Journal de la Societe de biologie最新文献

Melatonin is a neurohormone primarily synthesized in the pineal gland at night. It has numerous functions in various pathophysiological situations, including anti-oxidant properties at pharmacological concentrations (1 microM and above). It is believed that melatonin acts through three main targets: two 7TM receptors (MT1 and MT2) and one atypical binding site called MT3. This last binding site has been purified in our laboratory and is designated as quinone reductase 2 (QR2, E.C. 1.10.99.2). This enzyme has several individualistic features. It does not recognize standard nicotinamide derivatives as co-substrates, but rather, it recognizes rare ones such as N-ribosylnicotinamide. Among other features of this enzyme, two are of major importance: 1) experiments from Dr Jaiswal (Houston, Texas) laboratory with QR2-/- mice and with cells derived from them demonstrated that this enzyme is implicated in the toxicological activation of menadione, and thus, may have an activation rather than a detoxification role, as formerly believed, and 2) the polyphenol resveratrol, a molecule with anti-oxidant properties, is a potent inhibitor of QR2 ( approximately 30 nM). This talk will briefly summarize these findings, and will present our working hypotheses, molecular tools and findings on several aspects of the possible relationship between QR2 and melatonin, in particular those suggesting a mechanism for the anti-oxidant activity of melatonin.

Deciphering the mechanisms underlying skeletal muscle differentiation in mammals is an important challenge. Cell differentiation involves complex pathways regulated at both transcriptional and post-transcriptional levels. Recent observations have revealed the importance of small (20-25 base pairs) non-coding RNAs (microRNAs or miRNAs) that are expressed in both lower organisms and in mammals. miRNAs modulate gene expression by affecting mRNA translation or stability. In lower organisms, miRNAs are essential for cell differentiation during development; some miRNAs are involved in maintenance of the differentiated state. We have shown that miR-181, a microRNA that is strongly upregulated during differentiation, participates in establishing the muscle phenotype. Moreover, our results suggest that miR-181 downregulates the homeobox protein Hox-A11 (a repressor of the differentiation process), thus establishing a functional link between miR-181 and the complex process of mammalian skeletal muscle differentiation. Therefore, miRNAs can be involved in the establishment of a differentiated phenotype - even when they are not expressed in the corresponding fully differentiated tissue.

In the fission yeast Schizosaccharomyces pombe, formation of pericentromeric heterochromatin involves RNA interference (RNAi). Recent data indicate that two RNAi complexes, RITS (RNA-induced transcriptional silencing complex) and RDRC (RNA-directed RNA polymerase complex), their respective enzymatic activity, and RNA polymerase II are essential for RNAi-mediated heterochromatin formation. At the site where heterochromatin formation takes place, RNA polymerase II synthesizes an RNA that would serve as an RNA platform to recruit in a siRNA-dependent manner RITS and RDRC, and thereby initiate heterochromatin assembly. Once recruited, RITS and RDRC seem to also contribute to the processing of the RNA platform. Therefore, RNAi-driven heterochromatin assembly appears to take place through a dynamic process of RNA synthesis, RNA-dependant recruitment of RNAi complexes and RNA degradation that all occur in cis.

Advanced glycation of collagens contributes to development of micro- and macrovascular complications in diabetes. Since flavonoids are potent natural antioxidants, it was interesting to examine their effect on the formation of a cross-linking advanced glycation endproduct, pentosidine, in collagen incubated with glucose. Monomeric flavonoids (25 and 250 microM) markedly reduced pentosidine/hydroxyproline values in a concentration- and structure-dependent manner. Procyanidin oligomers from grape seed were more active than pine bark procyanidin oligomers. Oligomers are known to be cleaved into monomers in the gastric milieu and monomeric flavonoids to be absorbed and recovered at micromolar concentrations (with a long plasmatic half-life) in extracellular fluids, in contact with collagens. In conclusion, flavonoids are very potent inhibitors of pentosidine formation in collagens, active at micromolar concentrations; these concentrations might be achieved in plasma of diabetic patients after oral intake of flavonoids.

The field of Maillard reaction in food has recently re-emerged. This reaction which takes place between carbohydrates and proteins at a high cooking temperatures and causes the formation of flavor and yellow to brown colors was already well documented. Little is known, however, about the formation of other Maillard reaction products (MRPs) which may be toxic: the so-called glycotoxins. It is well recognized that only 10% of these have been identified so far, and improved analytical methods are needed for the discovery of more of the neo-formed contaminants. Only a few studies as yet have focused on the digestion, metabolism and excretion of fructoselysine, carboxymethyllysine, pentosidine, acrylamide, the MRPs which have already been identified. MRPs have been shown to be present at significant amounts in a variety of industrially and domestically heat-treated foodstuffs but their absorption appears to be limited and they are readily excreted. Clinical studies indicate, none the less, that the typical Western diet, which contains a high MRPs content, may have an impact on human health. The main effects are observed on the glucose and lipid metabolisms, and on inflammatory mediators. However, the physiopathological role of the ingested MRPs has yet to be investigated in detail, so no conclusive recommendations can be given at present regarding their possible toxic effects.

A significant part of the world ocean is characterized by low absolute nutrients and chlorophyll concentrations. In these oligotrophic environments, bacteria are very abundant and play a vital role in the remineralization of the dissolved organic matter. Bacteria adapted to oligotrophic waters differ from those adapted to richer environments by some genetic and metabolic characteristics. Culture techniques in bacteriology are based on rich media and do not allow the growth of most marine bacteria. New techniques have been developed for the culture of oligotrophic bacteria, which allow to isolate unknown bacteria. Pelagibacter ubique and Sphingopyxis alaskensis belong to these bacteria recently isolated from the marine environment and their study yielded better understanding of how marine bacteria adapt to oligotrophic conditions.

Planar cell polarity (PCP) genes were originally identified in invertebrates (Drosophila Melanogaster) for their role in the uniform orientation of a structure within the plane of the epithelium (hair, group of cells). During the last five years, numerous studies have shown that vertebrate, but more importantly, mammalian homologues of some of these genes are involved in various developmental processes such as neural tube closure, polycystic kidney disease, inner ear functions (hearing, balance) or Bardet Biedl syndrome. These processes rely on a set of genes whose PCP function is conserved in mammals and Drosophila Melanogaster for some, or only present in mammals for others. In 2003, the inner ear was identified as a model to study PP in mammals and allowed the identification of the first important genes. These genes encode a variety of cell surface molecules as well as intracellular adapters whose molecular mechanisms are still poorly understood. It is clear that the identification of the PP pathways in mammals will come from a comparison with the genes in Drosophila, but also from the identification of genes specific to mammals.

RNA interference was the first regulation by small RNA to be described in detail. It was initially identified in C. elegans as a sequence-specific post-transcriptional silencing induced by double stranded RNA. There are two main steps in the process, the cleavage of long double stranded RNA molecules into small interfering RNA of about twenty nucleotides and the incorporation of these small molecules into a protein complex to which it confers a sequence specific interaction with RNA substrates. The "classical" RNA interference is associated with the cleavage and the subsequent degradation of the targeted RNA which in its simplest form can be carried out by a single protein (Argonaute 2 in mammals) and a small interfering RNA. The cleavage requires a near perfect complementarity between the substrate and the small guide present in the complex; this sequence specificity and the catalytic nature of the process create an almost ideal tool to silence any gene for which the sequence is known. However several considerations limit the efficacy and the specificity of this process. Foremost is our current inability to restrict the activity of small regulatory RNA to this RNA cleavage pathway which leads to the activation of other cellular regulations some of which have a lower level of sequence specificity than RNA interference. A better understanding of these regulatory pathways will be necessary in order to achieve the specific and efficient silencing that experimentalists dream of.

Tumor progression is now relatively well understood with changes at cellular and molecular levels. However mechanisms of the metastatic process are still not well elucidated. Several important questions remain unsolved to established new therapies. Moreover we need experimental animal models mimicking human metastatic disease to investigate and discover new targets for future therapies. These experimental approaches have to be coupled with pathological and clinical researches. Different experts will present the state of our knowledge in this domain.