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Biomedical subjects

J C Debouzy

Publications and source records attributed to J C Debouzy.

At least 19 recordsLinked to original sources
PubMed2006

Neurophysiologic effects at low level 1.8 GHz radiofrequency field exposure: a multiparametric approach on freely moving rats.

Deleterious effects on healthcare and particularly disruption of the cholinergic system have been reported after exposure to radiofrequency field at low power density. This work presents a 72 hours multiparametric study, where cholinergic system was investigated using a neurochemical, electrophysiological and physiological approaches. Free moving rats were exposed 24 hours to RF GSM signal at 1.8 GHz at low power density (1.2 and 9 W/m(2)). Acetylcholine (ACh) release in the hippocampus was simultaneously monitored using the microdialysis technique, electroencephalogram (EEG), electromyogram (EMG) and subcutaneous temperature. A spectral analysis of EEG was also performed and sleep stages were determined. After experimental time, the animals were sacrificed and a NMR study was performed on lipid brain extract. No significant parameters modification was observed under RF exposure. The only significant difference was the lack of increase in time spent in REM sleep, the third day, for the 1.2 W/m(2) group. This observation appeared difficult to explain and could not be reasonably related with RF exposure. Similarly, the NMR study also failed to show any effect of RF.

Acetylcholine↗
PubMed2003

[In vitro uranyle affinity of per (3,6-anhydro-2-O-carboxyméthyle)-alpha-cyclodextrin and conditions required for in vivo application].

Per (3.6-anhydro-2-O-carboxymethyle)- alpha-cyclodextrin ([1]) is a polydentate analog of EDTA, a well-known cation chelating reagent. [1] exhibits strong affinities in vitro for lanthanids, cobalt and also for uranyl cations. Hence, a 1:1 stoechiometry and a high affinity for uranyle (6<logK<7) is found in vitro. Moreover, [1] is not hemolytic and exhibits not lettral properties in mice (LD(50)=42mM). In vivo injection at supralethal amounts of uranyl complex of [1] prevents immediate death in mice while unable to protect against later death. Pharmacocinetic studies show that a dissociation of the complex occurs lead to the release of free uranyle. Other complexation assays using [1] grafted tissues show that chelating properties for lead and uranyle differ from thoses observed in vitro.

Animals↗
PubMed2003

Hydrolytic properties of per (3,6-anhydro, 2-O-carboxymethyl) alpha cyclodextrin complexes of Ce (III) and Eu (III): application to soman (GD) degradation.

Per (3,6-anhydro-2-O-carboxymethyle) alpha-cyclodextrin ([ACX]) is a polydentate analog of EDTA, a well-known cation chelating reagent. ACX exhibits strong affinities in vitro for uranyl, cobalt and also for lanthanids such as Europium and Cerium. The hydrolytic activities of ACX-Eu and ACX-Ce complex were directly tested on an organophosphorous compound: the neurotoxic Soman (GD), an inhibitor of acetylcholinesterase (ACHE from rat brain). It was found a three fold reduction of soman activity when measured in the presence of Ce-ACX complex. Conversely, Eu-ACX effect did not result in soman inhibition variation under physiological conditions. It is suggested that, considering usual organometallic complex of cyclodextrin, such direct complexes would be of interest in the design of pseudo-enzyme systems for phosphoester hydrolysis.

Animals↗
PubMed2002

Effects of exposure to low level radiofrequency fields on acetylcholine release in hippocampus of freely moving rats.

Some central cholinergic effects have been reported in animals after acute exposure to radiofrequency electromagnetic field at low intensity. We studied acetylcholine (ACh) release in the brain of freely moving rats exposed for 1 h during the day to a 2.45 GHz continuous wave radiofrequency field (RF) (2 or 4 mW/cm(2)) or exposed for 1 or 14 h during the night to a 800 MHz field modulated at 32 Hz (AM 200 mW/cm(2)). Measurements were performed by microdialysis using a membrane implanted through the upper CA1 region of the hippocampus. After irradiation with the 2.45 GHz RF, rats exposed at 2 mW/cm(2) did not show a significant modification of Ach release, whereas those exposed at 4 mW/cm(2) showed a significant 40% decrease in mean ACh release from hippocampus. This decrease was maximal at 5 h post exposure. Exposure to the 800 MHz RF for 1 h did not cause any significant effect, but exposure for 14 hrs induced a significant 43% decrease in ACh release during the period 11 p.m.-4 a.m. compared to control rats. In the control group we observed an increase of ACh release at the beginning of the night, which was linked to the waking period of rats. This normal increase was disturbed in rats exposed overnight to the 800 MHz RF. This work indicates that neurochemical modification of the hippocampal cholinergic system can be observed during and after an exposure to low intensity RF.

Acetylcholine↗
PubMed2002

Phospholipid matrix as a target for sulfur mustard (HD): NMR study in model membrane systems.

Although the interactions of sulfur mustard (HD) with nucleic acids and proteins have been well studied, the toxic interactions with the membrane matrix and specially the phospholipid bilayer have so far been poorly investigated. We have used several NMR techniques to study these interactions: 1H NMR to observe the localization of HD in membranes of small unilamellar vesicles (SUV) of lecithin; 31P NMR to verify the hypothesis of pore formation in membranes of large unilamellar vesicles (LUV); and pseudo solid state 31P and 2H NMR to analyze the dynamic consequences of the presence of HD in multilayer dispersions of dimyristoylphosphatidylcholine (DMPC). Immediate and late modifications of the DMPC-HD complexes have been observed at the macroscopic and microscopic levels. After intoxication, HD is spontaneously incorporated into the membrane and locates at the level of the chain methylene groups. This incorporation occurs without formation of pores in the membrane. The presence of HD in the phospholipid dispersion differentially increases the membrane fluidity depending upon the level involved. Weak at the superficial level (phosphate group), this increase is dose-dependent on progression into the membrane. This increase is related to a lowering of transition temperature when measured at the chain level. Macroscopically, HD induces dose- and time-dependent modifications of the DMPC-HD complexes, leading to the formation of an optically transparent gel. This gel formation is confirmed at a microscopic level, where all structures disappear after intoxication.

Dimyristoylphosphatidylcholine↗
PubMed2001

Solution structure of 2-(pyrido[1,2-e]purin-4-yl)amino-ethanol intercalated in the DNA duplex d(CGATCG)2.

The solution structure of the complex formed between d(CGATCG)(2) and 2-(pyrido[1,2-e]purin-4-yl)amino-ethanol, a new antitumor drug under design, has been resolved using NMR spectroscopy and restrained molecular dynamic simulations. The drug molecule intercalates between each of the CpG dinucleotide steps with its side chain lying in the minor groove. Analysis of NMR data establishes a weak stacking interaction between the intercalated ligand and the DNA bases; however, the drug/DNA affinity is enhanced by a hydrogen bond between the hydroxyl group of the end of the intercalant side chain and the amide group of guanine G6. Unrestrained molecular dynamic simulations performed in a water box confirm the stability of the intercalation model. The structure of the intercalated complex enables insight into the structure-activity relationship, allowing rationalization of the design of new antineoplasic agents.

Antineoplastic Agents↗
PubMed2001

Modulation of intercalating properties of pyrido[1,2-e]purins via side-chain modifications: NMR and MD studies.

Two pyrido[1,2-e]purins with different side chain lengths have been synthesized to test their ability to intercalate inside DNA. The interactions of these drugs with synthetic oligodeoxy nucleotide d(CGATCG)2 have been studied with 1H and 31P NMR spectroscopy experiments. Molecule 1, rather amphiphilic (Log(P) = 1.3, due to its hydroxypropyl side chain) can intercalate GC sites of the mini helix, under a fast exchange mechanism and a 2:1 stoechiometry. The presence of a six methylen side chain in 2 (hydroxyhexyl side chain) is responsible for a relatively poor solubility of this molecule in water (log P = 2.3). Binding, rather than intercalation, of 2 to the external GC pairs is observed, severely limited by the formation of aggregates. Models for the intercalation of 1, are proposed using energy minimizations and Molecular Dynamics (MD) calculations subject to restraints from experimental nOe connectivities. Simulations and experiments both indicate fast exchange of 1 in its intercalation site.

DNA↗
PubMed2000

Non-thermal effects of continuous 2.45 GHz microwaves on Fas-induced apoptosis in human Jurkat T-cell line.

Non-thermal effects of microwaves (MWs) are one of the main issues studied for revising standards. The effects of MW exposure on apoptosis at non-thermal level (48 h, 2.45 GHz, 5 mW/cm2) have been studied. Results obtained assess non-thermal MW effects on Fas, but neither on butyrate- nor on ceramide-induced apoptosis in human Jurkat T-cell line. These data show that MW interacts either with Fas pathway between receptor and caspase-3 activation or on membrane proteins (i.e. Fas receptor or neurosphyngomyelinase).

Apoptosis↗
PubMed2000

[Substituted cyclodextrins as chelating reagents for ethers, thioethers and yperite].

The complexation of mustard gas Cl(CH(2))(2)S(CH(2))(2) Cl, HD, yperite) and of ethers and thioethers derivatives by cyclodextrins: natural alpha-cyclodextrin (ACD) and substituted B-cyclodextrins was studied by NMR. A 1/1 stoechiometry was found in all cases, while affinity constants were found relatively weak (from 5 M(-1) to 100 M(-1)). However, these results show that chelation of HD by cyclodextrins can be reasonably expected, especially if chemical modifications provide stronger affinity constants.

Antidotes↗
PubMed2000

13C-NMR spectrum field and temperature dependence of 13CO bound to hemoglobin.

13Carbon monoxide (CO), when bound to hemoglobin, yields (13)C NMR resonances (CO-Fe resonances). 100% CO liganded tetrameric hemoglobin ((13)C-labelled CO) was prepared for (13)C-NMR observation. The information about exchange kinetics between the four subunits (2alpha and 2B), were derived by changing the temperature (in the range 275-313K) and the observation frequency (4.7T, 9.4T and 18.8T). The first results confirmed previous observations of slow exchange between free and bound (2alpha and 2B together) CO. Besides, the exchange between alpha and B subunits were found slow at the NMR timescale, even under 313K and 4.7T conditions. Furthermore, intermediate temperatures (283-303K) allowed the observation of broad unresolved lines at 9.4T, corresponding both to CSA contribution and exchange linebroadening. Finally, low temperatures (less than 277K, at 9.4T) provided four relatively broad - but clearly distinguishable lines - indicating that a slow exchange rate was reached between four Fe-CO geometries on the subunits. This also indicated that two main Fe-CO orientations were different, even between similar chains (alpha1-alpha2 and B1-B2).

Carbon Isotopes↗
PubMed1999

The interactions of substituted pyrido[1,2-e]purines with oligonucleotides depend on the amphiphilic properties of their side chain.

Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesized to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)2. [1] is very hydrophobic due to a phenyl residue in its side chain. It only shows limited interactions with the minihelix without any evidence of intercalation. [2] and [3], on the other hand, have one ([2]) or two ([3]) hydroxyl groups in their acyl chain and present rather amphiphilic properties. The result is a similar intercalation of these derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and 31P chemical shift variations. Models for the intercalation of [2] are proposed using energy minimizations and molecular dynamics (MD) calculations subject to restraints from nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of [2] in its intercalation site.

Animals↗
PubMed1999

Sesquiterpene lactone glycosides from Lapsana communis L. subsp. communis.

From the latex of Lapsana communis L. subps. communis, five guaianolide glycosides were identified: crepiside E, tectoroside and three new ones: 3-O-beta-D-glucopyranosyl-8-O-beta-acetyl-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-4(15),10(14),11(13)-triene-6,12-olide, 3-O-beta-D-glucopyranosyl-8-O-beta-acetyl-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-3(4),10(14), 11(13)-triene-15-methyl-6,12-olide, and 3-O-beta-glucopyranosyl-8-O-beta-(4-hydroxyphenyl)-lactyl-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-3(4),10(14),11(13)-triene-15-methyl-6,12-olide. Their structures were established by spectroscopic methods.

Animals↗
PubMed1998

Mechanism of alpha-cyclodextrin induced hemolysis. 2. A study of the factors controlling the association with serine-, ethanolamine-, and choline-phospholipids.

A nuclear magnetic resonance (NMR) spectroscopy and molecular modeling study of the interaction between alpha-cyclodextrin (alpha-CD) and phospholipids with serine, ethanolamine, or choline headgroups is presented. The experimental approach is based on 31P and 1H NMR measurements on small unilamellar vesicles (SUV), multilamellar systems (MLV), and aqueous suspensions of lipids using a direct complex preparation with alpha-CD. Molecular dynamics computer simulations are used to investigate the trajectory of alpha-CD in the vicinity of a membrane surface and the influence of the charge and dipole moment of the phospholipid headgroups. These factors of charge and orientation of dipole moment seem to play a key role in the interaction of phospholipids with alpha-CD and reflect very well the experimentally observed selectivity of the phospholipid -alpha-CD approach. However, with this approach, there is no evidence for the formation of a complex with the phospholipid headgroup (except for phosphatidylinositol) that results from electrostatic forces. Rather, after a possible extraction of the lipid from the membrane, a classical inclusion of the sn-2 chain in the cavity of alpha-CD occurs. This step depends on the alkyl chain length and saturation state of the lipids as well as on their organization (i.e., as vesicles or dispersions). Based on our results, chemical modifications of the alpha-CD molecule to control the hemolytic properties of alpha-CD are discussed.

Computer Simulation↗
PubMed1998

Interaction of per 3,6-anhydro-alpha cyclodextrins (alpha 36CD) and lead-alpha 36CD complex with biological systems.

The interactions of per (3,6 anhydro) alpha cyclodextrin (alpha 36CD) and of lead-alpha 36CD complex with biological systems were tested by NMR, ESR and electronic microscopy using erythrocytes and model membranes. It was found that the haemolytic activity of alpha 36CD alone was seven fold lower than that of natural alpha cyclodextrin (evaluated by the concentration inducing 50% haemolysis, DH50 = 35 mM). Conversely, the formation of the complex resulted in an increase of haemolytic properties, with DH50 of 1 mM. The mechanism proposed was an increased membrane diffusion by endocytosis of the complex, leading to higher amounts of intracellular lead.

Chelating Agents↗
PubMed1998

[Modulation of interactions of pyridopyrines with membrane systems: an NMR study of the role of side chains].

Interactions of three pryridopurines differing by their side chain, -SCH2-Phe [1], -SCH2-CHOH-CH3 [2], and -SCH2-CHOH-CH2OH [3], with model membranes were studied by proton, phosphorus and carbon NMR. Their incorporation in phospholipid multilayers induced a membrane rigidification without altering ther main bilayer structure nor the phase transition. Depending on the more or less amphiphilic properties, these molecule have different behavior when included in small unilamellar vesicles: hydrophobic [1] is found in the deepest part of the membrane, while [2] lies at an intermediate location in the layer. [3] is more hydrophilic: its aromatic moiety is in the intermediate part of the membrane whereas the side chain is found oriented towards the superficial part of the layer. Furthermore, the amphiphilic molecule [2] has transmembrane transport abilities when in the presence of large unilamellar vesicles.

Kinetics↗
PubMed1997

Mechanism of alpha-cyclodextrin-induced hemolysis. 1. The two-step extraction of phosphatidylinositol from the membrane.

It has been suggested that the interaction of cyclodextrins with the lipid components of the erythrocyte membranes is the determining factor in the hemolysis induced by these cyclic oligosaccharides. In the case of alpha-cyclodextrin (cyclomaltohexose), phospholipids have been identified as the cell target. In our study, evidence for the interaction between alpha-cyclodextrin and different phospholipids has been obtained using synthetic membranes. Since phosphatidylinositol (PI) showed the strongest affinity for alpha-cyclodextrin, it has been selected to investigate the respective contributions of the polar head group and the aliphatic chains to the association process using 31P, 2H, and 1H NMR spectroscopy. In this work, we describe the two-step extraction of PI from the membrane following its association with alphaCD: a cyclodextrin molecule is first attracted to the membrane surface by electrostatic remote interactions and associates with the lipid head group. Then the whole PI molecule is extracted, and inclusion of its unsaturated sn-2 acyl chain into another alphaCD molecule occurs in the bulk.

Cyclodextrins↗