Regulation of P-Glycoprotein during Oxidative Stress
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ABSTRACT:
SUBMITTER: Shchulkin A
PROVIDER: S-EPMC10885963 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:The proteasome plays a pivotal role in the cellular response to oxidative stress. Here, we used biochemical and mass spectrometric methods to investigate structural changes in the 26S proteasomes from yeast and mammalian cells exposed to hydrogen peroxide (H?O?). Oxidative stress induced the dissociation of the 20S core particle from the 19S regulatory particle of the 26S proteasome, which resulted in loss of the activities of the 26S proteasome and accumulation of ubiquitinated proteins. H?O? triggered the increased association of the proteasome-interacting protein Ecm29 with the purified 19S particle. Deletion of ECM29 in yeast cells prevented the disassembly of the 26S proteasome in response to oxidative stress, and ecm29 mutants were more sensitive to H?O? than were wild-type cells, suggesting that separation of the 19S and 20S particles is important for cellular recovery from oxidative stress. The increased amount of free 20S core particles was required to degrade oxidized proteins. The Ecm29-dependent dissociation of the proteasome was independent of Yap1, a transcription factor that is critical for the oxidative stress response in yeast, and thus functions as a parallel defense pathway against H?O?-induced stress.
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Project description:There exists a strong link between oxidative stress, renal dopaminergic system, and hypertension. It is reported that reactive oxygen species attenuate renal proximal tubular dopamine receptor (D1R) function, which disrupts sodium regulation and leads to hypertension. However, the mechanisms for renal D1R dysfunction are not clear. We investigated the role of redox-sensitive transcription factors AP1 and SP3 in transcriptional suppression of D1R gene and subsequent D1R signaling. Human kidney proximal tubular cells were treated with a pro-oxidant l-buthionine sulfoximine (BSO) with and without an antioxidant tempol. In human kidney cells, BSO caused oxidative stress and reduced D1R mRNA and membrane receptor expression. Incubation of human kidney cells with SKF38393, a D1R agonist, caused a concentration-dependent inhibition of Na/K-ATPase. However, SKF38393 failed to inhibit Na/K-ATPase in BSO-treated cells. BSO increased AP1 and SP3 nuclear expression. Transfection with AP1- or SP3-specific siRNA abolished BSO-induced D1R downregulation. Treatment of rats with BSO for 4 weeks increased oxidative stress and SP3-AP1 expression and reduced D1R numbers in renal proximal tubules. These rats exhibited high blood pressure, and SKF38393 failed to inhibit proximal tubular Na/K-ATPase activity. Control rats were kept on tap water. Tempol per se had no effect on D1R expression or other signaling molecules but prevented BSO-induced oxidative stress, SP3-AP1 upregulation, and D1R dysfunction in both human kidney cells and rats. These data show that oxidative stress via AP1-SP3 activation suppresses D1R transcription and function. Tempol mitigates oxidative stress, blocks AP1-SP3 activation, and prevents D1R dysfunction and hypertension.
| S-EPMC4393374 | biostudies-literature
Project description:ATP-binding cassette (ABC) transporters, in particular P-glycoprotein (encoded by ABCB1), are important and selective elements of the blood-brain barrier (BBB), and they actively contribute to brain homeostasis. Changes in ABCB1 expression and/or function at the BBB may not only alter the expression and function of other molecules at the BBB but also affect brain environment. Over the last decade, a number of reports have shown that ABCB1 actively mediates the transport of beta amyloid (Aβ) peptide. This finding has opened up an entirely new line of research in the field of Alzheimer's disease (AD). Indeed, despite intense research efforts, AD remains an unsolved pathology and effective therapies are still unavailable. Here, we review the crucial role of ABCB1 in the Aβ transport and how oxidative stress may interfere with this process. A detailed understanding of ABCB1 regulation can provide the basis for improved neuroprotection in AD and also enhanced therapeutic drug delivery to the brain.
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Project description:AimsMitochondrial cytochrome c oxidase (COX) subunit 5 and cytochrome c (Cyc) exist in two isoforms, transcriptionally regulated by oxygen in yeast. The gene pair COX5a/CYC1 encodes the normoxic isoforms (Cox5a and iso1-Cyc) and the gene pair COX5b/CYC7 encodes the hypoxic isoforms (Cox5b and iso2-Cyc). Rox1 is a transcriptional repressor of COX5b/CYC7 in normoxia. COX5b is additionally repressed by Ord1. Here, we investigated whether these pathways respond to environmental and mitochondria-generated oxidative stress.ResultsThe superoxide inducer menadione triggered a significant de-repression of COX5b and CYC7. Hydrogen peroxide elicited milder de-repression effects that were enhanced in the absence of Yap1, a key determinant in oxidative stress resistance. COX5b/CYC7 was also de-repressed in wild-type cells treated with antimycin A, a mitochondrial bc1 complex inhibitor that increases superoxide production. Exposure to menadione and H2O2 enhanced both, Hap1-independent expression of ROX1 and Rox1 steady-state levels without affecting Ord1. However, oxidative stress lowered the occupancy of Rox1 on COX5b and CYC7 promoters, thus inducing their de-repression.InnovationReactive oxygen species (ROS)-induced hypoxic gene expression in normoxia involves the oxygen-responding Rox1 transcriptional machinery. Contrary to what occurs in hypoxia, ROS enhances Rox1 accumulation. However, its transcriptional repression capacity is compromised.ConclusionROS induce expression of hypoxic COX5b and CYC7 genes through an Ord1- and Hap1-independent mechanism that promotes the release of Rox1 from or limits the access of Rox1 to its hypoxic gene promoter targets.
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Project description:Osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) is a central event in bone formation. However, oxidative stress has a deleterious impact on BM-MSC osteogenesis. In this study, we hypothesized that oxidative stress influenced BM-MSC osteogenesis differently in the early or late stages, in which silent information regulator type 1 (SIRT1) played a critical role. A continuous exposure to sublethal concentrations of hydrogen peroxide (H2 O2 ), ranging from 25 to 100 µM for 21 days, resulted in the complete inhibition of BM-MSC osteogenesis. We found that a 7-day treatment with H2 O2 inhibited the lineage commitment of BM-MSCs toward osteoblasts, as evidenced by a significant reduction of alkaline phosphatase activity (a typical marker for early osteogenesis). However, moderate oxidative stress did not affect late-differentiated BM-MSCs, as there were comparable levels of matrix mineralization (a typical marker for late osteogenesis). In addition, we observed a spontaneous up-regulation of SIRT1 and intracellular antioxidant enzymes such as superoxide dismutase 2, catalase, and glutathione peroxidase 1, which accounted for the enhanced resistance to oxidative stress upon osteogenic differentiation. Activation of SIRT1 by resveratrol rescued the effect of H2 O2 on early-differentiated BM-MSCs and inhibition of SIRT1 by nicotinamide intensified the effect of H2 O2 on late-differentiated BM-MSCs, indicating that the SIRT1-mediated pathway was actively involved in MSC osteogenesis and antioxidant mechanisms. Our findings uncovered the relationship between SIRT1 and resistance to H2 O2 -induced oxidative stress during BM-MSC osteogenesis, which could provide a new strategy for protecting MSCs from extracellular oxidative stress.
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Project description:BackgroundThe impact of blood flow regulation and oxidative stress during exercise in cystic fibrosis (CF) has yet to be investigated.MethodsA maximal graded exercise test was conducted to determine exercise capacity (VO2 peak) and peak workload in 14 pediatric patients with mild CF (age 14±3y, FEV1 93±16 % predicted) and 14 demographically-matched controls. On a separate visit, participants performed submaximal cycling up to 60% of peak workload where brachial artery blood velocity was determined using Doppler ultrasound. Retrograde and antegrade components were further analyzed as indices of blood flow regulation.ResultsThe cumulative AUC for retrograde velocity was lower in patients versus controls (1770±554 vs. 3440±522cm, P=0.038). In addition, an exaggerated oxidative stress response during exercise occurred in patients only (P=0.004).ConclusionThese data suggest that patients with mild CF exhibit impaired blood flow regulation and an exaggerated oxidative stress response to submaximal exercise.
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Project description:Increased arterial pressure, angiotensin II, and cytokines each result in feedback inhibition of renin gene expression. Because angiotensin II and cytokines can stimulate reactive oxygen species production, we tested the hypothesis that oxidative stress may be a mediator of this inhibition. Treatment of renin-expressing As4.1 cells with the potent cytokine tumor necrosis factor-alpha caused an increase in the steady-state levels of cellular reactive oxygen species, which was reversed by the antioxidant N-acetylcysteine. Exogenous H(2)O(2) caused a dose- and time-dependent decrease in the level of endogenous renin mRNA and decreased the transcriptional activity of a 4.1-kb renin promoter fused to luciferase, which was maximal when the renin enhancer was present. The effect of H(2)O(2) appeared to be specific to renin, because there was no change in the expression of beta-actin or cyclophilin mRNA or transcriptional activity of the SV40 promoter. The tumor necrosis factor-alpha-induced decrease in renin mRNA was partially reversed by either N-acetylcysteine or panepoxydone, a nuclear factor kappaB (NFkappaB) inhibitor. Interestingly, H(2)O(2) did not induce NFkappaB in As4.1 cells, and panepoxydone had no effect on the downregulation of renin mRNA by H(2)O(2). The transcriptional activity of a cAMP response element-luciferase construct was decreased by both tumor necrosis factor-alpha and H(2)O(2). These data suggest that cellular reactive oxygen species can negatively regulate renin gene expression via an NFkappaB-independent mechanism involving the renin enhancer and inhibiting cAMP response element-mediated transcription. Our data further suggest that tumor necrosis factor-alpha decreases renin expression through both NFkappaB-dependent and NFkappaB-independent mechanisms, the latter involving the production of reactive oxygen species.
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Project description:Oxidative stress drives cell death in a number of diseases including ischemic stroke and neurodegenerative diseases. A better understanding of how cells recover from oxidative stress is likely to lead to better treatments for stroke and other diseases. The recent evidence obtained in several models ties the process of lysosomal exocytosis to the clearance of protein aggregates and toxic metals. The mechanisms that regulate lysosomal exocytosis, under normal or pathological conditions, are only beginning to emerge. Here we provide evidence for the biphasic effect of oxidative stress on lysosomal exocytosis. Lysosomal exocytosis was measured using the extracellular levels of the lysosomal enzyme beta-hexosaminidase (ß-hex). Low levels or oxidative stress stimulated lysosomal exocytosis, but inhibited it at high levels. Deletion of the lysosomal ion channel TRPML1 eliminated the stimulatory effect of low levels of oxidative stress. The inhibitory effects of oxidative stress appear to target the component of lysosomal exocytosis that is driven by extracellular Ca2+. We propose that while moderate oxidative stress promotes cellular repair by stimulating lysosomal exocytosis, at high levels oxidative stress has a dual pathological effect: it directly causes cell damage and impairs damage repair by inhibiting lysosomal exocytosis. Harnessing these adaptive mechanisms may point to pharmacological interventions for diseases involving oxidative proteotoxicity or metal toxicity.
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Project description:Proteasome is central to proteostasis maintenance, as it degrades both normal and damaged proteins. Herein, we undertook a detailed analysis of proteasome regulation in the in vivo setting of Drosophila melanogaster. We report that a major hallmark of somatic tissues of aging flies is the gradual accumulation of ubiquitinated and carbonylated proteins; these effects correlated with a ~50% reduction of proteasome expression and catalytic activities. In contrast, gonads of aging flies were relatively free of proteome oxidative damage and maintained substantial proteasome expression levels and highly active proteasomes. Moreover, gonads of young flies were found to possess more abundant and more active proteasomes than somatic tissues. Exposure of flies to oxidants induced higher proteasome activities specifically in the gonads, which were, independently of age, more resistant than soma to oxidative challenge and, as analyses in reporter transgenic flies showed, retained functional antioxidant responses. Finally, inducible Nrf2 activation in transgenic flies promoted youthful proteasome expression levels in the aged soma, suggesting that age-dependent Nrf2 dysfunction is causative of decreasing somatic proteasome expression during aging. The higher investment in proteostasis maintenance in the gonads plausibly facilitates proteome stability across generations; it also provides evidence in support of the trade-off theories of aging.
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