Les protéines de choc thermique (heat shock proteins). I : Classification, structure, fonctions et implications dans les processus pathologiques

All living systems have evolved mechanisms to maintain homeostasis in the face of rapid environmental changes. When exposed to elevated temperatures, most of the cells activate the synthesis of a specific group of proteins called Heat Shock Proteins (Hsps). This heat shock response, under control of specific transcription factors, the Heat Shock factors (HSF), is an evolutionarily conserved mechanism, from bacteria to humans. Heat Shock Proteins are classified into families according to their molecular weight (Hsp 25, 40, 70, 90, 105). They play the role of molecular chaperones by binding and protecting other molecules (proteins, RNAs). The function of Hsp is to prevent accumulation of non-native proteins either by assisting proper folding of polypeptides or by driving them to proteosome pathway for degradation. Hsps are involved in various pathological processes that are accompanied by protein alterations such as chronic or degenerative diseases. This review describes structural and functional characteristics of the six main Hsps classes. It also focuses on their respective role in highly studied pathologies. The diversity of Hsps implications in these diseases explains that they became recently a strategic target in development of new therapeutic strategies.Tout organisme est doté de mécanismes lui permettant de résister à de brusques changements de son environnement. Exposées à une température anormalement élevée, la plupart des cellules activent l’expression d’une classe particulière de protéines appelées les protéines de choc thermique (Heat Shock Proteins, Hsps). Cette réponse cellulaire au choc thermique placée sous le contrôle de facteurs de trans-cription spécifiques, les facteurs de choc thermique (Heat shock factor, HSF) est un mécanisme conservé au travers de l’évolution depuis les bactéries jusqu’à l’homme. Les protéines de choc thermique qui sont divisées en familles désignées par leur masse moléculaire (Hsp25, 40, 70, 90, 105) font partie des molé-cules chaperons qui s’associent à d’autres molécules (protéines, ARNs) et en protègent la destinée. Le rôle des Hsp est d’empêcher l’accumulation de protéines anormales en aidant à conformer correctement les polypeptides ou en les dirigeant vers le protéosome qui les détruit. En tant que chaperons, les Hsp sont impliquées dans de nombreux processus pathologiques qui s’accompagnent d’altérations des protéines comme les maladies chroniques et dégénératives. Cette revue décrit les spécificités structurelles et fonc-tionnelles des six familles principales d'Hsp ainsi que leur intervention à différents niveaux dans les patho-logies les mieux étudiées. La multiplicité de l'implication des Hsp dans ces phénomènes pathologiques les désigne comme cibles privilégiées dans le développement de nouvelles stratégies thérapeutiques

An organizing center in a planar model of neuronal excitability

The paper studies the excitability properties of a generalized FitzHugh-Nagumo model. The model differs from the purely competitive FitzHugh-Nagumo model in that it accounts for the effect of cooperative gating variables such as activation of calcium currents. Excitability is explored by unfolding a pitchfork bifurcation that is shown to organize five different types of excitability. In addition to the three classical types of neuronal excitability, two novel types are described and distinctly associated to the presence of cooperative variables

Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo - in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

Background: Previous studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin.Methods: To study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)—induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE).Results: Rapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1β. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE.Conclusions: These results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo

Malignant Catarrhal Fever Induced by Alcelaphine herpesvirus 1 Is Associated with Proliferation of CD8+ T Cells Supporting a Latent Infection

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. Experimentally, WD-MCF can be induced in rabbits. The lesions observed are very similar to those described in natural host species. Here, we used the rabbit model and in vivo 5-Bromo-2′-Deoxyuridine (BrdU) incorporation to study WD-MCF pathogenesis. The results obtained can be summarized as follows. (i) AlHV-1 infection induces CD8+ T cell proliferation detectable as early as 15 days post-inoculation. (ii) While the viral load in peripheral blood mononuclear cells remains below the detection level during most of the incubation period, it increases drastically few days before death. At that time, at least 10% of CD8+ cells carry the viral genome; while CD11b+, IgM+ and CD4+ cells do not. (iii) RT-PCR analyses of mononuclear cells isolated from the spleen and the popliteal lymph node of infected rabbits revealed no expression of ORF25 and ORF9, low or no expression of ORF50, and high or no expression of ORF73. Based on these data, we propose a new model for the pathogenesis of WD-MCF. This model relies on proliferation of infected CD8+ cells supporting a predominantly latent infection