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2. Evaluating Plasmodium falciparum automatic detection and parasitemia estimation: A comparative study on thin blood smear images.

Author

Acherar, Aniss, Tannier, Xavier, Tantaoui, Ilhame, Brossas, Jean-Yves, Thellier, Marc, and Piarroux, Renaud

Subjects
CONVOLUTIONAL neural networks, PLASMODIUM falciparum, PARASITEMIA, BLOOD parasites, COMPARATIVE studies
Abstract

Malaria is a deadly disease that is transmitted through mosquito bites. Microscopists use a microscope to examine thin blood smears at high magnification (1000x) to identify parasites in red blood cells (RBCs). Estimating parasitemia is essential in determining the severity of the Plasmodium falciparum infection and guiding treatment. However, this process is time-consuming, labor-intensive, and subject to variation, which can directly affect patient outcomes. In this retrospective study, we compared three methods for measuring parasitemia from a collection of anonymized thin blood smears of patients with Plasmodium falciparum obtained from the Clinical Department of Parasitology-Mycology, National Reference Center (NRC) for Malaria in Paris, France. We first analyzed the impact of the number of field images on parasitemia count using our framework, MALARIS, which features a top-classifier convolutional neural network (CNN). Additionally, we studied the variation between different microscopists using two manual techniques to demonstrate the need for a reliable and reproducible automated system. Finally, we included thin blood smear images from an additional 102 patients to compare the performance and correlation of our system with manual microscopy and flow cytometry. Our results showed strong correlations between the three methods, with a coefficient of determination between 0.87 and 0.92. [ABSTRACT FROM AUTHOR]

Published
2024
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3. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Author

Fersing, Cyril, Boudot, Clotilde, Castera-Ducros, Caroline, Pinault, Emilie, Hutter, Sébastien, Paoli-Lombardo, Romain, Primas, Nicolas, Pedron, Julien, Seguy, Line, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Stigliani, Jean-Luc, Brossas, Jean-Yves, Paris, Luc, Valentin, Alexis, Wyllie, Susan, Fairlamb, Alan H., Boutet-Robinet, Élisa, Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Destere, Alexandre, Mazier, Dominique, Rathelot, Pascal, Courtioux, Bertrand, Azas, Nadine, Verhaeghe, Pierre, and Vanelle, Patrice

Published
2020
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5. Improving the Detection of Epidemic Clones in Candida parapsilosis Outbreaks by Combining MALDI-TOF Mass Spectrometry and Deep Learning Approaches

Author

Mohammad, Noshine, primary, Normand, Anne-Cécile, additional, Nabet, Cécile, additional, Godmer, Alexandre, additional, Brossas, Jean-Yves, additional, Blaize, Marion, additional, Bonnal, Christine, additional, Fekkar, Arnaud, additional, Imbert, Sébastien, additional, Tannier, Xavier, additional, and Piarroux, Renaud, additional

Published
2023
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9. New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi

Author

Pedron, Julien, Boudot, Clotilde, Brossas, Jean-Yves, Pinault, Emilie, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Boutet-Robinet, Elisa, Destere, Alexandre, Tronnet, Antoine, Bergé, Justine, Bonduelle, Colin, Deraeve, Céline, Pratviel, Geneviève, Stigliani, Jean-Luc, Paris, Luc, Mazier, Dominique, Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Malzert-Freón, Aureĺie, Wyllie, Susan, Milne, Rachel, Fairlamb, Alan, Valentin, Alexis, Courtioux, Bertrand, Verhaeghe, Pierre, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Université de Limoges (UNILIM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), University of Dundee, Paul Sabatier University, Région Occitanie, Wellcome Trust (WT105021), Institut Pasteur de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Immunologie et de Maladies Infectieuses (CIMI), LCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, France, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Immunité et Infection, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR113-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Biochemistry, Medical Sciences Institute, Dundee University, Dundee, Grelier, Elisabeth, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Letter, Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei, 01 natural sciences, Biochemistry, Drug Discovery, parasitic diseases, NTR1, [CHIM.COOR]Chemical Sciences/Coordination chemistry, redox potentials, biology, 010405 organic chemistry, Chemistry, 8-nitroquinolin-2(1H)-ones, Organic Chemistry, [CHIM.COOR] Chemical Sciences/Coordination chemistry, biology.organism_classification, In vitro, 0104 chemical sciences, 3. Good health, 010404 medicinal & biomolecular chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pharmacophore
Abstract

International audience; An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = −0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

Published
2020

10. Identification and characterization of novel enhanced cell penetrating peptides for anti-cancer cargo delivery

Author

Zhang, Xiguang, Brossas, Jean Yves, Parizot, Christophe, Zini, Jean Marc, and Rebollo, Angelita

Subjects
peptide internalization, cell penetrating peptides, peptide stablity, Research Paper
Abstract

Cell penetrating peptides (CPP) are able cross the membrane and to transport cargos, presenting a great potential in drug delivery and diagnosis. In this paper, we have identified novel natural or synthetic CPPs. We have validated their rapid and efficient time and dose-dependent penetration, the absence of toxicity, the intracellular localization and the stability to proteases degradation, one of the main bottlenecks of peptides. Moreover, we have associate a cargo (an interfering peptide blocking the association of the serine/threonine phosphatase PP2A to its inhibitor, the oncogene SET) to the new generated shuttles and showed that they new bi-functional peptides keep the original properties of the shuttle and, in addition, are able to induce apoptosis due to the properties of the cargo. The CPPs identified in this study have promising perspectives for future anti-cancer drug delivery.

Published
2017

11. Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Author

Simon‐Gracia, Lorena, primary, Savier, Eric, additional, Parizot, Christophe, additional, Brossas, Jean Yves, additional, Loisel, Severine, additional, Teesalu, Tambet, additional, Conti, Filomena, additional, Charlotte, Frederic, additional, Scatton, Olivier, additional, Aoudjehane, Lynda, additional, and Rebollo, Angelita, additional

Published
2020
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14. Secretome analysis of Trypanosoma cruzi by proteomics studies

Author

Brossas, Jean-Yves, Gulin, Julián Ernesto Nicolás, Bisio, Margarita Maria Catalina, Chapelle, Manuel, Marinach-Patrice, Carine, Bordessoules, Mallaury, Palazon Ruiz, George, Vion, Jeremy, Paris, Luc, Altcheh, Jaime, and Mazier, Dominique

Subjects
Proteomics, Life Cycles, Serum Proteins, Cell Lines, Protozoan Proteins, lcsh:Medicine, Ciencias de la Salud, Protozoology, Biochemistry, Heat Shock Response, Tandem Mass Spectrometry, Chlorocebus aethiops, Medicine and Health Sciences, Parasitología, purl.org/becyt/ford/3.4 [https], lcsh:Science, Cellular Stress Responses, Protozoans, Trypanosoma Cruzi, Eukaryota, purl.org/becyt/ford/3.1 [https], Bioquímica y Biología Molecular, Medicina Básica, Cell Processes, Protozoan Life Cycles, Electrophoresis, Polyacrylamide Gel, purl.org/becyt/ford/3 [https], Biological Cultures, Research Article, Neglected Tropical Diseases, Trypanosoma, CIENCIAS MÉDICAS Y DE LA SALUD, Trypanosoma cruzi, Tecnologías que involucran la identificación de ADN, proteínas y enzimas, y cómo influyen en el conjunto de enfermedades y mantenimiento del bienestar, Research and Analysis Methods, Microbiology, Biotecnología de la Salud, purl.org/becyt/ford/3.3 [https], Virology, parasitic diseases, Parasitic Diseases, Animals, Chagas Disease, Vero Cells, Protozoan Infections, lcsh:R, Host Cells, Organisms, Biology and Life Sciences, Proteins, Cell Biology, Trypomastigotes, Tropical Diseases, Parasitic Protozoans, lcsh:Q, Parasitic Disease, Viral Transmission and Infection, Developmental Biology, Chromatography, Liquid
Abstract

Background: Chagas disease is a debilitating often fatal disease resulting from infection by the protozoan parasite Trypanosoma cruzi. Chagas disease is endemic in 21 countries of the Americas, and it is an emerging disease in other countries as a result of migration. Given the chronic nature of the infection where intracellular parasites persist for years, the diagnosis of T. cruzi by direct detection is difficult, whereas serologic tests though sensitive may yield false-positive results. The development of new rapid test based on the identification of soluble parasitic antigens in serum would be a real innovation in the diagnosis of Chagas disease. Methods: To identify new soluble biomarkers that may improve diagnostic tests, we investigated the proteins secreted by T. cruzi using mass spectrometric analyses of conditioned culture media devoid of serum collected during the emergence of trypomastigotes from infected Vero cells. In addition, we compared the secretomes of two T. cruzi strains from DTU Tc VI (VD and CL Brener). Results: Analysis of the secretome collected during the emergence of trypomastigotes from Vero cells led to the identification of 591 T. cruzi proteins. Three hundred sixty three proteins are common to both strains and most belong to different multigenic super families (i.e. TcS, GP63, MASP, and DGF1). Ultimately we have established a list of 94 secreted proteins, common to both DTU Tc VI strains that do not belong to members of multigene families. Conclusions: This study provides the first comparative analysis of the secretomes from two distinct T. cruzi strains of DTU TcVI. This led us to identify a subset of common secreted proteins that could potentially serve as serum markers for T. cruzi infection. Their potential could now be evaluated, with specific antibodies using sera collected from patients and residents from endemic regions. Fil: Brossas, Jean Yves. Inserm; Francia. Universite de Paris VI; Francia. Hôpital Pitié-Salpêtrière; Francia Fil: Gulin, Julián Ernesto Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas.; Argentina Fil: Bisio, Margarita María Catalina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas.; Argentina Fil: Chapelle, Manuel. Bruker Daltonics; Francia Fil: Marinach Patrice, Carine. Inserm; Francia. Universite de Paris VI; Francia Fil: Bordessoulles, Mallaury. Universite de Paris VI; Francia. Inserm; Francia Fil: Palazon Ruiz, George. Inserm; Francia Fil: Vion, Jeremy. Inserm; Francia Fil: Paris, Luc. Hôpital Pitié-Salpêtrière; Francia. Universite de Paris VI; Francia Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas.; Argentina Fil: Mazier, Dominique. Inserm; Francia. Universite de Paris VI; Francia. Hôpital Pitié-Salpêtrière; Francia

Published
2017

16. Secretome analysis of Trypanosoma cruzi by proteomics studies

Author

Brossas, Jean-Yves, primary, Gulin, Julián Ernesto Nicolás, additional, Bisio, Margarita Maria Catalina, additional, Chapelle, Manuel, additional, Marinach-Patrice, Carine, additional, Bordessoules, Mallaury, additional, Palazon Ruiz, George, additional, Vion, Jeremy, additional, Paris, Luc, additional, Altcheh, Jaime, additional, and Mazier, Dominique, additional

Published
2017
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18. Rapid Species Diagnosis for Invasive Candidiasis Using Mass Spectrometry

Author

Marinach-Patrice, Carine, primary, Fekkar, Arnaud, additional, Atanasova, Ralitsa, additional, Gomes, Johanna, additional, Djamdjian, Laura, additional, Brossas, Jean-Yves, additional, Meyer, Isabelle, additional, Buffet, Pierre, additional, Snounou, Georges, additional, Datry, Annick, additional, Hennequin, Christophe, additional, Golmard, Jean-Louis, additional, and Mazier, Dominique, additional

Published
2010
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19. MALDI-TOF MS-based drug susceptibility testing of pathogens: The example ofCandida albicansand fluconazole

Author

Marinach, Carine, primary, Alanio, Alexandre, additional, Palous, Martine, additional, Kwasek, St��phanie, additional, Fekkar, Arnaud, additional, Brossas, Jean-Yves, additional, Brun, Sophie, additional, Snounou, Georges, additional, Hennequin, Christophe, additional, Sanglard, Dominique, additional, Datry, Annick, additional, Golmard, Jean-Louis, additional, and Mazier, Dominique, additional

Published
2009
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25. New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi .

Author

Pedron J, Boudot C, Brossas JY, Pinault E, Bourgeade-Delmas S, Sournia-Saquet A, Boutet-Robinet E, Destere A, Tronnet A, Bergé J, Bonduelle C, Deraeve C, Pratviel G, Stigliani JL, Paris L, Mazier D, Corvaisier S, Since M, Malzert-Fréon A, Wyllie S, Milne R, Fairlamb AH, Valentin A, Courtioux B, and Verhaeghe P

Abstract

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1 H )-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum , T. brucei brucei , and T. cruzi , in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 ( E ° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma , and appears to be a good candidate to search for novel antitrypanosomal lead compounds., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Published
2020
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26. L-DNase II associated with active process during ethanol induced cell death in ARPE-19.

Author

Brossas JY, Tanguy R, Brignole-Baudouin F, Courtois Y, Torriglia A, and Tréton J

Subjects
Blotting, Western, Cell Death drug effects, Cells, Cultured, Cycloheximide pharmacology, DNA Fragmentation drug effects, Electrophoresis, Agar Gel, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Fluorescent Antibody Technique, Indirect, Humans, Pigment Epithelium of Eye metabolism, Poly(ADP-ribose) Polymerases metabolism, Protein Synthesis Inhibitors pharmacology, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Serpins genetics, Endodeoxyribonucleases metabolism, Ethanol pharmacology, Pigment Epithelium of Eye drug effects, Serpins metabolism
Abstract

Purpose: To analyse the mechanism of ethanol-induced cell death, and particularly, the activation of the leucocyte elastase inhibitor (LEI) pathway., Methods: Cultured ARPE-19 cells were exposed to 0-13% ethanol for 24 h. Cytotoxicity was estimated by morphologic changes within the nucleus and breakdown of DNA, assessed by agarose gel electrophoresis or flow cytometry cell sorter. Poly(ADP-ribose)polymerase cleavage (PARP) was determined by western blot analysis. Changes in transcription and translation of LEI were assessed by analysis of mRNA levels and expression of protein product (immunohistochemistry), respectively., Results: We established the ability of ethanol to induce cell death in ARPE-19 cells. After a 24 h incubation with 4% ethanol, 50% of the cells died; all the cells died in the presence of 10% ethanol. After ethanol incubation, we observed nuclear condensation and DNA fragmentation; the amount of fragmentation was proportional to the ethanol level. By flow cytometry analysis and agarose gel electrophoresis, the pattern of DNA cleavage exhibited a sub-G1 peak, suggesting necrotic cell death. However, other observations, i.e. nuclei shrinkage, PARP cleavage and inhibition of cell death by cycloheximide, and activation of a caspase independent LEI/DNase II pathway were observed and are features associated with apoptotic cell death. During ethanol stress, an LEI/L-DNase II intermediate was lost, leading to complete activation L-DNase II (24 kDa). RT-PCR analysis showed an early and specific increase of the LEI mRNA. Cycloheximide inhibited LEI synthesis and protected cells against apoptosis., Conclusions: Our data indicate that ethanol stress on ARPE-19 cells can induce a pathway which is a form of programmed cell death with characteristics of both apoptosis and necrosis, possibly by triggering conversion of LEI to L-DNase II.

Published
2004

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