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1.
Redox Signaling from Mitochondria: Signal Propagation and Its Targets.
Ježek, P, Holendová, B, Plecitá-Hlavatá, L
Biomolecules. 2020;(1)
Abstract
Progress in mass spectroscopy of posttranslational oxidative modifications has enabled researchers to experimentally verify the concept of redox signaling. We focus here on redox signaling originating from mitochondria under physiological situations, discussing mechanisms of transient redox burst in mitochondria, as well as the possible ways to transfer such redox signals to specific extramitochondrial targets. A role of peroxiredoxins is described which enables redox relay to other targets. Examples of mitochondrial redox signaling are discussed: initiation of hypoxia-inducible factor (HIF) responses; retrograde redox signaling to PGC1α during exercise in skeletal muscle; redox signaling in innate immune cells; redox stimulation of insulin secretion, and other physiological situations.
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2.
A thermodynamically-constrained mathematical model for the kinetics and regulation of NADPH oxidase 2 complex-mediated electron transfer and superoxide production.
Tomar, N, Sadri, S, Cowley, AW, Yang, C, Quryshi, N, Pannala, VR, Audi, SH, Dash, RK
Free radical biology & medicine. 2019;:581-597
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Abstract
Reactive oxygen species (ROS) play an important role in cell signaling, growth, and immunity. However, when produced in excess, they are toxic to the cell and lead to premature aging and a myriad of pathologies, including cardiovascular and renal diseases. A major source of ROS in many cells is the family of NADPH oxidase (NOX), comprising of membrane and cytosolic components. NOX2 is among the most widely expressed and well-studied NOX isoform. Although details on the NOX2 structure, its assembly and activation, and ROS production are well elucidated experimentally, there is a lack of a quantitative and integrative understanding of the kinetics of NOX2 complex, and the various factors such as pH, inhibitory drugs, and temperature that regulate the activity of this oxidase. To this end, we have developed here a thermodynamically-constrained mathematical model for the kinetics and regulation of NOX2 complex based on diverse published experimental data on the NOX2 complex function in cell-free and cell-based assay systems. The model incorporates (i) thermodynamics of electron transfer from NADPH to O2 through different redox centers of the NOX2 complex, (ii) dependence of the NOX2 complex activity upon pH and temperature variations, and (iii) distinct inhibitory effects of different drugs on the NOX2 complex activity. The model provides the first quantitative and integrated understanding of the kinetics and regulation of NOX2 complex, enabling simulation of diverse experimental data. The model also provides several novel insights into the NOX2 complex function, including alkaline pH-dependent inhibition of the NOX2 complex activity by its reaction product NADP+. The model provides a mechanistic framework for investigating the critical role of NOX2 complex in ROS production and its regulation of diverse cellular functions in health and disease. Specifically, the model enables examining the effects of specific targeting of various enzymatic sources of pathological ROS which could overcome the limitations of pharmacological efforts aimed at scavenging ROS which has resulted in poor outcomes of antioxidant therapies in clinical studies.
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3.
Depressive symptoms in hip fracture patients are associated with reduced monocyte superoxide production.
Duggal, NA, Beswetherick, A, Upton, J, Hampson, P, Phillips, AC, Lord, JM
Experimental gerontology. 2014;:27-34
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Abstract
Ageing is accompanied by reduced functioning of the immune system, termed immunesenescence which is associated with increased risk of infection and mortality. However the immune system does not operate in isolation and can be modified by many environmental factors, including stress. In this study we determined whether physical stress (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system, specifically on monocyte numbers and function. We assessed immune function in 101 hip fracture patients (81 female) 6weeks and 6months after injury and 43 healthy age matched controls (28 females). Thirty-eight of the hip fracture group were found to be depressed at the 6week sampling. No differences in peripheral monocyte count, distribution of monocyte subsets or TNFα secretion were observed between hip fracture patients and healthy controls. However we observed significantly reduced superoxide production in response to Escherichia coli in the monocytes of hip fracture patients who developed depressive symptoms compared with non-depressed hip fracture patients (p=0.002) or healthy controls (p=0.008) 6weeks after the fracture which remained decreased 6months following injury. In previous studies we have shown an effect of depression on neutrophil superoxide generation in hip fracture patients, suggesting a particular susceptibility of this aspect of immune cell function to psychological stress.
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Effect of academic psychological stress in post-graduate students: the modulatory role of cortisol on superoxide release by neutrophils.
Ignacchiti, MD, Sesti-Costa, R, Marchi, LF, Chedraoui-Silva, S, Mantovani, B
Stress (Amsterdam, Netherlands). 2011;(3):290-300
Abstract
Experimental and clinical evidence shows that neutrophils play an important role in the mechanism of tissue injury in immune complex diseases through the generation of reactive oxygen species. In this study, we examined the influence of academic psychological stress in post-graduate students on the capacity of their blood neutrophils to release superoxide when stimulated by immune complexes bound to nonphagocytosable surfaces and investigated the modulatory effect of cortisol on this immune function. The tests were performed on the day before the final examination. The state-trait anxiety inventory questionnaire was used to examine whether this stressful event caused emotional distress. In our study, the psychological stress not only increased plasma cortisol concentration, but it also provoked a reduction in superoxide release by neutrophils. This decrease in superoxide release was accompanied by diminished mRNA expression for subunit p47(phox) of the phagocyte superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase. These inhibitory effects were also observed by in vitro exposure of neutrophils from control volunteers to 10(- 7) M hydrocortisone, and could be prevented by the glucocorticoid receptor antagonist RU-486. These results show that in a situation of psychological stress, the increased levels of cortisol could inhibit superoxide release by neutrophils stimulated by IgG immune complexes bound to nonphagocytosable surfaces, which could attenuate the inflammatory state.
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One-electron reduction of N-chlorinated and N-brominated species is a source of radicals and bromine atom formation.
Pattison, DI, O'Reilly, RJ, Skaff, O, Radom, L, Anderson, RF, Davies, MJ
Chemical research in toxicology. 2011;(3):371-82
Abstract
Hypochlorous (HOCl) and hypobromous (HOBr) acids are strong bactericidal oxidants that are generated by the human immune system but are implicated in the development of many human inflammatory diseases (e.g., atherosclerosis, asthma). These oxidants react readily with sulfur- and nitrogen-containing nucleophiles, with the latter generating N-halogenated species (e.g., chloramines/bromamines (RR'NX; X = Cl, Br)) as initial products. Redox-active metal ions and superoxide radicals (O(2)(•-)) can reduce N-halogenated species to nitrogen- and carbon-centered radicals. N-Halogenated species and O(2)(•-) are generated simultaneously at sites of inflammation, but the significance of their interactions remains unclear. In the present study, rate constants for the reduction of N-halogenated amines, amides, and imides to model potential biological substrates have been determined. Hydrated electrons reduce these species with k(2) > 10(9) M(-1) s(-1), whereas O(2)(•-) reduced only N-halogenated imides with complex kinetics indicative of chain reactions. For N-bromoimides, heterolytic cleavage of the N-Br bond yielded bromine atoms (Br(•)), whereas for other substrates, N-centered radicals and Cl(-)/Br(-) were produced. High-level quantum chemical procedures have been used to calculate gas-phase electron affinities and aqueous solution reduction potentials. The effects of substituents on the electron affinities of aminyl, amidyl, and imidyl radicals are rationalized on the basis of differential effects on the stabilities of the radicals and anions. The calculated reduction potentials are consistent with the experimental observations, with Br(•) production predicted for N-bromosuccinimide, while halide ion formation is predicted in all other cases. These data suggest that interaction of N-halogenated species with O(2)(•-) may produce deleterious N-centered radicals and Br(•).
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Arsenic alters monocyte superoxide anion and nitric oxide production in environmentally exposed children.
Luna, AL, Acosta-Saavedra, LC, Lopez-Carrillo, L, Conde, P, Vera, E, De Vizcaya-Ruiz, A, Bastida, M, Cebrian, ME, Calderon-Aranda, ES
Toxicology and applied pharmacology. 2010;(2):244-51
Abstract
Arsenic (As) exposure has been associated with alterations in the immune system, studies in experimental models and adults have shown that these effects involve macrophage function; however, limited information is available on what type of effects could be induced in children. The aim of this study was to evaluate effects of As exposure, through the association of inorganic As (iAs) and its metabolites [monomethylated arsenic (MMA) and dimethylated arsenic (DMA)] with basal levels of nitric oxide (NO(-)) and superoxide anion (O(2)(-)), in peripheral blood mononuclear cells (PBMC) and monocytes, and NO(-) and O(2)(-) produced by activated monocytes. Hence, a cross-sectional study was conducted in 87 children (6-10 years old) who had been environmentally exposed to As through drinking water. Levels of urinary As species (iAs, MMA and DMA) were determined by hydride generation atomic absorption spectrometry, total As (tAs) represents the sum of iAs and its species; tAs urine levels ranged from 12.3 to 1411 microg/g creatinine. Using multiple linear regression models, iAs presented a positive and statistical association with basal NO(-) in PBMC (beta=0.0048, p=0.049) and monocytes (beta=0.0044, p=0.044), while basal O(2)(-) had a significant positive association with DMA (beta=0.0025, p=0.046). In activated monocytes, O(2)(-) showed a statistical and positive association with iAs (beta=0.0108, p=0.023), MMA (beta=0.0066, p=0.022), DMA (beta=0.0018, p=0.015), and tAs (beta=0.0013, p=0.015). We conclude that As exposure in the studied children was positively associated with basal levels of NO(-) and O(2)(-) in PBMC and monocytes, suggesting that As induces oxidative stress in circulating blood cells. Additionally, this study showed a positive association of O(2)(-) production with iAs and its metabolites in stimulated monocytes, supporting previous data that suggests that these cells, and particularly the O(2)(-) activation pathway, are relevant targets for As toxicity.
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Perioperative treatment with human growth hormone down-regulates apoptosis and increases superoxide production in PMN from patients undergoing infrarenal abdominal aortic aneurysm repair.
Decker, D, Springer, W, Tolba, R, Lauschke, H, Hirner, A, von Ruecker, A
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2005;(3):193-9
Abstract
BACKGROUND Recombinant human growth hormone (hGH) therapy has a beneficial effect on catabolism and wound healing after major surgery. Polymorphonuclear neutrophils (PMN) play an important role in this context. In a prospective, double-blind, randomized, placebo-controlled trial we studied the effect of perioperative hGH treatment on postoperative wound healing and on changes in superoxide generation and susceptibility to apoptosis of PMN in elderly patients undergoing elective abdominal aortic aneurysm repair. METHODS Seven patients were treated with high-dose hGH (16 U/d) for nine days, seven patients with a placebo. IGF-I, neutrophil count, O2-production induced by opsonized zymosan and apoptosis of PMN were measured and correlated with clinical outcome. RESULTS Perioperative hGH treatment more than doubled the O2- production in PMN before and 24 h after surgery (p < 0.01). The long-term capacity of PMN to generate O2 in vitro was prolonged (p < 0.001) in the hGH group. Spontaneous and Fas-inducible apoptosis was strongly down-regulated in PMN after surgery in all patients (p < 0.01). hGH-treatment distinctly reduced apoptosis in PMN before and after surgery (p < 0.01). Clinical outcome was similar in both groups. CONCLUSION Perioperative hGH treatment results in an enhanced O2- production in PMN and in a prolongation of the functional life span of these cells. This may improve immune function and help to overcome the postoperative anergic state of the immune system especially in elderly individuals.
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Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms.
Levitt, ML, Kassem, B, Gooding, WE, Miketic, LM, Landreneau, RJ, Ferson, PF, Keenan, R, Yousem, SA, Lindberg, CA, Trenn, MR, et al
Lung cancer (Amsterdam, Netherlands). 2004;(3):335-44
Abstract
PURPOSE To define the maximum tolerated dose (MTD) and the nature of the toxicities associated with gemcitabine given as a short infusion to patients with non-small cell lung cancer (NSCLC). Secondary objectives were to monitor immunologic response, clinical response, and survival. PATIENTS AND METHODS Thirty-two patients diagnosed with advanced inoperable NSCLC and performance status of 0 or 1 participated in this study. Patients consisted of 22 males and 10 females whose median age was 62 years (range 32-79). Gemcitabine was administered as a 30 min infusion once weekly for 3 weeks followed by 1 week of rest. Patients were enrolled at six gemcitabine dose levels ranging from 1000 to 3500 mg/m2. Patients completed a median of four cycles (range 1-17). Responses were evaluated after every two cycles. RESULTS Toxicity was evaluated in all 32 patients. The MTD was not reached as gemcitabine was well tolerated at all dose levels. Grade 4 toxicity occurred in three (9%) patients: pulmonary and lymphocytopenia in one patient each, and both neurocortical and cardiac in one patient. Grade 3 toxicity was found in a total of 20 (63%) patients: pulmonary in 10 (31%) patients; pain in 6 (19%) patients; liver toxicity in 6 (19%) patients; leukopenia and lymphocytopenia in 5 (16%) patients each; anemia, nausea, and cardiac toxicity in 3 (9%) patients each; proteinuria and infection in 2 (6%) patients each; and hemorrhage in 1 (3%) patient. Of the 29 patients evaluable for response, seven objective responses were achieved: six at the 2200 mg/m2 dose level and one at the 2800 mg/m2 dose level. The distribution of responses differed significantly by dose (P = 0.0124 by the exact chi-square test for independence). The overall response rate was 24.1% (95% CI, 10.3-43.5%). At 6 h post-infusion, there was a significant increase in spontaneous tumor necrosis factor (TNF) release and stimulated interleukin (IL)-2 production, and significant decreases in total white blood cell and lymphocyte counts (CD3+, CD8+, and CD16+ lymphocytes) and resting and stimulated superoxide production by formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate, and opsonized zymosan (OPS-Z). At 24 h post-infusion, there were significant decreases in total lymphocyte count, lymphocyte subsets (CD3+, CD4-, CD8+, CD56+, CD19+), and in resting and stimulated superoxide production by fMLP and OPS-Z. There also appeared to be an association between the levels of spontaneous TNF release and the severity of both gastrointestinal (GI) and pulmonary toxicities. CONCLUSION Gemcitabine given as a short infusion was well tolerated at the dose levels of 1000-3500 mg/m2. The MTD was not reached. Toxicities appeared to be cumulative with multiple cycles. Gemcitabine appears to have activity against NSCLC. Although there was a differential dose-response rate among dose levels, increasing the gemcitabine dose beyond 2200mg/m2 did not show increased clinical response. Gemcitabine appears to modulate the immune response, which may in turn mediate both response and toxicity, although no statistically significant correlation between immune and clinical response was detected.
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[The superoxide theory of pathogenesis and therapy of immune disorders].
Lebedev, VV
Vestnik Rossiiskoi akademii meditsinskikh nauk. 2004;(2):34-40
Abstract
On the basis of the understanding that there are common development mechanisms for the inflammatory and immune reactions it was established that the activity of the oxidant-antioxidant system (OAS) correlates not only with a severity of the inflammatory reaction but also with a degree of immune disorders. Such disorders were studied in patients with endogenous uveitis and with cancer of the esophagus or uterine cervix, i.e. those nosological forms, which are normally accompanied by OAS decompensation, which comprised a lower activity of primary antioxidants (superoxides of dismutase, catalase, lactoferrin, ceruloplasmin etc.) in patients with pronounced immune disorders. Moreover, a lower content of secondary antioxidants, like vitamin A, ascorbic acid and tocopherol, was registered in the blood of patients with immune disorders. The suppression of the antioxidant system was concomitant with an essentially increased level of lipid peroxidation in all patients. Besides, it was noted that there were intensifying signs of immune disorders primarily observed during irradiation chemotherapy. In this context, a clear-cut correlation was established, in monitoring the body immune status, between degrees of free-radical formation and lipid peroxidation, on the one hand, and an activity of detoxication-system antioxidants, on the other hand,. The OAS correction by direct or indirect-action antioxidants normally improves the clinical course of immune impairments. The indirect-action antioxidants, e.g. synthetic regulatory peptide "Imunofan", induce the increasing activity of primary endogenous antioxidants. An activation of the detoxication antioxidant system, brings about, in such cases, a lower content of inflammation mediators, a recovery of cell-immunity indices and lower parameters of body auto-sensitization. Finally, the antioxidant system in patients with chronic inflammatory or oncological disorders, when recovered, ensures the correction of cell immunity and cuts the number of auto-immune reactions and of other immune disturbances.
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10.
alpha-tocopherol supplementation decreases production of superoxide and cytokines by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic individuals.
van Tits, LJ, Demacker, PN, de Graaf, J, Hak-Lemmers, HL, Stalenhoef, AF
The American journal of clinical nutrition. 2000;(2):458-64
Abstract
BACKGROUND alpha-Tocopherol plays an important role in protecting LDL against oxidation. However, additional effects of alpha-tocopherol at the intracellular level may contribute to the clinical outcome of intervention studies. OBJECTIVE We investigated whether alpha-tocopherol influences the inflammatory responses of immune cells in normolipidemic and hypertriglyceridemic subjects. DESIGN RRR-alpha-Tocopherol was administered for 6 wk at a dose of 600 IU (402 mg)/d to 12 primary hypertriglyceridemic and 8 normolipidemic (fasting triacylglycerol >3.0 and <2.0 mmol/L, respectively) subjects. Cytokine production [tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-8] by mononuclear cells and superoxide production by polymorphonuclear cells and in diluted whole blood were determined before and after the intervention. RESULTS Cytokine and superoxide production did not differ significantly between hypertriglyceridemic and normolipidemic subjects. alpha-Tocopherol supplementation resulted in a 2- to 3-fold increase in the concentration of alpha-tocopherol in plasma and LDL. Whereas superoxide production in response to phorbol 12-myristate 13-acetate decreased in all subjects, response to oxidized LDL increased in 19 of 20 subjects. Response to opsonized zymosan before alpha-tocopherol supplementation was not significantly different from that after supplementation. Lipopolysaccharide-induced cytokine production by mononuclear cells decreased after supplementation with alpha-tocopherol. CONCLUSIONS alpha-Tocopherol differentially influences inflammatory responses of immune cells. These effects of alpha-tocopherol may be relevant in chronic inflammatory processes such as atherogenesis.