Inhibition of Acrolein-Induced Apoptosis by the Antioxidant<i>N</i>-Acetylcysteine

Tanel, André; Averill‐Bates, Diana A.

doi:10.1124/jpet.106.114678

Cited by 59 publications

(36 citation statements)

References 39 publications

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“…5 It has been also reported that acrolein-induced apoptosis is inhibited by N-acetylcysteine. 29 However, the level of putrescine increased together with that of spermine and spermidine, and spermidine was higher than spermine by treatment with N-acetylcysteine (see Figure 4C). This indicates that N-acetylcysteine functions after acrolein is formed by SMO and AcPAO, and that the increase of 3 kinds of polyamines at the locus of infarction is a result of the decrease of tissue damage due to infarction.…”

Section: Discussionmentioning

confidence: 99%

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Saiki

Nishimura

Ishii

et al. 2009

Stroke

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Background and Purpose-We recently found that increases in plasma levels of protein-conjugated acrolein and polyamine oxidases, enzymes that produce acrolein, are good markers for stroke. The aim of this study was to determine whether the level of protein-conjugated acrolein is increased and levels of spermine and spermidine, the substrates of acrolein production, are decreased at the locus of infarction. Methods-A unilateral infarction was induced in mouse brain by photoinduction after injection of Rose Bengal. The volume of the infarction was analyzed using the public domain National Institutes of Health image program. The level of protein-conjugated acrolein at the locus of infarction and in plasma was measured by Western blotting and enzyme-linked immunosorbent assay, respectively. The levels of polyamines at the locus of infarction and in plasma were measured by high-performance liquid chromatography. Results-The level of protein-conjugated acrolein was greatly increased, and levels of spermine and spermidine were decreased at the locus of infarction at 24 hours after the induction of stroke. The size of infarction was significantly decreased by N-acetylcysteine, a scavenger of acrolein. It was also found that the increases in the protein-conjugated acrolein, polyamines, and polyamine oxidases in plasma were observed after the induction of stroke. Key Words: acrolein Ⅲ brain infarction Ⅲ neuroprotective agents Ⅲ polyamines Ⅲ risk factors B rain stroke is a serious pathology. However, there is a lack of good biomarkers for the early phase of stroke. We recently found that increased levels of protein-conjugated acrolein (PC-Acro) and the enzymes responsible for its production, polyamine oxidases (spermine oxidase and acetylpolyamine oxidase), are good biomarkers for human stroke. 1 We also found that measurement of PC-Acro together with interleukin-6 and C-reactive protein makes it possible to identify small infarctions, that is, silent brain infarction, with high sensitivity (89%) and specificity (91%). 2 This tool for early identification of stroke may help in the application of suitable therapy to delay or reduce aggravation of stroke. Conclusions-The results indicate that the induction of infarction is well correlated with the increase in protein-It is thought that cell damage is mainly caused by reactive oxygen species (ROS) 3 such as superoxide anion radical (O 2 Ϫ⅐ ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (⅐OH). However, when we compared the toxicity of acrolein (CH 2 ϭCHCHO) and ROS, we found that acrolein was more toxic than H 2 O 2 4 and slightly more toxic than ⅐OH 5 in cell culture systems. Furthermore, acrolein is thought to be produced by lipid peroxidation, 6 but we found that it was more effectively produced from 2 polyamines (spermine and spermidine), 1 which are abundant and essential for cell growth in eukaryotic cells. 7 Acrolein is spontaneously formed from 3-aminopropanal (NH 2 [CH 2 ] 2 CHO) produced from spermine by spermine oxidase (SMO) and less effectively from 3-acetam...

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Section: Discussionmentioning

confidence: 99%

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Saiki

Nishimura

Ishii

et al. 2009

Stroke

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“…7). A recent report noted the ability of NAC (1 mM for 24 hr) to increase clonogenic survival in CHO cells exposed to acrolein and to diminish acrolein-induced markers of apoptosis in these cells (Tanel and Averill-Bates, 2007). Either co-treatment, or 6-hr pre-treatment, of cells with 0.3 mM NAC protected the SN56 mouse cholinergic neuronal cell line from 100 μM acrolein (Wood et al, 2007).…”

Section: Acrolein-mediatedmentioning

confidence: 99%

“…Furthermore, the tubule cells were serum-deprived for 24 hr before acrolein treatment (Schwerdt et al, 2006) whereas the HMEC-1 cells in our studies were not. In CHO cells, one hour or longer exposure to 30-50 fmol acrolein per cell is required to cause a significant increase in toxicity (Tanel and AverillBates, 2005;Tanel and Averill-Bates, 2007). A 48-hr exposure to 200 μM acrolein was damaging to human A549 cells, whereas 100 μM was not (Hoshino et al, 2001).…”

Section: Acrolein-mediatedmentioning

confidence: 99%

Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells

Szadkowski¹,

Myers²

2008

Toxicology

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Acrolein is a reactive aldehyde that is a widespread environmental pollutant and can be generated endogenously from lipid peroxidation. The thioredoxin (Trx) system in endothelial cells plays a major role in the maintenance of cellular thiol redox balance, and is critical for cell survival. Normally, cells maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. In human microvascular endothelial cells, Trx1 was more sensitive than Trx2 to oxidation by acrolein. A 30-minute exposure to 2.5 μM acrolein caused partial oxidation of Trx1 but not Trx2. The active site dithiol of Trx1 was essentially completely oxidized by 5 μM acrolein whereas 12.5 μM was required for complete oxidation of Trx2. Partial recovery of the Trx1 redox status was observed over a 4 hour acrolein-free recovery period, with increases in the reduced form and decreases in the fully oxidized form. For cells treated with 2.5 or 5 μM acrolein the recovery did not require protein synthesis, whereas protein synthesis was required for the return of reduced Trx1 in cells treated with 12.5 μM acrolein. Pretreatment of cells with N-acetylcysteine (NAC) resulted in partial protection of Trx1 from oxidation by acrolein. In cells treated with acrolein for 30 min, followed by a 14-to 16-hr acrolein-free period, small but significant cytotoxic effects were observed with 2.5 μM acrolein whereas all cells were adversely affected by ≥ 12.5 μM. NAC pretreatment significantly decreased the percentage of stressed cells subsequently exposed to 5 or 12.5 μM acrolein. Given the critical role of the thioredoxins in cell survival, the ability of acrolein to oxidize both thioredoxins should be taken into account for a thorough understanding of its cytotoxic effects.

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“…In addition, a,~-unsaturated aldehydes can induce oxidative stress in cells by depleting cellular reduced glutathione, thereby altering signal transduction pathways in cells. At low concentrations, acrolein is known to trigger apoptotic cell death by mechanisms that involve activation of mitochondrial death pathways and caspases (Burcham and Fontaine, 2001 ;Stevens and Maier, 2008;Tanel and Averill-Bates, 2007). Caspases, particularly caspase 3, which can cleave substrates, such as poly(ADP-ribose) polymerase (PARP), actin and laminin, are widely used as markers for apoptosis in different cell types.…”

Section: The Nuclear Factor Kappa B (Nf -Kb)mentioning

confidence: 99%

“…Previous experiments demonstrate that treatment of cells with acrolein led to increased acrolein-protein adducts and enhanced caspase 3 activation resulting in proteolytic cleavage ofPARP (Burcham and Fontaine, 2001;Tanel and Averill-Bates, 2007). We measured the levels of acrolein-protein adduct in cells transfected with Aldh I a I-specific siRNA and noted that the levels of acrolein-protein adducts (P I, P2, P3)…”

Section: Ablation Of Aldhlal Gene Expression Increases Acrolein-inducmentioning

confidence: 99%

Cytotoxicity and cellular response to alpha, beta-unsaturated aldehydes : role of aldehyde dehydrogenases.

Makia¹

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Inhibition of Acrolein-Induced Apoptosis by the AntioxidantN-Acetylcysteine

Cited by 59 publications

References 39 publications

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells

Cytotoxicity and cellular response to alpha, beta-unsaturated aldehydes : role of aldehyde dehydrogenases.

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