G protein-coupled receptor (GPCR) pharmacogenomics

The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome. Many fundamentals of pharmacogenetics were established for G protein-coupled receptor (GPCR) genes because they are primary targets for a large number of therapeutic drugs. Functional studies, demonstrating likely-pathogenic and pathogenic GPCR variants, have been integral to establishing models used for in silico analysis. Variants in GPCR genes include both coding and non-coding single nucleotide variants and insertion or deletions (indels) that affect cell surface expression (trafficking, dimerization, and desensitization/downregulation), ligand binding and G protein coupling, and variants that result in alternate splicing encoding isoforms/variable expression. As the breadth of data on the GPCR genome increases, we may expect an increase in the use of drug labels that note variants that significantly impact the clinical use of GPCR-targeting agents. We discuss the implications of GPCR pharmacogenomic data derived from the genomes available from individuals who have been well-phenotyped for receptor structure and function and receptor-ligand interactions, and the potential benefits to patients of optimized drug selection. Examples discussed include the renin-angiotensin system in SARS-CoV-2 (COVID-19) infection, the probable role of chemokine receptors in the cytokine storm, and potential protease activating receptor (PAR) interventions. Resources dedicated to GPCRs, including publicly available computational tools, are also discussed.</p

Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection

Chagas' disease is caused by infection with the parasite Trypanosoma cruzi. We report that infected, but not uninfected, human endothelial cells (ECs) released thromboxane A2 (TXA2). Physical chromatography and liquid chromatography-tandem mass spectrometry revealed that TXA2 is the predominant eicosanoid present in all life stages of T. cruzi. Parasite-derived TXA2 accounts for up to 90% of the circulating levels of TXA2 in infected wild-type mice, and perturbs host physiology. Mice in which the gene for the TXA2 receptor (TP) has been deleted, exhibited higher mortality and more severe cardiac pathology and parasitism (fourfold) than WT mice after infection. Conversely, deletion of the TXA2 synthase gene had no effect on survival or disease severity. TP expression on somatic cells, but not cells involved in either acquired or innate immunity, was the primary determinant of disease progression. The higher intracellular parasitism observed in TP-null ECs was ablated upon restoration of TP expression. We conclude that the host response to parasite-derived TXA2 in T. cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA2 may result in novel therapeutic targets for a disease with limited treatment options

Receptors and signal transduction for eicosanoids in human tissues

Dottorato di ricerca in farmacologia e tossicologia. 11. ciclo. A.a. 1998-99. Coordinatore F. Clementi. Docente guida S. NicosiaConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

Corrosion diagnosis of reinforced concrete beams after 40 years exposure in marine environment by non destructive tools

International audienceThis paper describes the detailed experimental program of the French national project “benchmark des poutres de la Rance”. It presents a corrosion diagnosis of prestressed beams after 40 years exposure in natural marine environment. It includes results from non destructive testing tools, complementary laboratory tests and destructive analyses. This project will provide a large database on the corrosion state of reinforced concrete beams after 40 years exposure in a marine environment (mechanical, electrochemical and physico-chemical properties) and will allow studying the sensitivity of NDT tools to evaluate corrosion risk within reinforced concrete structures. These results will be given to the modellers in order to complete their test conditions in the framework of the validation of mechanical models.Cet article decrit le programme experimental mis en place dans le cadre du Benchmark des poutres de la Rance. Il presente le diagnostic vis-a-vis de la corrosion de poutres en beton precontraint ayant sejourne 40 ans en environnement marin. Ce papier inclut les resultats issus des techniques d-auscultation non destructive, les tests complementaires en laboratoire et les analyses destructives. Ce projet permet de beneficier d-une large banque de donnees sur l-etat de corrosion des poutres apres 40 annees (mecanique, electrochimiques et proprietes physico-chimiques) et d-apprecier la sensibilite des techniques non destructives pour evaluer des risques de corrosion au sein de structures en beton precontraint. Ces resultats sont fournis aux equipes de modelisation afin de completer leurs conditions de tests en vue de la validation des modeles de comportement mecanique