Biomedical subjects

J L Bernier

Publications and source records attributed to J L Bernier.

At least 19 recordsLinked to original sources

PubMed2004

ECG characterization of paroxysmal atrial fibrillation: parameter extraction and automatic diagnosis algorithm.

Paroxysmal atrial fibrillation (PAF) is one of the most common heart arrhythmias. It is very difficult to detect unless an explicit Atrial Fibrillation episode occurs during the exploration. The present paper describes a number of low level parameters extracted from ECG traces where no Atrial Fibrillation process is present. The ability of this parameter set to characterize PAF patients is studied and discussed. Based on these parameters a modular automatic classification algorithm for PAF diagnosis is developed and evaluated.

Algorithms↗

PubMed2000

Antioxidant actions of ovothiol-derived 4-mercaptoimidazoles: glutathione peroxidase activity and protection against peroxynitrite-induced damage.

4-Mercaptoimidazoles derived from the naturally occurring antioxidants, ovothiols, were tested for their glutathione peroxidase-like (GSH Px-like) activity and protection against peroxynitrite-induced damage. All the thiol compounds displayed similar significant GSH Px-like activities, which are however weaker than that of the reference compound, ebselen. The inhibitions of the peroxynitrite-dependent oxidation of Evans blue dye and dihydrorhodamine 123 showed that the thiol compounds substituted on position 5 of the imidazole ring were nearly as effective as ebselen while the C-2 substituted ones were less effective. Both assays corroborate the large superiority of mercaptoimidazoles over glutathione as inhibitors of peroxynitrite-dependent oxidation.

Antioxidants↗

PubMed2000

Antioxidant properties of di-tert-butylhydroxylated flavonoids.

Epidemiological evidence suggests an inverse relationship between dietary intake of flavonoids and cardiovascular risk. The biological activities of flavonoids are related to their antioxidative effects, but they also can be mutagenic, due to the prooxidant activity of the catechol pattern. To prevent these problems, we synthesized new flavonoids where one or two di-tert-butylhydroxyphenyl (DBHP) groups replaced catechol moiety at position 2 of the benzopyrane heterocycle. Two DBHP moieties can also be arranged in an arylidene structure or one DBHP fixed on a chalcone structure. Position 7 on the flavone and arylidene or position 4 on the chalcone was substituted by H, OCH(3), or OH. New structures were compared with quercetin and BHT in an LDL oxidation system induced by Cu(II) ions. Arylidenes and chalcones had the best activities (ED(50) = 0.86 and 0.21) compared with vitamin E, BHT, and quercetin (ED(50) = 10.0, 7. 4, and 2.3 microM). Activity towards stable free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) was measured by log Z and ECR(50) parameters. Synthesized flavones proved to be poor DPPH radical scavengers, the activity increasing with the number of DBHP units. In contrast, arylidenes and chalcones were stronger DPPH radical scavengers (log Z > 3, 0.3 < ECR(50) < 2.12) than BHT (log Z = 0.75, ECR(50) = 12.56) or quercetin (log Z = 2.76, ECR(50) = 0.43). Unlike quercetin, synthesized compounds neither chelated nor reduced copper, proving that these new flavonoids had no prooxidant activity in vitro.

Amidines↗

PubMed2000

4-Mercaptoimidazoles derived from the naturally occurring antioxidant ovothiols 1. Antioxidant properties.

4-Mercaptoimidazoles derived from the naturally occurring family of antioxidants, the ovothiols, were assayed for their antioxidant properties. These compounds are powerful HOCl scavengers, more potent than the aliphatic thiol N-acetylcysteine. They react slowly with hydrogen peroxide with second order rate constants of 0.13-0.89 M(-1)s(-1). Scavenging of hydroxyl radical occurs at a diffusion-controlled rate (k=2.0-5.0 x 10(10)M(-1)s(-1)) for the most active compounds, which are also able to inhibit copper-induced LDL peroxidation. The combination of radical scavenging and copper chelating properties may explain the inhibitory effects on LDL peroxidation. Two molecules of mercaptoimidazole can chelate a copper ion and form a square planar complex detected by EPR. Compounds bearing an electron-withdrawing group on position 2 of the imidazole ring are the most potent antioxidant molecules in this series.

Antioxidants↗

PubMed2000

4-Mercaptoimidazoles derived from the naturally occurring antioxidant ovothiols 2. Computational and experimental approach of the radical scavenging mechanism.

The radical-scavenging mechanism of fourteen 4-mercaptoimidazoles, derived from the natural family of ovothiols, was studied via a QSAR approach, cyclic voltammetry, ESR and NMR spectroscopy. A significant correlation was found between the DPPH scavenging abilities of test compounds and thermodynamic parameters like overall ease of disulphide formation. The production of a disulphide compound via thiyl radical formation is proposed. Upon DPPH scavenging, hydrogen abstraction from thiols yields transient short-lived thiyl radicals, which were characterised by ESR and rapidly dimerise to form a disulphide compound. Cyclic voltammetry showed that the best DPPH scavengers exhibit low oxidation potentials for their oxidation to disulphides.

Antioxidants↗

PubMed2000

Purification of human ceruloplasmin as a by-product of C1-inhibitor.

Human ceruloplasmin (Cp) has been purified from cryoprecipitate-poor plasma as a by-product of the C1-inhibitor production chain. Highly purified Cp was obtained by subsequent ion-exchange chromatography on sulfate-Fractogel EMD and TMAE-Fractogel EMD. Treatments for viral safety included application of the solvent-detergent method and two nanofiltration steps using 35- and 15-nm pore size filters at the end of the process. Overall antigen yield was 95 (+/-5) %. Purified human ceruloplasmin was studied by electron spin resonance (ESR) to characterize its different types of copper complexes and to check its antioxidant properties. We distinguished three types of complexes: one type-2 Cu(II) with g// = 2.25 and A// = 180 G and two type-I Cu(II) exhibiting different narrow hyperfine splitting (A// = 72 G and A// = 90 G) with close g// (2.20 and 2.21). Purified Cp has a specific activity of 24.5+/-0.2 mU/mg of proteins. This process provides a method for Cp purification that could be easily integrated into modern plasma fractionation.

Antioxidants↗

PubMed1999

DNA cleavage by hydroxy-salicylidene-ethylendiamine-iron complexes.

Bis(hydroxy)salen.Fe complexes were designed as self-activated chemical nucleases. The presence of a hy-droxyl group on the two salicylidene moieties serve to form a hydroquinone system cooperating with the iron redox system to facilitate spontaneous formation of free radicals. We compared the DNA binding and cleaving properties of the ortho -, meta- and para -(bishydroxy) salen.Fe complexes with that of the corresponding chelate lacking the hydroxyl groups. DNA melting temperature studies indicated that the para complex exhibits the highest affinity for DNA. In addition, this para compound was considerably more potent at cleaving supercoiled plasmid DNA than the regio-isomeric ortho - and meta -hydroxy-salen.Fe complexes, even in the absence of a reducing agent, such as dithiothreitol used to activate the metal complex. The DNA cleaving activity of the para isomer is both time and concentration dependent and the complexed iron atom is absolutely essential for the sequence uniform cleavage of DNA. From a mechanistic point of view, electron spin resonance measurements suggest that DNA contributes positively to the activation of the semi-quinone system and the production of ligand radical species responsible for subsequent strand scission in the absence of a reducing agent. The para -hydroxy-salen.Fe complex has been used for detecting sequence-specific drug-DNA interactions. Specific binding of Hoechst 33258 to AT sequences and chromomycin to GC sequences were shown. The para -bis(hydroxy)salen.Fe derivative complements the tool box of footprinting reagents which can be utilised to produce efficient cleavage of DNA.

Animals↗

PubMed1999

Stimulus correlation and adaptive motion detection using spiking neurons.

Stimulus correlation and adaptive movement detection, among other tasks can be performed with VLSI general-purpose neurons that have controllable steady and transient responses. This paper presents experimental results of simple neural primitives based on the CMOS neuron approach described in [11]. Stimulus correlation experiments illustrate the well defined behavior of the CMOS approach. This basic primitive is used to implement motion detectors with adaptive capabilities that enable it to work efficiently in a wide velocity range.

Action Potentials↗

PubMed1999

A new measurement of noise immunity and generalization ability for MLPs.

This paper shows a quantitative relation between the regularization techniques, the generalization ability, and the sensitivity of the Multilayer Perceptron (MLP) to input noise. Although many studies about these topics have been presented, in most cases only one of the problems is addressed, and only experimentally obtained evidence is provided to illustrate some kind of correlation between generalization, noise immunity and the use of regularization techniques to obtain a set of weights after training that provides the corresponding MLP with generalization ability and noise immunity. Here, a new measurement of noise immunity for a MLP is presented. This measurement, which is termed Mean Squared Sensitivity (MSS), explicitly evaluates the Mean Squared Error (MSE) degradation of a MLP when it is perturbed by input noise, and can be computed from the statistical sensitivities (previously proposed) of the output neurons. The MSS provides an accurate evaluation of the MLP performance loss when its inputs are perturbed by noise and can also be considered a measurement of the smoothness of the error surface with respect to the inputs. Thus, as the MSS can be used to evaluate the noise immunity or the generalization ability, it gives a criterion to select among different weight configurations that present a similar MSE after training.

Models, Neurological↗

PubMed1998

Synthesis, DNA binding, topoisomerase II inhibition and cytotoxicity of two guanidine-containing anthracene-9,10-diones.

Two anthraquinone derivatives of the anticancer drugs mitoxantrone and ametantrone were examined for their ability to bind to DNA and to modulate the formation of topoisomerase-DNA cleavable complexes in vitro. The guanidinium groups introduced at the termini of the two aminoethylamino side chains of mitoxantrone can reinforce the interaction with DNA as judged from thermal denaturation studies with calf thymus DNA and polynucleotides. Footprinting experiments indicate that the binding to DNA of compound SR107 lacking the 5,8-hydroxyl substituents is essentially nonspecific whereas its congener SR 103 interacts preferentially with GC-rich sequences, particularly those containing 5'-(A/T)CG sites. Compound SR103, which bears two hydroxyl groups on the anthraquinone chromophore, promotes the cleavage of DNA by topoisomerase II and is cytotoxic toward human KB carcinoma cells in vitro. In contrast, the analogue SR107, which lacks OH groups, has no effect on topoisomerase II and is not cytotoxic.

Anthraquinones↗

PubMed1996

One-electron oxidation of ergothioneine and analogues investigated by pulse radiolysis: redox reaction involving ergothioneine and vitamin C.

Redox reactions of endogenous and exogenous sulphur-containing compounds are involved in protection against oxidative damage arising from the incidence and/or treatment of many diseases, including cancer. We have investigated, via pulse radiolysis, the one-electron oxidation of ergothioneine, a molecule with antioxidant properties which is detected at millimolar concentrations in certain tissues and fluids subject to oxidative stress, including erythrocytes and plasma. The spectrum of the transient species, assigned to the product of one-electron oxidation, observed after reaction of ergothioneine with the oxidizing radicals OH., N3. and CCl3O2. has a maximum absorption at 520 nm and is very similar to that obtained by oxidation of analogous molecules such as 2-mercaptoimidazole, 1-methyl-2-mercaptoimidazole, S-methyl- and S,N-dimethyl-ergothioneine. In the presence of vitamin C, the oxidized form of ergothioneine is repaired by a rapid reduction (k = 6.3 x 10(8) M(-1).s(-1)) producing ascorbyl radicals. This co-operative interaction between ergothionine and ascorbate, similar to that previously observed between vitamin E and ascorbate, may contribute to essential biological redox protection.

Antioxidants↗

PubMed1996

DNA recognition by two mitoxantrone analogues: influence of the hydroxyl groups.

The clinically useful anticancer drug mitoxantrone intercalates preferentially into 5'-(A/T)CG and 5'-(A/T)CA sites on DNA. The 5,8 hydroxyl substituents on its anthracenedione chromophore are available to interact with the double helix. Footprinting experiments with two anthraquinone derivatives structurally related to mitoxantrone and ametantrone have been undertaken to assess the influence of the hydroxyl groups on the DNA recognition process. The results confirm that they do play a role in the recognition of preferred nucleotide sequences and suggest that the binding of anthraquinones to a 5'-(A/T)CG site is dependent on the presence of the 5,8 hydroxyl substitutes whereas binding to 5'-(A/T)CA sites appears to proceed just as well without them.

Antineoplastic Agents↗

PubMed1996

Antioxidant properties of hydroxy-flavones.

The antioxidant properties of 24 hydroxy-flavones were evaluated. Results show that 2',3',4'-OH substitution on the B ring plays a crucial role in radical scavenger activity in the DPPH assay and in the inhibitory effect on pereoxydation of tissue lipids in the MDA test. The formation of stable radicals for this type of compounds has been studied by ESR. In addition, it has been found that 7-hydroxy-flavones are potent competitive inhibitors of xanthine oxidase. It is proposed that the C-7 OH of flavones may take the place of the C-2 or C-6 OH of xanthine in the active site of the enzyme. A C-4' OH or C-4' OMe substitution on the 7-hydroxy flavones is not favourable to a fit in the active site. The 2',3',4'-trihydroxy-flavones inhibited XO by another process, which remains to be determined. In summary, this study provides evidence that hydroxy-flavones exhibit interesting antioxidant properties expressed either by the capacity to scavenge free radicals (for 2',3',4'-trihydroxy-flavones) or to competitively inhibit xanthine oxidase (for 7-hydroxy-flavones). These compounds may be drug candidates for treating pathologies related to free radical oxidation.

Antioxidants↗

PubMed1996

Salen-anthraquinone conjugates. Synthesis, DNA-binding and cleaving properties, effects on topoisomerases and cytotoxicity.

A series of amidoethylamino-anthraquinone derivatives bearing either one or two salen (bis(salicylidene)ethylenediamine) moieties complexed with CuII or NiII have been synthesized, and their DNA-binding and cleaving properties examined. The effects of the mono- and di-substituted anthracenedione-salen conjugates on DNA cleavage mediated by topoisomerases I and II have also been determined, as well as their cytotoxicity toward human KB cells. The anthraquinone-salen. NiII conjugates bind to GC-rich sequences in DNA, but do not cleave the macromolecule. By contrast, the anthraquinone-salen. CuII hybrids do not recognize particular nucleotide sequences but efficiently induce single-strand breaks in DNA after activation. The 5,8-dihydroxy-anthraquinone conjugates are more cytotoxic and more potent toward topoisomerase II than the non-hydroxylated analogues, but they are less cytotoxic than the salen-free anthraquinones. The attachment of a salen. CuII complex to the anthraquinone chromophore can confer DNA cleaving properties in vitro, but this is at the expense of cytotoxic activity. Anthraquinone-salen. CuII complexes may find useful employ as footprinting probes for investigating ligand-DNA interactions.

Anthraquinones↗

PubMed1994

Benzoselenazolinone derivatives designed to be glutathione peroxidase mimetics feature inhibition of cyclooxygenase/5-lipoxygenase pathways and anti-inflammatory activity.

Two series of compounds, substituted benzoselenazolinones and their opened analogs, diselenides, were prepared. The diselenides were designed according to the available SAR about glutathione peroxidase mimics and were expected to have activity. An initial series of tests was performed in order to assess the glutathione peroxidase and antioxidant activity of the diselenides compared to their cyclized analogs. The diselenides were shown to be very potent (up to 3 times the activity of ebselen), whereas the benzoselenazolinones were inactive, thus confirming our hypothesis. A second series of tests was done to determine the anti-inflammatory potency of the two series. Both were found to be potent on cyclooxygenase and 5-lipoxygenase pathways (up to 95% inhibition at 10(-5) M). Some compounds were selective, and the variations in the activity allowed us to draft some structure-activity relationships. The most interesting compound of each series, 6-benzoylbenzoselenazolinone and bis[(2-amino-5-benzoyl)phenyl] diselenide, was tested in vivo on the rat foot edema induced with different phlogistic agents and was shown to have some anti-inflammatory properties.

Animals↗

PubMed1993

Synthesis and antitumor properties of an anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-L-His.

A new molecule 4 [(GGH-DAE)2DHQ] associating the 1,4,5,8-tetrahydroxyanthraquinone ring (DHQ) of the antitumor drug mitoxantrone (2), two diaminoethylene chains (DAE), and the metal-chelating peptide Gly-Gly-His (GGH) has been synthesized. Such a molecule presents characteristics able to induce antitumor activity: compound 4 intercalates into DNA as measured by delta Tm, fluorescence quenching, and viscometry; ESR studies demonstrate that several types of Cu complexes are formed depending on pH; and the production of free radicals, as evidenced by spin-trapping, is enhanced by 4. In vitro, in leukemia cells L1210 and mammary cells MCF7, 4 is slightly less cytostatic than mitoxantrone, but substantially less toxic. In vivo, in leukemia P388 on mice, a T/C value of 230 is obtained at 25 mg/kg, higher than the one of mitoxantrone, which is toxic at the same dose.

Animals↗

PubMed1992

Synthesis of a biospecific adsorbent for the purification of the three human retinoic acid receptors by affinity chromatography.

The total synthesis of an affinity gel suitable for the purification of retinoic acid receptors (hRARs) is reported. A chalcone derived from a potent retinobenzoic acid (Ch55) was chosen as the ligand and fixed to an immobilized matrix by coupling with the N-hydroxysuccinimide ester of agarose (Affi-Gel 10, Bio-Rad Laboratories). Efficiencies of purification of the different human RARs were tested, using recombinant receptors produced with the baculovirus expression system.

Carrier Proteins↗

PubMed1992

The coordination of copper(II) to 1-hydroxy-4-(glycyl-histidyl-lysine)-anthraquinone; a synthetic model of anthraquinone anti-cancer drugs.

Results are reported of a pH-metric and spectroscopic (CD and ESR) study of the complexes formed between the pseudo-peptide 1-hydroxy-4-(Gly-His-Lys)-anthraquinone (Q-GHK) since, when complexed to copper ions, Q-GHK has been shown to be very effective in promoting the formation of free radicals and inducing DNA cleavage. Q-GHK forms very stable complexes with copper, the major species being bonded to three nitrogen donors in the coordination plane: an imidazole-N of the His residue and the peptide nitrogens of the Gly and His residues. This species is probably stabilized through bonding of the fourth planar coordination site of Cu(II) to the 9-anthraquinone oxygen. At high Q-GHK:copper ratios a second Q-GHK molecule is coordinated through its imidazole-N donor.

Anthraquinones↗