Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor \u3b3. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents

Diagnostico tecnico y transferencia de tecnologia en el manejo del cultivo de arroz para la zona de santa lucia

TRABAJO QUE PROVEE DE UNA GUIA TECNICA PARA LA OPTIMIZACION DE LOS RECURSOS A EMPLEARSE EN LA PRODUCCION ARROCERA EN LA ZONA DE SANTA LUCIA. PARA LA CONSECUCION DE ESTE TRABAJO FUE NECESARIO REALIZAR UN DIAGNOSTICO TECNICO MEDIANTE ENCUESTAS Y ANALISIS DE CAMPO, LUEGO DE ESTO SE HICIERON INTERPRETACIONES DE LOS RESULTADOS, RECONOCIENDO LAS FALENCIAS TECNICAS QUE SE PRESENTABAN. CON ESTA INFORMACION SE LEVANTO UNA GUIA DEL CULTIVO PARA ESTA ZONA, LA CUAL SE BASO EN LA TOPOGRAFIA DEL TERRENO, IRRIGACION, ANALISIS DE SUELOS, ANALISIS FOLIARES. CULMINANDO CON TRANSFERENCIA DE TECNOLOGIA, DIFUSION DE LAS TECNICAS PROPUESTAS A TRAVES DE CHARLAS Y TALLERES A LAS PERSONAS INVOLUCRADAS DIRECTAMENTE

Computer-Assisted Discovery and Structural Optimization of a Novel Retinoid X Receptor Agonist Chemotype

As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding sites, available synthetic RXR ligands are lipophilic, and their structural diversity is limited. Here, we disclose the computer-assisted discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal chemistry

Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti‐asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver‐related metabolic diseases

Energy transition pathways to a low-carbon Europe in 2050: the degree of cooperation and the level of decentralization

In the framework of the Paris Agreement, the European Union (EU) will have to firmly set decarbonization targets to 2050. However, the viability on these targets is an ongoing discussion. The European Commission has made several propositions for energy and climate "roadmaps". In this regard, this paper contributes by analyzing alternative pathways derived in a unique modelling process. As part of the SET-Nav project, we defined four pathways to a clean, secure and efficient energy system - taking different routes. Two key uncertainties shape the SET-Nav pathways: the level of cooperation (i.e. cooperation versus entrenchment) and the level of decentralization (i.e. decentralization versus path dependency). All four pathways achieve an 85-95% emissions reduction by 2050. We include a broad portfolio of options under distinct framework conditions by comprehensively analyzing all energy-consuming and energy-providing sectors as well as the general economic conditions. We do this by applying a unique suite of linked models developed in the SET-Nav project. By linking more than ten models, we overcome the traditional limitation of models that cover one single sector while at the same time having access to detail sectoral data and expertise. In this paper, we focus on the implications for the energy demand sectors (buildings, transport, and industry) and the electricity supply mix in Europe and compare our insights of the electricity sector to the scenarios of the recent European Commission (2018a) report "A clean Planet for all"

Controlling intramolecular interactions in the design of selective, high-affinity, ligands for the CREBBP Bromodomain

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise ten domains through which they interact with >400 proteins, making them important transcriptional coactivators, and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable binding of acetylated lysine residues from histones, and a number of other important proteins, including p53, p73, E2F and GATA1. Here we report work to develop a high affinity, small molecule, ligand for the CREBBP and EP300 bromodomains [(−)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc, and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2), inhibition of the CREBBP/EP300 bromodomain results in enhanced stabilization of HIF-1α