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Chemical Research in Toxicology Aug 2020Cigarette smoking is an important source of human exposure to toxicants and carcinogens and contributes significantly to cancer morbidity and mortality worldwide....
Quantitative Liquid Chromatography-Nanoelectrospray Ionization-High-Resolution Tandem Mass Spectrometry Analysis of Acrolein-DNA Adducts and Etheno-DNA Adducts in Oral Cells from Cigarette Smokers and Nonsmokers.
Cigarette smoking is an important source of human exposure to toxicants and carcinogens and contributes significantly to cancer morbidity and mortality worldwide. Acrolein, a widespread environmental pollutant, is present in relatively high amounts in cigarette smoke and can react directly with DNA to form DNA adducts, which serve as important biomarkers for the assessment of exposure to acrolein and its potential role in smoking related cancer. Etheno-DNA adducts are promutagenic DNA lesions that can derive from exogenous chemicals as well as endogenous sources, including lipid peroxidation. In this study, we developed a combined method for the quantitation of (6/)-3-(2'-deoxyribos-1'-yl)-5,6,7,8,-tetrahydro-6-hydroxypyrimido[1,2-]purine-10(3)-one (α-OH-Acr-dGuo), (8/)-3-(2'-deoxyribos-1'-yl)-5,6,7,8,-tetrahydro-8-hydroxypyrimido[1,2-]purine-10(3)-one (γ-OH-Acr-dGuo), 1,-etheno-dAdo (εdAdo), and 3,-etheno-dCyd (εdCyd) adducts in oral rinse and cytobrush DNA from smokers and nonsmokers by liquid chromatography-nanoelelctrospray ionization-high-resolution tandem mass spectrometry (LC-NSI-HRMS/MS). For oral rinse samples, there was a statistically significant difference between the levels of α-OH-Acr-dGuo, γ-OH-Acr-dGuo, εdAdo, and εdCyd in smokers (12.1 ± 17.9, 163 ± 227, 182 ± 568, and 194 ± 400 adducts/10 nucleotides, respectively) and nonsmokers (1.85 ± 2.08, 5.95 ± 4.23, 7.69 ± 11.7, and 6.07 ± 10.9 adducts/10 nucleotides, respectively). For cytobrush samples, there was a statistically significant difference between the levels of γ-OH-Acr-dGuo and εdAdo in smokers (259 ± 540 and 82.9 ± 271 adducts/10 nucleotides, respectively) and nonsmokers (7.37 ± 5.09 and 16.2 ± 30.2 adducts/10 nucleotides, respectively) but not for α-OH-Acr-dGuo and εdCyd. Our results demonstrate that oral mucosa cells are an excellent source of material for evaluating DNA adducts to be used as biomarkers of tobacco smoke exposure and molecular changes potentially related to cancer.
Topics: Acrolein; Adult; Cell Line; Chromatography, Liquid; DNA Adducts; Humans; Molecular Structure; Non-Smokers; Smokers; Tandem Mass Spectrometry
PubMed: 32635726
DOI: 10.1021/acs.chemrestox.0c00223 -
Journal of Neurochemistry Jun 2017Acrolein is one of the most toxic byproducts of lipid peroxidation, and it has been shown to be associated with multiple pathological processes in trauma and diseases,...
Acrolein is one of the most toxic byproducts of lipid peroxidation, and it has been shown to be associated with multiple pathological processes in trauma and diseases, including spinal cord injury, multiple sclerosis, and Alzheimer's disease. Therefore, suppressing acrolein using acrolein scavengers has been suggested as a novel strategy of neuroprotection. In an effort to identify effective acrolein scavengers, we have confirmed that dimercaprol, which possesses thiol functional groups, could bind and trap acrolein. We demonstrated the reaction between acrolein and dimercaprol in an abiotic condition by nuclear magnetic resonance spectroscopy. Specifically, dimercaprol is able to bind to both the carbon double bond and aldehyde group of acrolein. Its acrolein scavenging capability was further demonstrated by in vitro results that showed that dimercaprol could significantly protect PC-12 cells from acrolein-mediated cell death in a dose-dependent manner. Furthermore, dimercaprol, when applied systemically through intraperitoneal injection, could significantly reduce acrolein contents in spinal cord tissue following a spinal cord contusion injury in rats, a condition known to have elevated acrolein concentration. Taken together, dimercaprol may be an effective acrolein scavenger and a viable candidate for acrolein detoxification.
Topics: Acrolein; Animals; Body Weight; Cell Death; Dimercaprol; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Free Radical Scavengers; L-Lactate Dehydrogenase; Magnetic Resonance Spectroscopy; Male; PC12 Cells; Rats; Spinal Cord; Spinal Cord Injuries
PubMed: 28301040
DOI: 10.1111/jnc.14025 -
Nutrients Aug 2022In this study, the effects of cinnamaldehyde and curcumin on Akt2, a serine/threonine protein kinase central to the insulin signaling pathway, were examined in...
In this study, the effects of cinnamaldehyde and curcumin on Akt2, a serine/threonine protein kinase central to the insulin signaling pathway, were examined in preadipocytes. Cinnamaldehyde or curcumin treatment increased Akt2 phosphorylation at multiple sites including T450 and Y475, but had no effect on Akt2 phosphorylation at S474, which is critical for Akt2 activation. Surprisingly, insulin treatment with cinnamaldehyde or curcumin increased p-Akt2 (S474) by 3.5-fold versus insulin treatment alone. Furthermore, combined cinnamaldehyde, curcumin, and insulin treatment increased p-Akt2 (S474) by 7-fold versus insulin treatment alone. Interestingly, cinnamaldehyde and curcumin inhibited both serine/threonine phosphatase 2A (PP2A) and protein tyrosine phosphatase 1B (PTP1B). Akt2 activation is a multistep process that requires phosphorylation at T450 for proper folding and maturation, and phosphorylation of both Y475 and S474 for stabilization of the catalytic domain. It is plausible that by inhibiting PP2A and PTP1B, cinnamaldehyde and curcumin increase phosphorylation at T450 and Y475, and prime Akt2 for insulin-stimulated phosphorylation at S474. Notably, the combination of a PP2A inhibitor, okadaic acid, and a PTP1B inhibitor increased p-Akt2 (S474), even in the absence of insulin. Future combinations of PP2A and PTP1B inhibitors provide a rational platform to engineer new therapeutics for insulin resistance syndrome.
Topics: Acrolein; Curcumin; Enzyme Inhibitors; Insulin; Phosphorylation; Serine
PubMed: 36014807
DOI: 10.3390/nu14163301 -
Computational and Mathematical Methods... 2022Airway inflammation, airway hypersecretion, and airway remodeling are believed to be involved in the process of lung fibrosis. Nowadays, acrolein is widely used to...
Airway inflammation, airway hypersecretion, and airway remodeling are believed to be involved in the process of lung fibrosis. Nowadays, acrolein is widely used to establish the model of airway remodeling. An active component of propolis, named caffeic acid phenethyl ester (CAPE), is recognized as an inhibitor of the NF-B pathway and shows anti-inflammatory effect. The purpose of this study was to investigate the protective effect of CAPE on acrolein-induced airway remodeling. 24 mice were divided into 4 groups: control group; acrolein group, mice received acrolein (inhalation of acrolein for 20 days); CAPE group, mice received CAPE (30 mg/kg); and acrolein+CAPE group, mice received acrolein and CAPE. After 20 days, lung tissue was removed for histopathology and immunohistochemical evaluations. TGF-1 and Muc5ac levels were measured at the protein and molecular levels. Additionally, the phospho-P65/P65 values in the airway smooth muscle cells treated with TGF-1 or CAPE were detected by Western blot. The results showed that compared with the control, subepithelial collagen deposition, airway inflammation, and peribronchus fibrosis were inhibited in the group treated with CAPE. Furthermore, TGF-1 was significantly decreased in the acrolein+CAPE group compared with the acrolein group. Additionally, we identified CAPE inhibited P65 phosphorylation. However, CAPE did not inhibit the Muc5ac overproduction and hypersecretion induced by acrolein. In conclusion, as an inhibitor of the NF-B pathway, CAPE attenuated the release of TGF-1 which inhibited the fibrogenic progress induced by acrolein in mice and took no effect on inhibiting airway mucus hypersecretion.
Topics: Acrolein; Airway Remodeling; Animals; Inflammation; Mice; NF-kappa B; Transforming Growth Factor beta1
PubMed: 35432586
DOI: 10.1155/2022/4984634 -
Environmental Toxicology and... Apr 2021Establishing accurate dosimetry is important for assessing the toxicity of xenobiotics as well as for comparing responses between different test systems. In this study,...
Establishing accurate dosimetry is important for assessing the toxicity of xenobiotics as well as for comparing responses between different test systems. In this study, we used acrolein as a model toxicant and defined the concentration-response relationships of the key adverse responses in normal human bronchial epithelial (NHBE) cells and human mucoepidermoid pulmonary carcinoma (NCI-H292) cells. Direct trace analysis of intracellular free acrolein is extremely challenging, if not impossible. Therefore, we developed a new method for indirectly estimating the intracellular uptake of acrolein. A 10-min treatment was employed to capture the rapid occurrence of the key alkylation reactions of acrolein. Responses, including protein carbonylation, GSH depletion, and GSH-acrolein (GSH-ACR) adduct formation, were all linearly correlated with acrolein uptake in both cell types. Compared to the NCI-H292 mucoepidermoid carcinoma cells, NHBE cells were more sensitive to acrolein exposure. Furthermore, results from the time-course studies demonstrated that depletion and conjugation of GSH were the primary adverse events and directly associated with the cytotoxicity induced by acrolein. In summary, these data suggest that cell susceptibility to acrolein exposure is closely associated with acrolein uptake and formation of GSH-ACR adducts. The dosimetric analysis presented in this study may provide useful information for computational modeling and risk assessment of acrolein using different test systems.
Topics: Acrolein; Cell Line; Cell Survival; Epithelial Cells; Glutathione; Humans; Lung; Lung Neoplasms; Protein Carbonylation
PubMed: 33385576
DOI: 10.1016/j.etap.2020.103576 -
Carcinogenesis Jun 2022DNA adducts are central in the mechanism of carcinogenesis by genotoxic agents. We compared levels of a DNA adduct of acrolein, a genotoxic carcinogen found in...
DNA adducts are central in the mechanism of carcinogenesis by genotoxic agents. We compared levels of a DNA adduct of acrolein, a genotoxic carcinogen found in e-cigarette vapor, in oral cell DNA of e-cigarette users and non-users of any tobacco or nicotine product. e-Cigarette users and non-users visited our clinic once monthly for 6 months, and oral brushings and urine samples were collected. For this study, we analyzed oral cell DNA adducts from three monthly visits in e-cigarette users and non-users as confirmed by urinary cyanoethyl mercapturic acid and total nicotine equivalents. DNA was isolated from the oral brushings and analyzed by a validated liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method for the acrolein DNA adduct 8R/S-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10-(3H)-one (γ-OH-Acr-dGuo). The median value of this DNA adduct in the e-cigarette users was 179 fmol/µmol dGuo (range 5.0 - 793 fmol/µmol dGuo) while that for non-users was 21.0 fmol/µmol dGuo (range 5.0 - 539 fmol/µmol dGuo), P = 0.001. These results demonstrate for the first time that e-cigarette users have elevated levels of a carcinogen-DNA adduct in their oral cells.
Topics: Acrolein; Carcinogens; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Electronic Nicotine Delivery Systems; Nicotine; Spectrometry, Mass, Electrospray Ionization
PubMed: 35239969
DOI: 10.1093/carcin/bgac026 -
MBio Jan 2018Acrolein is a highly reactive electrophile causing toxic effects, such as DNA and protein adduction, oxidative stress, endoplasmic reticulum stress, immune dysfunction,...
Acrolein is a highly reactive electrophile causing toxic effects, such as DNA and protein adduction, oxidative stress, endoplasmic reticulum stress, immune dysfunction, and membrane damage. This Opinion/Hypothesis provides an overview of endogenous and exogenous acrolein sources, acrolein's mode of action, and its metabolic fate. Recent reports underpin the finding that gut microbial glycerol metabolism leading to the formation of reuterin is an additional source of endogenous acrolein. Reuterin is an antimicrobial multicomponent system consisting of 3-hydroxypropionaldehyde, its dimer and hydrate, and also acrolein. The major conclusion is that gut microbes can metabolize glycerol to reuterin and that this transformation occurs Given the known toxicity of acrolein, the observation that acrolein is formed in the gut necessitates further investigations on functional relevance for gut microbiota and the host.
Topics: Acrolein; Gastrointestinal Microbiome; Gastrointestinal Tract; Glycerol; Humans; Microbiota
PubMed: 29339426
DOI: 10.1128/mBio.01947-17 -
Neuroscience Jun 2016Although lipid peroxidation has long been associated with spinal cord injury (SCI), the specific role of lipid peroxidation-derived byproducts such as acrolein in...
Although lipid peroxidation has long been associated with spinal cord injury (SCI), the specific role of lipid peroxidation-derived byproducts such as acrolein in mediating damage remains to be fully understood. Acrolein, an α-β unsaturated aldehyde, is highly reactive with proteins, DNA, and phospholipids and is considered as a second toxic messenger that disseminates and augments initial free radical events. Previously, we showed that acrolein increased following traumatic SCI and injection of acrolein induced tissue damage. Here, we demonstrate that microinjection of acrolein into the thoracic spinal cord of adult rats resulted in dose-dependent tissue damage and functional deficits. At 24h (acute) after the microinjection, tissue damage, motoneuron loss, and spinal cord swelling were observed on sections stained with Cresyl Violet. Luxol fast blue staining further showed that acrolein injection resulted in dose-dependent demyelination. At 8weeks (chronic) after the microinjection, cord shrinkage, astrocyte activation, and macrophage infiltration were observed along with tissue damage, neuron loss, and demyelination. These pathological changes resulted in behavioral impairments as measured by both the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and grid walking analysis. Electron microscopy further demonstrated that acrolein induced axonal degeneration, demyelination, and macrophage infiltration. These results, combined with our previous reports, strongly suggest that acrolein may play a critical causal role in the pathogenesis of SCI and that targeting acrolein could be an attractive strategy for repair after SCI.
Topics: Acrolein; Animals; Astrocytes; Axons; Dose-Response Relationship, Drug; Female; Locomotion; Myelin Sheath; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries
PubMed: 27058147
DOI: 10.1016/j.neuroscience.2016.03.054 -
Scientific Reports Nov 2016Glycerol/diol dehydratases catalyze the conversion of glycerol to 3-hydroxypropionaldehyde (3-HPA), the basis of a multi-component system called reuterin. Reuterin has...
Glycerol/diol dehydratases catalyze the conversion of glycerol to 3-hydroxypropionaldehyde (3-HPA), the basis of a multi-component system called reuterin. Reuterin has antimicrobial properties and undergoes chemical conjugation with dietary heterocyclic amines (HCAs). In aqueous solution reuterin is in dynamic equilibrium with the toxicant acrolein. It was the aim of this study to investigate the extent of acrolein formation at various physiological conditions and to determine its role in biological and chemical activities. The application of a combined novel analytical approach including IC-PAD, LC-MS and NMR together with specific acrolein scavengers suggested for the first time that acrolein, and not 3-HPA, is the active compound responsible for HCA conjugation and antimicrobial activity attributed to reuterin. As formation of the HCA conjugate was observed in vivo, our results imply that acrolein is formed in the human gut with implications on detoxification of HCAs. We propose to re-define the term reuterin to include acrolein.
Topics: Acrolein; Anti-Bacterial Agents; Gastrointestinal Microbiome; Glyceraldehyde; Humans; Propane
PubMed: 27819285
DOI: 10.1038/srep36246 -
Molecular Nutrition & Food Research May 2022Acrolein (ACR), a lipid peroxidation product, pathologically participates in various chronic diseases. In vitro evidence suggestes that dietary dihydrochalcones (DHCs)...
SCOPE
Acrolein (ACR), a lipid peroxidation product, pathologically participates in various chronic diseases. In vitro evidence suggestes that dietary dihydrochalcones (DHCs) potentiate safe and alternative therapeutics to synthetic pharmaceuticals for ACR scavenging. Here, to investigate whether ingested DHCs could trap ACR and thereof result in reductions in endogenous ACR in mice is aimed.
METHODS AND RESULTS
Three doses of phloretin (25, 100, and 400 mg kg ), a major dietary DHC, are orally administrated to mice and 24 h urine and fecal samples are collected, respectively. High-resolution MS-based targeted metabolomics reveal for the first time that phloretin and its oxidized metabolite are able to trap endogenous ACR via formation of ACR conjugates. Quantification further demonstrate that a) more than 13% of ingested phloretin can dose-dependently trap 0.77-9.92 nmol of ACR within 24 h; b) phloretin ingestion leads to marked reductions in both free ACR and ACR metabolites in mouse urine compared to control; and c) trapping reactions by phloretin can account for up to 20.1% of the total decreases in endogenous ACR, depending on the administration doses.
CONCLUSION
Findings from this study indicate that regular consumption of DHCs-rich diets holds great promise to alleviate the development of ACR-associated chronic diseases.
Topics: Acrolein; Animals; Chalcones; Eating; Lipid Peroxidation; Mice; Phloretin
PubMed: 35194934
DOI: 10.1002/mnfr.202101107