Oxidation of proteins: Basic principles and perspectives for blood proteomics

Plants are versatile in terms of tolerance and adaptive mechanisms toward severe abiotic stresses. The most deleterious effects of abiotic stresses are the production of highly toxic species known as reactive oxygen species (ROS) and reactive nitrogen species (RNS). These species are produced in different cellular compartments within the plant body as a by-product of metabolic processes in the form of radical and nonradical species; however, their production is amplified when plants encounter abiotic stresses. These ROS and RNS molecules at low concentration act as signaling molecules but at higher concentration enforce harsh oxidative stress damaging cell protein, lipids, and nucleic acid. Thus, homeostasis of ROS and RNS is required to maintain at optimal levels to prevent damage. Plants have antioxidant system that comprises two components, i.e., enzymatic and nonenzymatic antioxidant defense system, which maintains ROS and RNS homeostasis inside cells. Thus, there is a delicate equilibrium between ROS and RNS production, and their scavenging system inside the cell, which helps the 72plant to survive from the toxic effects of these species. In this chapter, we will be discussing ROS and RNS generation, sites of production, and their vital role in acting as messenger molecules as well as inducers of oxidative damage under various abiotic stresses. Further, this chapter will focus on the mechanism of ROS production, oxidative stress, and antioxidant defense mechanisms under several stressful environmental conditions.

This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain‐Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stress in vitro than are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore result in vivo in selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A2. Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosine (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced

The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain's vascular tone's vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or those presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, potentially impacting cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. RNS, particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone under conditions of high oxidative stress. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, and explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.

Protein Oxidation in Aging, Disease, and Oxidative Stress

Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants

Cell signaling by reactive nitrogen and oxygen species in atherosclerosis

Oxidative stress has been implicated in the pathogenesis of many chronic inflammatory disorders, including respiratory diseases. In healthy individuals the production of damaging reactive oxygen species (ROS) and reactive nitrogen species (RNS) is balanced by the presence of endogenous and exogenous anti-oxidants. Oxidative stress occurs when there is an imbalance towards excessive levels of ROS and RNS when antioxidant defences are defective. However, the presence of increased ROS and RNS is not always detrimental as both are used within normal physiological processes in healthy tissues. These can be as diverse as acting as second messengers and modulating redox-sensitive intracellular signalling pathways, to regulating blood pressure and acting as defence mechanisms against pathogens. Mild and acute levels of oxidative stress can be tolerated and even adapted to. It is, however, when individuals are exposed to chronic episodes of oxidative stress that cellular damage can occur leading to pathology.

Chapter 1 - Pathophysiological, toxicological, and immunoregulatory roles of reactive oxygen and nitrogen species (RONS)

Simple SummaryThe nitric oxide donor, NCX4040, a non-steroidal anti-inflammatory-NO donor, is cytotoxic to a number of human tumors, including ovarian tumors cells. It has been shown to be safe in vivo. While the precise mechanism of action of NCX4040 is not clear at this time, NCX4040 has been reported to generate both reactive oxygen species (ROS) and reactive nitrogen species (RNS), causing significant DNA damage in tumor cells. In this study, we provide evidence that NCX4040 induces the differential induction of oxidative stress genes, inflammatory response genes (TNF, IL-1, IL-6 and COX2), DNA damage response and MAP kinase response genes in human ovarian tumor cells. Our studies strongly suggest that formation of ROS/RNS from both induction of NOX and CHAC1 which causes a significant depletion of GSH that results in oxidative stress. Furthermore, NCX4040 treatment induced TNF-dependent pathways which further increases oxidative stress in ovarian tumor cells, resulting in enhanced NCX4040-mediated cell death from apoptosis and/or ferroptosis.The nitric oxide donor, NCX4040 is a non-steroidal anti-inflammatory-NO donor and has been shown to be extremely cytotoxic to a number of human tumors, including ovarian tumors cells. We have found that NCX4040 is cytotoxic against both OVCAR-8 and its adriamycin-selected OVCAR-8 variant (NCI/ADR-RES) tumor cell lines. While the mechanism of action of NCX4040 is not entirely clear, we as well as others have shown that NCX4040 generates reactive oxygen species (ROS) and induces DNA damage in tumor cells. Recently, we have reported that NCX4040 treatment resulted in a significant depletion of cellular glutathione, and formation of both reactive oxygen and nitrogen species (ROS/RNS), resulting in oxidative stress in these tumor cells. Furthermore, our results indicated that more ROS/RNS were generated in OVCAR-8 cells than in NCI/ADR-RES cells due to increased activities of superoxide dismutase (SOD), glutathione peroxidase and transferases expressed in NCI/ADR-RES cells. Further studies suggested that NCX4040-induced cell death may be mediated by peroxynitrite formed from NCX4040 in cells. In this study we used microarray analysis following NCX4040 treatment of both OVCAR-8 and its ADR-resistant variant to identify various molecular pathways involved in NCX4040-induced cell death. Here, we report that NCX4040 treatment resulted in the differential induction of oxidative stress genes, inflammatory response genes (TNF, IL-1, IL-6 and COX2), DNA damage response and MAP kinase response genes. A mechanism of tumor cell death is proposed based on our findings where oxidative stress is induced by NCX4040 from simultaneous induction of NOX4, TNF-α and CHAC1 in tumor cell death.

Background:Myocardial preconditioning using volatile anesthetics such as isoflurane and sevoflurane have beneficial effects in decreasing morbidity in cardiac surgical patients. Studies in animal models have indicated that reactive oxygen and nitrogen species probably play a role in mediating these effects. However, data from human studies are scarce and the differential effect of sevoflurane vs. isoflurane on reactive oxygen species (ROS) and reactive nitrogen species (RNS) has not been studied extensively.Materials and Methods:Randomized clinical control trial comparing preconditioning effects of volatile agents isoflurane and sevoflurane when administered during coronary artery bypass surgeries on cardiopulmonary bypass (CPB). Serum samples were collected at 3 time points before induction, after cross clamp release and one hour after separation from CPB. Levels of oxidative stress markers and nitric oxide were analyzed in these samples.Results:Hemodynamic indices, cardio-pulmonary bypass duration, and ICU stay were similar between the groups. CKMB values 12 hours post-op were decreased in majority of patients in the sevoflurane group compared to isoflurane. Serum malondialdehyde and nitrate levels were lower with sevoflurane (P < 0.05) when compared to the isoflurane group, but no significant differences in protein carbonyl content or protein thiol content were evident between the 2 groups. Sevoflurane also prevented the decrease in total thiols during later stages of surgery.Conclusions:Volatile anesthetics, isoflurane and sevoflurane modulate oxidative and nitrosative stress during CABG. Between the two pre-conditioning agents, isoflurane seems to provide better protection during the pre-bypass period, while sevoflurane provides protection during both pre- as well as post-bypass period.

Cardiac Metallothionein Synthesis in Streptozotocin-Induced Diabetic Mice, and Its Protection against Diabetes-Induced Cardiac Injury

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are central regulators of monocyte and macrophage biology, shaping their survival, differentiation, migration, and effector functions. In monocytes and macrophages, ROS and RNS arise from endogenous sources, such as mitochondria, NADPH oxidases, and myeloperoxidase, and from exogenous stimuli including pathogens, damaged tissues, and environmental oxidants. These reactive intermediates converge on redox-sensitive pathways such as NF-κB, Nrf2/HO-1, mitochondrial ROS signalling, and the NLRP3 inflammasome, thereby integrating metabolic stress with inflammatory activation. Redox balance is a key determinant of macrophage polarization: heightened ROS and RNS production drives pro-inflammatory M1 programs, whereas tightly regulated oxidative signalling supports M2 phenotypes associated with tissue repair and resolution. In chronic inflammatory disorders, notably atherosclerosis, oxidative stress amplifies monocyte recruitment, foam-cell formation, plaque instability, and maladaptive immunometabolic responses. The aim of this review is to recapitulate the major sources and functions of ROS and RNS in monocytes and macrophages and to synthesize current evidence on how these pathways collectively maintain or disrupt immune homeostasis. We further highlight emerging therapeutic strategies, such as NOX inhibitors, mitochondrial-targeted antioxidants, and Nrf2 activators, that seek to restore redox balance and offer promising avenues for the treatment of cardiovascular and immune-mediated diseases.

This review highlights the relationship between the metabolism of reactive oxygen species (ROS), reactive nitrogen species (RNS), and H2S-reactive sulfur species (RSS). These three metabolic pathways, collectively termed reactive oxygen, nitrogen, and sulfur species (RONSS), constitute a conglomerate of reactions that function as an energy dissipation mechanism, in addition to allowing environmental signals to be transduced into cellular information. This information, in the form of proteins with posttranslational modifications or signaling metabolites derived from RONSS, serves as an inducer of many processes for redoxtasis and metabolic adjustment to the changing environmental conditions to which plants are subjected. Although it is thought that the role of reactive chemical species was originally energy dissipation, during evolution they seem to form a cluster of RONSS that, in addition to dissipating excess excitation potential or reducing potential, also fulfils essential signaling functions that play a vital role in the stress acclimation of plants. Signaling occurs by synthesizing many biomolecules that modify the activity of transcription factors and through modifications in thiol groups of enzymes. The result is a series of adjustments in plants' gene expression, biochemistry, and physiology. Therefore, we present an overview of the synthesis and functions of the RONSS, considering the importance and implications in agronomic management, particularly on the biostimulation of crops.

Significance: Reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) act as signaling molecules, regulating gene expression, enzyme activity, and physiological responses. However, excessive amounts of these molecular species can lead to deleterious effects, causing cellular damage and death. This dual nature of ROS, RNS, and RSS presents an intriguing conundrum that calls for a new paradigm. Recent Advances: Recent advancements in the study of photosynthesis have offered significant insights at the molecular level and with high temporal resolution into how the photosystem II oxygen-evolving complex manages to prevent harmful ROS production during the water-splitting process. These findings suggest that a dynamic spatiotemporal arrangement of redox reactions, coupled with strict regulation of proton transfer, is crucial for minimizing unnecessary ROS formation. Critical Issues: To better understand the multifaceted nature of these reactive molecular species in biology, it is worth considering a more holistic view that combines ecological and evolutionary perspectives on ROS, RNS, and RSS. By integrating spatiotemporal perspectives into global, cellular, and biochemical events, we discuss local pH or proton availability as a critical determinant associated with the generation and action of ROS, RNS, and RSS in biological systems. Future Directions: The concept of localized proton availability will not only help explain the multifaceted nature of these ubiquitous simple molecules in diverse systems but also provide a basis for new therapeutic strategies to manage and manipulate these reactive species in neural disorders, pathogenic diseases, and antiaging efforts.

Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. In the neurodegenerative diseases, oxidative stress has been implicated in amyotrophic lateral sclerosis, Parkinson disease, Huntington disease, and Alzheimer disease (AD). The neurodegenerative disorder receiving the most attention has been AD, in which an increase occurs in oxidation of brain lipids, carbohydrates, proteins, and DNA. Some of the products of oxidation have been found in the major histopathologic alterations in AD: the neurofibrillary tangles (NFTs) and senile plaques (reviewed in Markesbery and Carney 1 and Ceballos-Picot 2 ). These oxidative modifications are closely associated with a subtle inflammatory process in the brain in AD. Oxidative stress refers to a state in which free radicals and their products are in excess of antioxidant defense mechanisms. This imbalance can occur as a result of increased free radical production or a decrease in antioxidant defenses. Free radicals are defined as any atom or molecule that has one or more unpaired electrons in its outer shell. The reduction of molecular oxygen to water is a major source of potent radicals. The initial step in this reaction yields the superoxide radical, which produces hydrogen peroxide by addition of an electron. The reduction of hydrogen peroxide yields the highly reactive hydroxyl radical. These radicals plus singlet oxygen are called reactive oxygen species (ROS). Several reactive nitrogen species, nitric oxide, and peroxynitrite also are important modulators of oxidative stress. These free radicals and others are capable of reacting with lipids, proteins, nucleic acids, and other molecules and altering their structure and function. Oxidative stress can lead to alterations in cells with an accumulation of oxidized products such as aldehydes and isoprostanes from lipid peroxidation, protein carbonyls from protein oxidation, and base ad