Nonpeptide Urotensin-II receptor agonists and antagonists: review and structure-activity relationships

Human Urotensin-II (hU-II) is a cyclic 11-amino acid peptide that plays a role in cardiovascular homeostasis. Its receptor is a member of the class A of G-protein-coupled receptors, called GPR14. In recent years, several nonpeptide ligands have been reported in the literature. Most were identified by high-throughput screening and optimized by medicinal chemistry methods. Other nonpeptide ligands were discovered starting from the 3D structure of hU-II or other ligands. They were identified by a virtual screening approach based on a 3D pharmacophore or by structural similarity with others cyclic peptides. In this review, nonpeptide agonists and antagonists are presented in relation to structure-activity relationships.     

Exosomes from bronchoalveolar fluid of tolerized mice prevent allergic reaction

Exosomes are nanovesicles originating from multivesicular bodies that are secreted by a variety of cell types. The dual capability of exosomes to promote immunity or to induce tolerance has prompted their clinical use as vehicles for vaccination against different human diseases. In the present study, the effect of allergen-specific exosomes from tolerized mice on the development of allergen-induced allergic response was determined using a mouse model. Mice were tolerized by respiratory exposure to the olive pollen allergen Ole e 1. Exosome-like vesicles were isolated from bronchoalveolar lavage fluid of the animals by the well-established filtration and ultracentrifugation procedure, characterized by electron microscopy, Western blot, and FACS analyses, and assessed in a prophylactic protocol. To this end, BALB/c mice were intranasally treated with tolerogenic exosomes or naive exosomes as control, 1 wk before sensitization/challenge to Ole e 1. Blood, lungs, and spleen were collected and analyzed for immune responses. Intranasal administration of tolerogenic exosomes inhibited the development of IgE response, Th2 cytokine production, and airway inflammation--cardinal features of allergy--and maintained specific long-term protection in vivo. This protective effect was associated with a concomitant increase in the expression of the regulatory cytokine TGF-beta. These observations demonstrate that exosomes can induce tolerance and protection against allergic sensitization in mice. Thus, exosome-based vaccines could represent an alternative to conventional therapy for allergic diseases in humans.     

Novel 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles as PPARgamma agonists

A series of 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles has been synthesized and tested for PPARgamma agonist activity. SAR were developed and revealed that 6-acyl-2(3H)-benzothiazolone derivatives with 1,3-dicarbonyl group were the most potent. IP administration of compound 22 exhibited comparable levels of glucose and triglyceride correction to PO administration of rosiglitazone in the ob/ob mouse studies.     

Frequency-dependent reproductive success in female common lizards: a real-life hawk–dove–bully game?

Alternative strategies are characterised by context-dependent fitness payoffs, which means that their fitness depends on the frequency and the nature of their interactions with one or more strategies. The analysis of the variation of the fitness of each strategy in different social environments can elucidate the evolutionary dynamics played by the strategies. In the common lizard, three female colour types (yellow, orange and mixed) are associated with alternative reaction norms in reproduction and social behaviour that signal alternative strategies. To clarify the nature of colour-specific interactions and their influence on female fitness, we analysed the response of female reproductive success to an experimental manipulation of colour frequencies in natural populations. We found that juvenile body condition at birth for all colour types was negatively affected by the local frequency of yellow females. In addition, we found that mixed females had higher clutch hatching success in the populations where orange females were frequent. These results prove that female reproduction is sensitive to the social environment, and are consistent with a scenario of a hawk–dove–bully game, in which yellow females are aggressive hawks, orange females non-aggressive doves, and mixed females have a context-dependent bully strategy. In this system, the plastic bully strategy would confer a reproductive advantage to putative heterozygotes in some social environments, which could allow the maintenance of the system through context-dependent overdominance effects.     

Two microtubule-associated proteins of Arabidopsis MAP65s promote antiparallel microtubule bundling

The Arabidopsis MAP65s are a protein family with similarity to the microtubule-associated proteins PRC1/Ase1p that accumulate in the spindle midzone during late anaphase in mammals and yeast, respectively. Here we investigate the molecular and functional properties of AtMAP65-5 and improve our understanding of AtMAP65-1 properties. We demonstrate that, in vitro, both proteins promote the formation of a planar network of antiparallel microtubules. In vivo, we show that AtMAP65-5 selectively binds the preprophase band and the prophase spindle microtubule during prophase, whereas AtMAP65-1-GFP selectively binds the preprophase band but does not accumulate at the prophase spindle microtubules that coexists within the same cell. At later stages of mitosis, AtMAP65-1 and AtMAP65-5 differentially label the late spindle and phragmoplast. We present evidence for a mode of action for both proteins that involves the binding of monomeric units to microtubules that “zipper up” antiparallel arranged microtubules through the homodimerization of the N-terminal halves when adjacent microtubules encounter.     

<Emphasis Type="Italic">Arabidopsis</Emphasis>eIF2α kinase GCN2 is essential for growth in stress conditions and is activated by wounding

Background  

Phosphorylation of eIF2α provides a key mechanism for down-regulating protein synthesis in response to nutrient starvation or stresses in mammalian and yeast cells. However, this process has not been well characterized in plants     

Evaluation morphologique des spermatozoïdes

Semen analysis, as defined by World Health Organisation (WHO), is a fundamental step in the work-up of infertile couples. Spermatozoa morphology has been recognised as the best predictive factor in natural fertility, and in intrauterine insemination and classicalin vitro fertilisation. Ultrastructural spermatozoa abnormalities are the only sperm alterations likely to influence the outcome of ICSI. However, these abnormalities cannot be detected by conventional microscopy (¥100 or ¥200–400). Bartoov et al. (2002) developed a real-time spermatozoa observation system using a ¥6600 magnification called MSOME (Magnification Motile Sperm Morphology Examination). Spermatozoa abnormalities detected with this technique are vacuoles localised on spermatozoa heads with variable number, size and site (nucleus or acrosome). Spermatozoa evaluation using MSOME could be performed to predict the probability of fertilisation by these spermatozoa either spontaneously or after assisted reproductive technology.     

Role of transposable elements in trypanosomatids

Transposable elements constitute 2-5% of the genome content in trypanosomatid parasites. Some of them are involved in critical cellular functions, such as the regulation of gene expression in Leishmania spp. In this review, we highlight the remarkable role extinct transposable elements can play as the source of potential new functions.     

Three-dimensional model of the human urotensin-II receptor: docking of human urotensin-II and nonpeptide antagonists in the binding site and comparison with an antagonist pharmacophore model

Human urotensin-II (hU-II) is a cyclic peptide that plays a central role in cardiovascular homeostasis and is considered to be the most potent mammalian vasoconstrictor identified to date. It is a natural ligand of the human urotensin-II (hUT-II) receptor, a member of the family of rhodopsin-like G-protein-coupled receptors. To understand the molecular interactions of hU-II and certain antagonists with the hUT-II receptor, a model of the hUT-II receptor in an active conformation with all its connecting loops was constructed by homology modeling. The initial model was placed in a pre-equilibrated lipid bilayer and re-equilibrated by several procedures of energy minimization and molecular dynamics simulations. Docking studies were performed for hU-II and for a series of nonpeptide hUT-II receptor antagonists in the active site of the modeled receptor structure. Results of the hU-II docking study are in agreement with our previous work and with experimental data showing the contribution of the extracellular loops II and III to ligand recognition. The docking of hU-II nonpeptide antagonists allows identification of key molecular interactions and confirms a previously reported hU-II antagonist pharmacophore model. The results of the present studies will be used in structure-based drug design for developing novel antagonists for the hUT-II receptor.