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Biomedical subjects

E Niki

Publications and source records attributed to E Niki.

At least 37 records · Page 2Linked to original sources
PubMed1999

1-Methyl-4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium.

We have studied the interaction of coenzyme Q with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)), the real neurotoxin to cause Parkinson's disease. Incubation of MPTP or MPDP(+) with rat brain synaptosomes induced complete reduction of endogenous ubiquinone-9 and ubiquinone-10 to corresponding ubiquinols. The reduction occurred in a time- and MPTP/MPDP(+) concentration-dependent manner. The reduction of ubiquinone induced by MPDP(+) went much faster than that by MPTP. MPTP did not reduce liposome-trapped ubiquinone-10, but MPDP(+) did. The real toxin MPP(+) did not reduce ubiquinone in either of the systems. The reduction by MPTP but not MPDP(+) was completely prevented by pargyline, a type B monoamine oxidase (MAO-B) inhibitor, in the synaptosomes. The results indicate that involvement of MAO-B is critical for the reduction of ubiquinone by MPTP but that MPDP(+) is a reductant of ubiquinone per se. It is suggested that ubiquinone could be an electron acceptor from MPDP(+) and promote the conversion from MPDP(+) to MPP(+) in vivo, thus accelerating the neurotoxicity of MPTP.

1-Methyl-4-phenylpyridinium↗
PubMed1999

Formation of phospholipid hydroperoxides and its inhibition by alpha-tocopherol in rat brain synaptosomes induced by peroxynitrite.

Peroxynitrite resulted from the reaction of nitric oxide and superoxide anion has been implicated in the genesis of neurotoxicity. In this study, the oxidation of phospholipids in rat brain synaptosomes induced by peroxynitrite generated from 3-morpholinosydnonimine (SIN-1) was studied in vitro. The formation and accumulation of phospholipid hydroperoxides, including phosphatidylcholine hydroperoxide (PCOOH) and phosphatidyl-ethanolamine hydroperoxide (PEOOH) in rat brain synaptosomes induced by peroxynitrite, were observed. PEOOH and PCOOH were formed rapidly and SIN-1 concentration-dependently. The hydroperoxides formed in synaptosomes were unstable and it was suggested that phospholipase A2 played a role in degradation of the hydroperoxides. The endogenous alpha-tocopherol acted as a potent antioxidant. It was oxidized very rapidly and concentration-dependently by SIN-1 to alpha-tocopheryl quinone. Furthermore, uric acid was found to be an effective antioxidant in inhibiting oxidative damage to synaptosomal lipids induced by SIN-1. The results provide direct evidence to show that peroxynitrite can not only deplete alpha-tocopherol, but also cause production of phospholipid hydroperoxides resulting in disrupted brain tissue.

Acetophenones↗
PubMed1999

Oxidation of low density lipoprotein and plasma by 15-lipoxygenase and free radicals.

It is generally accepted that the oxidation of pentadiene structures of polyunsaturated lipids by lipoxygenase (LOX) is regio- and enantio-specific, while the free radical-mediated lipid peroxidation gives stereo-random racemic products. It was confirmed that the oxidation of human low density lipoprotein (LDL) by 15-LOX from rabbit reticulocytes gave phosphatidylcholine (PC) and cholesteryl ester (CE) hydroperoxides regio-, stereo- and enantio-specifically. 15-LOX also oxidized human plasma to give specific PC and CE hydroperoxides in spite of the presence of high concentrations of antioxidants. More CE hydroperoxides were formed than PC hydroperoxides from LDL, but the reverse order was observed for plasma oxidation. The S/R ratio of the hydroperoxides decreased during long time incubation but remained significantly larger than one, while free radical-mediated oxidation of LDL and plasma gave racemic products.

Animals↗
PubMed1999

Dynamics of antioxidant action of ubiquinol: a reappraisal.

The dynamics of action of ubiquinol as an antioxidant against lipid peroxidation was reinvestigated and compared with that of alpha-tocopherol. It was found that ubiquinol was 2.5 and 1.9 times more reactive than alpha-tocopherol toward phenoxyl and peroxyl radicals, respectively, at 25 degrees C in ethanol and that it was capable of donating two hydrogen atoms toward oxygen radicals but that the apparent stoichiometric number decreased in the inhibition of lipid peroxidation, to even smaller than 1, due to its autoxidation. The autoxidation of ubiquinol proceeded even in the micelles and liposomal membranes in aqueous dispersions as well as in organic homogeneous solution. The apparent antioxidant activity of ubiquinol was smaller than that of alpha-tocopherol against lipid peroxidation in organic solution as judged from either rate of oxidation or duration of inhibition period. They exerted similar antioxidant potency against lipid peroxidation in the membranes and micelles in aqueous dispersions. The combination of ubiquinol and alpha-tocopherol was suggested to be effective.

Antioxidants↗
PubMed1999

Vitamin E protects against polymorphonuclear leukocyte-dependent adhesion to endothelial cells.

We evaluated the effects of alpha-Toc on surface expression of CD11b/CD18 on polymorphonuclear leukocytes (PMN) stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and oxidized low-density lipoprotein (oxLDL). Incubation of PMN with fMLP (1 microM) or oxLDL (100 microg/mL) increased CD11b/CD18 expression; pretreatment with alpha-Toc reduced in a dose-dependent manner. PMN obtained from healthy adults ingesting 600 mg alpha-Toc per day for 10 days were similarly incubated with fMLP or oxLDL; the surface level of CD11b/CD18 was inversely correlated with serum alpha-Toc concentrations. Adherence of PMN to human umbilical vein endothelial cells was increased by fMLP or oxLDL stimulation but reduced by alpha-Toc pretreatment or anti-CD18 monoclonal antibodies. cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) activity in PMN was also assayed. A PKC inhibitor, but not a PKA inhibitor, suppressed CD11b/CD18 up-regulation, and alpha-Toc slightly decreased fMLP- and oxLDL-induced activation of PKC. These results suggest that alpha-Toc may prevent inflammation by both reducing CD11b/ CD18 up-regulation and decreasing PMN-dependent adherence to EC.

CD18 Antigens↗
PubMed1999

Action of quinolinic and indolinonic aminoxyls as radical-scavenging antioxidants.

The kinetic studies on the actions of quinolinic and indolinonic aminoxyls in the oxidation of lipid peroxidation induced by free radicals were carried out to evaluate their antioxidant activity. These aminoxyls showed a similar reactivity toward peroxyl radical with alpha-tocopherol. The antioxidant efficacies of aminoxyls against oxidation of methyl linoleate in homogeneous solution were smaller than that of alpha-tocopherol. Hydroxylamine, a reduced form of aminoxyl, possessed a comparative antioxidant efficacy with alpha-tocopherol and was capable of suppressing the consumption of alpha-tocopherol. Aminoxyls showed more potent antioxidant activity than alpha-tocopherol against the oxidation of methyl linoleate micelles induced by peroxyl radical or by a combination of copper ion and hydrogen peroxide. These results suggest that quinolinic and indolinonic aminoxyls may act as potent antioxidants against lipid peroxidation, especially in the presence of a good reductant which reduces aminoxyl radicals to hydroxylamines.

Antioxidants↗
PubMed1999

Elevation of antioxidant potency in the brain of mice by low-dose gamma-ray irradiation and its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage.

The elevation of endogenous thiol-related antioxidants and free radical scavenging enzymes in the brain of C57BL/6 female mice after low-dose gamma-ray irradiation and its inhibitory effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage were investigated. The brain level of the reduced form of glutathione (GSH) increased soon after irradiation with 50 cGy of gamma-rays, reached a maximum at 3 h post-treatment, and remained elevated until 12 h. Thioredoxin (TRX) was also transiently increased after irradiation. The activities of free radical scavenging enzymes, including Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, were significantly induced after irradiation as well. Cerebral malondialdehyde was remarkably elevated by MPTP treatment, and this elevation was suppressed by pre-irradiation (50 cGy). The contents of GSH and TRX were significantly decreased by MPTP treatment in comparison with those of the control group. These reductions both seemed to be attenuated by pre-irradiation with gamma-rays. These results suggest that low-dose gamma-ray irradiation induces endogenous antioxidative potency in the brain of mice and might be effective for the prevention and/or therapy of various reactive oxygen species-related neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease.

Analysis of Variance↗
PubMed1999

Comparative study on dynamics of antioxidative action of alpha-tocopheryl hydroquinone, ubiquinol, and alpha-tocopherol against lipid peroxidation.

Alpha-tocopheryl quinone is a metabolite of alpha-tocopherol (TOH) in vivo. The antioxidant action of its reduced form, alpha-tocopheryl hydroquinone (TQH2), has received much attention recently. In the present study, the antioxidative activity of TQH2 was studied in various systems in vitro and compared with that of ubiquinol-10 (UQH2) or TOH to obtain the basic information on the dynamics of the antioxidant action of TQH2. First, their hydrogen-donating abilities were investigated in the reaction with galvinoxyl, a stable phenoxyl radical, and TQH2 was found to possess greater second-order rate constant (1.0 x 10(4) M(-1) s(-1)) than UQH2 (6.0 x 10(3) M(-1) s(-1)) and TOH (2.4 x 10(3) M(-1) s(-1)) at 25 degrees C in ethanol. The stoichiometric numbers were obtained as 1.9, 2.0, and 1.0 for TQH2, UQH2, and TOH, respectively, in reducing galvinoxyl. Second, their relative reactivities toward peroxyl radicals were assessed in competition with N,N'-diphenyl-p-phenylenediamine (DPPD) and found to be 6.0 (TQH2), 1.9 (UQH2), and 1.0 (TOH). Third, their antioxidant efficacies were evaluated in the oxidation of methyl linoleate in organic solvents and in aqueous dispersions. The antioxidant potency decreased in the order TOH > UQH2 > TQH2, as assessed by either the extent of the reduction in the rate of oxidation or the duration of inhibition period. The reverse order of their reactivities toward radicals and their antioxidant efficacies was interpreted by the rapid autoxidation of TQH2 and UQH2, carried out by hydroperoxyl radicals. Although neither TQH2 nor UQH2 acted as a potent antioxidant by itself, they acted as potent antioxidants in combination with TOH. TQH2 and UQH2 reduced alpha-tocopheroxyl radical to spare TOH, whereas TOH suppressed the autoxidation of TQH2 and UQH2. In the micelle oxidation, the antioxidant activities of TQH2, UQH2, and TOH were similar, whereas 2,2,5,7,8-pentamethyl-6-chromanol exerted much more potent efficacy than TQH2, UQH2, or TOH. These results clearly show that the antioxidant potencies against lipid peroxidation are determined not only by their chemical reactivities toward radicals, but also by the fate of an antioxidant-derived radical and the mobility of the antioxidant at the microenvironment.

Antioxidants↗
PubMed1999

Dynamics of action of bisphenol as radical-scavenging antioxidant against lipid peroxidation in solution and liposomal membranes.

Probucol is used commercially as an antiatherogenic drug. Bisphenol is formed in vivo as a metabolite of probucol. The structure of bisphenol suggests the antioxidant function but its capacity has not been studied in detail. In the present study, dynamics of the antioxidant action of bisphenol were studied in several model systems and compared with those of probucol and alpha-tocopherol. The reactivity toward radicals and antioxidant activity of bisphenol per se were found to be much smaller than those of alpha-tocopherol or N,N'-diphenyl-p-phenylenediamine (DPPD) but stronger than probucol. However, bisphenol spared alpha-tocopherol in the oxidation of phosphatidylcholine liposomal membranes and it spared DPPD and acted as a synergist against the oxidant of methyl linoleate in solution. These results imply that bisphenol may act as a potent antioxidant in combination with other antioxidants.

Anticholesteremic Agents↗
PubMed1999

Action of pyrroloquinolinequinol as an antioxidant against lipid peroxidation in solution.

The activities of pyrroloquinoline quinone (PQQ), a coenzyme of methanol dehydrogenase and amine oxidase, and its reduced form pyrroloquinoline quinol (PQQH2) as an antioxidant have been measured in solution. PQQH2 was stable in the absence of oxygen but rapidly auto-oxidized to PQQ in the presence of oxygen in water. PQQH2 was stable in an aprotic solvent such as acetonitrile, even in air. PQQ did not exert appreciable antioxidant activity, whereas PQQH2 exerted higher reactivity than alpha-tocopherol toward galvinoxyl radical and peroxyl radical. PQQH2 acted as a potent antioxidant against the oxidation of methyl linoleate in acetonitrile induced by azo compound and produced a clear induction period, from which the apparent stoichiometric number was obtained as 1.1. PQQH2 reduced the alpha-tocopheroxyl radical and spared alpha-tocopherol in the oxidation of methyl linoleate. These results suggest that PQQH2 may act as a potent antioxidant, particularly in combination with alpha-tocopherol.

Animals↗
PubMed1999

An in vitro coculture model of transmigrant monocytes and foam cell formation.

To analyze in vitro the migration of monocytes to the subendothelial space, their differentiation into macrophages, and the subsequent formation of foam cells in vitro, we have developed a 2-coculture system with rabbit aortic endothelial cells (AECs), aortic smooth muscle cells (SMCs), and a mixture of matrix proteins on polyethylene filters in chemotaxis chambers. AECs were seeded on a mixture of type I and IV collagen with or without various types of serum lipoproteins (method 1) or on matrix proteins secreted by SMCs (method 2). In these coculture systems, rabbit AECs can maintain a well-preserved monolayer for up to 2 weeks. When human CD14-positive monocytes were added to the upper medium of the system, with monocyte chemotactic protein-1 treatment approximately 60% of the monocytes transmigrated within 24 hours and were retained for up to 7 days, whereas without MCP-1 treatment, <30% of monocytes transmigrated. On day 1, transmigrant monocytes were negative for immunostaining of type I and II macrophage scavenger receptors but by day 3, became positive for scavenger receptors as well as other macrophage markers. When oxidized low density lipoprotein was added to the matrix layer of the method I coculture, on day 4 transmigrant cells exhibited lipid deposit droplets, and by day 7, they had the appearance of typical foam cells. Some of the transmigrant cells recovered in the lower medium on day 7 also appeared to be foam cells, indicating foam cell motility and escape from the coculture layer through the filter. In summary, this coculture system is a useful in vitro tool to dissect the cellular and molecular events that make up the process of foam cell formation.

Animals↗
PubMed1998

Antiatherogenic effects of the antioxidant BO-653 in three different animal models.

Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2, 2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of alpha-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.

Animals↗
PubMed1998

Acrolein is a product of lipid peroxidation reaction. Formation of free acrolein and its conjugate with lysine residues in oxidized low density lipoproteins.

Lipoprotein peroxidation, especially the modification of apolipoprotein B-100, has been implicated to play an important role in the pathogenesis of atherosclerosis. However, there have been few detailed insights into the chemical mechanism of derivatization of apolipoproteins during oxidation. In the present study, we provide evidence that the formation of the toxic pollutant acrolein (CH2=CH-CHO) and its conjugate with lysine residues is involved in the oxidative modification of human low density lipoprotein (LDL). Upon incubation with LDL, acrolein preferentially reacted with lysine residues. To determine the structure of acrolein-lysine adduct in protein, the reaction of acrolein with a lysine derivative was carried out. Employing Nalpha-acetyllysine, we detected a single product, which was identified to be a novel acrolein-lysine adduct, Nalpha-acetyl-Nepsilon-(3-formyl-3,4-dehydropiperidino )lysine. The acid hydrolysis of the adduct led to the derivative that was detectable with amino acid analysis. It was revealed that, upon in vitro incubation of LDL with acrolein, the lysine residues that had disappeared were partially recovered by Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine. In addition, we found that the same derivative was detected in the oxidatively modified LDL with Cu2+ and that the adduct formation was correlated with LDL peroxidation assessed by the consumption of alpha-tocopherol and cholesteryl ester and the concomitant formation of cholesteryl ester hydroperoxide. Enzyme-linked immunosorbent assay that measures free acrolein revealed that a considerable amount of acrolein was released from the Cu2+-oxidized LDL. Furthermore, metal-catalyzed oxidation of arachidonate was associated with the formation of acrolein, indicating that polyunsaturated fatty acids including arachidonate represent potential sources of acrolein generated during the peroxidation of LDL. These results indicate that acrolein is not just a pollutant but also a lipid peroxidation product that could be ubiquitously generated in biological systems.

Acrolein↗
PubMed1998

Protein-bound acrolein: potential markers for oxidative stress.

Acrolein (CH2==CH---CHO) is known as a ubiquitous pollutant in the environment. Here we show that this notorious aldehyde is not just a pollutant, but also a lipid peroxidation product that could be ubiquitously generated in biological systems. Upon incubation with BSA, acrolein was rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a putative marker of oxidatively modified proteins under oxidative stress. To verify the presence of protein-bound acrolein in vivo, the mAb (mAb5F6) against the acrolein-modified keyhole limpet hemocyanin was raised. It was found that the acrolein-lysine adduct, Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine, constitutes an epitope of the antibody. Immunohistochemical analysis of atherosclerotic lesions from a human aorta demonstrated that antigenic materials recognized by mAb5F6 indeed constituted the lesions, in which intense positivity was associated primarily with macrophage-derived foam cells and the thickening neointima of arterial walls. The observations that (i) oxidative modification of low-density lipoprotein with Cu2+ generated the acrolein-low-density lipoprotein adducts and (ii) the iron-catalyzed oxidation of arachidonate in the presence of protein resulted in the formation of antigenic materials suggested that polyunsaturated fatty acids are sources of acrolein that cause the production of protein-bound acrolein. These data suggest that the protein-bound acrolein represents potential markers of oxidative stress and long-term damage to protein in aging, atherosclerosis, and diabetes.

Acrolein↗
PubMed1998

Action of 21-aminosteroid U74006F as an antioxidant against lipid peroxidation.

The dynamics of the action of the 21-aminosteroid U74006F as an antioxidant against lipid peroxidation were studied in organic solution and membranes. It was confirmed that the reactivities of this compound toward stable phenoxyl radical and peroxyl radical were quite low. In fact, U74006F did not exert appreciable antioxidant effect against the free radical-driven oxidation of methyl linoleate in acetonitrile solution. However, it suppressed the oxidation of phosphatidylcholine liposomal membranes into which it was incorporated in a concentration-dependent manner. The 21-aminosteroid U74006F did not exert any sparing effect on the rate of alpha-tocopherol consumption in the oxidation of methyl linoleate in solution, but when they were simultaneously incorporated into the membrane, U74006F spared alpha-tocopherol and exerted a synergistic effect against the oxidation of liposomal membranes. This suggests that lipophilic U74006F acts as an antioxidant against lipid peroxidation through a physicochemical and not a pure chemical mechanism, and that a physical interaction with the liposomal membrane may facilitate the inhibition of lipid peroxidation with U74006F.

Antioxidants↗
PubMed1998

2,2'-Azobis (4-methoxy-2,4-dimethylvaleronitrile), a new lipid-soluble azo initiator: application to oxidations of lipids and low-density lipoprotein in solution and in aqueous dispersions.

Both hydrophilic and hydrophobic azo radical initiators are useful for in vitro studies on lipid peroxidation and its inhibition by antioxidants. In the present study, a new lipophilic azo compound, 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (MeO-AMVN), was introduced and its action as an initiator of lipid peroxidation was examined. MeO-AMVN decomposed about 15 times as fast as 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN), a widely used lipophilic azo initiator, and MeO-AMVN-initiated free radical-mediated peroxidations of lipids in organic solution and in micelles, membranes, and low-density lipoprotein in aqueous dispersions with much smaller concentration than AMVN. The rate of chain initiation by MeO-AMVN varied significantly with the medium and decreased with increasing viscosity of the medium. The advantage and cautions for using MeO-AMVN as a lipophilic radical source have been discussed and it has been concluded that MeO-AMVN, when properly used, is a useful radical initiator of lipid peroxidations especially in micelles, membranes, and lipoproteins.

Acetonitriles↗