Formation Of Reactive Aldehydes Research Articles

Lipid peroxidation-derived modification and its effect on the activity of glutathione peroxidase 1

Oxidative stress and the resulting lipid peroxidation are associated with various pathological states, including neurodegenerative diseases and cancer. The end products of lipid peroxidation, such as 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal (HNE), and methylglyoxal (MG), exert several biological effects through modification of various cellular components, including DNA and proteins. Glutathione peroxidase 1 (GPx1) is an intracellular antioxidant enzyme that uses glutathione (GSH) to reduce a variety of peroxides, thereby modulating cellular oxidative stress and redox-mediated responses. GPx1 contains nucleophilic amino acids at its active (one Sec) and GSH-binding (four Arg and one Lys) sites. We found that lipid peroxidation-derived reactive aldehydes (ONE, HNE, and MG) modified the GSH-binding site, resulting in the inhibition of GPx1 activity. Mass spectrometry-based proteomic analysis identified the sites modified by each aldehyde (ONE, 14 sites; HNE, 7 sites; MG, 9 sites). The GSH-binding sites modified were as follows: ONE, Arg57, 103, 184, and 185; HNE, Lys91; MG, Arg103. Upon incubation of GPx1 with each aldehyde, ONE reduced GPx1 activity more significantly than did HNE or MG in a dose- and time-dependent manner. The addition of GSH to GPx1 3 h after incubation with ONE prevented further inhibition by trapping ONE as a ONE-GSH adduct. However, the activity of GPx1 was not restored to the initial level, indicating that ONE modified GPx1 irreversibly. This study suggests that oxidative damage to lipids, resulting in the formation of reactive aldehydes, can amplify cellular oxidative stress via direct inactivation of GPx1, which increases the production of intracellular peroxides.

Nuclear localization of NRF2 in stroma of HER2 positive and triple-negative breast cancer

Breast cancer is one of the leading causes of cancer-related mortality in women. During tumor growth, periods of hypoxia are followed by reoxygenation due to neovascularisation leading to disturbed redox homeostasis. ROS (Reactive Oxygen Species) produced under hypoxia activate HIF1α. ROS can also activate the major antioxidant transcription factor NRF2, but also cause damage to biomolecules. Lipids are susceptible to peroxidation, as evidenced by the formation of reactive aldehydes, among which, HNE (4-hydroxynonenal) is the most studied one. Knowing that HIF1α (Hypoxia Inducing Factor 1α) is associated with breast cancer malignancy, we aimed to investigate its correlation with HNE and NRF2 (Nuclear factor erythroid 2-related factor 2). Our results show that HIF1α is activated in breast cancer, indicating an increase in ROS but not followed by HNE production. On the other hand, NRF2 was increased in all types of breast cancer suggesting that oxidative stress is present in these pathologies, but also supporting HIF1α. Interestingly, NRF2 was activated in HER2 positive and TNBC, indicating the role of stromal NRF2 in breast cancer malignancy.

4-Hydroxy-2-nonenal attenuates 8-oxoguanine DNA glycosylase 1 activity.

Elevated cellular oxidative stress and oxidative DNA damage are key contributors to impaired cardiac function in diabetes. During chronic inflammation, reactive oxygen species (ROS)-induced lipid peroxidation results in the formation of reactive aldehydes, foremost of which is 4-hydroxy-2-nonenal (4HNE). 4HNE forms covalent adducts with proteins, negatively impacting cellular protein function. During conditions of elevated oxidative stress, oxidative DNA damage such as modification by 8-hydroxydeoxyguanosine (8OHdG) is repaired by 8-oxoguanine glycosylase-1 (OGG-1). Based on these facts, we hypothesized that 4HNE forms adducts with OGG-1 inhibiting its activity, and thus, increases the levels of 8OHG in diabetic heart tissues. To test our hypothesis, we evaluated OGG-1 activity, 8OHG and 4HNE in the hearts of leptin receptor deficient db/db mice, a type-2 diabetic model. We also treated the recombinant OGG-1 with 4HNE to measure direct adduction. We found decreased OGG-1 activity (P > .05), increased 8OHG (P > .05) and increased 4HNE adducts (P > .05) along with low aldehyde dehydrogenase-2 activity (P > .05). The increased colocalization of OGG-1 and 4HNE in cardiomyocytes suggest 4HNE adduction on OGG-1. Furthermore, colocalization of 8OHG and OGG-1 with mitochondrial markers TOM 20 and aconitase, respectively, indicated significant levels of oxidatively-induced mtDNA damage and implicated a role for mitochondrial OGG-1 function. In vitro exposure of recombinant OGG-1 (rOGG-1) with increasing concentrations of 4HNE resulted in a concentration-dependent decrease in OGG-1 activity. Mass spectral analysis of trypsin digests of 4HNE-treated rOGG-1 identified 4HNE adducts on C28, C75, C163, H179, H237, C241, K249, H270, and H282. In silico molecular modeling of 4HNE-K249 OGG-1 and 4HNE-H270 OGG-1 mechanistically supported 4HNE-mediated enzymatic inhibition of OGG-1. In conclusion, these data support the hypothesis that inhibition of OGG-1 by direct modification by 4HNE contributes to decreased OGG-1 activity and increased 8OHG-modified DNA that are present in the diabetic heart.

Correction: Formation of reactive aldehydes (MDA, HHE, HNE) during the digestion of cod liver oil: comparison of human and porcine in vitro digestion models

Correction for 'Formation of reactive aldehydes (MDA, HHE, HNE) during the digestion of cod liver oil: comparison of human and porcine in vitro digestion models' by Cecilia Tullberg et al., Food Funct., 2016, 7, 1401-1412.

Abstract 4051: Lipid peroxidation-derived DNA adduct formation in obesity-related hepatocarcinogenesis

Abstract In this study we are investigating the role and mechanism of formation of Lipid-peroxidation (LPO)-derived DNA adduct formation in obesity-related hepatocarcinogenesis. Obesity has been implicated as a risk factor for many types of cancer, particularly hepatocellular carcinoma (HCC). HCC incidence correlates with the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in the US. The mechanisms underlying this increased risk of liver cancer in the obese population are still unclear. Liver tissue damage from fat accumulation in NAFLD and NASH produce inflammation and increased levels of reactive oxygen species (ROS). ROS induce LPO of polyunsaturated fatty acids (PUFAs) in cell membranes leading to the formation of reactive aldehydes, such as acrolein and 4-hydroxy-2-nonenal (HNE), which react with DNA forming the DNA adducts γ-OHPdG and DHH-ϵdA, respectively. γ-OHPdG is derived from ω-6 and ω-3 PUFAs, while DHH-ϵdA is specifically from ω-6 fatty acids. Previous data has indicated that mutational hotspots targeted by γ-OHPdG and DHH-ϵdA may be within key cancer driver genes, such as p53. Research has shown that B-6 mice fed a high fat diet (HFD) develop fatty liver disease and eventually HCC. The livers of B-6 mice fed a HFD showed an increased ω-6/ω-3 PUFAs ratio. We have detected and quantified γ-OHPdG and DHH-ϵdA by LC-MS/MS in livers from six healthy individuals and six NAFLD patients and found that levels of DHH-ϵdA in the DNA of the fatty liver samples were nearly three-fold higher than that in normal liver samples. Preliminary in vitro data using primary human hepatocytes has indicated that treatment with oleic and palmitic acid promote the formation of γ-OHPdG. Similarly, treatment of these cells with the epoxide of HNE, 2,3-epoxy-4-hydroxynonanal (EH), and the omega-6 fatty acid, arachidonic acid, induce the formation of DHH-ϵdA, supporting the proposed mechanism of adduct formation. In an 80-week tumor bioassay using C57Bl/6J mice on a HFD, we have observed through live-animal MRI imaging and immunohistochemistry, an increase in pro-inflammatory white adipose tissue accumulation, infiltration of fat into the liver and an increase in overall body weight compared to a low fat diet control. In addition, in mice fed a HFD combined with the green-tea derived antioxidant Theaphenon E, we observed through MRI, reduction in body weight gain, white adipose tissue, and lipid accumulation in liver. Theaphenon E has the potential to decrease fat accumulation and inflammation within the liver that lead to decreases in LPO-derived adduct formation and consequently, the mutations critical for HCC development. Citation Format: Heidi Coia, Hongyi Guan, Ying Fu, Marcin Dyba, Fung-Lung Chung. Lipid peroxidation-derived DNA adduct formation in obesity-related hepatocarcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4051.

Alcohol, Aldehydes, Adducts and Airways.

Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with alcohol use disorder who smoke cigarettes. In addition to the above aldehydes, several other aldehydes like 4-hydroxynonenal, formaldehyde and acrolein are also detected in the lung due to exposure to toxic gases, vapors and chemicals. These aldehydes react with nucleophilic targets in cells such as DNA, lipids and proteins to form both stable and unstable adducts. This adduction may disturb cellular functions as well as damage proteins, nucleic acids and lipids. Among several adducts formed in the lung, malondialdehyde DNA (MDA-DNA) adduct and hybrid malondialdehyde-acetaldehyde (MAA) protein adducts have been shown to initiate several pathological conditions in the lung. MDA-DNA adducts are pre-mutagenic in mammalian cells and induce frame shift and base-pair substitution mutations, whereas MAA protein adducts have been shown to induce inflammation and inhibit wound healing. This review provides an insight into different reactive aldehyde adducts and their role in the pathogenesis of lung disease.

Autoantibodies against basement membrane collagen type IV are associated with myocardial infarction

BackgroundCollagen type IV is the major constituent of basement membranes underlying endothelial cells and is important for endothelial cell attachment and function. Autoantibodies against native collagen type IV have been found in various autoimmune diseases. Oxidation of LDL in the vascular wall results in the formation of reactive aldehydes, which could modify surrounding matrix proteins. Like oxidized LDL, these modified matrix proteins are likely to induce immune responses. We examined whether autoantibodies against native or aldehyde-modified collagen type IV are associated with myocardial infarction. MethodsIgM and IgG against native and aldehyde-modified collagen type IV were measured by ELISA in serum from 387 survivors of a first myocardial infarction and 387 age- and sex-matched controls. ResultsPost-infarction patients had significantly increased levels of IgM against native collagen type IV, and IgG against native collagen type IV was present at detectable level in 17% of patients as opposed to 7% of controls (p<0.001). Controlling for major cardiovascular risk factors demonstrated that the presence of IgG against native collagen type IV was associated with myocardial infarction (OR 2.9 (1.6–5.4), p=0.001). Similarly, subjects in the highest quartile of IgM against native collagen type IV had increased risk of having suffered myocardial infarction (OR 3.11 (1.8–5.4), p<0.001) after adjusting for cardiovascular risk factors. In contrast, IgG against aldehyde-modified collagen type IV was decreased in myocardial infarction patients, but this association was not independent of established cardiovascular risk factors. ConclusionAutoantibodies against collagen type IV are associated with myocardial infarction independently of traditional cardiovascular risk factors.

4-Hydroxy-2-nonenal, an oxidative stress marker in crevicular fluid and serum in type 2 diabetes with chronic periodontitis.

Objective:Chronic periodontitis (CP) is a common, chronic inflammatory disease initiated by bacteria, which has an increased prevalence and severity in patients with type 2 diabetes mellitus (t2 DM). A variety of reactive oxygen species are able to cause direct damage to proteins, deoxyribonucleic acid, carbohydrates and lipids. Lipid peroxidation is always combined with the formation of reactive aldehydes like 4-Hydroxy-2-nonenal (HNE). The purpose of this study was to determine the presence of the HNE-His adducts levels in serum and gingival crevicular fluid (GCF) in t2 DM among CP subjects and to find an association, if any.Materials and Methods:A total of 40 subjects (20 males and 20 females) were selected based on their clinical parameters into three groups: Group 1 (10 healthy), Group 2 (15 subjects, CP without t2 DM), Group 3 (15 subjects, CP with t2 DM). Serum and GCF samples were collected to estimate the levels of the HNE-His adducts by the enzyme linked immunosorbent assay.Results:The mean HNE-His adducts concentration both in serum and GCF was highest for Group 3 followed by Group 2 and least in Group 1.Conclusions:All samples in each group tested positive for HNE-His adducts assay. Serum and GCF HNE-His adducts concentration both in t2 DM with CP and non-diabetic CP subjects were higher than the healthy controls. Further large scale longitudinal studies should be carried out to confirm positive correlations.

Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure.

Experimental evidence has suggested that semicarbazide-sensitive amine oxidase is involved in vascular endothelial damage and in the process of atherosclerosis, through the formation of reactive aldehydes, hydrogen peroxide and ammonia from endogenous substrates. Recent evidence indicates that semicarbazide-sensitive amine oxidase may be identical with the vascular adhesion protein-1. In patients with diabetes mellitus and chronic heart failure the plasma activity is raised relative to the severity of the disease. The prognostic value of plasma semicarbazide-sensitive amine oxidase is not known. Plasma semicarbazide-sensitive amine oxidase activity was measured at baseline in patients with moderate to severe chronic heart failure who participated in a large European study (PRIME-II). The 372 patients who took part in a pre-defined substudy in The Netherlands were investigated and a survival follow-up (maximum 5.4 years, mean 3.4 years) was carried out. Within the follow-up period 195 patients died. Plasma semicarbazide-sensitive amine oxidase was higher at baseline in those who died than in the survivors (653+/-258 vs 540+/-242 mU. l(-1), P<0.001). Dividing the patients into two groups according to plasma values above or below the median value of 550 mU. l(-1), semicarbazide-sensitive amine oxidase was found to be a prognostic parameter for survival, both in univariate (P<0.0001) and in multivariate (P=0.0106) analysis. Semicarbazide-sensitive amine oxidase values >550 mU. l(-1)had a 1. 50 (95% CI, 1.10-2.04) times increased risk of death. The finding that plasma semicarbazide-sensitive amine oxidase is an independent prognostic marker for mortality in chronic heart failure supports the concept that an elevated plasma semicarbazide-sensitive amine oxidase level has deleterious effects, possibly due to vascular endothelial damage.

TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload.

We have shown that lipid peroxidation stimulates collagen-alpha 1 (I) gene transcription in cultured cells. Because iron is a transitional metal known to induce lipid peroxidation, we investigated whether hepatic lipid peroxidation modulates collagen gene expression in iron-overloaded rats. In this animal model of hemochromatosis, we show colocalization with iron in the hepatic acinar zone 1 of both lipid peroxidation and increased collagen-alpha 1 (I) transcripts, using immunohistochemistry for malondialdehyde-protein adducts and in situ hybridization, respectively. Iron overload stimulated the expression of the cytokine transforming growth factor-beta (TGF-beta) in acinar zone 1, in spite of the minor degree of hepatocellular necrosis and inflammation. The formation of reactive aldehydes and TGF-beta, both inducers of collagen gene expression, may play a role in the stimulation of hepatic collagen production in iron overload. These mechanisms could be a link between iron overload and fibrosis in genetic hemochromatosis.

Ascorbic acid stimulation of collagen biosynthesis independent of hydroxylation

Ascorbic acid stimulates collagen gene expression in cultured fibroblasts but mechanisms responsible for this effect are poorly understood. In the presence of the transitional metal iron, ascorbic acid could induce lipid peroxidation with the formation of reactive aldehydes. Because another aldehyde, acetaldehyde, the first metabolite of ethanol, also stimulates collagen transcription in cultured fibroblasts, we investigated whether ascorbic acid induces lipid peroxidation in cultured cells and if this is the mechanism by which ascorbic acid stimulates collagen gene expression. Ascorbic acid (0.2 mmol/L) induced lipid peroxidation and stimulated collagen alpha 1(I) gene transcription in cultured human fibroblasts. Inhibition of the ascorbic acid-induced lipid peroxidation in cultured human fibroblasts with alpha-tocopherol (50 mumol/L) or methylene blue (10 mumol/L) prevented the stimulation of collagen gene expression. Addition of malondialdehyde (200 mumol/L), a product of lipid peroxidation, to cultured human fibroblasts also increased two- to threefold collagen production and procollagen alpha 1(I) mRNA levels. Thus, ascorbic acid induces lipid peroxidation and reactive aldehydes, and this step may be necessary for stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts.

Formation of reactive aldehydes from fatty acids in a iron(2+)/hydrogen peroxide oxidation system

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFormation of reactive aldehydes from fatty acids in a iron(2+)/hydrogen peroxide oxidation systemHirotoshi Tamura, Kazumi Kitta, and Takayuki ShibamotoCite this: J. Agric. Food Chem. 1991, 39, 3, 439–442Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://doi.org/10.1021/jf00003a002RIGHTS & PERMISSIONSArticle Views592Altmetric-Citations66LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (482 KB) Get e-Alerts Get e-Alerts

Stimulation of Collagen Gene Expression by Ascorbic Acid in Cultured Human Fibroblasts: A role for lipid peroxidation?

Ascorbic acid stimulates collagen gene expression in cultural fibroblasts (Lyons, B. L., and Schwartz, R. L. (1984) Nucleic Acids Res. 12, 2569-2579), but the mechanisms responsible for this effect are poorly understood. In the presence of the transitional metal iron, ascorbic acid could induce lipid peroxidation with the formation of reactive aldehydes. Since another aldehyde, acetaldehyde, the first metabolite of ethanol, also stimulates collagen transcription in cultured fibroblasts (Brenner, D. A., and Chojkier, M. (1987) J. Biol. Chem 262, 17690-17696), we investigated whether ascorbic acid induces lipid peroxidation in cultured cells and if this is the mechanism by which ascorbic acid stimulates collagen gene expression. Ascorbic acid (0.2 mM) induced lipid peroxidation in cultured human fibroblasts judging by the production of thiobarbituric acid-reactive substances and carbonyl groups, and by the presence of malondialdehyde- and 4-hydroxynonenal-protein adducts. Ascorbic acid stimulated (2-3-fold) the net production of collagen relative to total proteins, the levels of procollagen alpha 1 (I) mRNA and the transcription of this gene. Inhibition of the ascorbic acid-induced lipid peroxidation in cultured human fibroblasts with alpha-tocopherol (50 microM) or methylene blue (10 microM) prevented the stimulation of collagen gene expression. The addition of malondialdehyde (200 microM), a product of lipid peroxidation, to cultured human fibroblasts also increased 2-3-fold collagen production and procollagen alpha 1 (I) mRNA levels. Thus, ascorbic acid induces lipid peroxidation and reactive aldehydes and this step may be necessary for the stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts.

Studies of combustion processes leading to ignition of isomeric hexanes

The extent of overall reaction at various temperatures preceding ignition, and the ignition characteristics, of the isomeric hexanes have been studied in air at atmospheric pressure in a quartz reaction chamber. The degree and the position of branching, particularly when the latter involves an alteration in the number and type of C H bonds, markedly affect the preflame and ignition behaviour. In general, the greater the degree of branching of the molecule (that is, the greater the proportion of tertiary C H bonds to secondary C H bonds) the higher the temperature at which reactions commence, the lower the overall extent of preflame reaction, and the higher the ignition temperature. The cool flame activity can be solely related to the methylene groups in the molecule: 2,3-dimethylbutane, which has no methylene groups, does not show the cool flame phenomenon while with the other isomers the cool flame activity increases with increasing number of methylene groups. The apparent decrease in oxidation tendency of the hydrocarbons with increasing proportion of tertiary C H bonds to secondary C H bonds, in spite of the lower bond strengths of the former, is attributed to the formation of unreactive ketones from the tertiary centres and the formation of reactive aldehydes from the secondary centres. The olefins formed in the combustion process are considered to be largely responsible for the negative temperature coefficient which follows the cool flame region. At high temperatures beyond the zone of negative temperature coefficient, where ketones are no longer inert in comparison with aldehydes, and olefins are incapable of inhibiting reactions because of their proneness to oxidative degradation, the results on the preflame and ignition behaviour of the isomeric hexanes are more in accord with the nature and the strength of the various bonds comprising the molecule. The present results provide a means of interpretation and coordination of much of the earlier work on these hydrocarbons, including that carried out in gasoline engines.