EROS protein: Decoding its pivotal role in redox homeostasis and disease pathogenesis

Significance: Metformin has been proposed as a treatment for systemic lupus erythematosus (SLE). The primary target of metformin, the electron transport chain complex I in the mitochondria, is associated with redox homeostasis in immune cells, which plays a critical role in the pathogenesis of autoimmune diseases. This review addresses the evidence and knowledge gaps on whether a beneficial effect of metformin in lupus may be due to a restoration of a balanced redox state. Recent Advances: Clinical trials in SLE patients with mild-to-moderate disease activity and preclinical studies in mice have provided encouraging results for metformin. The mechanism by which this therapeutic effect was achieved is largely unknown. Metformin regulates redox homeostasis in a context-specific manner. Multiple cell types contribute to SLE, with evidence of increased mitochondrial oxidative stress in T cells and neutrophils. Critical Issues: The major knowledge gaps are whether the efficacy of metformin is linked to a restored redox homeostasis in the immune system, and if it does, in which cell types it occurs? We also need to know which patients may have a better response to metformin, and whether it corresponds to a specific mechanism? Finally, the identification of biomarkers to predict treatment outcomes would be of great value. Future Directions: Mechanistic studies must address the context-dependent pharmacological effects of metformin. Multiple cell types as well as a complex disease etiology should be considered. These studies must integrate the rapid advances made in understanding how metabolic programs direct the effector functions of immune cells. Antioxid. Redox Signal. 36, 462-479.

An imbalance between oxidants and antioxidants in the body can lead to oxidative stress, which is one of the major causes of neurodegenerative diseases. The gut microbiota contains trillions of beneficial bacteria that play an important role in maintaining redox homeostasis. In the last decade, the microbiota-gut-brain axis has emerged as a new field that has revolutionized the study of the pathology, diagnosis, and treatment of neurodegenerative diseases. Indeed, a growing number of studies have found that communication between the brain and the gut microbiota can be accomplished through the endocrine, immune, and nervous systems. Importantly, dysregulation of the gut microbiota has been strongly associated with the development of oxidative stress-mediated neurodegenerative diseases. Therefore, a deeper understanding of the relationship between the gut microbiota and redox homeostasis will help explain the pathogenesis of neurodegenerative diseases from a new perspective and provide a theoretical basis for proposing new therapeutic strategies for neurodegenerative diseases. In this review, we will describe the role of oxidative stress and the gut microbiota in neurodegenerative diseases and the underlying mechanisms by which the gut microbiota affects redox homeostasis in the brain, leading to neurodegenerative diseases. In addition, we will discuss the potential applications of maintaining redox homeostasis by modulating the gut microbiota to treat neurodegenerative diseases, which could open the door for new therapeutic approaches to combat neurodegenerative diseases.

Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Increased production of reactive oxygen species (ROS) and oxidative stress are known to play a key role in the pathogenesis of type 2 diabetes (T2D); however, the relationship between genes encoding a multi-subunit ROS-generated enzyme NADPH oxidase and disease susceptibility remains unexplored. The present pilot study investigated whether single-nucleotide polymorphisms (SNP) at the RAC1 gene (Rac family small GTPase 1), a molecular switcher of NADPH oxidase, are associated with the risk of T2D, glucose metabolism and redox homeostasis. DNA samples from 3206 unrelated Russian subjects (1579 T2D patients and 1627 controls) were genotyped for six common SNPs rs4724800, rs7784465, rs10951982, rs10238136, rs836478 and rs9374 of RAC1 using the MassArray-4 system. SNP rs7784465 was associated with an increased risk of T2D (p=.0003), and significant differences in the RAC1 haplotypes occurred between the cases and controls (p=.005). Seventeen combinations of RAC1 genotypes showed significant associations with T2D risk (FDR <0.05). Associations of RAC1 polymorphisms with T2D were modified by environmental factors such as sedentary lifestyle, psychological stresses, a dietary deficit of fresh fruits/vegetables and increased carbohydrate intake. RAC1 polymorphisms were associated with biochemical parameters in diabetics: rs7784465 (p=.015) and rs836478 (p=.028) with increased glycated haemoglobin, rs836478 (p=.005) with increased fasting blood glucose, oxidized glutathione (p=.012) and uric acid (p=.034). Haplotype rs4724800A-rs7784465C-rs10951982G-rs10238136A-rs836478C-rs9374G was strongly associated with increased levels of hydrogen peroxide (p<.0001). Thus, polymorphisms in the RAC1 gene represent novel genetic markers of type 2 diabetes, and their link with glucose metabolism and disease pathogenesis is associated with the changes in redox homeostasis.

Graphical Abstract Abstract Energy, as the main driving force of biological processes, is inextricably linked to life, which represents a continuous flow and utilization of energy. At the center of this process are mitochondria, serving as the primary source of cellular energy. An important point of mitochondrial function is the uncoupling of cellular respiration, a process that influences redox-metabolic homeostasis by modulating both energy expenditure and the production of reactive oxygen species. This is mediated by uncoupling proteins (UCPs), which are involved in the control of ATP synthesis, maintenance of redox homeostasis, thermogenesis, and the regulation of nutrient metabolism. Given their crucial role in redox regulation and energy metabolism, UCPs are under investigation for their possible role in redox-metabolic reprogramming during disease pathogenesis. This review aims to discuss UCPs in relation to the pathophysiology of metabolic diseases such as obesity, diabetes, metabolic dysfunction–associated steatotic liver disease, and cancer, with a focus on their impact on redox homeostasis in order to better understand the potential therapeutic relevance.

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.

Reactive oxygen species (ROS) are well recognized for playing a dual role as both deleterious and beneficial species. ROS are products of normal cellular metabolism and under physiological conditions, participate in maintenance of cellular 'redox homeostasis. Overproduction of ROS, results in oxidative stress. Oxidative stress is a deleterious process that leads to lung damage and consequently to various disease states. The lung is a highly specialized organ that facilitates uptake of oxygen and release of carbon dioxide. Persistent inhalation of the invading pathogens or toxic agents may result in overwhelming production of ROS. Oxidants initiate a number of pathologic processes, including inflammation of the airways, which may contribute to the pathogenesis and/or exacerbation of airways disease. During inflammation, enhanced ROS production may induce recurring DNA damage, inhibition of apoptosis, and activation of protooncogenes by initiating signal transduction pathways. Therefore, it is conceivable that chronic inflammation-induced production of ROS in the lung may predispose individuals to lung diseases. In this review, we discuss mechanisms of oxidant stress in the lung, the role of oxidants in lung disease pathogenesis and exacerbation.

Free radicals and antioxidants in normal physiological functions and human disease

Redox biology is a rapidly developing area of research due to the recent evidence for general importance of redox control for numerous cellular functions under both physiological and pathophysiological conditions. Understanding of redox homeostasis is particularly relevant to the understanding of the aging process. The link between reactive oxygen species (ROS) and accumulation of age-associated oxidative damage to macromolecules is well established, but remains controversial and applies only to a subset of experimental models. In addition, recent studies show that ROS may function as signaling molecules and that dysregulation of this process may also be linked to aging. Many protein factors and pathways that control ROS production and scavenging, as well as those that regulate cellular redox homeostasis, have been identified. However, much less is known about the mechanisms by which redox signaling pathways influence longevity. In this review, we discuss recent advances in the understanding of the molecular basis for the role of redox signaling in aging. Recent studies allowed identification of previously uncharacterized redox components and revealed complexity of redox signaling pathways. It would be important to identify functions of these components and elucidate how distinct redox pathways are integrated with each other to maintain homeostatic balance. Further characterization of processes that coordinate redox signaling, redox homeostasis, and stress response pathways should allow researchers to dissect how their dysregulation contributes to aging and pathogenesis of various age-related diseases, such as diabetes, cancer and neurodegeneration.

Maintenance of integrity and function of the gastric mucosa (GM) requires a high regeneration rate of epithelial cells during the whole life span. The health of the gastric epithelium highly depends on redox homeostasis, antioxidant defense, and activity of detoxifying systems within the cells, as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular, second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in physiological adaptive reactions and signaling, but they are also thought to be implicated in the pathogenesis of numerous gastric diseases. Molecular mechanisms and consequences of increased production of HNE, and its protein adducts, in response to stressors during acute and chronic gastric injury, are well studied. However, several important issues related to the role of HNE in gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, or the relevance of antioxidants for HNE-related redox homeostasis in GM, still need more studies and new comprehensive approaches. In this regard, preclinical studies and clinical intervention trials are required, which should also include the use of state-of-the-art analytical techniques, such as HNE determination by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), as well as modern mass-spectroscopy methods.

The regulation of protein acetylation influences the redox homeostasis to protect the heart

Reactive oxygen species (ROS) generated within cells or, more generally, in a tissue environment, may easily turn into a source of cell and tissue injury. Aerobic organisms have developed evolutionarily conserved mechanisms and strategies to carefully control the generation of ROS and other oxidative stress-related radical or non-radical reactive intermediates (that is, to maintain redox homeostasis), as well as to 'make use' of these molecules under physiological conditions as tools to modulate signal transduction, gene expression and cellular functional responses (that is, redox signalling). However, a derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, can play a significant role in the pathogenesis of major human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis. This review has been designed to first offer a critical introduction to current knowledge in the field of redox research in order to introduce readers to the complexity of redox signalling and redox homeostasis. This will include ready-to-use key information and concepts on ROS, free radicals and oxidative stress-related reactive intermediates and reactions, sources of ROS in mammalian cells and tissues, antioxidant defences, redox sensors and, more generally, the major principles of redox signalling and redox-dependent transcriptional regulation of mammalian cells. This information will serve as a basis of knowledge to introduce the role of ROS and other oxidative stress-related intermediates in contributing to essential events, such as the induction of cell death, the perpetuation of chronic inflammatory responses, fibrogenesis and much more, with a major focus on hepatic chronic wound healing and liver fibrogenesis.

Reactive oxygen species (ROS) are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions. This review focuses on the antioxidant system’s roles in maintaining redox homeostasis. Especially, glutathione (GSH) is the most important thiol-containing molecule, as it functions as a redox buffer, antioxidant, and enzyme cofactor against oxidative stress. In the brain, dysfunction of GSH synthesis leading to GSH depletion exacerbates oxidative stress, which is linked to a pathogenesis of aging-related neurodegenerative diseases. Excitatory amino acid carrier 1 (EAAC1) plays a pivotal role in neuronal GSH synthesis. The regulatory mechanism of EAAC1 is also discussed.

Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury.

Reactive oxygen species (ROS; e.g., superoxide [O2•-] and hydrogen peroxide [H2O2]) and reactive nitrogen species (RNS; e.g., nitric oxide [NO•]) at the physiological level function as signaling molecules that mediate many biological responses, including cell proliferation, migration, differentiation, and gene expression. By contrast, excess ROS/RNS, a consequence of dysregulated redox homeostasis, is a hallmark of cardiovascular disease. Accumulating evidence suggests that both ROS and RNS regulate various metabolic pathways and enzymes. Recent studies indicate that cells have mechanisms that fine-tune ROS/RNS levels by tight regulation of metabolic pathways, such as glycolysis and oxidative phosphorylation. The ROS/RNS-mediated inhibition of glycolytic pathways promotes metabolic reprogramming away from glycolytic flux toward the oxidative pentose phosphate pathway to generate nicotinamide adenine dinucleotide phosphate (NADPH) for antioxidant defense. This review summarizes our current knowledge of the mechanisms by which ROS/RNS regulate metabolic enzymes and cellular metabolism and how cellular metabolism influences redox homeostasis and the pathogenesis of disease. A full understanding of these mechanisms will be important for the development of new therapeutic strategies to treat diseases associated with dysregulated redox homeostasis and metabolism. Antioxid. Redox Signal. 34, 1319-1354.