PubMed Central (PMC3 - NLM DTD)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).
Antioxidants & Redox Signaling
Mostrando recursos 1 - 20 de 740
Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress - Brnjic, Slavica; Mazurkiewicz, Magdalena; Fryknäs, Mårten; Sun, Chao; Zhang, Xiaonan; Larsson, Rolf; D'Arcy, Pádraig; Linder, Stig
Aims: b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. Results: We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic...
Harnessing Proteasome Dynamics and Allostery in Drug Design - Gaczynska, Maria; Osmulski, Pawel A.
Significance: The proteasome is the essential protease that is responsible for regulated cleavage of the bulk of intracellular proteins. Its central role in cellular physiology has been exploited in therapies against aggressive cancers where proteasome-specific competitive inhibitors that block proteasome active centers are very effectively used. However, drugs regulating this essential protease are likely to have broader clinical usefulness. The non-catalytic sites of the proteasome emerge as an attractive alternative target in search of highly specific and diverse proteasome regulators. Recent Advances: Crystallographic models of the proteasome leave the false impression of fixed structures with minimal molecular dynamics lacking long-distance...
Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics - Parrow, Nermi L.; Leshin, Jonathan A.; Levine, Mark
Significance: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10 g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of...
Antioxidant Activity of Sestrin 2 Controls Neuropathic Pain After Peripheral Nerve Injury - Kallenborn-Gerhardt, Wiebke; Lu, Ruirui; Syhr, Katharina M.J.; Heidler, Juliana; von Melchner, Harald; Geisslinger, Gerd; Bangsow, Thorsten; Schmidtko, Achim
Aims: Neuropathic pain is a chronic debilitating disease that is often unresponsive to currently available treatments. Emerging lines of evidence indicate that reactive oxygen species (ROS) are required for the development and maintenance of neuropathic pain. However, little is known about endogenous mechanisms that neutralize the pain-relevant effects of ROS. In the present study, we tested whether the stress-responsive antioxidant protein Sestrin 2 (Sesn2) blocks the ROS-induced neuropathic pain processing in vivo.
Results: We observed that Sesn2 mRNA and protein expression was up-regulated in peripheral nerves after spared nerve injury, a well-characterized model of neuropathic pain. Sesn2 knockout (Sesn2−/−) mice exhibited...
In Vivo Consequence of Vitamin C Insufficiency in Liver Injury: Vitamin C Ameliorates T-Cell-Mediated Acute Liver Injury in Gulo(−/−) Mice - Bae, Seyeon; Cho, Chung-Hyun; Kim, Hyemin; Kim, Yejin; Kim, Hang-Rae; Hwang, Young-il; Yoon, Jung Hwan; Kang, Jae Seung; Lee, Wang Jae
l-ascorbic acid (vitamin C) insufficiency is considered one of the major risk factors for the development of liver disease. However, its specific effects and related mechanisms in vivo are largely unknown. The objective of this study was to investigate the in vivo protective role of vitamin C and its related mechanisms in liver injury with Gulo(−/−) mice that cannot synthesize vitamin C like humans due to the lack of l-gulonolactone-γ-oxidase (Gulo), an essential enzyme for vitamin C synthesis. Results: When liver injury was induced in Gulo(−/−) mice by injection of concanavalin A (Con A), there was greater extensive liver damage...
Role of Vitamin C in the Function of the Vascular Endothelium - May, James M.; Harrison, Fiona E.
Significance: Vitamin C, or ascorbic acid, has long been known to participate in several important functions in the vascular bed in support of endothelial cells. These functions include increasing the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation, inhibiting apoptosis, scavenging radical species, and sparing endothelial cell-derived nitric oxide to help modulate blood flow. Although ascorbate may not be able to reverse inflammatory vascular diseases such as atherosclerosis, it may well play a role in preventing the endothelial dysfunction that is the earliest sign of many such diseases. Recent Advances: Beyond simply preventing scurvy,...
Evaluation of Vitamin C for Adjuvant Sepsis Therapy - Wilson, John X.
Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models...
Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease - Rebec, George V.
Significance: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA–glutamate interaction...
Trientine Reduces BACE1 Activity and Mitigates Amyloidosis via the AGE/RAGE/NF-κB Pathway in a Transgenic Mouse Model of Alzheimer's Disease - Wang, Chun-Yan; Xie, Jing-Wei; Xu, Ye; Wang, Tao; Cai, Jian-Hui; Wang, Xu; Zhao, Bao-Lu; An, Li; Wang, Zhan-You
Aims: There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1) double transgenic (Tg) AD model mice. Results: We observed that Trien reduced the level of advanced glycation end products (AGEs), and decreased Aβ deposition and synapse loss...
Suicide Gene-Mediated Sequencing Ablation Revealed the Potential Therapeutic Mechanism of Induced Pluripotent Stem Cell-Derived Cardiovascular Cell Patch Post-Myocardial Infarction - Wang, Yuhua; Huang, Wei; Liang, Jialiang; Wen, Zhili; Chang, Dehua; Kang, Kai; Wang, Jiapeng; Xu, Meifeng; Millard, Ronald W.; Wang, Yigang
Aims: This study is designed to assess the protective cardiac effects after myocardial infarction (MI) of (i) cardiovascular progenitor cells (PC) differentiated directly into cardiomyocytes (CM) and endothelial cells (ECs) at the injury site, as separable from the effects of (ii) paracrine factors released from PC. Results:
In vivo: bi-cell patch containing induced pluripotent stem cell (iPSC)-derived CM and EC (BIC) was transplanted onto the infarcted heart. BIC were transduced with herpes simplex virus thymidine kinase “suicide” gene driven by cardiac NCX1 or endothelial vascular endothelium-cadherin promoter. IGF-1α and VEGF levels released from ischemic tissues were significantly enhanced in the BIC...
The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses - Horwitz, Lawrence D.; Horwitz, Marcus A.
Significance: Exochelins are lipid- and water-soluble siderophores of Mycobacterium tuberculosis with unique properties that endow them with exceptional pharmacologic utility. Exochelins can be utilized as probes to decipher the role of iron in normal and pathological states, and, since they rapidly cross cell membranes and chelate intracellular iron with little or no toxicity, exochelins are potentially useful for the treatment of a number of iron-dependent pathological phenomena. Recent Advances: In animal models, exochelins have been demonstrated to have promise for the treatment of transfusion-related iron overload, restenosis after coronary artery angioplasty, cancer, and oxidative injury associated with acute myocardial infarction...
Mn Porphyrin Regulation of Aerobic Glycolysis: Implications on the Activation of Diabetogenic Immune Cells - Delmastro-Greenwood, Meghan M.; Votyakova, Tatyana; Goetzman, Eric; Marre, Meghan L.; Previte, Dana M.; Tovmasyan, Artak; Batinic-Haberle, Ines; Trucco, Massimo M.; Piganelli, Jon D.
Aims: The immune system is critical for protection against infections and cancer, but requires scrupulous regulation to limit self-reactivity and autoimmunity. Our group has utilized a manganese porphyrin catalytic antioxidant (MnTE-2-PyP5+, MnP) as a potential immunoregulatory therapy for type 1 diabetes. MnP has previously been shown to modulate diabetogenic immune responses through decreases in proinflammatory cytokine production from antigen-presenting cells and T cells and to reduce diabetes onset in nonobese diabetic mice. However, it is unclear whether or not MnP treatment can act beyond the reported inflammatory mediators. Therefore, the hypothesis that MnP may be affecting the redox-dependent bioenergetics of...
Human GGT2 Does Not Autocleave into a Functional Enzyme: A Cautionary Tale for Interpretation of Microarray Data on Redox Signaling - West, Matthew B.; Wickham, Stephanie; Parks, Eileen E.; Sherry, David M.; Hanigan, Marie H.
Aims: Human γ-glutamyltranspeptidase 1 (hGGT1) is a cell-surface enzyme that is a regulator of redox adaptation and drug resistance due to its glutathionase activity. The human GGT2 gene encodes a protein that is 94% identical to the amino-acid sequence of hGGT1. Transcriptional profiling analyses in a series of recent publications have implicated the hGGT2 enzyme as a modulator of disease processes. However, hGGT2 has never been shown to encode a protein with enzymatic activity. The aim of this study was to express the protein encoded by hGGT2 and each of its known variants and to assess their stability, cellular localization,...
A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia - Anavi, Sarit; Hahn-Obercyger, Michal; Margalit, Raanan; Madar, Zecharia; Tirosh, Oren
Aims: The current study aim was to elucidate the antihypoglycemic role and mechanism of inducible nitric oxide synthase (iNOS) under inflammatory stress. Methods: Liver inflammatory stress was induced in wild-type (WT) and iNOS-knockout (iNOS−/−) mice by lipopolysaccharide (LPS) (5 mg/kg) with and without the background of nonalcoholic steatohepatitis (NASH)-Induced by high cholesterol diet (HCD, 6 weeks). Results: HCD led to steatohepatitis in WT and iNOS−/− mice. LPS administration caused marked liver inflammatory damage only in cholesterol-fed mice, which was further exacerbated in the absence of iNOS. Glucose homeostasis was significantly impaired and included fatal hypoglycemia and inhibition of glycogen decomposition. In...
Transcriptional Regulation of Yeast Oxidative Phosphorylation Hypoxic Genes by Oxidative Stress - Liu, Jingjing; Barrientos, Antoni
Aims: Mitochondrial 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. Results: The 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,...
Redox and Reactive Oxygen Species Regulation of Mitochondrial Cytochrome c Oxidase Biogenesis - Bourens, Myriam; Fontanesi, Flavia; Soto, Iliana C.; Liu, Jingjing; Barrientos, Antoni
Significance: Cytochrome c oxidase (COX), the last enzyme of the mitochondrial respiratory chain, is the major oxygen consumer enzyme in the cell. COX biogenesis involves several redox-regulated steps. The process is highly regulated to prevent the formation of pro-oxidant intermediates. Recent Advances: Regulation of COX assembly involves several reactive oxygen species and redox-regulated steps. These include: (i) Intricate redox-controlled machineries coordinate the expression of COX isoenzymes depending on the environmental oxygen concentration. (ii) COX is a heme A-copper metalloenzyme. COX copper metallation involves the copper chaperone Cox17 and several other recently described cysteine-rich proteins, which are oxidatively folded in the...
Do Vicinal Disulfide Bridges Mediate Functionally Important Redox Transformations in Proteins? - de Araujo, Aline Dantas; Herzig, Volker; Windley, Monique J.; Dziemborowicz, Sławomir; Mobli, Mehdi; Nicholson, Graham M.; Alewood, Paul F.; King, Glenn F.
Vicinal disulfide bridges, in which a disulfide bond is formed between adjacent cysteine residues, constitute an unusual but expanding class of potential allosteric disulfides. Although vicinal disulfide rings (VDRs) are relatively uncommon, they have proven to be functionally critical in almost all proteins in which they have been discovered. However, it has proved difficult to test whether these sterically constrained disulfides participate in functionally important redox transformations. We demonstrate that chemical replacement of VDRs with dicarba or diselenide bridges can be used to assess whether VDRs function as allosteric disulfides. Our approach leads to the hypothesis that not all VDRs...
Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na+/K+-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats - Ge, Shun-Na; Zhao, Man-Man; Wu, Dong-Dong; Chen, Ying; Wang, Yi; Zhu, Jian-Hua; Cai, Wen-Jie; Zhu, Yi-Zhun; Zhu, Yi-Chun
Aims: The role of hydrogen sulfide (H2S) in renal sodium and water homeostasis is unknown. We investigated whether H2S promoted Na+/K+-ATPase endocytosis via the H2S/EGFR/gab1/PI3K/Akt pathway in renal tubular epithelial cells. Results: H2S decreased Na+/K+-ATPase activity and induced its endocytosis in renal tubular epithelial cells, which was abrogated by small interfering RNA (siRNA) knockdown of epidermal growth factor receptor (EGFR) and gab1, a dominant-negative mutant of Akt and PI3K inhibitors. H2S increased EGFR, gab1, PI3K, and Akt phosphorylation in both renal tubular epithelial cells and kidneys of chronic salt-loaded rats. These increases were abrogated by siRNA knockdown of EGFR, but...