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Biomedical subjects

Marc Lemaire

Publications and source records attributed to Marc Lemaire.

At least 19 recordsLinked to original sources
PubMed2006

Protein crystallography under xenon and nitrous oxide pressure: comparison with in vivo pharmacology studies and implications for the mechanism of inhaled anesthetic action.

In contrast with most inhalational anesthetics, the anesthetic gases xenon (Xe) and nitrous oxide (N(2)O) act by blocking the N-methyl-d-aspartate (NMDA) receptor. Using x-ray crystallography, we examined the binding characteristics of these two gases on two soluble proteins as structural models: urate oxidase, which is a prototype of a variety of intracellular globular proteins, and annexin V, which has structural and functional characteristics that allow it to be considered as a prototype for the NMDA receptor. The structure of these proteins complexed with Xe and N(2)O were determined. One N(2)O molecule or one Xe atom binds to the same main site in both proteins. A second subsite is observed for N(2)O in each case. The gas-binding sites are always hydrophobic flexible cavities buried within the monomer. Comparison of the effects of Xe and N(2)O on urate oxidase and annexin V reveals an interesting relationship with the in vivo pharmacological effects of these gases, the ratio of the gas-binding sites' volume expansion and the ratio of the narcotic potency being similar. Given these data, we propose that alterations of cytosolic globular protein functions by general anesthetics would be responsible for the early stages of anesthesia such as amnesia and hypnosis and that additional alterations of ion-channel membrane receptor functions are required for deeper effects that progress to "surgical" anesthesia.

Anesthetics↗
PubMed2006

Connection between the Rag4 glucose sensor and the KlRgt1 repressor in Kluyveromyces lactis.

The RAG4 gene encodes for the sole transmembrane glucose sensor of Kluyveromyces lactis. A rag4 mutation leads to a fermentation-deficient phenotype (Rag- phenotype) and to a severe defect in the expression of the major glucose transporter gene RAG1. A recessive extragenic suppressor of the rag4 mutation has been identified. It encodes a protein (KlRgt1) 31% identical to the Saccharomyces cerevisiae Rgt1 regulator of the HXT genes (ScRgt1). The Klrgt1 null mutant displays abnormally high levels of RAG1 expression in the absence of glucose but still presents an induction of RAG1 expression in the presence of glucose. KlRgt1 is therefore only a repressor of RAG1. As described for ScRgt1, the KlRgt1 repressor function is controlled by phosphorylation in response to high glucose concentration and this phosphorylation is dependent on the sensor Rag4 and the casein kinase Rag8. However, contrary to that observed with ScRgt1, KlRgt1 is always bound to the RAG1 promoter. This article reveals that the key components of the glucose-signaling pathway are conserved between S. cerevisiae and K. lactis, but points out major differences in Rgt1 regulation and function that might reflect different carbon metabolism of these yeasts.

Amino Acid Sequence↗
PubMed2006

Nitrous oxide and xenon prevent amphetamine-induced carrier-mediated dopamine release in a memantine-like fashion and protect against behavioral sensitization.

BACKGROUND: Amphetamine administration induces stimulation-independent dopamine release in the nucleus accumbens (NAcc) through reverse dopamine transport, a critical neurochemical event involved in its psychostimulant action, and furthermore decreases stimulation-dependent vesicular dopamine release. These effects may involve possible indirect glutamatergic mechanisms. METHODS: We investigated the effects of nitrous oxide and xenon, which possess antagonistic action at the N-methyl-D-aspartate (NMDA) receptor, on brain slices ex vivo on amphetamine-induced changes in carrier-mediated and KCl-evoked dopamine release in the NAcc, and in vivo on amphetamine-induced locomotor sensitization. RESULTS: Like the low-affinity NMDA receptor antagonist memantine, but not the prototypical compound MK-801, nitrous oxide and xenon at appropriate concentrations blocked both the increase in carrier-mediated dopamine release and locomotor sensitization produced by amphetamine. CONCLUSIONS: In contrast to what has generally been found using prototypical NMDA receptor antagonists, these data regarding the effect of memantine, nitrous oxide, and xenon support the hypothesis that activation of certain NMDA receptors (possibly those containing the NR1a/NR2D subunit) in the NAcc is involved in the amphetamine-induced increase in carrier-mediated dopamine release and the development of behavioral sensitization to amphetamine. Nitrous oxide, xenon, and memantine may be of therapeutic interest for treating drug dependence.

Amphetamine↗
PubMed2005

Efficient access to 2-aryl-3-substituted benzo[b]thiophenes.

[reaction: see text] Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose a method for the synthesis of 2-arylbenzo[b]thiophenes with heteroatoms at the 3-positions directly from the benzo[b]thiophene core by using an aromatic nucleophilic substitution reaction and Heck-type coupling. This methodology provides 2-aryl-3-amino or phenoxybenzo[b]thiophenes in about 35% overall yield in 5 steps.

Cyclization↗
PubMed2005

Nitrous oxide revisited: evidence for potent antihyperalgesic properties.

BACKGROUND: Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-D-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-D-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats. METHODS: First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 microg/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats. RESULTS: When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats. CONCLUSIONS: Nitrous oxide, an N-methyl-D-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.

Analgesics↗
PubMed2005

Potentially neuroprotective and therapeutic properties of nitrous oxide and xenon.

Despite the beneficial effects of prototypical glutamatergic receptor antagonists in animal models, the pharmacological attempts by the use of such agents have met with very limited clinical success because these compounds produce adverse side effects and possess an intrinsic neurotoxicity at neuroprotective and therapeutic concentrations. Interestingly, nitrous oxide and xenon, which are anesthetic gases with a remarkably safe clinical profile, have been shown to be effective inhibitors of the NMDA receptor. We briefly review accumulating evidence that nitrous oxide and xenon at subanesthetic concentrations may have potentially neuroprotective and therapeutic properties, with a particular focus on their beneficial effects on ischemia-induced neuronal death and amphetamine-induced sensitization. Nitrous oxide at 75-vol% and xenon up to 70-vol% reduce ischemia-induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decrease NMDA-induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity. Nitrous oxide at 75-vol% and xenon at 50-vol% further reduced amphetamine-induced locomotor sensitization in rodents. However, at a higher concentration of 75-vol%, xenon shows potentially neurotoxic properties and adverse side effects. Because both agents are rapidly eliminated from the body, it is plausible that their administration at appropriate subanesthetic neuroprotective and therapeutic concentrations may not be associated, in contrast with prototypical NMDA receptor antagonists, with adverse side effects and potentially neurotoxicity. Finally, the possible therapeutic implications in humans are discussed.

Anesthetics, Inhalation↗
PubMed2004

Genome evolution in yeasts.

Identifying the mechanisms of eukaryotic genome evolution by comparative genomics is often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. The hemiascomycete yeasts, with their compact genomes, similar lifestyle and distinct sexual and physiological properties, provide a unique opportunity to explore such mechanisms. We present here the complete, assembled genome sequences of four yeast species, selected to represent a broad evolutionary range within a single eukaryotic phylum, that after analysis proved to be molecularly as diverse as the entire phylum of chordates. A total of approximately 24,200 novel genes were identified, the translation products of which were classified together with Saccharomyces cerevisiae proteins into about 4,700 families, forming the basis for interspecific comparisons. Analysis of chromosome maps and genome redundancies reveal that the different yeast lineages have evolved through a marked interplay between several distinct molecular mechanisms, including tandem gene repeat formation, segmental duplication, a massive genome duplication and extensive gene loss.

Chromosomes, Fungal↗
PubMed2004

Simulation of the regional manifestation of asthma.

Asthma presents serious medical problems of global proportions. Clinical data suggest that the disease occurs preferentially at regions designated by large (0 </= I </= 5), central (6 </= I </= 11), and small (12 </= I </= 16) airways, where I defines branching generations within lungs. Our straightforward hypothesis, therefore, was that the efficacies of pharmacologic drugs proposed for the treatment and prophylaxis of asthma would be enhanced via their targeted delivery to appropriate sites. Hence, we have developed a mathematical model describing the behavior and fate of inhaled aerosols. Original algorithms have been derived to detail the physical manifestation of asthma as distinct components of smooth muscle constriction and inflammation. We have conducted a systematic analysis of the relative effects of morphology, ventilation, and particle size on aerosol deposition. Different intensities of asthma were simulated by reducing airway diameters by prescribed amounts. To show the real clinical applications of modeling, we have also simulated the performance of a popular nebulizer. Regarding therapeutic implications, it is clear that disease-induced changes in airway morphologies have pronounced effects on the administration of inhaled drugs. Likewise, ventilation affects both the total aerosol mass deposited and its relative spatial distribution among airways. By formulating these effects, the computer code allows drugs (e.g., bronchodilators for constriction, steroids for inflammation) to be selectively deposited. We suggest, therefore, that the code can be used in a complementary manner with clinical studies and can be integrated into aerosol therapy regimens.

Aerosols↗
PubMed2004

Enolase and glycolytic flux play a role in the regulation of the glucose permease gene RAG1 of Kluyveromyces lactis.

We isolated a mutant, rag17, which is impaired in glucose induction of expression of the major glucose transporter gene RAG1. The RAG17 gene encodes a protein 87% identical to S. cerevisiae enolases (Eno1 and Eno2). The Kleno null mutant showed no detectable enolase enzymatic activity and has severe growth defects on glucose and gluconeogenic carbon sources, indicating that K. lactis has a single enolase gene. In addition to RAG1, the transcription of several glycolytic genes was also strongly reduced in the DeltaKleno mutant. Moreover, the defect in RAG1 expression was observed in other mutants of the glycolytic pathway (hexokinase and phosphoglycerate kinase). Therefore, it seems that the enolase and a functional glycolytic flux are necessary for induction of expression of the Rag1 glucose permease in K. lactis.

Gene Expression Regulation, Fungal↗
PubMed2003

Reduction of ischemic brain damage by nitrous oxide and xenon.

Neuronal death after ischemia-induced brain damage depends largely upon the activation of the N-methyl-D-aspartate (NMDA) excitatory glutamate receptor that is a target for many putative neuroprotective agents. Whereas the NMDA receptors mediate ischemic brain damage, blocking them is deleterious in humans. Here, the authors investigated whether nitrous oxide or xenon, which are gaseous anesthetics with a remarkably safe clinical profile that have been recently demonstrated as effective inhibitors of the NMDA receptor, may reduce the following: (1) ischemia-induced brain damage in vivo, when given after occlusion of the middle cerebral artery (MCAO), a condition needed to make these potentially neuroprotective agents therapeutically valuable; or (2) NMDA-induced Ca2+ influx in cortical cell cultures, a major critical event involved in excitotoxic neuronal death. The authors have shown that both nitrous oxide at 75 vol% and xenon at 50 vol% reduce ischemic neuronal death in the cortex by 70% and further decrease NMDA-induced Ca2+ influx by 30%. In addition, xenon at 50%, but not nitrous oxide at 75 vol%, further decreases ischemic brain damage in the striatum (a subcortical structure that is known to be resistant to neuroprotective interventions). However, at a higher concentration (75 vol%), xenon exhibits potentially neurotoxic effects. The mechanisms of the neuroprotective and potentially neurotoxic effects of nitrous oxide and xenon, as well as the possible therapeutic implications in humans, are discussed.

Anesthetics, Inhalation↗
PubMed2002

Regulation of glycolysis by casein kinase I (Rag8p) in Kluyveromyces lactis involves a DNA-binding protein, Sck1p, a homologue of Sgc1p of Saccharomyces cerevisiae.

The casein kinase I (Rag8p) of Kluyveromyces lactis has previously been shown to regulate the transcription of the low-affinity glucose transporter gene RAG1. To study this regulation, we have isolated multicopy suppressors of the rag8 mutation. One of them, SCK1 (suppressor of casein kinase), was characterised. The predicted product of the gene has a DNA-binding signature of the basic-helix-loop-helix type. It has an overall identity of 38% with Sgc1p (Tye7p) of Saccharomyces cerevisiae. The sck1 null mutant exhibited a Rag- phenotype (which indicates a reduced flux of glycolysis) that can be complemented by the SGC1 gene of S. cerevisiae. The level of transcription of several glycolytic genes, including RAG1, was reduced about twofold in glucose media in the sck1 null mutant. Moreover, in a rag8 mutant, the expression of SCK1 was strongly affected. Altogether, the results suggest that the regulation of glycolysis by casein kinase I involves, at least in part, Sck1p in K. lactis.

Amino Acid Sequence↗
PubMed2002

The Ccr4-not complex and yTAF1 (yTaf(II)130p/yTaf(II)145p) show physical and functional interactions.

The Saccharomyces cerevisiae Ccr4-Not complex is a global regulator of transcription that is thought to regulate TATA binding protein (TBP) function at certain promoters specifically. In this paper, we show interactions between the essential domain of Not1p, which interacts with Not4p and Not5p, and the N-terminal domain of yTAF1. We isolated a temperature-sensitive nonsense allele of TAF1, taf1-4, which is synthetically lethal at the permissive temperature when combined with not4 and not5 mutants and which produces high levels of a C-terminally truncated yTAF1 derivative. Overexpression of C-terminally truncated yTAF1 is toxic in not4 or not5 mutants, whereas overexpression of full-length yTAF1 suppresses not4. Furthermore, mutations in the autoinhibitory N-terminal TAND domain of yTAF1 suppress not5, and the overexpression of similar mutants does not suppress not4. We find that, like Not5p, yTAF1 acts as a repressor of stress response element-dependent transcription. Finally, we have evidence for stress-regulated occupancy of promoter DNA by Not5p and for Not5p-dependent regulation of yTAF1 association with promoter DNA. Taken together with our finding that Not1p copurifies with glutathione S-transferase-yTaf1 in large complexes, these results provide the first molecular evidence that the Ccr4-Not complex might interact with yTAF1 to regulate its association at promoters, a function that might in turn regulate the autoinhibitory N-terminal domain of yTAF1.

Cell Cycle Proteins↗