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1. The abietane diterpene taxodione contributes to the antioxidant activity of rosemary by-product in muscle tissue

Author

Sylvie Rapior, Nathalie Saint, Guillaume Bouguet, Françoise Fons, Alessandra Lo Cicero, Barbara Vernus, Xavier Nissan, Sylvie Morel, Béatrice Chabi, Gilles Carnac, Anne Bonnieu, Manon Vitou, Gérald Hugon, Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Morel S., Saint N., Vitou M., Lo Cicero A., Nissan X., Vernus B., Chabi B., Bonnieu A., Hugon G., Fons F., Bouguet G., Rapior S., Carnac G., Université Paul-Valéry - Montpellier 3 (UM3)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul-Valéry - Montpellier 3 (UM3)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), Entreprise Flore en Thym, MORNET, Dominique, Université Paul-Valéry - Montpellier 3 (UPVM)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), and Université Paul-Valéry - Montpellier 3 (UPVM)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, Antioxidant, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Post-mortem, Medicine (miscellaneous), Stem cells, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Protein oxidation, Carnosol, Rosmarinus, Myoblasts, 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, [CHIM]Chemical Sciences, TX341-641, Food science, Carnosic acid, Abietane, 030109 nutrition & dietetics, Nutrition and Dietetics, biology, Nutrition. Foods and food supply, Skeletal muscle, 04 agricultural and veterinary sciences, biology.organism_classification, 040401 food science, medicine.anatomical_structure, chemistry, [SDE]Environmental Sciences, Diterpene, Food Science
Abstract

International audience; Research on rosemary antioxidant activity and its potential use in human health and food applications is focused on rosemary leaves and two main bioactive compounds carnosic acid and carnosol. However, many other, not-yet identified molecules could be present, especially in rosemary by-products. In this study, we first showed that rosemary stem extract was the most efficient in protecting human skeletal muscle cells against oxidation. Then, using bioassay-guided fractionation, we identified taxodione, an abietane diterpene, as the main bioactive molecule in the rosemary stem extract. We demonstrated that taxodione protects skeletal muscle cells from hydrogen peroxide-induced cytotoxic damage (by monitoring ROS production, H2AX phosphorylation and CHOP gene expression). Moreover, we showed that taxodione reduces lipid and protein oxidation in post-mortem mice and beef muscles during refrigerated storage. In conclusion, our results indicate that taxodione extracted from rosemary stems, a cheap and unused resource of natural antioxidants, limits oxidation in muscle tissue.

Published
2019

2. Metformin decreases progerin expression and alleviates pathological defects of Hutchinson–Gilford progeria syndrome cells

Author

Marc Peschanski, Anne-Laure Jaskowiak, Nicolas Lévy, Anne-Laure Egesipe, Sophie Blondel, Xavier Nissan, Alessandra Lo Cicero, Annachiara De Sandre-Giovannoli, Claire Navarro, Egesipe A.-L., Blondel S., Lo Cicero A., Jaskowiak A.-L., Navarro C., De Sandre-Giovannoli A., Levy N., Peschanski M., and Nissan X.

Subjects
0301 basic medicine, Premature aging, congenital, hereditary, and neonatal diseases and abnormalities, Aging, Article, LMNA, 03 medical and health sciences, Progeria, 0302 clinical medicine, medicine, Induced pluripotent stem cell, integumentary system, business.industry, Genetic disorder, nutritional and metabolic diseases, medicine.disease, Progerin, Metformin, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Geriatrics and Gerontology, business, Lamin, medicine.drug
Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease. A diabetes drug with a proven track record in the clinic may also offer an alternative treatment for a rare 'premature aging' disorder. A genetic mutation in patients with Hutchinson-Gilford progeria syndrome (HGPS) produces a defective protein called progerin, which causes children to develop skeletal, cardiovascular and other symptoms normally seen in the elderly. Researchers led by Xavier Nissan at I-Stem in France have demonstrated that metformin triggers a biochemical 'switch' that causes cells to decrease their production of progerin, and instead generate an alternative, non-toxic protein. Relative to untreated cells, metformin-treated cells were less prone to develop structural abnormalities or undergo premature maturation. Importantly, doctors have used metformin for over 20 years, suggesting that such a treatment approach should be safe for HGPS patients.

Published
2016

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