The diverse family of Cys-loop receptors in Caenorhabditis elegans: insights from electrophysiological studies.

Cys-loop receptors integrate a large family of pentameric ligand-gated ion channels that mediate fast ionotropic responses in vertebrates and invertebrates. Their vital role in converting neurotransmitter recognition into an electrical impulse makes these receptors essential for a great variety of physiological processes. In vertebrates, the Cys-loop receptor family includes the cation-selective channels, nicotinic acetylcholine and 5-hydroxytryptamine type 3 receptors, and the anion-selective channels, GABAA and glycine receptors, whereas in invertebrates, the repertoire is significantly larger. The free-living nematode Caenorhabditis elegans has the largest known Cys-loop receptor family as well as unique receptors that are absent in vertebrates and constitute attractive targets for anthelmintic drugs. Given the large number and variety of Cys-loop receptor subunits and the multiple possible ways of subunit assembly, C. elegans offers a large diversity of receptors although only a limited number of them have been characterized to date. C. elegans has emerged as a powerful model for the study of the nervous system and human diseases as well as a model for antiparasitic drug discovery. This nematode has also shown promise in the pharmaceutical industry search for new therapeutic compounds. C. elegans is therefore a powerful model organism to explore the biology and pharmacology of Cys-loop receptors and their potential as targets for novel therapeutic interventions. In this review, we provide a comprehensive overview of what is known about the function of C. elegans Cys-loop receptors from an electrophysiological perspective.

Regulation of nicotinic acetylcholine receptors by post-translational modifications.

Nicotinic acetylcholine receptors (nAChRs) comprise a family of pentameric ligand-gated ion channels widely distributed in the central and peripheric nervous system and in non-neuronal cells. nAChRs are involved in chemical synapses and are key actors in vital physiological processes throughout the animal kingdom. They mediate skeletal muscle contraction, autonomic responses, contribute to cognitive processes, and regulate behaviors. Dysregulation of nAChRs is associated with neurological, neurodegenerative, inflammatory and motor disorders. In spite of the great advances in the elucidation of nAChR structure and function, our knowledge about the impact of post-translational modifications (PTMs) on nAChR functional activity and cholinergic signaling has lagged behind. PTMs occur at different steps of protein life cycle, modulating in time and space protein folding, localization, function, and protein-protein interactions, and allow fine-tuned responses to changes in the environment. A large body of evidence demonstrates that PTMs regulate all levels of nAChR life cycle, with key roles in receptor expression, membrane stability and function. However, our knowledge is still limited, restricted to a few PTMs, and many important aspects remain largely unknown. There is thus a long way to go to decipher the association of aberrant PTMs with disorders of cholinergic signaling and to target PTM regulation for novel therapeutic interventions. In this review we provide a comprehensive overview of what is known about how different PTMs regulate nAChR.

The nematode serotonin-gated chloride channel MOD-1: A novel target for anthelmintic therapy.

Anthelmintics are used to treat human and veterinary parasitic diseases and to reduce crop and livestock production loss associated with parasitosis. The free-living nematode Caenorhabditis elegans, a model system for anthelmintic drug discovery, has a serotonin (5-HT)-gated chloride channel, MOD-1, which belongs to the Cys-loop receptor family and modulates locomotory and behavioral functions. Since MOD-1 is unique to nematodes, it is emerging as an attractive anthelmintic drug target, but details of MOD-1 function are unclear. Here, we revealed novel aspects of MOD-1 function from the molecular level to the organism level and identified compounds targeting this receptor, which may provide new directions for anthelmintic drug discovery. We used whole-cell current recordings from heterologously expressed MOD-1 to show that tryptamine (Tryp), a weak partial agonist of vertebrate serotonin type 3 (5-HT3) receptors, efficaciously activates MOD-1. A screen for modulators revealed that GABAergic ligands piperazine (PZE) and muscimol reduce 5-HT-elicited currents, thus identifying novel MOD-1 allosteric inhibitors. Next, we performed locomotor activity assays, and we found 5-HT and Tryp rapidly decrease worm motility, which is reversible only at low 5-HT concentrations. Mutants lacking MOD-1 are partially resistant to both drugs, demonstrating its role in locomotion. Acting as an antagonist of MOD-1, we showed PZE reduces the locomotor effects of exogenous 5-HT. Therefore, Tryp- and PZE-derived compounds, acting at MOD-1 through different molecular mechanisms, emerge as promising anthelmintic agents. This study enhances our knowledge of the function and drug selectivity of Cys-loop receptors and postulates MOD-1 as a potential target for anthelmintic therapy.

Orthosteric and Allosteric Activation of Human 5-HT3A Receptors.

The serotonin type 3 receptor (5-HT3) is a ligand-gated ion channel that converts the binding of the neurotransmitter serotonin (5-HT) into a transient cation current that mediates fast excitatory responses in peripheral and central nervous systems. Information regarding the activation and modulation of the human 5-HT3 type A receptor has been based only on macroscopic current measurements because of its low ion conductance. By constructing a high-conductance human 5-HT3A receptor, we here revealed mechanistic information regarding the orthosteric activation by 5-HT and by the partial agonist tryptamine, and the allosteric activation by the terpenoids, carvacrol, and thymol. Terpenoids potentiated macroscopic currents elicited by the orthosteric agonist and directly elicited currents with slow-rising phases and submaximal amplitudes. At the single-channel level, activation by orthosteric and allosteric agonists appeared as openings in quick succession (bursts) that showed no ligand concentration dependence. Bursts were grouped into long-duration clusters in the presence of 5-HT and even longer in the presence of terpenoids, whereas they remained isolated in the presence of tryptamine. Kinetic analysis revealed that allosteric and orthosteric activation mechanisms can be described by the same scheme that includes transitions of the agonist-bound receptor to closed intermediate states before opening (priming). Reduced priming explained the partial agonism of tryptamine; however, equilibrium constants for gating and priming were similar for 5-HT and terpenoid activation. Thus, our kinetic analysis revealed that terpenoids are efficacious agonists for 5-HT3A receptors. These findings not only extend our knowledge about the human 5-HT3A molecular function but also provide novel insights into the mechanisms of action of allosteric ligands, which are of increasing interest as therapeutic drugs in all the superfamily.

Quality of life in children with kidney transplant: Systematic review.

OBJECTIVE: To identify in the literature studies that evaluate the quality of life in pediatric patients with kidney transplant through use of specific, validated instruments in Pediatrics. METHOD: Systematic review of the literature with searches conducted in the following databases: Medline, PubMed, LILACS, CINAHL, SciELO and Cochrane Library. Main keywords: Quality of life, Kidney transplantation and Pediatrics. RESULTS: A total of 366 studies were selected and eight observational studies were included that evaluated the quality of life of children with kidney transplant by means of evaluation instruments of quality of life. CONCLUSION: The quality of life of children with kidney transplant is inferior compared to healthy children. The post-transplant period presents better results compared to pre-transplant children. The identification of mental, physical and social conditions related to the quality of life of this population allows for better planning the assistance provided to them.

Quality of life in children with kidney transplant: Systematic review / La Calidad de vida en niños trasplantados renales: Revisión sistemática / Qualidade de vida em crianças transplantadas renais: Revisão sistemática

ABSTRACT Objective: To identify in the literature studies that evaluate the quality of life in pediatric patients with kidney transplant through use of specific, validated instruments in Pediatrics. Method: Systematic review of the literature with searches conducted in the following databases: Medline, PubMed, LILACS, CINAHL, SciELO and Cochrane Library. Main keywords: Quality of life, Kidney transplantation and Pediatrics. Results: A total of 366 studies were selected and eight observational studies were included that evaluated the quality of life of children with kidney transplant by means of evaluation instruments of quality of life. Conclusion: The quality of life of children with kidney transplant is inferior compared to healthy children. The post-transplant period presents better results compared to pre-transplant children. The identification of mental, physical and social conditions related to the quality of life of this population allows for better planning the assistance provided to them.

RESUMEN Objetivo: Identificar en la literatura estudios que evalúan la calidad de vida de pacientes pediátricos trasplantados renales a través de instrumentos específicos y validados en pediatría. Método: Revisión Sistemática de la Literatura con investigaciones realizadas en los bancos de datos: Medline, PubMed, LILACS, CINAHL, SciELO e Biblioteca Cochrane. Principales descriptores: Quality of life, Kidney transplantation and Pediatrics. Resultados: Se seleccionaron 366 estudios e incluyó ocho estudios observacionales que evaluaron la calidad de vida de los niños trasplantados renales por medio de instrumentos de evaluación de la Calidad de Vida. Conclusión: La calidad de vida de los niños trasplantados renales es inferior en comparación con los niños sanos. El período post trasplante presenta resultados mejores comparados a los niños pretrasplante. La identificación de las condiciones mentales, físicas y sociales relacionadas a la Calidad de Vida de esa población abre posibilidades para la mejor planificación de la asistencia prestada.

RESUMO Objetivo: Identificar na literatura estudos que avaliam a qualidade de vida de pacientes pediátricos transplantados renais através de instrumentos específicos e validados em pediatria. Método: Revisão Sistemática da Literatura com pesquisas realizadas nos bancos de dados: Medline, PubMed, LILACS, CINAHL, SciELO e Biblioteca Cochrane. Principais descritores: Quality of life, Kidney transplantation and Pediatrics. Resultados: Foram selecionados 366 estudos e incluído oito estudos observacionais que avaliaram a qualidade de vida das crianças transplantadas renais por meio de instrumentos de avaliação da Qualidade de Vida. Conclusão: A qualidade de vida de crianças transplantadas renais é inferior quando comparadas as crianças saudáveis. O período pós transplante apresentam resultados melhores comparadas às crianças pré-transplante. A identificação das condições mentais, físicas e sociais relacionadas à Qualidade de Vida dessa população abre possibilidades para o melhor planejamento da assistência prestada.

(3R,4S,5R,6R,7S)-3,4,5,7-Tetrahydroxyconidine, an azetidine analogue of 6,7-diepicastanospermine and a conformationally constrained d-deoxyaltronojirimycin, from l-arabinose.

The synthesis from l-arabinose of an azetidine analogue of 6,7-diepicastanospermine and its glycosidase inhibition profile are described.

Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol.

Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.

Azetidine iminosugars from the cyclization of 3,5-di-O-triflates of α-furanosides and of 2,4-di-O-triflates of ß-pyranosides derived from glucose.

Primary amines with either 3,5-di-O-ditriflates of α-furanosides or 2,4-di-O-triflates of ß-pyranosides form bicyclic azetidines in high yield.

Inhibition of nonmammalian glycosidases by azetidine iminosugars derived from stable 3,5-di-O-triflates of pentoses.

Efficient ring closure of stable crystalline 3,5-di-O-triflates of pentofuranosides with amines to form azetidines allowed preliminary evaluation of four-ring iminosugars as glycosidase inhibitors; significant and specific inhibition of nonmammalian α-glucosidases is shown by L-xylo- and L-arabino-iminosugar azetidines.