Yeast translation elongation factor eIF5A expression is regulated by nutrient availability through different signalling pathways

Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types; the eIF5A-2 isoform is absent in most cells but becomes overexpressed in many metastatic cancers. Several reports have connected eIF5A and mitochondria because it co-purifies with the organelle or its inhibition reduces respiration and mitochondrial enzyme levels. However, the mechanisms of eIF5A mitochondrial function, and whether eIF5A expression is regulated by the mitochondrial metabolism, are unknown. We analysed the expression of yeast eIF5A isoforms Tif51A and Tif51B under several metabolic conditions and in mutants. The depletion of Tif51A, but not Tif51B, compromised yeast growth under respiration and reduced oxygen consumption. Tif51A expression followed dual positive regulation: by high glucose through TORC1 signalling, like other translation factors, to promote growth and by low glucose or non-fermentative carbon sources through Snf1 and heme-dependent transcription factor Hap1 to promote respiration. Upon iron depletion, Tif51A was down-regulated and Tif51B up-regulated. Both were Hap1-dependent. Our results demonstrate eIF5A expression regulation by cellular metabolic status

Targeting metabolic syndrome: Novel Benzopyrans and Quinolines as Peroxisome Proliferator-Activated Receptor agonists

For several decades, nature has provided a vast array of secondary metabolites with extensive therapeutic potential. The resulting immense interest has led to the pursuit of semi-synthetic and synthetic compounds modeled after natural products. Since its origin, our research group has dedicated efforts towards the isolation of bioactive secondary metabolites from plants within the Annonaceae family. Specifically, the benzopyran scaffold has attracted significant interest, as it was successfully isolated by our research group from the stem bark of Polyalthia cerasoides (Annonaceae), the first member of a new class of 2-prenylated benzopyrans, the natural polycerasoidol. Subsequently, polycerasoidol showed a dual full PPARα/γ agonist activity and anti-inflammatory effects, and emerged as a new hit compound with therapeutic potential to regulate lipid metabolism and glucose homeostasis. In a hit-to-lead strategy, the main objective of this thesis was set to develop new drugs based on the natural structure of polycerasoidol, potentially useful for the treatment of metabolic syndrome and associated cardiovascular comorbidities. To this end, the following specific objectives were proposed: 1. Synthesis and biological studies of a novel 2-prenylated benzopyran Synthesis of 2-(ethyl 4'-methylheptenoate)-6-(p-fluorobenzyloxy)-2-(methyl)-benzodihydropyran (BP-2) In vitro studies to determine the PPAR activity and the potential anti-inflammatory effects In vivo studies in a mice model of metabolic syndrome 2. Synthesis and biological studies of two series of novel 2- and 3-prenylated quinolines and tetrahydroquinolines Synthesis of two series of 2- and 3-prenylated quinolines and tetrahydroquinolines In vitro studies to determine the PPAR activity, the potential anti-inflammatory effects, and structure-activity relationships. In vivo studies in a mice model of metabolic syndrome In CHAPTER I of this Doctoral Thesis, the implications of PPAR receptors in targeting metabolic syndrome, highlighting the recent contributions of our group to the synthesis of biologically active benzopyrans, is briefly introduced. In CHAPTER II, the synthesis and evaluation of a novel benzopyran with PPAR activity are discussed. In the first section, the bibliographic background that led to the synthesis of 2-prenylated benzopyrans, including the methodology selected to develop BP-2, as well as the PPAR activity of benzopyrans is compiled. In the second section, the total synthesis of a novel 2-prenylated benzopyran is described, together with a description of the PPAR activity and molecular modeling studies carried out. In the third section, in vitro studies with BP-2 are presented, highlighting the potential anti-inflammatory effects of BP-2 by studying leukocyte-endothelium interactions. In the fourth section, in vivo studies performed using an ob/ob mouse model are described. The biochemical and anti-inflammatory effects were assessed. In CHAPTER III, the synthesis of novel quinolines and tetrahydroquinolines based on the benzopyran scaffold is described, and the PPAR activity of novel compounds is demonstrated. In the first section, the bibliographic background that led to the synthesis of quinolines and tetrahydroquinolines, including the methodology selected to develop our compounds, as well as the PPAR activity, is described. In the second section, the synthesis and biological studies of two series of 2-prenylated and 3-prenylated quinolines and tetrahydroquinolines are presented, including PPAR activity assessment and molecular modeling studies. Based on the generated data, a structure-PPAR activity relationship was established. In the third section, in vitro studies are described, including the activity of the compounds on a PPAR target gene and the evaluation of the potential anti-inflammatory effects of the lead candidates. Finally, in the fourth section, biochemical studies performed on an ob/ob mice model are described.Instituto de Salud Carlos III - Contrato PFISEuropean Molecular Biology Organization - Scientific Exchange GrantBritish Pharmacological Society - Best Poster Prize - Drug Discovery/Development3 - Salut i Benesta

Synthesis of 2-aminopropyl benzopyran derivatives as potential agents against triple-negative breast cancer

Synthesis of three series of 2-aminopropyl derivatives containing a benzopyran nucleus was performed to evaluate their performance against triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB- 436) and normal breast epithelial cells (MCF10A). For the three series, the cytotoxic activity was as follows: N-methylated derivatives (tertiary amines) 5b, 6b, and 7b > secondary amine benzopyrans 5, 6, and 7 > quaternary amine salts 5c, 6c, and 7c > free phenolic derivatives 5a, 6a, and 7a. The structure-activity relationship showed the importance of the presence of an amine group and a p-fluorobenzyloxy substituent in the chromanol ring (IC50 values from 1.5 μM to 58.4 μM). In addition, 5a, 5b, 6a, and 7b displayed slight selectivity towards tumor cells. Compounds 5, 5a, 5b, 6, 6a, 6c, 7, and 7b showed apoptotic/necrotic effects due to, at least in part, an increase in reactive oxygen species generation, whereas 5b, 5c, 6b, 7a, and 7c caused cell cycle arrest in the G1 phase. Further cell-based mechanistic studies revealed that 5a, 6a, and 7b, which were the most promising compounds, downregulated the expression of Bcl-2, while 5b downregulated the expression of cyclins CCND1 and CCND2. Therefore, 2-aminopropyl benzopyran derivatives emerge as new hits and potential leads for developing useful agents against breast cancer

Synthesis of 2-Prenylated Alkoxylated Benzopyrans by Horner-Wadsworth-Emmons olefination with PPARα/γ Agonist Activity

International audienceWe have synthesized series of 2-prenylated benzopyrans as analogs of the natural polycerasoidol, a dual PPARα/γ agonist with anti-inflammatory effect. The prenylated side chain consists of five-or nine-carbons with an α-alkoxy-α,β-unsaturated ester moiety. Prenylation was introduced via Grignard reaction, followed by Johnson-Claisen rearrangement, and the α-alkoxy-α,βunsaturated ester moiety by the Horner-Wadsworth-Emmons reaction. Synthetic derivatives showed high efficacy to activate both hPPARα and hPPARγ as dual PPARα/γ agonists. These prenylated benzopyrans emerge as lead compounds potentially useful for preventing cardiometabolic diseases

Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity

Background and purpose Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. Experimental approach BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARβ/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. Key results BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARβ/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPARβ/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. Conclusion and implications BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications

Synthesis and biological studies of "Polycerasoidol" and "trans-δ-Tocotrienolic acid" derivatives as PPARα and/or PPARγ agonists

International audience2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARα, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPARγ. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARα/γ activation. Therefore, 2-prenylated benzopyrans of sevenand nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders

Differential Effects of Biologics on Psoriasis-Related Vascular Inflammation and Risk of Thrombosis

Programa Estatal de I+D+i Orientada a los Retos de la Sociedad from Ministerio de Ciencia, Innovación y Universidades and European Regional Development Fund (Spain) [RTI2018-094436-B-I00]; Ministerio de Sanidad y Consumo CIBERehd (Spain) [CB06/04/0071]; Generalitat Valenciana (Spain) [PROMETEO/2018/141]; Proyectos Grupos Emergentes [GV/2019/043]; and Universidad Europea (Spain) (2018/UEM32 and 2019/UEM29].8.551 JCR (2020) Q1, 4/69 Dermatology1.951 SJR (2020) Q1, 54/438 BiochemistryNo data IDR 2020UE

Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity

Background and purpose: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. Experimental approach: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARβ/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. Key results: BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARβ/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPARβ/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. Conclusion and implications: BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications.Fil: Marques, Patrice. Universidad de Valencia; EspañaFil: Villarroel Vicente, Carlos. Universidad de Valencia; EspañaFil: Collado, Aida. Universidad de Valencia; EspañaFil: García, Ainhoa. Universidad de Valencia; EspañaFil: Vila, Laura. Hospital Clinico Universitario de Valencia; EspañaFil: Duplan, Isabelle. University Of Lille.; FranciaFil: Hennuyer, Nathalie. University Of Lille.; FranciaFil: Garibotto, Francisco Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Dacquet, Catherine. No especifíca;Fil: Staels, Bart. University Of Lille.; FranciaFil: Piqueras, Laura. Universidad de Valencia; EspañaFil: Cortes, Diego. Universidad de Valencia; EspañaFil: Sanz, María Jesús. Universidad de Valencia; EspañaFil: Cabedo, Nuria. Universidad de Valencia; Españ

Learn to entrepreneurship: from the final degree project in the Degree of Chemical Engineering to the labor market

Se constituirá una Empresa de Ingeniería con un grupo de estudiantes del TFG del Grado en Ingeniería Química que diseñe una planta química. Diferentes agentes asesorarán en la búsqueda de financiación, diseminación y desarrollo de las actividades.An Engineering Company will be constituted with a group of students from the final degree project of the Degree in Chemical Engineering who design a chemical plant. Different agents will advise in the search for funding, dissemination and development of activities.Depto. de Ingeniería Química y de MaterialesFac. de Ciencias QuímicasFALSEUCMsubmitte