACT Dengue virus (DENV) is a mosquito-borne virus that infects upward of 300 million people annually and has the potential to cause fatal hemorrhagic fever and shock. While the parameters contributing to dengue immunopathogenesis remain unclear, the collapse of redox homeostasis and the damage induced by oxidative stress have been correlated with the development of inflammation and progression toward the more severe forms of disease. In the present study, we demonstrate that the accumulation of reactive oxygen species (ROS) late after DENV infection (>24 hpi) resulted from a disruption in the balance between oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. The DENV NS2B3 protease complex strategically targeted Nrf2 for degradation in a proteolysis-independent manner; NS2B3 licensed Nrf2 for lysosomal degradation. Impairment of the Nrf2 regulator by the NS2B3 complex inhibited the antioxidant gene network and contributed to the progressive increase in ROS levels, along with increased virus replication and inflammatory or apoptotic gene expression. By 24 hpi, when increased levels of ROS and antiviral proteins were observed, it appeared that the proviral effect of ROS overcame the antiviral effects of the interferon (IFN) response. Overall, these studies demonstrate that DENV infection disrupts the regulatory interplay between DENV-induced stress responses, Nrf2 antioxidant signaling, and the host antiviral immune response, thus exacerbating oxidative stress and inflammation in DENV infection. IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen that threatens 2.5 billion people in more than 100 countries annually. Dengue infection induces a spectrum of clinical symptoms, ranging from classical dengue fever to severe dengue hemorrhagic fever or dengue shock syndrome; however, the complexities of DENV immunopathogenesis remain controversial. Previous studies have reported the importance of the transcription factor Nrf2 in the control of redox homeostasis and antiviral/inflammatory or death responses to DENV. Importantly, the production of reactive oxygen species and the subsequent stress response have been linked to the development of inflammation and progression toward the more severe forms of the disease. Here, we demonstrate that DENV uses the NS2B3 protease complex to strategically target Nrf2 for degradation, leading to a progressive increase in oxidative stress, inflammation, and cell death in infected cells. This study underlines the pivotal role of the Nrf2 regulatory network in the context of DENV infection.

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Reactive Oxygen Species in Venous Thrombosis

International Journal of Molecular Sciences ◽

10.3390/ijms21061918 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1918 ◽

Cited By ~ 7

Author(s):

Clemens Gutmann ◽

Richard Siow ◽

Adam M. Gwozdz ◽

Prakash Saha ◽

Alberto Smith

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Venous Thrombosis ◽

Second Messengers ◽

Redox Homeostasis ◽

Reactive Oxygen ◽

Oxygen Species ◽

Effector Cells ◽

Systemic Oxidative Stress ◽

The Complement System

Reactive oxygen species (ROS) have physiological roles as second messengers, but can also exert detrimental modifications on DNA, proteins and lipids if resulting from enhanced generation or reduced antioxidant defense (oxidative stress). Venous thrombus (DVT) formation and resolution are influenced by ROS through modulation of the coagulation, fibrinolysis, proteolysis and the complement system, as well as the regulation of effector cells such as platelets, endothelial cells, erythrocytes, neutrophils, mast cells, monocytes and fibroblasts. Many conditions that carry an elevated risk of venous thrombosis, such as the Antiphospholipid Syndrome, have alterations in their redox homeostasis. Dietary and pharmacological antioxidants can modulate several important processes involved in DVT formation, but their overall effect is unknown and there are no recommendations regarding their use. The development of novel antioxidant treatments that aim to abrogate the formation of DVT or promote its resolution will depend on the identification of targets that enable ROS modulation confined to their site of interest in order to prevent off-target effects on physiological redox mechanisms. Subgroups of patients with increased systemic oxidative stress might benefit from unspecific antioxidant treatment, but more clinical studies are needed to bring clarity to this issue.

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Redox Regulation and Oxidative Stress: The Particular Case of the Stallion Spermatozoa

Antioxidants ◽

10.3390/antiox8110567 ◽

2019 ◽

Vol 8 (11) ◽

pp. 567 ◽

Cited By ~ 11

Author(s):

Fernando J. Peña ◽

Cristian O’Flaherty ◽

José M. Ortiz Rodríguez ◽

Francisco E. Martín Cano ◽

Gemma L. Gaitskell-Phillips ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Redox Regulation ◽

Redox Homeostasis ◽

Reactive Oxygen ◽

Mitochondrial Activity ◽

Oxygen Species ◽

Redox Biology ◽

Major Interest ◽

And Oxidative Stress

Redox regulation and oxidative stress have become areas of major interest in spermatology. Alteration of redox homeostasis is recognized as a significant cause of male factor infertility and is behind the damage that spermatozoa experience after freezing and thawing or conservation in a liquid state. While for a long time, oxidative stress was just considered an overproduction of reactive oxygen species, nowadays it is considered as a consequence of redox deregulation. Many essential aspects of spermatozoa functionality are redox regulated, with reversible oxidation of thiols in cysteine residues of key proteins acting as an “on–off” switch controlling sperm function. However, if deregulation occurs, these residues may experience irreversible oxidation and oxidative stress, leading to malfunction and ultimately death of the spermatozoa. Stallion spermatozoa are “professional producers” of reactive oxygen species due to their intense mitochondrial activity, and thus sophisticated systems to control redox homeostasis are also characteristic of the spermatozoa in the horse. As a result, and combined with the fact that embryos can easily be collected in this species, horses are a good model for the study of redox biology in the spermatozoa and its impact on the embryo.

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The copper chaperone CcsA coupling with superoxide dismutase SodA mediates oxidative stress response in Aspergillus fumigatus

Applied and Environmental Microbiology ◽

10.1128/aem.01013-21 ◽

2021 ◽

Author(s):

Wenlong Du ◽

Pengfei Zhai ◽

Shuai Liu ◽

Yuanwei Zhang ◽

Ling Lu

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Stress Response ◽

Aspergillus Fumigatus ◽

Fungal Pathogens ◽

Oxidative Stress Response ◽

Superoxide Dismutases ◽

Oxygen Species ◽

Oxidative Response

Superoxide dismutases (SODs) are important metalloenzymes that protect fungal pathogens against the toxic effects of reactive oxygen species (ROS) generated by host defense mechanisms during the infection process. The activation of Cu/Zn-SOD1 is found to be dependent on its c haperone Ccs1 ( c opper c haperone for S OD1). However, the role of Ccs1 ortholog in the human pathogen Aspergillus fumigatus and how these SODs coordinate to mediate oxidative stress response remain elusive. Here, we demonstrated that A. fumigatus CcsA, a Saccharomyces cerevisiae Ccs1 ortholog, is required for cells in response to oxidative response and the activation of Sod1. Deletion of ccsA resulted in increased ROS accumulation and enhanced sensitivity to oxidative stress due to loss of SodA activity. Molecular characterization of CcsA revealed that the conserved CXC motif is required not only for the physical interaction with SodA but also for the oxidative stress adaption. Notably, addition of Mn 2+ or overexpression of cytoplasmic Mn-SodC could rescue the defects of the ccsA or sodA deletion mutant, indicating the important role of Mn 2+ and Mn-SodC in ROS detoxification; however, deletion of CcsA-SodA complex could not affect A. fumigatus virulence. Collectively, our findings demonstrate that CcsA functions as a Cu/Zn-Sod1 chaperone that participates in the adaptation to oxidative stress in A. fumigatus and provide a better understanding of the CcsA-SodA complex-mediated oxidative stress response in filamentous fungi. IMPORTANCE Reactive oxygen species (ROS) produced by phagocytes have been reported to participate in the killing of fungal pathogens. Superoxide dismutases (SODs) are considered to be the first defense line against superoxide anions. Characterizing the regulatory mechanisms of SOD activation is important for understanding how fungi adapt to oxidative stress in hosts. Our findings demonstrated that CcsA functions as a SodA chaperone in A. fumigatus and that the conserved CXC motif within CcsA is required for its interaction with SodA and the CcsA-SodA-mediated oxidative response. These data may provide new insights into how fungal pathogens adapt to oxidative stress via the CcsA-SodA complex.

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WIP Modulates Oxidative Stress through NRF2/KEAP1 in Glioblastoma Cells

Antioxidants ◽

10.3390/antiox9090773 ◽

2020 ◽

Vol 9 (9) ◽

pp. 773

Author(s):

Maribel Escoll ◽

Diego Lastra ◽

Natalia Robledinos-Antón ◽

Francisco Wandosell ◽

Inés María Antón ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Redox Homeostasis ◽

Reactive Oxygen ◽

Oxygen Species ◽

Interacting Protein ◽

Therapeutic Implications ◽

Cancer Cell Survival ◽

Autophagic Degradation ◽

Syndrome Protein

Due to their high metabolic rate, tumor cells produce exacerbated levels of reactive oxygen species that need to be under control. Wiskott–Aldrich syndrome protein (WASP)-interacting protein (WIP) is a scaffold protein with multiple yet poorly understood functions that participates in tumor progression and promotes cancer cell survival. However, its participation in the control of oxidative stress has not been addressed yet. We show that WIP depletion increases the levels of reactive oxygen species and reduces the levels of transcription factor NRF2, the master regulator of redox homeostasis. We found that WIP stabilizes NRF2 by restraining the activity of its main NRF2 repressor, the E3 ligase adapter KEAP1, because the overexpression of a NRF2ΔETGE mutant that is resistant to targeted proteasome degradation by KEAP1 or the knock-down of KEAP1 maintains NRF2 levels in the absence of WIP. Mechanistically, we show that the increased KEAP1 activity in WIP-depleted cells is not due to the protection of KEAP1 from autophagic degradation, but is dependent on the organization of the Actin cytoskeleton, probably through binding between KEAP1 and F-Actin. Our study provides a new role of WIP in maintaining the oxidant tolerance of cancer cells that may have therapeutic implications.

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