Our experiments were done to find out whether there are factors which influence the passage of the two major "risk factor proteins" LDL and fibrinogen, other than their plasma concentrations, from the blood into the arterial walls, where their accumulation is associated with atherogenesis. The results suggest that administration of a remarkable variety of pressor agents over a few days accelerate the uptake of both proteins by arterial walls, and that, in contrast, the process is no faster in rats that have been spontaneously, i.e., genetically, hypertensive for about 3 months. Considering our experimental findings in relation to human atherosclerotic disease, it is interesting that the risk of coronary heart disease and stroke is increased more than additively when both LDL or fibrinogen levels and systolic or diastolic blood pressures are high (18,46). If our work should point to some mechanistic connection between blood pressure and the accumulation of atherogenic plasma proteins in arterial walls, it would provide, at least in principle, an explanation for the epidemiological facts.
Calcium channel blockers are also termed calcium antagonists or calcium entry blockers. The use of calcium antagonists for the management of hypertension is well established. Their control of vascular tone is related to their interaction with the alpha 1 subunit of L-type calcium channels. This interaction is not simple since prolonged depolarisation promotes the inactivated state of the channels resulting in a change of affinity which is different for various molecules so far considered. The isoforms of alpha 1 subunits and the duration of the stimulus required to activate heart or vessels are important parameters to be considered with the nature of the molecule. Those parameters influence the vascular selectivity which is quantified as the ratio of the concentrations required to reduce by 50% the contraction of heart and of vessels. This selectivity is an important component in the therapeutic action. Another component of this action is the prevention of structural changes noted in heart and arteries. As well as lowering blood pressure, calcium channel blockers have also been found to exert blood pressure independent effects. For instance, they reduce cardiac and vascular hypertrophy and avoid renal damage. In the stroke-prone rat, such protective effects are accompanied by reduction of the salt-dependent overexpression of the gene of endothelin-1 and of fetal genes associated with cardiac hypertrophy. This paper summarizes available information about those components and discuss their significance.
Psychoactive drugs are used almost universally for the pleasure and benefits which they can provide, but they also cause sufficient harm that most societies have adopted policies to control and limit the amount of use. Science is increasingly called upon to provide a rational basis for these policies. However, the biological sciences and modern sociology have fundamentally different approaches to such issues, the former being based on the concept that there is an external reality which can be discovered only by objective means, the latter holding that social problems are defined strictly subjectively and can not be separated from the values and ideologies of the researchers. Since social policy affects all members of a society, and must reflect all of their attitudes, values and traditions, science can contribute only facts and probabilities, but society as a whole must assign the values and make the required choices.
Under certain environmental conditions, marine and freshwater phytoplankton may produce phycotoxins inhibitors of serine/thréonine protein phosphatases 1, 2A and 3. In the marine environment, dinoflagellates produce fatty polyethers: okadaic acid and its derivatives, the dinophysistoxins, which accumulate in shellfish and can cause diarrhetic shellfish poisoning (DSP) when ingested. In freshwater, the toxins are microcystins and nodularin, 7 or 5 amino acid cyclic peptides and are hepatotoxic. These toxins have caused massive poisoning of wild animals or domestic livestock and now are a health threat for humans through use of drinking and recreation water. Moreover, all these toxins are potent tumor promoters but belong to a new class, different from the TPA class, because they do not act on Protein Kinase C. Although the mutagenicity Ames test responds negatively, several results show their genotoxic potential, and therefore they are a health hazard through chronic exposition to low doses. Finally, okadaic acid, through its easy penetration in all cellular types can be used as a tool to study mechanisms involved in protein phosphorylation/dephosphorylation processes.
The scorpion venoms possess many neurotoxic peptides which constitute a group of molecular families with a common architecture and a high degree of polymorphism. This architecture is found also in circulating antimicrobial peptides belonging to the defensins family, which are especially structurally related to the blocking potassium channels neurotoxins. The diversification in functions with a unique architectural scheme is discussed taking in account the biophysiological characteristics of the scorpion order.
Cette revue est centree sur le(s) mecanisme(s) d’action des neurotoxines agissant sur l’inactivation des canaux Na actives par le potentiel de membrane. Les canaux Na sont des proteines transmembranaires fondamentales pour la signalisation electrique cellulaire. Ces proteines forment des pores dans la membrane plasmique dont l’ouverture et la fermeture, controlees par un systeme de « portes » et dependantes du temps et du potentiel de membrane, permettent des mouvements passifs d’ions. Les canaux Na ont trois proprietes fonctionnelles, principalement etudiees a l’aide de techniques electrophysiologiques et biochimiques, leur permettant d’assurer leur role dans la genese et la propagation du potentiel d’action : (1) une haute selectivite pour les ions Na, (2) une ouverture rapide (« activation ») responsable de la phase ascendante du potentiel d’action et (3) une fermeture tardive (« inactivation ») intervenant au niveau de la phase descendante du potentiel d’action. En tant que proteine fondamentale pour l’excitabilite membranaire, le canal Na est la cible specifique de diverses toxines animales et vegetales qui, en se fixant sur le canal, alterent son activite en affectant l’une ou/et l’autre de ses proprietes. Au moins six sites de fixation des toxines ont ete mis en evidence au niveau du canal Na neuronal. Cependant, seules les toxines interagissant avec quatre d’entre eux (sites 2, 3, 5 et 6) provoquent une alteration de l’inactivation du canal. Bien que le pourcentage maximal de canaux Na modifies par la fixation des neurotoxines sur les sites 2 (batrachotoxine et certains alcaloides), 3 (toxines de scorpion et toxines d’anemone de mer), 5 (brevetoxines et ciguatoxines) et 6 (-conotoxines) soit different selon le site considere, il n’en demeure pas moins que dans tous les cas, ces canaux ne s’inactivent pas. De plus, les canaux Na modifies par les toxines se fixant sur les sites 2, 5 et 6 s’activent a des valeurs de potentiel de membrane plus negatives que les canaux Na non modifies. Les consequences physiologiques des modifications des canaux Na, induites par la fixation des neurotoxines sur les sites 2, 3, 5 et 6, sont (i) une inhibition de l’excitabilite cellulaire due a une depolarisation importante de la membrane (site 2), (ii) une diminution de l’excitabilite cellulaire due a une forte augmentation de la duree des potentiels d’action (site 3) et (iii) une augmentation de l’excitabilite membranaire qui se traduit par l’apparition de potentiels d’action spontanes et repetitifs (sites 5 et 6). Les etudes biochimiques et electrophysiologiques realisees avec ces toxines, ainsi que la determination de leur structure moleculaire, ont permis d’obtenir des informations sur le fonctionnement et la structure du canal Na. Ainsi, plusieurs modeles representant les differents etats des canaux Na ont ete proposes pour rendre compte des modifications de leur inactivation provoquees par les neurotoxines. De plus, la localisation des sites 2, 3, 5 et 6 de fixation de ces toxines en a ete deduite sur le canal Na neuronal et l’identification moleculaire du (des) site(s) de reconnaissance de certaines d’entre elles a ete etablie au niveau de la sous-unite constituant la proteine-canal Na.
For a long time, extracellular proteinases were thought to be expressed by the cancerous cells and only able to cleave extracellular matrix components, in order to promote tumor cell invasion. Recent works have now demonstrated that these proteinases are currently synthesized by stromal fibroblastic cells and that some of them may exhibit additive function(s). These findings lead to a new therapeutical concept leading to target the activity of stromal proteinases, and most notably of the matrix metalloproteinases.
We have shown that given cytokines are capable of inducing the expression of transcription factors of the Ets family in two very distinct cell types: 1) endothelial cells of blood vessels, but only during neovascularization, and 2) fibrocytic cells from stroma surrounding tumors, but only if these tumors bear characteristics of invasiveness. In such cases, the fibrocytic cells also express some metalloproteinases (collagenase 1, urkinase plasminogen activator, sometimes stromelysin1). In ex vivo reconstruction experiments, we demonstrate that the corresponding genes are directly up-regulated by the Ets family transcription factors, often associated with the transcription complex Jun/Fos. The proteinases are thought to dismantle the stroma and allow invasive tumors to proceed toward further expansion. We speculate that inactivation of the Ets factors could seriously hamper both neovascularization and tumor expansion.
Glucocorticoids are physiological molecules that are also extensively used in clinics as anti-inflammatory, immunosuppressive or anti-tumoral agents. Glucocorticoids can induce apoptosis on normal lymphoid cells and play a key role in the physiology of thymic selection. In clinics these molecules are also used for their potencies in inducing apoptosis of malignant lymphoid cells. Glucocorticoids are mediating their effects after binding to an intracellular receptor belonging to the steroid receptor superfamily: the glucocorticoid receptor (GR). Once activated, the GR, can mediate his effects through direct binding on the DNA or via protein/protein interactions with transcription factors. Depending on the type of lymphocytes, the mechanism of apoptosis induced by glucocorticoids fall roughly in two categories: induction of "death genes" by the activated GR (I kappa B, c-jun) or repression of survival factors (AP-1, c-Myc). In the case of thymic selection the mechanism is more subtle depending on the mutual repression of Nur77 and GR.
Cyclin A is a positive regulatory component of kinases required for the progression through S phase and for the transition between the G2 and M phases of the cell division cycle. Previous studies conducted in established cell lines and in primary human T lymphocytes, have demonstrated that the promoter of its gene is under negative transcriptional control in quiescent cells. The DNA sequences mediating this repression have been delineated through in vitro mutagenesis as well as in vivo genomic footprinting experiments. Indirect observations suggest the involvement of proteins related to the retinoblastoma tumor suppressor protein (pRb). Using primary fibroblasts from either pRb(-/-), p107(-/-), p130(-/-) or p107(-/-)/p130(-/-) mice, we show in this work that mutation of the pRb gene has the more profound effect on cyclin A transcription. Finally, normal fibroblasts cultured in suspension fail to express cyclin A and can no longer enter S phase and proliferate, revealing thus a dependence of cyclin A expression on cell anchorage. Our work suggests the existence of at least two sets of regulators controlling cell cycle progression. On the one hand, proteins like cyclin D1, whose expression is a direct consequence of the activation of the ras signalling pathway and on the other hand, proteins like cyclin A which are secondary response effectors. As a result, growth factor stimulation leads to a transcriptional activation of the former set, while the transcription of the latter set is under the control of a repressor whose effect is alleviated after triggering the ras cascade. The status of pRb thus dictates whether cells continue their progression through the cell cycle when ras is mutated, probably by allowing the uncontrolled expression of critical genes like cyclin A.
Regulation of homeostasic balance between cell proliferation and cell death, called apoptosis, is essential for development and maintenance of multicellular organisms. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically and evolutionarily conserved process that can become deranged when the components of the cellular apoptotic machinery are mutated, perturbated by viral gene products or present in inappropriated quantities. Analysis of the regulatory apoptotic pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases or autoimmune diseases. Our understanding of the regulation of apoptosis in health and disease is far from complete and the use of understanding into new therapeutic modalities has only begun to be approached.
La melatonine (N-acetyl-5 methoxy-tryptamine) est ume hormone secretee principalement par la glande pineale ou epiphyse et egalement produite, mais en beaucoup plus faible quantite, par la retine. Sa synthese est realisee a partir du tryptophane, l'enzyme cle de cette synthese etant la N-acetyl-transferase (NAT). Le rythme circadien de la melatonine est similaire chez l'Homme et dans toutes les especes experimentales etudiees a ce jour, avec des taux nocturnes 3 a 10 fois plus importants que le jour. Sa secretion et sa liberation dependent d'un grand nombre de facteurs exogenes et endogenes, par exemple l'age, le sexe, le stade pubertaire de developpement, le cycle menstruel, les medicaments et les saisons. La lumiere est un regulateur fondamental de la secretion de melatonine qui intervient par voie retino-hypothalamique. La melatonine est consideree comme un transducteur du signal lumineux donnant l'indication a l'organisme des jours courts et des jours longs (duree du jour et de la nuit). C'est le donneur de temps dont se sert l'organisme et qui lui permet de vivre en harmonie avec son environnement
Les venins de scorpion contiennent un grand nombre de neurotoxines peptidiques qui constituent un ensemble de familles moleculaires a haut degre de polymorphisme, mais qui ont en commun une architecture semblable. Cette architecture se retrouve dans des peptides antibacteriens circulants de la famille des defensines, qui s'apparentent tout particulierement a celle des neurotoxines actives sur les canaux potas sium. Cette diversification de fonctions a partir d'un schema structurel identique est discutee a la lumiere des caracteristiques biophysiologiques des scorpions.
