Mechanism of tiron as scavenger of superoxide ions and free electrons

Taiwo, Fatai A.

doi:10.1155/2008/953692

Cited by 69 publications

(59 citation statements)

References 14 publications

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“…Tiron and Mn(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), which act as superoxide reducing agents (Ledenev et al, 1986) or inhibit superoxide formation (Taiwo, 2008), completely blocked rapid bacterial death (Figure 5D). Trolox, an α-tocopherol derivative that scavenges free radicals, the hydrogen peroxide scavenger DMTU and the iron-chelator deferoxamine also reduced bacteria killing, but less than Tiron or MnTBAP, providing further evidence that superoxide anion is the first ROS species produced.…”

Section: Resultsmentioning

confidence: 98%

Cytotoxic Cells Kill Intracellular Bacteria through Granulysin-Mediated Delivery of Granzymes

Walch

Dotiwala

Mulik

et al. 2014

Cell

174

178

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Summary When killer lymphocytes recognize infected cells, perforin delivers cytotoxic proteases (granzymes) into the target cell to trigger apoptosis. What happens to intracellular bacteria during this process is unclear. Human, but not rodent, cytotoxic granules also contain granulysin, an antimicrobial peptide. Here we show that granulysin delivers granzymes into bacteria to kill diverse bacterial strains. In E. coli, granzymes cleave electron transport chain complex I and oxidative stress defense proteins, generating ROS that rapidly kill bacteria. ROS scavengers and bacterial antioxidant protein overexpression inhibit bacterial death. Bacteria overexpressing a GzmB-uncleavable mutant of the complex I subunit nuoF or strains that lack complex I still die, but more slowly, suggesting that granzymes disrupt multiple vital bacterial pathways. Mice expressing transgenic granulysin are better able to clear L. monocytogenes. Thus killer cells play an unexpected role in bacterial defense.

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Section: Resultsmentioning

confidence: 98%

Cytotoxic Cells Kill Intracellular Bacteria through Granulysin-Mediated Delivery of Granzymes

Walch

Dotiwala

Mulik

et al. 2014

Cell

174

178

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“…We found that COPD lung tissue has much higher levels of nitrotyrosine and 8-HG residues when compared with controls (indicating greater oxidative stress in the COPD samples), that NEP activity is directly inactivated by H 2 O 2 (which models the response of NEP to a number of oxidants in general), and that an antioxidant (tiron) prevents loss of NEP activity due to CSE, hypoxia, or H 2 O 2 , further strengthening this connection between reduced NEP activity and ROS in COPD. Although tiron acts as an SOD mimetic, it also is able to chelate certain metal ions, and has been shown to react with (''scavenge'') hydroxyl radicals (which are likely the major reactive species through which H 2 O 2 acts) at 100 times the rate that it reacts with superoxide radicals; tiron has been characterized as an electron trap (58). A preliminary experiment with other antioxidants with catalase-like activity suggests that, like these other antioxidants, in our experimental systems, tiron is able to combat oxidation by H 2 O 2 .…”

Section: Discussionmentioning

confidence: 99%

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Wick¹,

Buesing²,

Wehling³

et al. 2011

Am J Respir Crit Care Med

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Rationale: Studies with genetically engineered mice showed that decreased expression of the transmembrane peptidase neprilysin (NEP) increases susceptibility to hypoxic pulmonary vascular remodeling and hypertension; in hypoxic wild-type mice, expression is decreased early in distal pulmonary arteries, where prominent vascular remodeling occurs. Therefore, in humans with smoke-and hypoxia-induced vascular remodeling, as in chronic obstructive pulmonary disease (COPD), pulmonary activity/expression of NEP may likewise be decreased. Objectives: To test whether NEP activity and expression are reduced in COPD lungs and pulmonary arterial smooth muscle cells (SMCs) exposed to cigarette smoke extract or hypoxia and begin to investigate mechanisms involved. Methods: Control and advanced COPD lung lysates (n 5 13-14) were analyzed for NEP activity and protein and mRNA expression. As a control, dipeptidyl peptidase IV activity was analyzed. Lung sections were assessed for vascular remodeling and oxidant damage. Human pulmonary arterial SMCs were exposed to cigarette smoke extract, hypoxia, or H 2 O 2 , and incubated with antioxidants or lysosomal/proteasomal inhibitors. Measurements and Main Results: COPD lungs demonstrated areas of vascular rarification, distal muscularization, and variable intimal and prominent medial/adventitial thickening. NEP activity was reduced by 76%; NEP protein expression was decreased in alveolar walls and distal vessels; mRNA expression was also decreased. In SMCs exposed to cigarette smoke extract, hypoxia, and H 2 O 2 , NEP activity and expression were also reduced. Reactive oxygen species inactivated NEP activity; NEP protein degradation appeared to be substantially induced. Conclusions: Mechanisms responsible for reduced NEP activity and protein expression include oxidative reactions and protein degradation. Maintaining or increasing lung NEP may protect against pulmonary vascular remodeling in response to chronic smoke and hypoxia.Keywords: pulmonary hypertension; smooth muscle cell; smoking; oxidative stress; protein degradation Chronic obstructive pulmonary disease (COPD) is a leading cause of death; cigarette smoking is its number one risk factor (1). Pulmonary vascular remodeling, characterized by thickening, muscularization, and rarification of the distal vasculature (2-4), complicates COPD by contributing to pulmonary hypertension (PHTN) (3, 5). Many patients with COPD have mild PHTN at rest (6-8); however, the prevalence of exerciseinduced PHTN, which also may lead to right-sided heart failure in COPD (9), is much higher (. 91% [6,10]).COPD-associated PHTN is likely caused by initial injury of the pulmonary vascular endothelium by cigarette smoke (CS) (4), followed by inflammation and hypoxia, all of which may involve oxidant mechanisms (11,12). Factors that may contribute to variable susceptibility to COPD-associated PHTN, including interleukin-6 (IL-6) and the serotonin transporter (5HTT) (6,10,13,14), have been extensively investigated.Neprilysin (NEP, CD10) is a transmembrane ...

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“…The amount of ROS was measured to investigate the increased COX activity upon addition of ALA (Fig 5B). The changes in the amount of ROS were also determined when Tiron was added as a ROS scavenger [32,33]. ROS increased significantly after addition of ALA and/or SFC and was markedly suppressed under conditions where Tiron was added.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of COX in MKN45 cells by ALA+SFC (Fig 4) indicated that the leakage of superoxide anions from mitochondria most probably led to increased ROS (Fig 5). We used Tiron, an analog of vitamin E and a radical scavenger, as a ROS scavenger [32,33]. Tiron reduced ROS levels and showed recovery of cell proliferation (Fig 5).…”

Section: Discussionmentioning

confidence: 99%

Inverse correlation between heme synthesis and the Warburg effect in cancer cells

Sugiyama

Takahashi

Takahashi³

et al. 2019

Preprint

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Abstracts 12Cancer cells show a bias toward the glycolytic system over the conventional mitochondrial 13 electron transfer system for obtaining energy. This biased metabolic adaptation is called the Warburg 14 effect. Cancer cells also exhibit a characteristic metabolism, a decreased heme synthesizing ability. Here 15 we show that heme synthesis and the Warburg effect are inversely correlated. We used human gastric 16 cancer cell lines to investigate glycolytic metabolism and electron transfer system toward 17 promotion/inhibition of heme synthesis. Under hypoxic conditions, heme synthesis was suppressed and 18 the glycolytic system was enhanced. Addition of a heme precursor for the promotion of heme synthesis 19 led to an enhanced electron transfer system and inhibited the glycolytic system and vice versa. Enhanced 20 heme synthesis leads to suppression of cancer cell proliferation by increasing intracellular reactive oxygen 21 species levels. Collectively, the promotion of heme synthesis in cancer cells eliminated the Warburg effect 22 by shifting energy metabolism from glycolysis to oxidative phosphorylation. 3 23 33 CoA, which links the glycolytic pathway and TCA cycle. Thus, HIF-1 regulates PDK-1 and functions as 34 a modulator of glycolysis and TCA cycle. Moreover, HIF-1 induces glucose transporter-1 and glycolytic 35 enzymes [6,7] and consequently leads to increased lactic acid formation. Thus, HIF-1 shifts metabolism 36 from oxidative phosphorylation to glycolysis under hypoxic conditions [8,9], thereby promoting the 37 Warburg effect under hypoxia. 38 5-Aminolevulinic acid (ALA) is a precursor in the porphyrin synthesis pathway leading to heme 39 formation [10]. The rate-limiting enzyme in heme synthesis is the mitochondrial enzyme ALA synthase 4 40 (ALAS) [11]. ALA is metabolized to protoporphyrin IX (PpIX) by multiple enzymatic reactions while 41 between cytoplasm and mitochondria, and is finally synthesized into heme by the enzyme ferrochelatase, 42 which coordinates iron ion to porphyrin [12]. Administration of ALA into tumors leads to intracellular 43 accumulation of PpIX because cancer cells exert limited ferrochelatase activity [13,14]. Hypoxia is 44 believed to induce a reduction in PpIX accumulation [15,16]. To the best of our knowledge, the influence 45 of hypoxia on heme synthesis has not yet been clarified [17,18]. 46One of the advantages of the Warburg effect is the ability to suppress cytotoxic reactive oxygen 47 6 60 Methods 61

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Mechanism of tiron as scavenger of superoxide ions and free electrons

Cited by 69 publications

References 14 publications

Cytotoxic Cells Kill Intracellular Bacteria through Granulysin-Mediated Delivery of Granzymes

Cytotoxic Cells Kill Intracellular Bacteria through Granulysin-Mediated Delivery of Granzymes

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Inverse correlation between heme synthesis and the Warburg effect in cancer cells

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