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1. Meisosomes, folded membrane microdomains between the apical extracellular matrix and epidermis

Author

Dina Aggad, Nicolas Brouilly, Shizue Omi, Clara Luise Essmann, Benoit Dehapiot, Cathy Savage-Dunn, Fabrice Richard, Chantal Cazevieille, Kristin A Politi, David H Hall, Remy Pujol, and Nathalie Pujol

Subjects
extracellular matrix, cell–matrix interactions, eisosomes, skin, signal transduction, host-defense system, Medicine, Science, Biology (General), QH301-705.5
Abstract

Apical extracellular matrices (aECMs) form a physical barrier to the environment. In Caenorhabditis elegans, the epidermal aECM, the cuticle, is composed mainly of different types of collagen, associated in circumferential ridges separated by furrows. Here, we show that in mutants lacking furrows, the normal intimate connection between the epidermis and the cuticle is lost, specifically at the lateral epidermis, where, in contrast to the dorsal and ventral epidermis, there are no hemidesmosomes. At the ultrastructural level, there is a profound alteration of structures that we term ‘meisosomes,’ in reference to eisosomes in yeast. We show that meisosomes are composed of stacked parallel folds of the epidermal plasma membrane, alternately filled with cuticle. We propose that just as hemidesmosomes connect the dorsal and ventral epidermis, above the muscles, to the cuticle, meisosomes connect the lateral epidermis to it. Moreover, furrow mutants present marked modifications of the biomechanical properties of their skin and exhibit a constitutive damage response in the epidermis. As meisosomes co-localise to macrodomains enriched in phosphatidylinositol (4,5) bisphosphate, they could conceivably act, like eisosomes, as signalling platforms, to relay tensile information from the aECM to the underlying epidermis, as part of an integrated stress response to damage.

Published
2023
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2. Antagonistic fungal enterotoxins intersect at multiple levels with host innate immune defences.

Author

Xing Zhang, Benjamin W Harding, Dina Aggad, Damien Courtine, Jia-Xuan Chen, Nathalie Pujol, and Jonathan J Ewbank

Subjects
Genetics, QH426-470
Abstract

Animals and plants need to defend themselves from pathogen attack. Their defences drive innovation in virulence mechanisms, leading to never-ending cycles of co-evolution in both hosts and pathogens. A full understanding of host immunity therefore requires examination of pathogen virulence strategies. Here, we take advantage of the well-studied innate immune system of Caenorhabditis elegans to dissect the action of two virulence factors from its natural fungal pathogen Drechmeria coniospora. We show that these two enterotoxins have strikingly different effects when expressed individually in the nematode epidermis. One is able to interfere with diverse aspects of host cell biology, altering vesicle trafficking and preventing the key STAT-like transcription factor STA-2 from activating defensive antimicrobial peptide gene expression. The second increases STA-2 levels in the nucleus, modifies the nucleolus, and, potentially as a consequence of a host surveillance mechanism, causes increased defence gene expression. Our results highlight the remarkably complex and potentially antagonistic mechanisms that come into play in the interaction between co-evolved hosts and pathogens.

Published
2021
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3. Encapsulation of Upconversion Nanoparticles in Periodic Mesoporous Organosilicas

Author

Saher Rahmani, Chiara Mauriello Jimenez, Dina Aggad, Daniel González-Mancebo, Manuel Ocaña, Lamiaa M. A. Ali, Christophe Nguyen, Ana Isabel Becerro Nieto, Nadège Francolon, Erwan Oliveiro, Damien Boyer, Rachid Mahiou, Laurence Raehm, Magali Gary-Bobo, Jean-Olivier Durand, and Clarence Charnay

Subjects
upconversion, periodic mesoporous organosilica nanoparticles, cancer, Organic chemistry, QD241-441
Abstract

(1) Background: Nanomedicine has recently emerged as a promising field, particularly for cancer theranostics. In this context, nanoparticles designed for imaging and therapeutic applications are of interest. We, therefore, studied the encapsulation of upconverting nanoparticles in mesoporous organosilica nanoparticles. Indeed, mesoporous organosilica nanoparticles have been shown to be very efficient for drug delivery, and upconverting nanoparticles are interesting for near-infrared and X-ray computed tomography imaging, depending on the matrix used. (2) Methods: Two different upconverting-based nanoparticles were synthesized with Yb3+-Er3+ as the upconverting system and NaYF4 or BaLuF5 as the matrix. The encapsulation of these nanoparticles was studied through the sol-gel procedure with bis(triethoxysilyl)ethylene and bis(triethoxysilyl)ethane in the presence of CTAB. (3) Results: with bis(triethoxysilyl)ethylene, BaLuF5: Yb3+-Er3+, nanoparticles were not encapsulated, but anchored on the surface of the obtained mesoporous nanorods BaLuF5: Yb3+-Er3+@Ethylene. With bis(triethoxysilyl)ethane, BaLuF5: Yb3+-Er3+ and NaYF4: Yb3+-Er3+nanoparticles were encapsulated in the mesoporous cubic structure leading to BaLuF5: Yb3+-Er3+@Ethane and NaYF4: Yb3+-Er3+@Ethane, respectively. (4) Conclusions: upconversion nanoparticles were located on the surface of mesoporous nanorods obtained by hydrolysis polycondensation of bis(triethoxysilyl)ethylene, whereas encapsulation occurred with bis(triethoxysilyl)ethane. The later nanoparticles NaYF4: Yb3+-Er3+@Ethane or BaLuF5: Yb3+-Er3+@Ethane were promising for applications with cancer cell imaging or X-ray-computed tomography respectively.

Published
2019
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4. Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo

Author

Alexandra Vaccaro, Shunmoogum A. Patten, Dina Aggad, Carl Julien, Claudia Maios, Edor Kabashi, Pierre Drapeau, and J. Alex Parker

Subjects
TDP-43, ALS, Genetic models, Small molecules, ER stress, Neurodegeneration, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

C. elegans and D. rerio expressing mutant TAR DNA Binding Protein 43 (TDP-43) are powerful in vivo animal models for the genetics and pharmacology of amyotrophic lateral sclerosis (ALS). Using these small-animal models of ALS, we previously identified methylene blue (MB) as a potent suppressor of TDP-43 toxicity. Consequently here we investigated how MB might exert its neuroprotective properties and found that it acts through reduction of the endoplasmic reticulum (ER) stress response. We tested other compounds known to be active in the ER unfolded protein response in worms and zebrafish expressing mutant human TDP-43 (mTDP-43). We identified three compounds: salubrinal, guanabenz and a new structurally related compound phenazine, which also reduced paralysis, neurodegeneration and oxidative stress in our mTDP-43 models. Using C. elegans genetics, we showed that all four compounds act as potent suppressors of mTDP-43 toxicity through reduction of the ER stress response. Interestingly, these compounds operate through different branches of the ER unfolded protein pathway to achieve a common neuroprotective action. Our results indicate that protein-folding homeostasis in the ER is an important target for therapeutic development in ALS and other TDP-43-related neurodegenerative diseases.

Published
2013
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5. Large Pore Mesoporous Silica and Organosilica Nanoparticles for Pepstatin A Delivery in Breast Cancer Cells

Author

Saher Rahmani, Jelena Budimir, Mylene Sejalon, Morgane Daurat, Dina Aggad, Eric Vivès, Laurence Raehm, Marcel Garcia, Laure Lichon, Magali Gary-Bobo, Jean-Olivier Durand, and Clarence Charnay

Subjects
pepstatin A, mesoporous silica nanoparticles, mesoporous organosilica nanoparticles, cancer, Organic chemistry, QD241-441
Abstract

(1) Background: Nanomedicine has recently emerged as a new area of research, particularly to fight cancer. In this field, we were interested in the vectorization of pepstatin A, a peptide which does not cross cell membranes, but which is a potent inhibitor of cathepsin D, an aspartic protease particularly overexpressed in breast cancer. (2) Methods: We studied two kinds of nanoparticles. For pepstatin A delivery, mesoporous silica nanoparticles with large pores (LPMSNs) and hollow organosilica nanoparticles (HOSNPs) obtained through the sol–gel procedure were used. The nanoparticles were loaded with pepstatin A, and then the nanoparticles were incubated with cancer cells. (3) Results: LPMSNs were monodisperse with 100 nm diameter. HOSNPs were more polydisperse with diameters below 100 nm. Good loading capacities were obtained for both types of nanoparticles. The nanoparticles were endocytosed in cancer cells, and HOSNPs led to the best results for cancer cell killing. (4) Conclusions: Mesoporous silica-based nanoparticles with large pores or cavities are promising for nanomedicine applications with peptides.

Published
2019
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6. Mutant TDP-43 and FUS cause age-dependent paralysis and neurodegeneration in C. elegans.

Author

Alexandra Vaccaro, Arnaud Tauffenberger, Dina Aggad, Guy Rouleau, Pierre Drapeau, and J Alex Parker

Subjects
Medicine, Science
Abstract

Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Intracellular accumulations of wild type TDP-43 and FUS are observed in a growing number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. To better understand the mechanisms of TDP-43 and FUS toxicity we have created transgenic Caenorhabditis elegans strains that express full-length, untagged human TDP-43 and FUS in the worm's GABAergic motor neurons. Transgenic worms expressing mutant TDP-43 and FUS display adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. Additionally, mutant TDP-43 and FUS proteins are highly insoluble while wild type proteins remain soluble suggesting that protein misfolding may contribute to toxicity. Populations of mutant TDP-43 and FUS transgenics grown on solid media become paralyzed over 7 to 12 days. We have developed a liquid culture assay where the paralysis phenotype evolves over several hours. We introduce C. elegans transgenics for mutant TDP-43 and FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.

Published
2012
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7. Meisosomes, folded membrane platforms, link the epidermis to the cuticle in C. elegans

Author

Dina Aggad, Nicolas Brouilly, Shizue Omi, Clara L. Essmann, Benoit Dehapiot, Cathy Savage-Dunn, Fabrice Richard, Chantal Cazevieille, Kristin A. Politi, David H. Hall, Remy Pujol, Nathalie Pujol, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Turing Centre for Living Systems [Marseille] (TCLS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Department of Computer science [University College of London] (UCL-CS), University College of London [London] (UCL), College of Staten Island [CUNY] (CSI CUNY), City University of New York [New York] (CUNY), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Albert Einstein College of Medicine [New York], ANR-22-CE13-0037,SensoSkin,Comment la peau perçoit-elle les blessures?(2022), ANR-16-CONV-0001,CENTURI,CenTuri : Centre Turing des Systèmes vivants(2016), ANR-16-CE15-0001,ELEGINN,Analyse intégrée de l'immunité innée antifongique chez C. elegans(2016), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Aix Marseille Université (AMU), Neurobiologie de l'audition-plasticité synaptique, Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011)

Subjects
Epidermis (zoology), Chemistry, [SDV]Life Sciences [q-bio], Mutant, Extracellular, Integrated stress response, Cytoskeleton, Moulting, Process (anatomy), Cuticle (hair), Cell biology
Abstract

Apical extracellular matrices (aECMs) form a physical barrier to the environment. InC. elegans, the epidermal aECM, the cuticle, is composed mainly of different types of collagen, associated in circumferential ridges separated by furrows. Here, we show that in mutants lacking furrows, the normal intimate connection between the epidermis and the cuticle is lost, specifically at the lateral epidermis, where, in contrast to the dorsal and ventral epidermis, there are no hemidesmosomes. At the ultrastructural level, there is a profound alteration of structures that we term “meisosomes”, in reference to eisosomes in yeast. We show that meisosomes are composed of stacked parallel folds of the epidermal plasma membrane, alternately filled with cuticle. We propose that just as hemidesmosomes connect the dorsal and ventral epidermis, above the muscles, to the cuticle, meisosomes connect the lateral epidermis to it. Moreover, furrow mutants present marked modifications of the biomechanical properties of their skin and exhibit a constitutive damage response in the epidermis. As meisosomes co-localise to macrodomains enriched in phosphatidylinositol (4,5) bisphosphate, they might act, like eisosomes, as signalling platforms, to relay tensile information from the aECM to the underlying epidermis, as part of an integrated stress response to damage.

Published
2023

9. Fluorescent periodic mesoporous organosilica nanoparticles dual-functionalized via click chemistry for two-photon photodynamic therapy in cells

Author

Marie Maynadier, Laurence Raehm, Jean-Olivier Durand, Xavier Cattoën, Marcel Garcia, Maxime Klausen, Sébastien Picard, Dina Aggad, Guillaume Clermont, Chiara Mauriello Jimenez, Mireille Blanchard-Desce, Jonas G. Croissant, Emilie Genin, Michel Wong Chi Man, Magali Gary-Bobo, Olivier Mongin, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Optique et Matériaux (NEEL - OPTIMA), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Optique et Matériaux (OPTIMA )

Subjects
Fluorophore, Materials science, Singlet oxygen, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Biomedical Engineering, Nanoparticle, 02 engineering and technology, General Chemistry, General Medicine, 010402 general chemistry, 021001 nanoscience & nanotechnology, Photochemistry, 01 natural sciences, Fluorescence, 0104 chemical sciences, chemistry.chemical_compound, Mesoporous organosilica, chemistry, Click chemistry, General Materials Science, Photosensitizer, 0210 nano-technology, Mesoporous material, ComputingMilieux_MISCELLANEOUS
Abstract

The synthesis of ethenylene-based periodic mesoporous organosilica nanoparticles for two-photon imaging and photodynamic therapy of breast cancer cells is described. A dedicated two-photon absorbing fluorophore possessing four triethoxysilyl groups and having large two-photon absorption in the near IR region, and azidopropyltriethoxysilane were incorporated into the structure. The mesoporous nanoparticles of 100 nm diameter were further functionalized by means of click chemistry with a propargylated fluorescent bromo-quinoline photosensitizer able to generate singlet oxygen. The photophysical properties and two-photon absorption properties of the nanoparticles were investigated evidencing complementary contribution of the two dyes. Both dyes contribute to the two-photon absorption response of the mesoporous nanoparticles while efficient FRET from the two-photon fluorophore to the quinoline sensitizer is observed. The dual-functionalized nanoparticles were incubated with MCF-7 breast cancer cells. Two-photon confocal imaging demonstrated the endocytosis of the nanoparticles within cancer cells. Moreover, brief two-photon irradiation (3 scans of 1.57 s) at 760 nm at high laser power (3 W) was shown to induce 40% of cancer cell death demonstrating the potential of the dual-functionalized mesoporous organosilica nanoparticles for two-photon photodynamic therapy.

Published
2020
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10. Triphenylphosphonium-substituted phthalocyanine: Design, synthetic strategy, photoproperties and photodynamic activity

Author

Frédérique Brégier, Denis Durand, Vincent Sol, Ümit İşci, Bassem Jamoussi, Dina Aggad, Gülçin Ekineker, Mohamed Tarhouni, Fabienne Dumoulin, Magali Gary-Bobo, and Emel Önal

Subjects
Zn-phthalocyanine, chemistry.chemical_compound, 010405 organic chemistry, Chemistry, medicine.medical_treatment, Phthalocyanine, medicine, Photodynamic therapy, General Chemistry, 010402 general chemistry, Photochemistry, 01 natural sciences, 0104 chemical sciences
Abstract

In line with current efforts to direct PDT photosensitizers to specific organelles such as mitochondria, a triphenylphosphonium-tetrasubstituted Zn phthalocyanine was designed, taking into account synthetic constraints. Triphenylphosphonium moieties were successfully introduced on alkyl bromide substituents on a pre-formed phthalocyanine. Photophysical and photochemical measurements showed that the photoproperties of the Zn phthalocyanine core were not affected by the triphenylphosphonium groups. Biological investigations demonstrated the dark innocuousness of the phthalocyanine up to 1 [Formula: see text]M, a concentration that exhibited a powerful phototoxicity. Cell death was confirmed to be photodynamically induced thanks to reactive oxygen species detection experiments. Nonetheless, the triphenylphosphonium moieties did not promote the accumulation of the phthalocyanine in mitochondria as significantly as expected.

Published
2018
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11. Diazachlorin and diazabacteriochlorin for one- and two-photon photodynamic therapy

Author

Morgane Daurat, Jean-François Longevial, Tsubasa Nishimura, Dongho Kim, Juwon Oh, Sébastien Richeter, Wen Xi Chia, Ayaka Yamaji, Yoshihiro Miyake, Magali Gary-Bobo, Christophe Nguyen, Gakhyun Kim, Dina Aggad, Hiroshi Shinokubo, Sébastien Clément, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Soongsil University

Subjects
Models, Molecular, medicine.medical_treatment, education, Breast Neoplasms, Photodynamic therapy, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Catalysis, Two-photon excitation microscopy, In vivo, Cell Line, Tumor, Materials Chemistry, medicine, Animals, Humans, Zebrafish, health care economics and organizations, Photons, Photosensitizing Agents, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Metals and Alloys, General Chemistry, 021001 nanoscience & nanotechnology, In vitro, 3. Good health, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Photochemotherapy, MCF-7 Cells, Ceramics and Composites, Cancer research, Female, 0210 nano-technology
Abstract

International audience; Diazachlorin and diazabacteriochlorin have been prepared through reduction of diazaporphyrin and their in vitro and in vivo activity in photodynamic therapy has been investigated.

Published
2018
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12. Gemcitabine Delivery and Photodynamic Therapy in Cancer Cells via Porphyrin-Ethylene-Based Periodic Mesoporous Organosilica Nanoparticles

Author

Jean-Olivier Durand, Sébastien Richeter, Marie Maynadier, Jonas G. Croissant, Laure Lichon, Makhlouf Boufatit, Marcel Garcia, Laurence Raehm, Chiara Mauriello Jimenez, Danielle Laurencin, Dina Aggad, Soraya Dib, Shahad Alsaiari, Magali Gary-Bobo, and Niveen M. Khashab

Subjects
Materials science, Membrane permeability, medicine.medical_treatment, Energy Engineering and Power Technology, Nanotechnology, Photodynamic therapy, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Gemcitabine Hydrochloride, Biomaterials, chemistry.chemical_compound, Materials Chemistry, medicine, Photosensitizer, Renewable Energy, Sustainability and the Environment, 021001 nanoscience & nanotechnology, Porphyrin, Gemcitabine, 0104 chemical sciences, Mesoporous organosilica, chemistry, Cancer cell, Cancer research, 0210 nano-technology, medicine.drug
Abstract

Gemcitabine hydrochloride is an FDA-approved chemotherapeutic drug used in the treatment of various cancers. Several drawbacks of gemcitabine including its short in vivo half-life of 8-17 min associated with a rapid excretion by the kidneys and its poor membrane permeability have inspired research on a nanodelivery approach. In this study, we report ethylene-based periodic mesoporous organosilica nanoparticles (PMOs) for photodynamic therapy and the autonomous delivery of gemcitabine in cancer cells. Porphyrins were used as photosensitizers and were localized in the walls of the PMOs while a high loading capacity of gemcitabine was observed in the porous structure. Depending on the nature of the photosensitizer, and its aggregation state, we were able to perform one or two-photon photodynamic therapy. Two-photon excited photodynamic therapy combined with gemcitabine delivery led to a synergy and a very efficient cancer cell killing.

Published
2017
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13. Encapsulation of Upconversion Nanoparticles in Periodic Mesoporous Organosilicas

Author

Clarence Charnay, Christophe Nguyen, Dina Aggad, Manuel Ocaña, Magali Gary-Bobo, Rachid Mahiou, Lamiaa M. A. Ali, Erwan Oliveiro, Damien Boyer, Ana Isabel Becerro Nieto, Jean-Olivier Durand, Laurence Raehm, Nadège Francolon, Daniel González-Mancebo, Chiara Mauriello Jimenez, Saher Rahmani, Institut de Chimie de Clermont-Ferrand - Clermont Auvergne (ICCF), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Instituto de Ciencia de Materiales de Sevilla (ICMSE), Universidad de Sevilla / University of Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Agencia Estatal de Investigación (España), Agence Nationale de la Recherche (France), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Universidad de Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), and Clot, Eric

Subjects
Materials science, Condensation polymer, Pharmaceutical Science, Nanoparticle, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Article, Analytical Chemistry, lcsh:QD241-441, Fluorides, Drug Delivery Systems, lcsh:Organic chemistry, TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY, [CHIM] Chemical Sciences, Drug Discovery, Technology, Pharmaceutical, cancer, [CHIM]Chemical Sciences, Organosilicon Compounds, Yttrium, Physical and Theoretical Chemistry, Ytterbium, ComputingMilieux_MISCELLANEOUS, Cancer, upconversion, Ethane, Nanotubes, Hydrolysis, Organic Chemistry, periodic mesoporous organosilica nanoparticles, 021001 nanoscience & nanotechnology, Photon upconversion, 0104 chemical sciences, Mesoporous organosilica, Nanomedicine, Chemical engineering, Chemistry (miscellaneous), Drug delivery, Molecular Medicine, Nanoparticles, Nanorod, Periodic mesoporous organosilica nanoparticles, 0210 nano-technology, Mesoporous material, Upconversion, Erbium
Abstract

1) Background: Nanomedicine has recently emerged as a promising field, particularly for cancer theranostics. In this context, nanoparticles designed for imaging and therapeutic applications are of interest. We, therefore, studied the encapsulation of upconverting nanoparticles in mesoporous organosilica nanoparticles. Indeed, mesoporous organosilica nanoparticles have been shown to be very efficient for drug delivery, and upconverting nanoparticles are interesting for near-infrared and X-ray computed tomography imaging, depending on the matrix used. (2) Methods: Two different upconverting-based nanoparticles were synthesized with Yb3+-Er3+ as the upconverting system and NaYF4 or BaLuF5 as the matrix. The encapsulation of these nanoparticles was studied through the sol-gel procedure with bis(triethoxysilyl)ethylene and bis(triethoxysilyl)ethane in the presence of CTAB. (3) Results: with bis(triethoxysilyl)ethylene, BaLuF5: Yb3+-Er3+, nanoparticles were not encapsulated, but anchored on the surface of the obtained mesoporous nanorods BaLuF5: Yb3+-Er3+@Ethylene. With bis(triethoxysilyl)ethane, BaLuF5: Yb3+-Er3+ and NaYF4: Yb3+-Er3+nanoparticles were encapsulated in the mesoporous cubic structure leading to BaLuF5: Yb3+-Er3+@Ethane and NaYF4: Yb3+-Er3+@Ethane, respectively. (4) Conclusions: upconversion nanoparticles were located on the surface of mesoporous nanorods obtained by hydrolysis polycondensation of bis(triethoxysilyl)ethylene, whereas encapsulation occurred with bis(triethoxysilyl)ethane. The later nanoparticles NaYF4: Yb3+-Er3+@Ethane or BaLuF5: Yb3+-Er3+@Ethane were promising for applications with cancer cell imaging or X-ray-computed tomography respectively., This research was funded by ANR NanoptPDT. SR thanks the Erasmus Mundus program for a grant. This work has been supported by the Spanish Ministry of Science, Innovation and Universities (RTI2018-094426-B-I00).

Published
2019
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14. Porphyrin‐based bridged silsesquioxane nanoparticles for targeted two‐photon photodynamic therapy of zebrafish xenografted with human tumor

Author

Magali Gary-Bobo, Denis Durand, Makhlouf Boufatit, Soraya Dib, Jean-Olivier Durand, Ahmed Lakrafi, Alain Morère, Sofia Dominguez Gil, Vincent Chaleix, Dina Aggad, Nadir Bettache, Karim Bouchmella, Michel Wong Chi Man, Vincent Sol, Laurence Raehm, Guillaume Hery, Xavier Cattoën, Khaled El Cheikh, Chiara Mauriello Jimenez, Christophe Nguyen, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Optique et Matériaux (OPTIMA ), Institut Néel (NEEL), and Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Cancer Research, Porphyrins, medicine.medical_treatment, Nanoparticle, Breast Neoplasms, Photodynamic therapy, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 02 engineering and technology, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, 010402 general chemistry, 01 natural sciences, Theranostic Nanomedicine, chemistry.chemical_compound, Two-photon excitation microscopy, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Zebrafish, two-photon excitation, Photosensitizing Agents, bridged silsesquioxane nanoparticles, Lasers, human tumor targeting, Original Articles, Silanes, 021001 nanoscience & nanotechnology, Xenograft Model Antitumor Assays, Porphyrin, 3. Good health, 0104 chemical sciences, Microscopy, Fluorescence, Multiphoton, photodynamic therapy, Photochemotherapy, Oncology, chemistry, Injections, Intravenous, Cancer cell, Click chemistry, Biophysics, Nanoparticles, Nanomedicine, Female, 0210 nano-technology
Abstract

International audience; Background: Bridged silsesquioxane nanoparticles (BSNs) recently described represent a new class of nanoparticles exhibiting versatile applications and particularly a strong potential for nanomedicine.Aims: In this work, we describe the synthesis of BSNs from an octasilylated functional porphyrin precursor (PORBSNs) efficiently obtained through a click reaction. These innovative and very small-sized nanoparticles were functionalized with PEG and mannose (PORBSNs-mannose) in order to target breast tumors in vivo. Methods and Results: The structure of these nanoparticles is constituted of porphyrins J aggregates that allow two-photon spatiotemporal excitation of the nanoparticles. The therapeutic potential of such photoactivable nanoparticles was first studied in vitro, in human breast cancer cells in culture and then in vivo on zebrafish embryos bearing human tumors. These animal models were intravenously injected with 5 nL of a solution containing PORBSNs-mannose. An hour and half after the injection of photoactivable and targeted nanoparticles, the tumor areas were excited for few seconds with a two-photon beam induced focused laser. We observed strong tumor size decrease, with the involvement of apoptosis pathway activation.onclusion: We demonstrated the high targeting, imaging, and therapeutic potential of PORBSNs-mannose injected in the blood stream of zebrafish xenografted with human tumors.

Published
2019
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15. Degradable gold core–mesoporous organosilica shell nanoparticles for two-photon imaging and gemcitabine monophosphate delivery

Author

Saher Rahmani, Arnaud Chaix, Dina Aggad, Phuong Hoang, Niveen M. Khashab, Marcel Garcia, Magali Gary-Bobo, Basem Moosa, Clarence Charnay, Jean-Olivier Durand, and Abdulaziz Almalik

Subjects
Materials science, Process Chemistry and Technology, Biomedical Engineering, Energy Engineering and Power Technology, Nanoparticle, Nanotechnology, 02 engineering and technology, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, Industrial and Manufacturing Engineering, Gemcitabine, 0104 chemical sciences, Mesoporous organosilica, Two-photon excitation microscopy, Chemistry (miscellaneous), Materials Chemistry, medicine, Chemical Engineering (miscellaneous), Nanomedicine, 0210 nano-technology, Luminescence, Gold core, medicine.drug
Abstract

The synthesis of degradable gold core–mesoporous organosilica shell nanoparticles is described. The nanoparticles were very efficient for two-photon luminescence imaging of cancer cells and for in vitro gemcitabine monophosphate delivery, allowing promising theranostic applications in the nanomedicine field.

Published
2017
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16. Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles for two-photon photodynamic therapy or photoacoustic imaging

Author

Vefa Ahsen, Dina Aggad, Jean-Luc Coll, Serkan Alpugan, Michel Wong Chi Man, Marcel Garcia, Marie Maynadier, Laurence Raehm, Deniz Kutlu Tarakci, Philippe Maillard, Fabienne Dumoulin, Clarence Charnay, Jean-Olivier Durand, Maxime Henry, Magali Gary-Bobo, Xavier Cattoën, Véronique Josserand, Chiara Mauriello-Jimenez, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Optique et Matériaux (OPTIMA ), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of chemistry - Gebze Technical University, Gebze Teknik Üniversitesi [Gebze], Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Institut de Chimie du CNRS (INC)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], and NanoMedSyn

Subjects
Materials science, [CHIM.ORGA]Chemical Sciences/Organic chemistry, medicine.medical_treatment, Nanoparticle, Photodynamic therapy, [CHIM.MATE]Chemical Sciences/Material chemistry, 02 engineering and technology, 010402 general chemistry, 021001 nanoscience & nanotechnology, Photochemistry, 01 natural sciences, Porphyrin, Fluorescence, Silsesquioxane, 0104 chemical sciences, 3. Good health, chemistry.chemical_compound, chemistry, Two-photon excitation microscopy, Excited state, Phthalocyanine, medicine, General Materials Science, 0210 nano-technology, ComputingMilieux_MISCELLANEOUS
Abstract

Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles (BSPOR and BSPHT) were prepared. Their endocytosis in MCF-7 cancer cells was shown with two-photon excited fluorescence (TPEF) imaging. With two-photon excited photodynamic therapy (TPE-PDT), BSPOR was more phototoxic than BSPHT, which in contrast displayed a very high signal for photoacoustic imaging in mice.

Published
2017
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17. Large Pore Mesoporous Silica and Organosilica Nanoparticles for Pepstatin A Delivery in Breast Cancer Cells

Author

Laurence Raehm, Laure Lichon, Morgane Daurat, Clarence Charnay, Marcel Garcia, Dina Aggad, Magali Gary-Bobo, Jean-Olivier Durand, Mylene Sejalon, Eric Vivès, Jelena Budimir, Saher Rahmani, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Dispersity, Pharmaceutical Science, Nanoparticle, Peptide, Breast Neoplasms, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Article, pepstatin A, Analytical Chemistry, lcsh:QD241-441, chemistry.chemical_compound, Drug Delivery Systems, lcsh:Organic chemistry, Cell Line, Tumor, Drug Discovery, Pepstatins, Humans, cancer, [CHIM]Chemical Sciences, mesoporous silica nanoparticles, mesoporous organosilica nanoparticles, Physical and Theoretical Chemistry, chemistry.chemical_classification, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Mesoporous silica, 021001 nanoscience & nanotechnology, Silicon Dioxide, 0104 chemical sciences, 3. Good health, Membrane, Chemical engineering, Chemistry (miscellaneous), Cancer cell, Molecular Medicine, Nanomedicine, Nanoparticles, Female, 0210 nano-technology, Porosity, Pepstatin
Abstract

International audience; (1) Background: Nanomedicine has recently emerged as a new area of research, particularly to fight cancer. In this field, we were interested in the vectorization of pepstatin A, a peptide which does not cross cell membranes, but which is a potent inhibitor of cathepsin D, an aspartic protease particularly overexpressed in breast cancer. (2) Methods: We studied two kinds of nanoparticles. For pepstatin A delivery, mesoporous silica nanoparticles with large pores (LPMSNs) and hollow organosilica nanoparticles (HOSNPs) obtained through the sol-gel procedure were used. The nanoparticles were loaded with pepstatin A, and then the nanoparticles were incubated with cancer cells. (3) Results: LPMSNs were monodisperse with 100 nm diameter. HOSNPs were more polydisperse with diameters below 100 nm. Good loading capacities were obtained for both types of nanoparticles. The nanoparticles were endocytosed in cancer cells, and HOSNPs led to the best results for cancer cell killing. (4) Conclusions: Mesoporous silica-based nanoparticles with large pores or cavities are promising for nanomedicine applications with peptides.

Published
2019
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18. Hollow Organosilica Nanoparticles for Drug Delivery

Author

Christophe Nguyen, Saher Rahmani, Jelena Budimir, Alia Akrout, Morgane Daurat, Clarence Charnay, Magali Gary-Bobo, Dina Aggad, Laurence Raehm, Anastasia Godefroy, Hanene Largot, Jean-Olivier Durand, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Nanomedsyn

Subjects
Nanoparticle, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Gemcitabine Hydrochloride, medicine, [CHIM]Chemical Sciences, Microemulsion, skin and connective tissue diseases, Chemistry, digestive, oral, and skin physiology, technology, industry, and agriculture, General Chemistry, 021001 nanoscience & nanotechnology, Uniform size, Gemcitabine, 0104 chemical sciences, Methotrexate, MCF-7 breast cancer cells, Organosilica Nanoparticles, Drug delivery, Breast cancer cells, 0210 nano-technology, medicine.drug, Nuclear chemistry
Abstract

International audience; The sol‐gel synthesis of hollow organosilica nanoparticles incorporating amino groups with uniform size are described. These nanoparticles were successfully prepared via a microemulsion method. Then, the hollow nanoparticles were loaded with gemcitabine hydrochloride or methotrexate and studied in MCF‐7 breast cancer cells.

Published
2018
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19. Porous Porphyrin-Based Organosilica Nanoparticles for NIR Two-Photon Photodynamic Therapy and Gene Delivery in Zebrafish

Author

Nadir Bettache, Jonas G. Croissant, Vincent Chaleix, Michel Wong Chi Man, Mireille Rossel, Xavier Cattoën, Karen Tresfield, Niveen M. Khashab, Danielle Laurencin, Sébastien Richeter, Rachid Sougrat, Sébastien Clément, Jean-Olivier Durand, Chiara Mauriello Jimenez, Dina Aggad, Magali Gary-Bobo, Nicolas Cubedo, Erwan Oliviero, Marcel Garcia, Vincent Sol, Shahad Alsaiari, Marie Maynadier, Laurence Raehm, Manuel A. Roldan-Gutierrez, Clarence Charnay, Dorothée Berthomieu, Dalaver H. Anjum, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), King Abdullah University of Science and Technology (KAUST), KAUST Catalysis Center (KCC), King Abdullah University of Sciences & Technologie, Optique et Matériaux (OPTIMA ), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), NanoMedSyn, Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Dynamique moléculaire des interactions membranaires (DMIM), and Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)

Subjects
Materials science, medicine.medical_treatment, Confocal, Nanoparticle, Photodynamic therapy, Nanotechnology, 02 engineering and technology, Gene delivery, 010402 general chemistry, 01 natural sciences, Biomaterials, chemistry.chemical_compound, Two-photon excitation microscopy, Electrochemistry, medicine, Zebrafish, Multiphoton imaging, ComputingMilieux_MISCELLANEOUS, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, biology.organism_classification, Porphyrin, 0104 chemical sciences, Electronic, Optical and Magnetic Materials, chemistry, 0210 nano-technology
Abstract

C.M.J. and D.A. contributed equally to this work. The grant “Chercheur d'Avenir Languedoc-Roussillon” attributed to M.G.-B. and the ANR nanoptPDT are gratefully acknowledged. The authors thank L. Lichon for technical assistance. DFT calculations were performed using HPC resources from the CINES (projects x2016087394 and x2015087394), and from the CALMIP (Grant 2016-[P16042]). The authors thank MRI (Montpellier RIO Imaging platform) for confocal and multiphoton imaging facilities.

Published
2018
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20. Nanodiamond–PMO for two-photon PDT and drug delivery

Author

Rabah Boukherroub, Vanja Stojanovic, Yolanda Galàn Rubio, Ouahiba Hocine, Marcel Garcia, Dina Aggad, J.O. Durand, Nikola Knezevic, Chiara Mauriello Jimenez, Magali Gary-Bobo, Florina Teodorescu, Marie Maynadier, Laurence Raehm, Martina Seric, Sabine Szunerits, Jonas G. Croissant, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), NanoMedSyn, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), and NanoMedSyn (NMS)

Subjects
Materials science, Biomedical Engineering, Nanoparticle, Nanotechnology, 02 engineering and technology, 010402 general chemistry, Photochemistry, 01 natural sciences, Two-photon excitation microscopy, medicine, General Materials Science, Doxorubicin, Nanodiamond, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Reactive oxygen species, [CHIM.ORGA]Chemical Sciences/Organic chemistry, General Chemistry, General Medicine, 021001 nanoscience & nanotechnology, 0104 chemical sciences, 3. Good health, Mesoporous organosilica, chemistry, Drug delivery, Cancer cell, 0210 nano-technology, medicine.drug
Abstract

In this article, we highlight the properties of nanodiamonds (ND), which were encapsulated in periodic mesoporous organosilica nanoparticles (PMO) and were able to generate reactive oxygen species for photodynamic applications upon two-photon excitation (TPE). The ND@PMO nanoparticles were characterized by various techniques and were then loaded with the anti-cancer drug doxorubicin. The release of the drug was pH sensitive and a synergistic cancer cell killing effect was observed when cancer cells were incubated with doxorubicin-loaded ND@PMO and irradiated with two-photon excitation at 800 nm.

Published
2016
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21. Biocompatible Periodic Mesoporous Ionosilica Nanoparticles with Ammonium Walls: Application to Drug Delivery

Author

Morgane Daurat, Anastasia Godefroy, Dina Aggad, Afitz Da Silva, Magali Gary-Bobo, Philippe Dieudonné, Peter Hesemann, Jean-Olivier Durand, Roza Bouchal, Leïla Lesaffre, Clarence Charnay, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), NanoMedSyn, Laboratoire Charles Coulomb (L2C), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Materials science, Silicon dioxide, Nanoparticle, Nanotechnology, 02 engineering and technology, 010402 general chemistry, periodic mesoporous organosilica, 01 natural sciences, chemistry.chemical_compound, Drug Delivery Systems, Specific surface area, anion exchange, Ammonium Compounds, General Materials Science, Ammonium, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, Silicon Dioxide, 0104 chemical sciences, Mesoporous organosilica, ionosilica, chemistry, Drug delivery, drug delivery, nanoparticles, Particle size, 0210 nano-technology, Mesoporous material, Porosity
Abstract

International audience; Periodic mesoporous ionosilica nanoparticles with ammonium wallswere synthesized exclusively from a trisilylated ammonium precursor. The nanoparticlesdisplay a uniform particle size, together with a high specific surface area and anordered hexagonal pore architecture. Completely biocompatible in vitro and in vivo,the nanoparticles are efficiently endocytosed by RAW 264.7 macrophages and used ascarrier vehicles for anionic drugs. Diclofenac-loaded ionosilica nanoparticles are veryefficient in inhibiting lipopolysaccharides-induced inflammation.

Published
2017
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22. Porphyrins Conjugated with Peripheral Thiolato Gold(I) Complexes for Enhanced Photodynamic Therapy

Author

Dina Aggad, Marcel Garcia, Aurélien Lebrun, Arie van der Lee, Jean-François Longevial, Sébastien Clément, Khaled El Cheikh, Frederik Tielens, Alain Morère, Magali Gary-Bobo, Sébastien Richeter, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mesures Physiques, Université de Montpellier (UM), Institut Européen des membranes (IEM), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM), Spectroscopie, Modélisation, Interfaces pour L'Environnement et la Santé (LCMCP-SMiLES), Laboratoire de Chimie de la Matière Condensée de Paris (LCMCP), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Région Languedoc-Roussillon (Research Grant 'Chercheur(se)s d’Avenir—Editions 2013 and 2015', 2013–098085 and 2015- 005984) Program FEDER (Fonds Européen de Développement Régional), ANR-09-JCJC-0089,PORPH-NHC,Ligands ' Porphyrine-Carbène N-Hétérocyclique ' Réglables et Réactifs à des Stimuli Externes pour la Catalyse(2009), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), and Chemistry

Subjects
medicine.medical_treatment, porphyrinoids, Photodynamic therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Conjugated system, 010402 general chemistry, Photochemistry, 01 natural sciences, Chloride, Catalysis, chemistry.chemical_compound, medicine, Moiety, [CHIM.COOR]Chemical Sciences/Coordination chemistry, 010405 organic chemistry, Singlet oxygen, Organic Chemistry, General Chemistry, gold, glycoconjugates, 0104 chemical sciences, carbenes, chemistry, photodynamic therapy, Breast cancer cells, Carbene, medicine.drug
Abstract

International audience; Porphyrins fused to imidazolium salts across two neighboring beta-pyrrolic positions were used as N-heterocycliccarbene (NHC) precursors to anchor AuI-Cl complexes at their periphery. Synthesis of several thiolato-AuI complexes was then achieved by substituting chloride for thiolates. Photodynamic properties of these complexes were investigated: the data obtained show that the Au@S bonds could be cleaved upon irradiation. The proposed mechanism to explain the release of thiolate moiety involves the S atom oxidation by singlet oxygen generated in the course of irradiation. In view of photodynamic therapy (PDT) applications, these porphyrins fused to NHC-AuI complexes were tested as photosensitizers to kill MCF-7 breast cancer cells. Results show the important role played by the ancillary ligands (chloride versus thiolates) on the photodynamic effect.

Published
2017
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23. PEGylation rate influences peptide-based nanoparticles mediated siRNA delivery in vitro and in vivo

Author

S. Barrere-Lemaire, Gudrun Aldrian, Hélène Déméné, Véronique Viguier, Karidia Konate, Eric Vivès, Franck Couillaud, Dina Aggad, Quentin Seisel, Anaïs Vaissière, Coralie Genevois, Frédéric Fernandez, Sébastien Deshayes, Prisca Boisguerin, Aurélie Covinhes, Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Imagerie moléculaire et thérapies innovantes en oncologie (IMOTION), Université de Bordeaux (UB), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Male, Small interfering RNA, Embryo, Nonmammalian, Surface Properties, media_common.quotation_subject, Pharmaceutical Science, Peptide, Polyethylene glycol, Cell-Penetrating Peptides, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, In vivo, Receptor-Interacting Protein Serine-Threonine Kinase 2, Animals, Cysteine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], RNA, Small Interfering, Internalization, Luciferases, ComputingMilieux_MISCELLANEOUS, Zebrafish, media_common, chemistry.chemical_classification, Chemistry, technology, industry, and agriculture, Molecular biology, In vitro, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, Drug delivery, Biophysics, PEGylation, Nanoparticles
Abstract

Small interfering RNAs (siRNAs) present a strong therapeutic potential because of their ability to inhibit the expression of any desired protein. Recently, we developed the retro-inverso amphipathic RICK peptide as novel non-covalent siRNA carrier. This peptide is able to form nanoparticles (NPs) by self-assembling with the siRNA resulting in the fully siRNA protection based on its protease resistant peptide sequence. With regard to an in vivo application, we investigated here the influence of the polyethylene glycol (PEG) grafting to RICK NPs on their in vitro and in vivo siRNA delivery properties. A detailed structural study shows that PEGylation did not alter the NP formation (only decrease in zeta potential) regardless of the used PEGylation rates. Compared to the native RICK:siRNA NPs, low PEGylation rates (≤ 20%) of the NPs did not influence their cellular internalization capacity as well as their knock-down specificity (over-expressed or endogenous system) in vitro. Because the behavior of PEGylated NPs could differ in their in vivo application, we analyzed the repartition of fluorescent labeled NPs injected at the one-cell stage in zebrafish embryos as well as their pharmacokinetic (PK) profile after administration to mice. After an intra-cardiac injection of the PEGylated NPs, we could clearly determine that 20% PEG-RICK NPs reduce significantly liver and kidney accumulation. NPs with 20% PEGylation constitutes a modular, easy-to-handle drug delivery system which could be adapted to other types of functional moieties to develop safe and biocompatible delivery systems for the clinical application of RNAi-based cancer therapeutics.

Published
2017
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24. Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

Author

Lorne Zinman, Justin K. Ichida, Dina Aggad, Edor Kabashi, J. Alexander Parker, Xiao-Yan Wen, Alexandre La Fontaine, Gary A. B. Armstrong, Lawrence Korngut, Claudia Maios, Elsa Tremblay, Pierre Drapeau, Victor F. Rafuse, Shunmoogum A. Patten, Sorana Ciura, Richard Robitaille, Janet Petrillo, Jose A. Martinez, Jean-Pierre Julien, and Meijiang Liao

Subjects
0301 basic medicine, Drug Evaluation, Preclinical, Neuromuscular Junction, Neuromuscular transmission, Motility, Pharmacology, Neuromuscular junction, Calcium Channels, T-Type, Mice, 03 medical and health sciences, 0302 clinical medicine, Pimozide, Genetic model, Animals, Medicine, Amyotrophic lateral sclerosis, Caenorhabditis elegans, Zebrafish, biology, business.industry, Amyotrophic Lateral Sclerosis, Neurodegeneration, Drug Tolerance, General Medicine, Zebrafish Proteins, Neuromuscular Junction Diseases, medicine.disease, biology.organism_classification, 3. Good health, DNA-Binding Proteins, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Female, Calcium Channels, business, 030217 neurology & neurosurgery, Antipsychotic Agents, Research Article, medicine.drug
Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

Published
2017
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25. In Vivo Analysis of Ifn-γ1 and Ifn-γ2 Signaling in Zebrafish

Author

Philippe Herbomel, Jean-Pierre Levraud, Martine Mazel, Maria Leptin, Dina Aggad, Pierre Boudinot, Dirk Sieger, Georges Lutfalla, and Cornelia Stein

Subjects
Intracellular Fluid, Receptor complex, Molecular Sequence Data, Immunology, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Immunology and Allergy, Interferon gamma, Receptor, Zebrafish, Receptors, Interferon, 030304 developmental biology, Common gamma chain, Genetics, 0303 health sciences, Innate immune system, biology, Protein-Tyrosine Kinases, Zebrafish Proteins, biology.organism_classification, Isoenzymes, Interleukin 10, Larva, Cytokine receptor, Signal Transduction, 030215 immunology, medicine.drug
Abstract

The zebrafish genome contains a large number of genes encoding potential cytokine receptor genes as judged by homology to mammalian receptors. The sequences are too divergent to allow unambiguous assignments of all receptors to specific cytokines, and only a few have been assigned functions by functional studies. Among receptors for class II helical cytokines—i.e., IFNs that include virus-induced Ifns (Ifn-ϕ) and type II Ifns (Ifn-γ), together with Il-10 and its related cytokines (Il-20, Il-22, and Il-26)—only the Ifn-ϕ–specific complexes have been functionally identified, whereas the receptors for the two Ifn-γ (Ifn-γ1 and Ifn-γ2) are unknown. In this work, we identify conditions in which Ifn-γ1 and Ifn-γ2 (also called IFNG or IFN-γ and IFN-gammarel) are induced in fish larvae and adults. We use morpholino-mediated loss-of-function analysis to screen candidate receptors and identify the components of their receptor complexes. We find that Ifn-γ1 and Ifn-γ2 bind to different receptor complexes. The receptor complex for Ifn-γ2 includes cytokine receptor family B (Crfb)6 together with Crfb13 and Crfb17, whereas the receptor complex for Ifn-γ1 does not include Crfb6 or Crfb13 but includes Crfb17. We also show that of the two Jak2 paralogues present in the zebrafish Jak2a but not Jak2b is involved in the intracellular transmission of the Ifn-γ signal. These results shed new light on the evolution of the Ifn-γ signaling in fish and tetrapods and contribute toward an integrated view of the innate immune regulation in vertebrates.

Published
2010
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26. Photodynamic Therapy: Porous Porphyrin-Based Organosilica Nanoparticles for NIR Two-Photon Photodynamic Therapy and Gene Delivery in Zebrafish (Adv. Funct. Mater. 21/2018)

Author

Marcel Garcia, Nicolas Cubedo, Rachid Sougrat, Vincent Sol, Jean-Olivier Durand, Erwan Oliviero, Magali Gary-Bobo, Vincent Chaleix, Danielle Laurencin, Mireille Rossel, Karen Tresfield, Niveen M. Khashab, Xavier Cattoën, Nadir Bettache, Dorothée Berthomieu, Sébastien Clément, Chiara Mauriello Jimenez, Manuel A. Roldan-Gutierrez, Sébastien Richeter, Dina Aggad, Jonas G. Croissant, Michel Wong Chi Man, Marie Maynadier, Laurence Raehm, Dalaver H. Anjum, Shahad Alsaiari, and Clarence Charnay

Subjects
Materials science, biology, medicine.medical_treatment, Nanoparticle, Photodynamic therapy, 02 engineering and technology, Gene delivery, 010402 general chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, biology.organism_classification, 01 natural sciences, Porphyrin, 0104 chemical sciences, Electronic, Optical and Magnetic Materials, Biomaterials, chemistry.chemical_compound, Two-photon excitation microscopy, chemistry, Electrochemistry, Zebrafish embryo, medicine, Biophysics, 0210 nano-technology, Zebrafish
Published
2018
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27. Mesoporous silicon nanoparticles for targeted two-photon theranostics of prostate cancer

Author

Vanja Stojanovic, Alain Morère, Nikola Knezevic, Frédérique Cunin, Elise Bouffard, Sébastien Richeter, Arnaud Chaix, Philippe Maillard, Khaled El Cheikh, Dina Aggad, Magali Gary-Bobo, Marcel Garcia, Jean-Olivier Durand, Marie Maynadier, Laurence Raehm, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Nanomedsyn, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), NanoMedSyn, Distributed Programming Laboratory (LPD), Ecole Polytechnique Fédérale de Lausanne (EPFL), and Institut Curie, Research Center, PSL Research University

Subjects
Materials science, Silicon, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biomedical Engineering, Nanoparticle, chemistry.chemical_element, Photodynamic therapy, Nanotechnology, 02 engineering and technology, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, 010402 general chemistry, Porous silicon, 01 natural sciences, Prostate cancer, Two-photon excitation microscopy, medicine, [CHIM]Chemical Sciences, General Materials Science, technology, industry, and agriculture, General Chemistry, General Medicine, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, medicine.disease, equipment and supplies, 0104 chemical sciences, chemistry, 0210 nano-technology, Mesoporous material
Abstract

International audience; A novel non-toxic porous silicon nanoparticle grafted with a mannose-6-phosphate analogue and applicable in 2-photon imaging and photodynamic therapy was specifically designed for targeting prostate cancer cells.

Published
2016
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28. TDP-43 toxicity proceeds via calcium dysregulation and necrosis in aging Caenorhabditis elegans motor neurons

Author

Dina Aggad, Arnaud Tauffenberger, J. A. Parker, and Julie Vérièpe

Subjects
Aging, Endoplasmic Reticulum, Necrosis, medicine, Animals, Paralysis, Protease Inhibitors, Calcium Signaling, Amyotrophic lateral sclerosis, GABAergic Neurons, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Caspase, Calcium signaling, Motor Neurons, biology, Calpain, General Neuroscience, Endoplasmic reticulum, Neurodegeneration, Articles, medicine.disease, biology.organism_classification, Cell biology, DNA-Binding Proteins, Caspases, biology.protein, Calcium, Neuroscience, Intracellular, Locomotion
Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with either sporadic or genetic origins characterized by the progressive degeneration of motor neurons. At the cellular level, ALS neurons show protein misfolding and aggregation phenotypes. Transactive response DNA-binding protein 43 (TDP-43) has recently been shown to be associated with ALS, but the early pathophysiological deficits causing impairment in motor function are unknown. Here we usedCaenorhabditis elegansexpressing mutant TDP-43A315Tin motor neurons and explored the potential influences of calcium (Ca2+). Using chemical and genetic approaches to manipulate the release of endoplasmic reticulum (ER) Ca2+stores, we observed that the reduction of intracellular Ca2+([Ca2+]i) rescued age-dependent paralysis and prevented the neurodegeneration of GABAergic motor neurons. Our data implicate elevated [Ca2+]ias a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca2+-regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43A315T-associated neuronal toxicity. This work both underscores the potential of theC. eleganssystem to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca2+release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance.

Published
2014

29. The Two Groups of Zebrafish Virus-Induced Interferons Signal via Distinct Receptors with Specific and Shared Chains

Author

Ole J. Hamming, Rune Hartmann, Martine Mazel, Philippe Herbomel, Knud Erik Mogensen, Sergei V. Kotenko, Dina Aggad, Jean-Pierre Levraud, Georges Lutfalla, Pierre Boudinot, Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques (UM2), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Aarhus University [Aarhus], University of Medecine and Dentistry of New Jersey, Partenaires INRAE, Macrophages et Développement de l’Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and This work was funded by grants from Agence Nationale pour la Recherche (MIME2007), Institut Pasteur, and Institut National de la Recherche Agronomique (PTR231). O.J.H. was supported by The Danish Cancer Society (Grant no:95095721). R.H. was supported by a Novo Nordisk Foundation senior research grant and by grants from The Danish Medical Research Council (Grant no: 22-04-0704), The Carlsberg Foundation, and an Arne Hansen stipend. S.K. was supported by the U.S. Public Health Services (Grant R01 AI057468 from the National Institute of Allergy and Infectious Diseases)

Subjects
Immunology, Biology, Chromosomes, Virus, 03 medical and health sciences, 0302 clinical medicine, Animals, Immunology and Allergy, 5-HT5A receptor, Cysteine, Protein Structure, Quaternary, Receptor, Zebrafish, Gene, Conserved Sequence, Chromosome 12, Receptors, Interferon, 030304 developmental biology, Common gamma chain, Genetics, 0303 health sciences, Zebrafish Proteins, biology.organism_classification, Gene Components, Chromosome 3, Viruses, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interferons, Signal Transduction, 030215 immunology
Abstract

Because the availability of fish genomic data, the number of reported sequences for fish type II helical cytokines is rapidly growing, featuring different IFNs including virus-induced IFNs (IFNφ) and IFN-γ, and IL-10 with its related cytokines (IL-20, IL-22, and IL-26). Many candidate receptors exist for these cytokines and various authors have postulated which receptor chain would be involved in which functional receptor in fish. To date, only the receptor for zebrafish IFNφ1 has been identified functionally. Three genes encoding virus-induced IFNφs have been reported in zebrafish. In addition to these genes clustered on chromosome 3, we have identified a fourth IFNφ gene on chromosome 12. All these genes possess the intron-exon organization of mammalian λ IFNs. In the zebrafish larva, all induce the expression of reporter antiviral genes; protection in a viral challenge assay was observed for IFNφ1 and IFNφ2. Using a combination of gain- and loss-of-function experiments, we also show that all zebrafish IFNφs do not bind to the same receptor. Two subgroups of fish virus-induced IFNs have been defined based on conserved cysteines, and we find that this subdivision correlates with receptor usage. Both receptor complexes include a common short chain receptor (CRFB5) and a specific long chain receptor (CRFB1 or CRFB2).

Published
2009
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30. Correction: In Vivo Analysis of Ifn-γ1 and Ifn-γ2 Signaling in Zebrafish

Author

Philippe Herbomel, Maria Leptin, Jean-Pierre Levraud, Dina Aggad, Cornelia Stein, Martine Mazel, Dirk Sieger, Pierre Boudinot, and Georges Lutfalla

Subjects
Genetics, biology, Morpholino, Leptin, Immunology, Immunology and Allergy, In vivo analysis, biology.organism_classification, Zebrafish, Cell biology
Abstract

Aggad, D., C. Stein, D. Sieger, M. Mazel, P. Boudinot, P. Herbomel, J.-P. Levraud, G. Lutfalla, and M. Leptin. 2010. In vivo analysis of Ifn-γ1 and Ifn-γ2 signaling in zebrafish. J. Immunol . 185: [6774–6782][1]. Two errors appeared in the published morpholino sequences (Table II). In the

Published
2012
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