Host–parasite oxidative arms race: who will win?

Lymphoma is a blood cancer comprising various subtypes. Although effective therapies are available, some patients fail to respond to treatment and can suffer from side effects. Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, are known to enhance cancer cell survival, with thioredoxin reductase (TrxR) recently reported as a potential anticancer target. Since the GSH system can compensate for some Trx system functions, we investigated its response in three lymphoma cell lines after inhibiting TrxR activity with [Au(d2pype)2]Cl, a known TrxR inhibitor. [Au(d2pype)2]Cl increased intracellular reactive oxygen species (ROS) levels and induced caspase-3 activity leading to cell apoptosis through inhibiting both TrxR and glutathione peroxidase (Gpx) activity. Expression of the tumour suppresser gene TXNIP increased, while GPX1 and GPX4 expression, which are related to poor prognosis of lymphoma patients, decreased. Unlike SUDHL2 and SUDHL4 cells, which exhibited a decreased GSH/GSSG ratio after treatment, in KMH2 cells the ratio remained unchanged, while glutathione reductase and glutaredoxin expression increased. Since KMH2 cells were less sensitive to treatment with [Au(d2pype)2]Cl, the GSH system may play a role in protecting cells from apoptosis after TrxR inhibition. Overall, our study demonstrates that inhibition of TrxR represents a valid therapeutic approach for lymphoma.

Androgenic Regulation of Oxidative Stress in the Rat Prostate: Involvement of NAD(P)H Oxidases and Antioxidant Defense Machinery during Prostatic Involution and Regrowth

The glutathione system includes reduced (GSH) and oxidized (GSSG) forms of glutathione; the enzymes required for its synthesis and recycling, such as gamma-glutamate cysteine ligase (γ-GCL), glutathione synthetase (GS), glutathione reductase (GSR) and gamma glutamyl transpeptidase (γ-GGT); and the enzymes required for its use in metabolism and in mechanisms of defense against free radical-induced oxidative damage, such as glutathione s-transferases (GSTs) and glutathione peroxidases (GPxs). Glutathione functions in the central nervous system (CNS) include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. A common pathological hallmark in various neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's and Parkinson's diseases is the increase in oxidative stress and the failure of antioxidant systems, such as the decrease in the GSH content. The administration of exogenous neurohormone melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of GSH and the expression and activities of the GSH-related enzymes including γ-GCL, GPxs, and GSR. The exact mechanisms by which melatonin regulates the glutathione system are not fully understood. The main purpose of this short review is to discuss evidence relating to the potential common modulation signals between the glutathione system and melatonin in the CNS. The potential regulatory mechanisms and interactions between neurons and non-neuronal cells are also discussed.

Methionine is an essential sulfur-containing amino acid. To elucidate the influence of l-methionine on activation of the nuclear factor erythroid 2-related factor 2-antioxidant responsive element (Nrf2-ARE) antioxidant pathway to stimulate the endogenous antioxidant activity for depressing reactive oxygen species (ROS)-derived oxidative stress, male Wistar rats were orally administered l-methionine daily for 14 days. With the intake of l-methionine, Nrf2 was activated by l-methionine through depressing Keap1 and Cul3, resulting in upregulation of ARE-driven antioxidant expression (glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modulatory subunit, glutathione synthase (GS), catalase (CAT), superoxide dismutase (SOD), heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPx)) with increasing l-methionine availability. Upon activation of Nrf2, glutathione synthesis was increased through upregulated expression of methionine adenosyltransferase, S-adenosylhomocysteine hydrolase, cystathionine β-synthase, cystathionine γ-lyse, glutamate cysteine ligase (GCL) and GS, while hepatic expressions of methionine sulfoxide reductases (MsrA, MsrB2, MsrB3) and hepatic enzyme activities (CAT, SOD, GCL, GR, GST, GPx) were uniformly stimulated with increasing consumption of l-methionine. As a result, hepatic content of ROS and MDA were effectively reduced by l-methionine intake. The present study demonstrates that methionine availability plays a critical role in activation of the Nrf2-ARE pathway to induce an endogenous antioxidant response for depressing ROS-derived oxidative stress, which is primarily attributed to the stimulation of methionine sulfoxide reductase expression and glutathione synthesis. © 2019 Society of Chemical Industry.

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging.

In order to clarify whether erythrocyte superoxide dismutase (SOD) activity and glutathione system including reduced glutathione (GSH), glutathione peroxidase (G-Px), glutathione reductase (G-Red), glutathione S-transferase (GST) are impaired in men with Behchet's disease (BD) at the first diagnosed time, erythrocyte SOD activity, GSH level, activities of G-Px, G-Red and GST were determined in men with new diagnosed BD. Erythrocyte GSH level, G-Px and G-Red activities were found to be lower, SOD activity was found to be higher in the patients as compared the controls. There was no significant difference between patients and controls for GST activity. Significant positive correlations between GSH and G-Px, GSH and G-Red; significant negative correlations between GSH and SOD, G-Px and SOD, G-Red and SOD were determined. It was concluded that erythrocyte SOD activity and glutathione system are altered in men with new diagnosed BD. It was concluded that these alterations may be a contributory factor for tissue damage associated with BD.

The present study aimed at investigating the kinetic of inhibition of isoproturon to the GSH-associated enzymes [γ-glutamyl-cysteine synthetase (γ-GCS), glutathione synthetase (GS), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione peroxidase (GPX)] in wheat. Isoproturon, applied to 10-day-old seedlings for the following 12days, provoked significant reductions in shoot fresh and dry weights, protein, thiols and glutathione (GSH); however, oxidized glutathione (GSSG) was elevated while GSH/GSSG ratio was declined with concomitant significant inhibitions in the activities of γ-GCS, GS, GR, GST and GPX; the effect was time dependent. IC50 and Ki values of isoproturon were lowest for GPX, highest for both GST and GR, and moderate for both γ-GCS and GS. The herbicide markedly decreased Vmax of γ-GCS, GS and GPX but unchanged that of GST and GR; however, Km of γ-GCS, GS, GST and GR increased but unchanged for GPX. The pattern of response of changing Vmax, Km, Vmax/Km, kcat and kcat/Km for in vivo and in vitro tests of each enzyme seemed most likely similar. These results indicate that a malfunction to defense system was induced in wheat by isoproturon resulting in inhibitions in GSH-associated enzymes, the magnitude of inhibition was most pronounced in GPX followed by γ-GCS, GS, GST, and GR. These findings could conclude that isoproturon competitively inhibited GST and GR; however, the inhibition was noncompetitive for GPX but mixed for both γ-GCS and GS.

Formaldehyde induces lung inflammation by an oxidant and antioxidant enzymes mediated mechanism in the lung tissue

The role of glutathione reductase and related enzymes on cellular redox homoeostasis network

In the last decade, it has become clear that virtually all mammalian cells produce reactive oxygen species. It was generally believed that these were by-products of cellular respiration and metabolism, and that they exerted toxic effects, including DNA damage and lipid oxidation. Recent evidence has demonstrated that this concept is incorrect, and that reactive oxygen species are produced in a controlled fashion and likely have critical signaling functions. Likewise, antioxidant defenses play a crucial role in modulating the ambient steady-state levels of reactive oxygen species. Biological or pharmacological manipulation of endogenous antioxidants can have a profound effect on cellular function. Emerging evidence suggests that hydrogen peroxide (H2O2) plays a particularly important role in signal transduction. H2O2 is uncharged and is freely diffusible within and between cells. Compared with other reactive oxygen species, it is also quite stable. A major source of H2O2 is a membrane-bound NADH/NADPH oxidase, the activity of which is regulated by hormones, growth factors, and physical forces. The primary product of this enzyme system is superoxide (O2·−), which is rapidly dismutated to H2O2 by the superoxide dismutases. Removal of H2O2 is regulated by two important enzymes, …

Antioxidant enzymes glutathione peroxidase and glutathione reductase correlate with human embryo cell number

Both endothelin-1 and oxidative stress have important roles in the development of cardiovascular diseases such as hypertension and atherosclerosis. Limited information is available on the interaction between oxidative stress, the glutathione system and endothelin-1 in humans. We aimed to investigate the association of endothelin-1 with markers of oxidative stress and the antioxidant capacity in a biethnic South African cohort. This cross-sectional study included 195 black and 198 white South Africans. Serum endothelin-1 levels and oxidative stress-related markers such as reactive oxygen species (measured as serum peroxides), glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase were measured. In single, partial and multiple regression analyses endothelin-1 correlated positively with glutathione reductase activity (adj. R2=0.10; β=0.232; P=0.020) and negatively with antihypertension medication (P=0.02) and tended to correlate with glutathione reductase-to-glutathione peroxidase ratio (adj. R2=0.10; β=0.19; P=0.057) in black men. In white men, endothelin-1 correlated positively with ROS (adj. R2=0.09; β=0.26; P=0.01) and negatively with glutathione peroxidase activity (adj. R2=0.05; β=-0.23; P=0.02). In black women, endothelin-1 correlated negatively with total glutathione (adj. R2=0.22; β=-0.214; P=0.026). Endothelin-1 may contribute to glutathione reductase upregulation through increased reactive oxygen species production mediated via endothelin-1 in black men. In white men, we observed a negative association between glutathione peroxidase and endothelin-1, describing the expected physiological relationship between endothelin-1 and reactive oxygen species. Higher total glutathione levels may act as a counter-regulatory mechanism to protect against oxidative vascular damage attributed by endothelin-1 in black women.

Glutathione is among the important antioxidants to prevent oxidative stress. However, the relationships between abnormality in the glutathione system and pathophysiology of schizophrenia remain uncertain due to inconsistent findings on glutathione levels and/or glutathione-related enzyme activities in patients with schizophrenia. A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies, in which three metabolite levels (glutathione, glutathione disulfide, and total glutathione (glutathione+glutathione disulfide)) and five enzyme activities (glutathione peroxidase, glutathione reductase, glutamate-cysteine ligase, glutathione synthetase, and glutathione S-transferase) were measured with any techniques in both patients with schizophrenia and healthy controls, were included. Standardized mean differences were calculated to determine the group differences in the glutathione levels with a random-effects model. We identified 41, 9, 15, 38, and seven studies which examined glutathione, glutathione disulfide, total glutathione, glutathione peroxidase, and glutathione reductase, respectively. Patients with schizophrenia had lower levels of both glutathione and total glutathione and decreased activity of glutathione peroxidase compared to controls. Glutathione levels were lower in unmedicated patients with schizophrenia than those in controls while glutathione levels did not differ between patients with first-episode psychosis and controls. Our findings suggested that there may be glutathione deficits and abnormalities in the glutathione redox cycle in patients with schizophrenia. However, given the small number of studies examined the entire glutathione system, further studies are needed to elucidate a better understanding of disrupted glutathione function in schizophrenia, which may pave the way for the development of novel therapeutic strategies in this disorder.

Increased reactive oxygen species (ROS) from accumulated fat in obesity has been shown to elevate systemic oxidative stress, contributing to diabetes, hypertension, and coronary heart disease. Here, we investigated the effects of a flavonoid quercetin on the changes of gene expression associated with cellular antioxidant responses and adipogenesis during differentiation of 3T3‐L1 preadipocytes. The changes in levels of lipid, ROS, mRNA expression of PPARγ, glucose‐6‐phosphate dehydrogenase (G6PDH), glutathione reductase (GR), and catalase was determined. ROS production significantly increased in parallel with lipid accumulation in adipocytes, which correlated with increased mRNA expression of all of the genes. Exposure to 100µM quercetin inhibited PPARγ (~3‐fold) and G6PDH mRNAs (~4‐fold) as well as adipogenesis and ROS accumulation compared to control. Quercetin also markedly inhibited mRNA expression of GR and catalase (~5 and 3‐fold, respectively). The inhibition of PPARγ and G6PDH by quercetin likely prevented hexose monophosphate (HMP) pathway‐mediated NADPH generation required for lipid synthesis and GR activity. These observations suggest that, during adipogenesis, the antioxidant enzymes are positively regulated to manage oxidative stress from accumulating fat, and that the anti‐adipogenic action of quercetin may involve coordinated changes of cellular redox state in adipocytes

Reactive oxygen species (ROS) are crucial in cell metabolism and homeostasis. ROS can damage biomolecules and organelles. To date, the paradigm is that ROS are integral components of cellular signaling and various cellular functions. The widely used concept of “oxidative stress” has been refined into “oxidative distress,” wherein ROS reach damaging levels, and “oxidative eustress,” wherein ROS do not cause damage and contribute to homeostasis. However, it is essential to maintain a prooxidant/antioxidant balance. ROS play a significant role in medically relevant fungi and human health, including inflammation, cancer, metabolic diseases, and aging. The innate immune system is critical in defending against pathogenic fungi. Macrophages and other phagocytic immune cells, which are derived from monocyte differentiation, are involved in the first line of defense during microbial invasion. Several pathogenic fungi have developed mechanisms to evade phagocytosis. Antioxidant enzymes are vital in this context. For example, an opportunistic human fungal pathogen, relies on its ability to escape destruction by phagocytosis and the immune system. Its antioxidant defenses include the thioredoxin system (TrxR), peroxiredoxin (Prx), superoxide dismutases (SODs), catalases (CATs), and the glutathione system, which consists of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and glutaredoxin (Grx). In this chapter, we address the consequences of deleting or removing important genes involved in antioxidant defenses to observe the response to ROS.