Publications by authors named "Dmitry Litvinov"

29 Publications

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Intestinal and Hepatic Uptake of Dietary Peroxidized Lipids and Their Decomposition Products, and Their Subsequent Effects on Apolipoprotein A1 and Paraoxonase1.

Antioxidants (Basel) 2021 Aug 6;10(8). Epub 2021 Aug 6.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.

Both pro- and antiatherosclerotic effects have been ascribed to dietary peroxidized lipids. Confusion on the role of peroxidized lipids in atherosclerotic cardiovascular disease is punctuated by a lack of understanding regarding the metabolic fate and potential physiological effects of dietary peroxidized lipids and their decomposition products. This study sought to determine the metabolic fate and physiological ramifications of 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 13-HODE (13-hydroxyoctadecadienoic acid) supplementation in intestinal and hepatic cell lines, as well as any effects resulting from 13-HPODE or 13-HODE degradation products. In the presence of Caco-2 cells, 13-HPODE was rapidly reduced to 13-HODE. Upon entering the cell, 13-HODE appears to undergo decomposition, followed by esterification. Moreover, 13-HPODE undergoes autodecomposition to produce aldehydes such as 9-oxononanoic acid (9-ONA). Results indicate that 9-ONA was oxidized to azelaic acid (AzA) rapidly in cell culture media, but AzA was poorly absorbed by intestinal cells and remained detectable in cell culture media for up to 18 h. An increased apolipoprotein A1 (ApoA1) secretion was observed in Caco-2 cells in the presence of 13-HPODE, 9-ONA, and AzA, whereas such induction was not observed in HepG2 cells. However, 13-HPODE treatments suppressed paraoxonase 1 (PON1) activity, suggesting the induction of ApoA1 secretion by 13-HPODE may not represent functional high-density lipoprotein (HDL) capable of reducing oxidative stress. Alternatively, AzA induced both ApoA1 secretion and PON1 activity while suppressing ApoB secretion in differentiated Caco-2 cells but not in HepG2. These results suggest oxidation of 9-ONA to AzA might be an important phenomenon, resulting in the accumulation of potentially beneficial dietary peroxidized lipid-derived aldehydes.
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http://dx.doi.org/10.3390/antiox10081258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389297PMC
August 2021

Denaturation of human plasma high-density lipoproteins by urea studied by apolipoprotein A-I dissociation.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 01 19;1866(1):158814. Epub 2020 Sep 19.

Laboratory of Functional Genomics, Institute of Molecular Genetics of the Russian Academy of Sciences, Moscow, Russia.

We studied the mechanism of HDL denaturation with concomitant apoA-I dissociation with HDL preparations from 48 patients with a wide range of plasma HDL-C and evaluated the contribution of lipid-free apoA-I into cholesterol efflux from macrophage, in particular, mediated by cholesterol transporter ABCA1. We prepared HDL by precipitation of apoB-containing lipoproteins by polyethylene glycol and used the chaotropic agent urea to denature HDL preparations. Apo-I dissociation from urea-treated HDL was assessed by the increase of preβ-band fraction with agarose gel electrophoresis followed by electro transfer and immunodetection and by the increase of ABCA1-mediated efflux of fluorescent analogue BODIPY-Cholesterol from RAW 264.7 macrophages. The HDL denaturation is governed by a single transition to fully dissociated apoA-I and the transition cooperativity decreases with increasing HDL-C. The apoA-I release depends on phospholipid concentration of HDL preparation and HDL compositional and structural heterogeneity and is well described by apolipoprotein partition between aqueous and lipid phases. Dissociated apoA-I determines the increase of ABCA1-mediated efflux of BODIPY-Cholesterol from RAW 264.7 macrophages to patient HDL. The increase in apoA-I dissociation is associated with the increase of ABCA1 gene transcript in peripheral blood mononuclear cells from patients. The low level of plasma HDL particles may be compensated by their increased potency for apoA-I release, thus suggesting apoA-I dissociation as a new HDL functional property.
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http://dx.doi.org/10.1016/j.bbalip.2020.158814DOI Listing
January 2021

Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux.

Pharmaceut Med 2019 12;33(6):465-498

National Research Centre for Preventive Medicine, 10, Petroverigsky Street, 101990, Moscow, Russia.

Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing 'biological oxidations' activate cholesterol efflux and the substances influencing 'Signaling by GPCR and PTK6' inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.
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http://dx.doi.org/10.1007/s40290-019-00308-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101889PMC
December 2019

Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow-Berlin 2002.

J Cancer Res Clin Oncol 2019 Apr 6;145(4):1001-1012. Epub 2019 Mar 6.

Department of Pediatric Oncology/Hematology, Regional Oncological Hospital, Orenburg, Russia.

Purpose: Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow-Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR-) patients to 5000 U/m without jeopardizing efficacy.

Methods: Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m and in arm ASP-10000 (n = 354) 10 000 U/m IM.

Results: Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029).

Conclusion: Our findings suggest that weekly 5000 U/mE. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m for SR patients with childhood ALL.
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http://dx.doi.org/10.1007/s00432-019-02854-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435612PMC
April 2019

Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure.

J Membr Biol 2019 02 6;252(1):41-60. Epub 2018 Dec 6.

National Research Centre for Preventive Medicine, 10, Petroverigsky Street, Moscow, Russia, 101990.

ABCA1, ABCG1 transporters, and SR-B1 receptor are the major proteins involved in cholesterol efflux from cells. We superposed in silico the location of putative cholesterol (Chol)-binding motifs CRAC/CARC and CCM in human ABCA1, ABCG1, and SR-B1 with (1) transmembrane protein topology, (2) a profile of structural order of protein, and (3) with an influence of single amino acid substitutions on protein structure and function. ABCA1, ABCG1, and SR-B1 molecules contain 50, 19, and 13 Chol-binding motifs, respectively, that are localized either in membrane helices, or at membrane-water interface, or in water-exposed protein regions. Arginine residues in motifs that coincide with molecular recognition features within intrinsically disordered regions of the transporters are suggested to be important in cholesterol binding; cholesterol-arginine interaction may result in the induction of local order in protein structure. Chol-binding motifs in membrane helices may immobilize cholesterol, while motifs at membrane-water interface may be involved into the efflux of "active" cholesterol. Cholesterol may interfere with ATP binding in both nucleotide-binding domains of ABCA1 structure. For ABCA1 and ABCG1, but not for SR-B1, the presence of mirror code as a CARC-CRAC vector couple in the C-terminal helices controlling protein-cholesterol interactions in the outer and inner membrane leaflets was evidenced. We propose the role of Chol-binding motifs with different immersion in membrane in transport of different cholesterol pools by ABCA1 and ABCG1.
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http://dx.doi.org/10.1007/s00232-018-0056-5DOI Listing
February 2019

Relation of High-Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High-Density Lipoprotein-Related Genes in Mononuclear Cells to the HDL-Cholesterol Level.

Lipids 2018 10 15;53(10):979-991. Epub 2018 Nov 15.

Institute of Molecular Genetics of the Russian Academy of Sciences, 2, Kurchatov Square, 123182, Moscow, Russia.

The heterogeneity and content of human plasma high-density lipoprotein (HDL) related to their atheroprotective properties determined by various molecular and cellular mechanisms still remain to be completely clarified. For 29 atherosclerosis-free male subjects, we studied the relationship of plasma lipid levels and the content of apolipoprotein A-I (apoA-I)-containing HDL with preβ-electrophoretic mobility, the efficiency of BODIPY-cholesterol efflux from RAW 264.7 macrophages to apolipoprotein B (apoB)-deficient plasma, and the expression level of 22 genes related to HDL metabolism in mononuclear cells. A significant decrease in the absolute content of apoA-I in preβ-HDL was found in subjects with hypoalphalipoproteinemia compared with the subjects with hyperalphalipoproteinemia. The preβ-to-α-ratio of the apoA-I content was constant within the HDL-cholesterol (HDL-C) range 0.59 to 2.24 mM. However, this ratio was significantly increased with an increase in the plasma triacylglycerol (TAG) content from 0.59 to 3.42 mM. A correlation of the level of preβ-HDL with the basal and ABCA1-mediated efflux of cholesterol is shown. The transcript levels for six HDL-metabolizing genes (LDLR, LCAT, ABCA1, SCARB1, ZDHHC8, and BMP1) were decreased, while the transcript level of APOA1 gene was increased in mononuclear cells of subjects with hyperalphalipoproteinemia as compared with subjects with hypoalphalipoproteinemia. A reduction of the intracellular cholesterol level and inhibition of the expression of cholesterol transporters by nascent HDL in mononuclear cells from subjects with hyperalphalipoproteinemia are suggested. Hyperalphalipoproteinemia can be a driving force of the decreased flux of cholesteryl ester to the liver and the increased TAG hydrolysis. The atheroprotective effect of preβ-HDL in hypertriglyceridemia is proposed.
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http://dx.doi.org/10.1002/lipd.12104DOI Listing
October 2018

Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis.

J Lipids 2018 6;2018:3965054. Epub 2018 Aug 6.

National Research Centre for Preventive Medicine, 10 Petroverigsky Street, 101990 Moscow, Russia.

Cholesterol transport between intracellular compartments proceeds by both energy- and non-energy-dependent processes. Energy-dependent vesicular traffic partly contributes to cholesterol flux between endoplasmic reticulum, plasma membrane, and endocytic vesicles. Membrane contact sites and lipid transfer proteins are involved in nonvesicular lipid traffic. Only "active" cholesterol molecules outside of cholesterol-rich regions and partially exposed in water phase are able to fast transfer. The dissociation of partially exposed cholesterol molecules in water determines the rate of passive aqueous diffusion of cholesterol out of plasma membrane. ATP hydrolysis with concomitant conformational transition is required to cholesterol efflux by ABCA1 and ABCG1 transporters. Besides, scavenger receptor SR-B1 is involved also in cholesterol efflux by facilitated diffusion via hydrophobic tunnel within the molecule. Direct interaction of ABCA1 with apolipoprotein A-I (apoA-I) or apoA-I binding to high capacity binding sites in plasma membrane is important in cholesterol escape to free apoA-I. ABCG1-mediated efflux to fully lipidated apoA-I within high density lipoprotein particle proceeds more likely through the increase of "active" cholesterol level. Putative cholesterol-binding linear motifs within the structure of all three proteins ABCA1, ABCG1, and SR-B1 are suggested to contribute to the binding and transfer of cholesterol molecules from cytoplasmic to outer leaflets of lipid bilayer. Together, plasma membrane events and intracellular cholesterol metabolism and traffic determine the capacity of the cell for cholesterol efflux.
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http://dx.doi.org/10.1155/2018/3965054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106919PMC
August 2018

Cholesterol Efflux and Reverse Cholesterol Transport: Experimental Approaches.

Curr Med Chem 2016 ;23(34):3883-3908

National Research Centre for Preventive Medicine, 10, Petroverigsky Street, 101990 Moscow, Russia.

Background: Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. Radioactive in vitro cholesterol efflux assay (CEA) is the gold standard for determination of efflux at cellular level. Fluorescent tracers and stable isotope-labeled cholesterol gradually come into use as convenient tools for non-radioactive CEAs.

Results: We review the use of various tracer-based and tracer-free methods for CEAs and for measuring RCT with focus on macrophage-specific cholesterol efflux. CEA utilizing stable isotope-labeled cholesterol is equally reliable with radioactive assay and especially well suited for the determination of both cholesterol efflux and net cholesterol flux. Fluorescent tracers cannot fully mimic cholesterol; however, they are successfully applied in CEA in specific well-defined conditions. Fluorescent CEAs can be high throughput and can provide unique information on efflux from fast cholesterol pools or with single cell resolution. Enzymatic and chromatographic CEAs are net cholesterol flux assays, and they can be applied as efflux assays when used with specific acceptors only. In vivo tests are suited for studies of cholesterol efflux and RCT at the level of the organism. They include injection of tracer-loaded macrophages, a method suitable at present for animal models only, and recently invented modification of whole body tracer kinetics with multicompartment modeling that is capable to determine cholesterol efflux from macrophages.

Conclusion: Despite the decisive role of in vitro assays in our understanding of cholesterol efflux mechanism, the in vivo assays are highly desired to study cholesterol efflux in atherosclerotic lesions and RCT in whole body.
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http://dx.doi.org/10.2174/0929867323666160809093009DOI Listing
February 2017

Significance of Lipid-Free and Lipid-Associated ApoA-I in Cellular Cho-lesterol Efflux.

Curr Protein Pept Sci 2017 ;18(1):92-99

National Research Centre for Preventive Medicine, 10, Petroverigsky Street, 101990 Moscow, Russia.

The structure and stability of apolipoprotein (apo)A-I, the major apolipoprotein of human plasma high-density lipoproteins (HDL), determine the efficiency of the protein in the process of HDL generation and affect HDL properties in binding and exchanging its constituents, thus playing an essential role in reverse cholesterol transport. The equilibrium stability of an apoA-I molecule at the lipid interface (12.7 kcal/mol) predicted by a thermodynamic cycle for apolipoprotein folding-unfolding in water and at interface, largely exceeds apoA-I helix stability in HDL against chemical denaturation (3-5 kcal/mol). An ensemble of structures of lipid-bound apoA-I with different stabilities is assumed to exist. The conformational transitions between apoA-I conformers in water and lipid phases correspond to Lumry-Eyring model OL ⇔ CL ⇒ MW, where OL and CL are open and closed structures of HDLbound apoA-I, and MW is the molten globule in water. The model includes the reversible foldingunfolding transitions of N- and C-domains at HDL interface and apolipoprotein irreversible dissociation. We gathered published data on cholesterol efflux for apoA-I proteins with missense mutations in C-domain and calculated the stability of these mutants as a change of free energy relative to a wild type protein. Significant negative correlation was found between this stability and the efficiency of cAMP-stimulated cholesterol efflux. Thus, besides the known role of C-domain hydrophobicity, structure-destabilizing changes may significantly contribute to ABCA1-mediated cholesterol efflux by free apolipoprotein.
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http://dx.doi.org/10.2174/1389203717666160713150223DOI Listing
February 2017

Water-Soluble Components of Sesame Oil Reduce Inflammation and Atherosclerosis.

J Med Food 2016 Jul 27;19(7):629-37. Epub 2016 Jun 27.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA.

Atherosclerosis, a major form of cardiovascular disease, is now recognized as a chronic inflammatory disease. Nonpharmacological means of treating chronic diseases have gained attention recently. We previously reported that sesame oil aqueous extract (SOAE) has anti-inflammatory properties, both in vitro and in vivo. In this study, we have investigated the antiatherosclerotic properties of SOAE, and the mechanisms, through genes and inflammatory markers, by which SOAE might modulate atherosclerosis. Low-density lipoprotein receptor (LDL-R) knockout female mice were fed with either a high-fat (HF) diet or an HF diet supplemented with SOAE. Plasma lipids and atherosclerotic lesions were quantified after 3 months of feeding. Plasma samples were used for global cytokine array. RNA was extracted from both liver tissue and the aorta, and used for gene analysis. The high-fat diet supplemented with SOAE significantly reduced atherosclerotic lesions, plasma cholesterol, and LDL cholesterol levels in LDL-R(-/-) mice. Plasma inflammatory cytokines were reduced in the SOAE diet-fed animals, but not significantly, demonstrating potential anti-inflammatory properties of SOAE. Gene analysis showed the HF diet supplemented with SOAE reduced gene expression involved in inflammation and induced genes involved in cholesterol metabolism and reverse cholesterol transport, an anti-inflammatory process. Our studies suggest that a SOAE-enriched diet could be an effective nonpharmacological treatment for atherosclerosis by controlling inflammation and regulating lipid metabolism.
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http://dx.doi.org/10.1089/jmf.2015.0154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948257PMC
July 2016

Increased presence of oxidized low-density lipoprotein in the left ventricular blood of subjects with cardiovascular disease.

Physiol Rep 2016 Mar 31;4(6). Epub 2016 Mar 31.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida

OxidizedLDL(Ox-LDL) and oxidative stress have been implicated in both atherosclerosis and congestive heart failure (HF) development. Here, we tested whether Ox-LDLlevels in left ventricular blood (LVB) might differ from those of venous peripheral blood (PB), and whether the level might depend on cardiac function. We also tested whether theLDLmolecule is likely to have a longer residence time in the left ventricle ofHFsubjects with low ejection fraction (EF). The aim of this study was to determine Ox-LDLlevels, paraoxonase 1 (PON1) activity, and cholesterol efflux capacity (CEC) ofPBandLVB, and correlate these values withLVEF Sixty-oneHFpatients underwent preoperative transthoracic echocardiographic assessment of ventricular function.LVEFs were determined using Simpson's biplane technique.LVBandPBlevels of Ox-LDLwere determined, andPON1 activity and plasma cholesterol efflux capacity were measured. A significant increase in the levels of Ox-LDLinLVBwas noted as compared to levels inPB, even whenEFwas near normal. However, as ejection fraction decreased, the level of Ox-LDLinPBapproached that of theLVBPON1 activity and cholesterol efflux studies indicated increased oxidative stress inLVBand a decreased ability to promote cholesterol efflux from lipid-enriched macrophages. The results suggest thatLVBis more oxidatively stressed compared toPB, and thereforeLVtissue might be affected differently than peripheral tissues. We recently reported that brain natriuretic peptide (BNP), a marker forHF, is induced by Ox-LDL, so it is possible localized factors within theLVcould profoundly affect markers ofHF.
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http://dx.doi.org/10.14814/phy2.12726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814879PMC
March 2016

Anti-atherosclerotic and anti-inflammatory actions of sesame oil.

J Med Food 2015 Jan;18(1):11-20

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA.

Atherosclerosis, a major form of cardiovascular disease, has now been recognized as a chronic inflammatory disease. Nonpharmacological means of treating chronic diseases have gained attention recently. We previously reported that sesame oil has anti-atherosclerotic properties. In this study, we have determined the mechanisms by which sesame oil might modulate atherosclerosis by identifying genes and inflammatory markers. Low-density lipoprotein receptor knockout (LDLR(-/-)) female mice were fed with either an atherogenic diet or an atherogenic diet reformulated with sesame oil (sesame oil diet). Plasma lipids and atherosclerotic lesions were quantified after 3 months of feeding. Plasma samples were used for cytokine analysis. RNA was extracted from the liver tissue and used for global gene arrays. The sesame oil diet significantly reduced atherosclerotic lesions, plasma cholesterol, triglyceride, and LDL cholesterol levels in LDLR(-/-) mice. Plasma inflammatory cytokines, such as MCP-1, RANTES, IL-1α, IL-6, and CXCL-16, were significantly reduced, demonstrating an anti-inflammatory property of sesame oil. Gene array analysis showed that sesame oil induced many genes, including ABCA1, ABCA2, APOE, LCAT, and CYP7A1, which are involved in cholesterol metabolism and reverse cholesterol transport. In conclusion, our studies suggest that a sesame oil-enriched diet could be an effective nonpharmacological treatment for atherosclerosis by controlling inflammation and regulating lipid metabolism.
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http://dx.doi.org/10.1089/jmf.2014.0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281857PMC
January 2015

Aspirin may influence cellular energy status.

Eur J Pharmacol 2015 Feb 31;749:12-9. Epub 2014 Dec 31.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA. Electronic address:

In our previous findings, we have demonstrated that aspirin/acetyl salicylic acid (ASA) might induce sirtuins via aryl hydrocarbon receptor (Ah receptor). Induction effects included an increase in cellular paraoxonase 1 (PON1) activity and apolipoprotein A1 (ApoA1) gene expression. As predicted, ASA and salicylic acid (SA) treatment resulted in generation of H2O2, which is known to be an inducer of mitochondrial gene Sirt4 and other downstream target genes of Sirt1. Our current mass spectroscopic studies further confirm the metabolism of the drugs ASA and SA. Our studies show that HepG2 cells readily converted ASA to SA, which was then metabolized to 2,3-DHBA. HepG2 cells transfected with aryl hydrocarbon receptor siRNA upon treatment with SA showed the absence of a DHBA peak as measured by LC-MS/MS. MS studies for Sirt1 action also showed a peak at 180.9 m/z for the deacetylated and chlorinated product formed from N-acetyl lε-lysine. Thus an increase in Sirt4, Nrf2, Tfam, UCP1, eNOS, HO1 and STAT3 genes could profoundly affect mitochondrial function, cholesterol homeostasis, and fatty acid oxidation, suggesting that ASA could be beneficial beyond simply its ability to inhibit cyclooxygenase.
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http://dx.doi.org/10.1016/j.ejphar.2014.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352341PMC
February 2015

Ionizing radiation-inducible miR-27b suppresses leukemia proliferation via targeting cyclin A2.

Int J Radiat Oncol Biol Phys 2014 Sep 25;90(1):53-62. Epub 2014 Jun 25.

Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada. Electronic address:

Purpose: Ionizing radiation is a common carcinogen that is important for the development of leukemia. However, the underlying epigenetic mechanisms remain largely unknown. The goal of the study was to explore microRNAome alterations induced by ionizing radiation (IR) in murine thymus, and to determine the role of IR-inducible microRNA (miRNA/miR) in the development of leukemia.

Methods And Materials: We used the well-established C57BL/6 mouse model and miRNA microarray profiling to identify miRNAs that are differentially expressed in murine thymus in response to irradiation. TIB152 human leukemia cell line was used to determine the role of estrogen receptor-α (ERα) in miR-27b transcription. The biological effects of ectopic miR-27b on leukemogenesis were measured by western immunoblotting, cell viability, apoptosis, and cell cycle analyses.

Results: Here, we have shown that IR triggers the differential expression of miR-27b in murine thymus tissue in a dose-, time- and sex-dependent manner. miR-27b was significantly down-regulated in leukemia cell lines CCL119 and TIB152. Interestingly, ERα was overexpressed in those 2 cell lines, and it was inversely correlated with miR-27b expression. Therefore, we used TIB152 as a model system to determine the role of ERα in miR-27b expression and the contribution of miR-27b to leukemogenesis. β-Estradiol caused a rapid and transient reduction in miR-27b expression reversed by either ERα-neutralizing antibody or ERK1/2 inhibitor. Ectopic expression of miR-27b remarkably suppressed TIB152 cell proliferation, at least in part, by inducing S-phase arrest. In addition, it attenuated the expression of cyclin A2, although it had no effect on the levels of PCNA, PPARγ, CDK2, p21, p27, p-p53, and cleaved caspase-3.

Conclusion: Our data reveal that β-estradiol/ERα signaling may contribute to the down-regulation of miR-27b in acute leukemia cell lines through the ERK1/2 pathway, and that miR-27b may function as a tumor suppressor that inhibits cell proliferation by targeting cyclin A2.
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http://dx.doi.org/10.1016/j.ijrobp.2014.04.055DOI Listing
September 2014

Antioxidant and anti-inflammatory role of paraoxonase 1: implication in arteriosclerosis diseases.

N Am J Med Sci 2012 Nov;4(11):523-32

Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA.

Paraoxonase 1 (PON1) is a hydrolytic enzyme with wide range of substrates, and capability to protect against lipid oxidation. Despite of the large number of compounds that can be hydrolyzed by paraoxonase, the biologically relevant substrates are still not clearly determined. There is a massive in vitro and in vivo data to demonstrate the beneficial effects of PON1 in several atherosclerosis-related processes. The enzyme is primarily expressed in liver; however, it is also localized in other tissues. PON1 attracted significant interest as a protein that is responsible for the most of antioxidant properties of high-density lipoprotein (HDL). Several bioactive molecules such as dietary polyphenols, aspirin and its hydrolysis product salicylate, are known to stimulate PON1 transcription activation in mouse liver and HepG2 cell line. Studies on the activity, function, and genetic makeup have revealed a protective role of PON1. Some striking data were obtained in PON1 gene knockout and PON1 transgenic mouse models and in human studies. The goal of this review is to assess the current understanding of PON1 expression, enzymatic and antioxidant activity, and its atheroprotective effects. Results from in vivo and in vitro basic studies; and from human studies on the association of PON1 with coronary artery disease (CAD) and ischemic stroke will be discussed.
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http://dx.doi.org/10.4103/1947-2714.103310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503369PMC
November 2012

Peritoneal macrophages are distinct from monocytes and adherent macrophages.

Atherosclerosis 2011 Dec 16;219(2):475-83. Epub 2011 Sep 16.

Division of Cardiothoracic Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.

Objective: Peritoneal macrophages are used in many studies related to atherosclerosis. In situ, they are non-adherent and upon culturing, they adhere and function as scavengers of modified lipoproteins and dead apoptotic cells. They also produce growth factors, suggesting that they may provide life-supporting function as well. In this study, we propose that macrophage adherence plays a major role in their function and propose a novel concept that non-adherent macrophages are poor scavengers and may delay the process of apoptosis by secretion of growth factors.

Methods And Results: We analyzed non-adherent and adherent macrophages for changes in receptor expression, growth factor production and function by microarrays, real-time PCR, and western blot analyses. Our results indicate that adherent macrophages have increased expression of scavenger receptors as compared to fresh peritoneal cells. While genes for many growth factors were expressed in both non-adherent and adherent macrophages, the milk fat globule-epidermal growth factor 8 protein (MFG-E8) that recognizes and takes up apoptotic cells was specifically enhanced in non-adherent cells. Furthermore, early apoptotic endothelial cells demonstrated signs of delayed apoptosis when incubated in the presence of peritoneal lavage fluid that was shown to contain MFG-E8. Functional arrays indicated that peritoneal non-adherent macrophages represent a class of macrophages, distinct from either blood monocytes or adherent cultured macrophages.

Conclusions: These results suggest that the adherence status of macrophages may play a major role in their functions.
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http://dx.doi.org/10.1016/j.atherosclerosis.2011.09.014DOI Listing
December 2011

Evaluation of a gas chromatography method for azelaic acid determination in selected biological samples.

N Am J Med Sci 2010 Sep;2(9):397-402

Department of Laboratory and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA.

Background: Azelaic acid (AzA) is the best known dicarboxilic acid to have pharmaceutical benefits and clinical applications and also to be associated with some diseases pathophysiology.

Materials And Methods: We extracted and methylesterified AzA and determined its concentration in human plasma obtained from healthy individuals and also in mice fed AzA containing diet for three months.

Results: AzA was detected in Gas Chromatography (GC) and confirmed by Liquid chromatography mass spectrometry (LCMS), and gas chromatography mass spectrometry (GCMC). Our results have shown that AzA can be determined efficiently in selected biological samples by GC method with 1nM limit of detection (LoD) and the limit of quantification (LoQ); was established at 50nM. Analytical Sensitivity as assayed by hexane demonstrated an analytical sensitivity at 0.050nM. The method has demonstrated 8-10% CV batch repeatability across the sample types and 13-18.9% CV for the Within-Lab Precision analysis. The method has shown that AzA can efficiently be recovered from various sample preparation including liver tissue homogenate (95%) and human plasma (97%).

Conclusions: Because of its simplicity and lower limit of quantification, the present method provides a useful tool for determining AzA in various biological sample preparations.
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http://dx.doi.org/10.4297/najms.2010.2397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339096PMC
September 2010

Stereoselective additions of thiyl radicals to terminal ynamides.

Org Lett 2010 Jun;12(11):2650-2

Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA.

Two complementary sets of conditions for radical additions of thiols to terminal ynamides are described. The use of 1 equiv of thiol affords the cis-beta-thioenamide adducts in rapid fashion (10 min) and good dr, whereas employing excess thiol and longer reaction times favors the trans products.
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http://dx.doi.org/10.1021/ol1008679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878391PMC
June 2010

Total synthesis of the antimitotic bicyclic peptide celogentin C.

J Am Chem Soc 2010 Jan;132(3):1159-71

Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA.

An account of the total synthesis of celogentin C is presented. A right-to-left synthetic approach to this bicyclic octapeptide was unsuccessful due to an inability to elaborate derivatives of the right-hand ring. In the course of these efforts, it was discovered that the mild Braslau modification of the McFadyen-Stevens reaction offers a useful method of reducing recalcitrant esters to aldehydes. A left-to-right synthetic strategy was then examined. The unusual Leu-Trp side-chain cross-link present in the left-hand macrocycle was fashioned via a three-step sequence comprised of an intermolecular Knoevenagel condensation, a radical conjugate addition, and a SmI(2)-mediated nitro reduction. A subsequent macrolactamization provided the desired ring system. The high yield and concise nature of the left-hand ring synthesis offset the modest diastereoselectivity of the radical conjugate addition. Formation of the Trp-His side-chain linkage characteristic of the right-hand ring was then accomplished by means of an indole-imidazole oxidative coupling. Notably, Pro-OBn was required as an additive in this reaction. Detailed mechanistic investigations indicated that Pro-OBn moderates the concentration of NCS in the reaction mixture, thereby minimizing the production of an undesired dichlorinated byproduct. The natural product was obtained after macrolactamization and deprotection. The chemical shifts of the imidazole hydrogen atoms exhibited significant dependence on temperature, concentration, and pH. Antitumor screening indicated that celogentin C inhibits the growth of some cancer cell lines.
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http://dx.doi.org/10.1021/ja909870gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810426PMC
January 2010

Anti-atherosclerotic actions of azelaic acid, an end product of linoleic acid peroxidation, in mice.

Atherosclerosis 2010 Apr 12;209(2):449-54. Epub 2009 Oct 12.

Division of Cardiothoracic Surgery, Ohio State University Medical Center, Columbus, OH 43210-1292, USA.

Background: Atherosclerosis is a chronic inflammatory disease associated with the accumulation of oxidized lipids in arterial lesions. Recently we studied the degradation of peroxidized linoleic acid and suggested that oxidation is an essential process that results in the generation of terminal products, namely mono- and dicarboxylic acids that may lack the pro-atherogenic effects of peroxidized lipids. In continuation of that study, we tested the effects of azelaic acid (AzA), one of the end products of linoleic acid peroxidation, on the development of atherosclerosis using low density lipoprotein receptor knockout (LDLr(-/-)) mice.

Methods And Results: LDLr(-/-) mice were fed with a high fat and high cholesterol Western diet (WD group). Another group of animals were fed the same diet with AzA supplementation (WD+AzA group). After 4 months of feeding, mice were sacrificed and atherosclerotic lesions were measured. The results showed that the average lesion area in WD+AzA group was 38% (p<0.001) less as compared to WD group. The athero-protective effect of AzA was not related to changes in plasma lipid content. AzA supplementation decreased the level of CD68 macrophage marker by 34% (p<0.05).

Conclusions: The finding that AzA exhibits an anti-atherogenic effect suggests that oxidation of lipid peroxidation-derived aldehydes into carboxylic acids could be an important step in the body's defense against oxidative damage.
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http://dx.doi.org/10.1016/j.atherosclerosis.2009.09.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846213PMC
April 2010

Total synthesis of celogentin C.

Angew Chem Int Ed Engl 2009 ;48(33):6104-7

Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.

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http://dx.doi.org/10.1002/anie.200902425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559083PMC
October 2009

Alpha-tocopherol is ineffective in preventing the decomposition of preformed lipid peroxides and may promote the accumulation of toxic aldehydes: a potential explanation for the failure of antioxidants to affect human atherosclerosis.

Antioxid Redox Signal 2009 Jun;11(6):1237-48

Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, Louisiana, USA.

The decomposition of peroxidized lipids of low-density lipoprotein (LDL) has been suggested to be involved in atherosclerosis. In this study, an in vitro system with 13-hydroperoxylinoleic acid (13-HPODE) was used to determine the effects of antioxidants on its decomposition. Decomposition of 13-HPODE was not affected by alpha-tocopherol, several other antioxidants, or antioxidant enzymes. Moreover, the inclusion of alpha-tocopherol during the decomposition of 13-HPODE resulted in an accumulation of aldehydes. Further oxidation of aldehydes to carboxylic acids by a number of oxidases was prevented by alpha-tocopherol. Conversely, the formation of carboxylic acids may be conducive to plaque stabilization via immunomodulation, rapid degradation, and by calcium sequestration. Thus, the inhibition of formation of carboxylic acids could be a serious deleterious effect of antioxidant treatment. In contrast, alpha-keto acids, like pyruvic acid, promoted the conversion of 13-HPODE to 13-hydroxylinoleic acid (13-HODE) by readily undergoing decarboxylation into acetate. These observations suggest that agents that promote the reduction of lipid peroxides into lipid hydroxides could be far more effective in treating cardiovascular diseases as opposed alpha-tocopherol-like antioxidants that could affect additional steps in the oxidation cascade.
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http://dx.doi.org/10.1089/ars.2008.2248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842134PMC
June 2009

Lipid peroxidation and decomposition--conflicting roles in plaque vulnerability and stability.

Biochim Biophys Acta 2008 May 25;1781(5):221-31. Epub 2008 Mar 25.

Ohio State University, 410 West 10th Avenue, Columbus, OH 43210, USA.

The low density lipoprotein (LDL) oxidation hypothesis has generated considerable interest in oxidative stress and how it might affect atherosclerosis. However, the failure of antioxidants, particularly vitamin E, to affect the progression of the disease in humans has convinced even staunch supporters of the hypothesis to take a step backwards and reconsider alternatives. Preponderant evidence for the hypothesis came from animal antioxidant intervention studies. In this review we point out basic differences between animal and human atherosclerosis development and suggest that human disease starts where animal studies end. While initial oxidative steps in the generation of early fatty streak lesions might be common, the differences might be in the steps involved in the decomposition of peroxidized lipids into aldehydes and their further oxidation into carboxylic acids. We suggest that these steps may not be amenable to attenuation by antioxidants and antioxidants might actually counter the stabilization of plaque by preventing the formation of carboxylic acids which are anti-inflammatory in nature. The formation of such dicarboxylic acids may also be conducive to plaque stabilization by trapping calcium. We suggest that agents that would prevent the decomposition of lipid peroxides and promote the formation and removal of lipid hydroxides, such as paraoxonase (PON 1) or apo A1/high density lipoprotein (HDL) might be more conducive to plaque regression.
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http://dx.doi.org/10.1016/j.bbalip.2008.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430425PMC
May 2008

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms.

Atherosclerosis 2008 Aug 20;199(2):304-9. Epub 2008 Feb 20.

Division of Cardiothoracic Surgery, N-850 Doan Hall, 410 W 10th Avenue, Ohio State University, Columbus, OH 43210-1292, USA.

Previously we have shown that intestinal cells efficiently take up oxidized fatty acids (OxFAs) and that atherosclerosis is increased when animals are fed a high cholesterol diet in the presence of oxidized linoleic acid. Interestingly, we found that in the absence of dietary cholesterol, the oxidized fatty acid fed low-density lipoprotein (LDL) receptor negative mice appeared to have lower plasma triglyceride (TG) levels as compared to animals fed oleic acid. In the present study, we fed C57BL6 mice a normal mice diet supplemented with oleic acid or oxidized linoleic acid (at 18 mg/animal/day) for 2 weeks. After the mice were sacrificed, we measured the plasma lipids and collected livers for the isolation of RNA. The results showed that while there were no significant changes in the levels of total cholesterol and high-density lipoprotein cholesterol (HDLc), there was a significant decrease (41.14%) in the levels of plasma TG in the mice that were fed oxidized fatty acids. The decreases in plasma TG levels were accompanied by significant increases (P<0.001) in the expressions of APOA5 and acetyl-CoA oxidase genes as well as a significant (P<0.04) decrease in APOClll gene expression. Oxidized lipids have been suggested to be ligands for peroxisome proliferator-activated receptor (PPAR*). However, there were no increases in the mRNA or protein levels of PPAR* in the oxidized linoleic acid fed animals. These results suggest that oxidized fatty acids may act through an APOA5/APOClll mechanism that contributes to lowering of TG levels other than PPAR* induction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2007.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562931PMC
August 2008

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms.

Atherosclerosis 2008 Aug 20;199(2):304-9. Epub 2008 Feb 20.

Division of Cardiothoracic Surgery, N-850 Doan Hall, 410 W 10th Avenue, Ohio State University, Columbus, OH 43210-1292, USA.

Previously we have shown that intestinal cells efficiently take up oxidized fatty acids (OxFAs) and that atherosclerosis is increased when animals are fed a high cholesterol diet in the presence of oxidized linoleic acid. Interestingly, we found that in the absence of dietary cholesterol, the oxidized fatty acid fed low-density lipoprotein (LDL) receptor negative mice appeared to have lower plasma triglyceride (TG) levels as compared to animals fed oleic acid. In the present study, we fed C57BL6 mice a normal mice diet supplemented with oleic acid or oxidized linoleic acid (at 18 mg/animal/day) for 2 weeks. After the mice were sacrificed, we measured the plasma lipids and collected livers for the isolation of RNA. The results showed that while there were no significant changes in the levels of total cholesterol and high-density lipoprotein cholesterol (HDLc), there was a significant decrease (41.14%) in the levels of plasma TG in the mice that were fed oxidized fatty acids. The decreases in plasma TG levels were accompanied by significant increases (P<0.001) in the expressions of APOA5 and acetyl-CoA oxidase genes as well as a significant (P<0.04) decrease in APOClll gene expression. Oxidized lipids have been suggested to be ligands for peroxisome proliferator-activated receptor (PPAR*). However, there were no increases in the mRNA or protein levels of PPAR* in the oxidized linoleic acid fed animals. These results suggest that oxidized fatty acids may act through an APOA5/APOClll mechanism that contributes to lowering of TG levels other than PPAR* induction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2007.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562931PMC
August 2008

Esters of 2-iodoxybenzoic acid: hypervalent iodine oxidizing reagents with a pseudobenziodoxole structure.

J Org Chem 2005 Aug;70(16):6484-91

Department of Chemistry, University of Minnesota-Duluth, Duluth, Minnesota 55812, USA.

Esters of 2-iodoxybenzoic acid (IBX-esters) were prepared by the hypochlorite oxidation of the corresponding 2-iodobenzoate esters and isolated as chemically stable, microcrystalline products. These hypervalent iodine compounds are potentially valuable oxidizing reagents belonging to a new class of pentavalent iodine compounds with a pseudobenziodoxole structure. Methyl 2-iodoxybenzoate can be further converted to the diacetate or a bis(trifluoroacetate) derivative by treatment with acetic anhydride or trifluoroacetic anhydride, respectively. Single-crystal X-ray diffraction analysis of methyl 2-[(diacetoxy)iodosyl]benzoate 8a reveals a pseudobenziodoxole structure with three relatively weak intramolecular I...O interactions. The dimethyl and diisopropyl esters of 2-iodoxyisophthalic acid were prepared by oxidation of the respective iodoarenes with dimethyldioxirane. Single-crystal X-ray diffraction analysis of diisopropyl 2-iodoxyisophthalate 6b showed intramolecular I...O interaction with the carbonyl oxygen of only one of the two carboxylic groups, while NMR spectra in solution indicated equivalency of both ester groups. IBX-esters, methyl 2-[(diacetoxy)iodosyl]benzoate, and 2-iodoxyisophthalate esters can oxidize alcohols to the respective aldehydes or ketones in the presence of trifluoroacetic acid or boron trifluoride etherate. The bis(trifluoroacetate) derivative can oxidize alcohols to carbonyl compounds without acid catalyst.
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http://dx.doi.org/10.1021/jo051010rDOI Listing
August 2005

Extracellular catalase induces cyclooxygenase 2, interleukin 8, and stromelysin genes in primary human chondrocytes.

Biochimie 2004 Dec;86(12):945-50

Engelhardt Institute of Molecular Biology, the Russian Academy of Sciences, Vavilov street 32, Moscow 119991, Russia.

We investigated the expression of genes in response to exposure of primary human chondrocytes to extracellular catalase. The addition of catalase to culture medium caused a significant up-regulation of cyclooxygenase 2, interleukin 8, and stromelysin mRNA levels. Similar pattern of gene activation occurred in chondrocytes incubated with horseradish peroxidase. On the contrary, ebselen, a glutathione peroxidase mimetic agent, did not affect expression of catalase-inducible genes. Taken together, these observations imply that catalase action is mediated by its side peroxidase-like activity, rather than elimination of H2O2. Genistein suppressed catalase-mediated effects on gene expression. This finding implies that tyrosine kinases are implicated in underlying signaling pathway.
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http://dx.doi.org/10.1016/j.biochi.2004.07.014DOI Listing
December 2004

Preparation and structure of 2-iodoxybenzoate esters: soluble and stable periodinane oxidizing reagents.

Chem Commun (Camb) 2004 Jan 18(1):106-7. Epub 2003 Nov 18.

Department of Chemistry, University of Minnesota Duluth, Duluth, Minnesota 55812, USA.

Esters of 2-iodoxybenzoic acid (IBX-esters) are potentially valuable oxidizing reagents belonging to a new class of pentavalent iodine compounds with a pseudo benziodoxole structure.
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http://dx.doi.org/10.1039/b312961fDOI Listing
January 2004

Redox modulation of NO-dependent induction of interleukin 8 gene in monocytic U937 cells.

Cytokine 2003 Jul;23(1-2):15-22

Department of Molecular and Structural Biology, Aarhus University, Aarhus, Denmark.

We have examined the effects of various antioxidants and inhibitors of redox-sensitive signal transduction pathways on induction of interleukin 8 (IL-8) gene by NO in monocytic U937 cells. We have observed that nitrosoglutathione or another NO-generating compound spermine NONOate caused significant accumulation of IL-8 mRNA. Pretreatment of cells with pyrrolidine dithiocarbamate or with antioxidants, which scavenge hydroxyl radical, dimethyl sulfoxide (DMSO), or dimetylthiourea (DMTU) completely abrogated NO-dependent induction of IL-8 gene expression. The transcriptional activation of IL-8 gene was not affected by sodium formate or sodium salicylate, suggesting that suppression of the IL-8 gene induction is specific to the class of hydroxyl radical scavenger used. Furthermore, we have shown that IL-8 induction was not inhibited by catalase and the iron chelator deferoxamine, indicating that the inhibitory actions of DMSO and DMTU are not related to scavenging of reactive oxygen species produced from hydrogen peroxide in the iron-catalyzed reactions. Finally, we have not observed any significant inhibition of NO-dependent IL-8 gene induction by superoxide scavengers such as N-acetyl cysteine, uric acid, and superoxide dismutase. Therefore, it seems likely that in U937 cells, hydroxyl radicals or species with reactivity similar to hydroxyl radicals contribute to NO-mediated IL-8 gene induction.
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http://dx.doi.org/10.1016/s1043-4666(03)00114-5DOI Listing
July 2003
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