73 results on '"Laverny G"'
Search Results
2. Vitamin D and calcium intakes in general pediatric populations: A French expert consensus paper
- Author
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Bacchetta, J., Edouard, T., Laverny, G., Bernardor, J., Bertholet-Thomas, A., Castanet, M., Garnier, C., Gennero, I., Harambat, J., Lapillonne, A., Molin, A., Naud, C., Salles, J.P., Laborie, S., Tounian, P., and Linglart, A.
- Published
- 2022
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3. Le co-traitement par bêtabloquants supprime l’efficacité thérapeutique de la prednisone au cours des myopathies inflammatoires
- Author
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Giannini, M., primary, Rovito, D., additional, Debrut, L., additional, Keime, C., additional, Charles, A.L., additional, Lannes, B., additional, Geny, B., additional, Metzger, D., additional, Laverny, G., additional, and Meyer, A., additional
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- 2023
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4. OP0119 MUSCLE FIBRE PLAYS A CRUCIAL ROLE IN THE THERAPEUTIC RESPONSE OF MYOSITIS TO GLUCOCORTICOIDS THROUGH THE PARACRINE EFFECT OF EPINEPHRINE ON THE IMMUNE SYSTEM
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Giannini, M., primary, Rovito, D., additional, Debrut, L., additional, Lutzing, R., additional, Charles, A. L., additional, Geny, B., additional, Metzger, D., additional, Laverny, G., additional, and Meyer, A., additional
- Published
- 2023
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5. OP0117 PROTEASOME INHIBITION AS A NEW TREATMENT FOR DERMATOMYOSITIS: RESULTS OF A DRUG REPURPOSING ANALYSIS BASED ON THE TRANSCRIPTOMIC SIGNATURE OF PATIENTS’ PERIFASCICULAR FIBERS VALIDATED IN PRE-CLINICAL MODELS
- Author
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Debrut, L., primary, Giannini, M., additional, Keime, C., additional, Rovito, D., additional, Mertz, P., additional, Lannes, B., additional, Charles, A. L., additional, Metzger, D., additional, Geny, B., additional, Laverny, G., additional, and Meyer, A., additional
- Published
- 2023
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6. Conditional expression of Ki-RasG12V in the mammary epithelium of transgenic mice induces estrogen receptor alpha (ERα)-positive adenocarcinoma
- Author
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Andò, S, Malivindi, R, Catalano, S, Rizza, P, Barone, I, Panza, S, Rovito, D, Emprou, C, Bornert, J-M, Laverny, G, and Metzger, D
- Published
- 2017
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7. A New Murine Model of Sustainable and Durable Chronic Critical Limb Ischemia Fairly Mimicking Human Pathology
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Lejay, A., Choquet, P., Thaveau, F., Singh, F., Schlagowski, A., Charles, A.-L., Laverny, G., Metzger, D., Zoll, J., Chakfe, N., and Geny, B.
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- 2015
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8. L’inhibition du protéasome comme nouveau traitement de la dermatomyosite : résultats d’une analyse de repositionnement médicamenteux basée sur la signature transcriptomique des fibres périfasciculaires des patients validée dans des modèles pré-cliniques
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Debrut, L., primary, Giannini, M., additional, Keime, C., additional, Daniella, R., additional, Mertz, P., additional, Béatrice, L., additional, Daniel, M., additional, Geny, B., additional, Laverny, G., additional, and Meyer, A., additional
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- 2022
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9. Au cours des myosites la fibre musculaire squelettique joue un rôle crucial dans la réponse thérapeutique aux glucocorticoïdes
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Margherita, G., primary, Rovito, D., additional, Debrut, L., additional, Duteil, D., additional, Charles, A.L., additional, Laverny, G., additional, Geny, B., additional, Metzger, D., additional, and Meyer, A., additional
- Published
- 2021
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10. OP0247 IN MYOSITIS MUSCLE FIBRE PLAYS A DIRECT AND CRITICAL ROLE IN THERAPEUTIC RESPONSE TO GLUCOCORTICOIDS
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Giannini, M., primary, Laverny, G., additional, Duteil, D., additional, Rovito, D., additional, Charles, A. L., additional, Geny, B., additional, Metzger, D., additional, and Meyer, A., additional
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- 2021
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11. OP0243 AN APPROACH COMBINING TRANSCRIPTOMIC AND TOPOGRAPHIC ANALYSIS REVEALS A POTENTIAL ROLE OF PROTEASOME AND AUTOPHAGY DEREGULATION IN THE PATHOPHYSIOLOGY OF DERMATOMYOSITIS
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Debrut, L., primary, Laverny, G., additional, Mertz, P., additional, Giannini, M., additional, Pizzimenti, M., additional, Charlot, A., additional, Keime, C., additional, Lannes, B., additional, Metzger, D., additional, Geny, B., additional, Sibilia, J., additional, and Meyer, A., additional
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- 2021
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12. Caractérisation des mécanismes qui sous-tendent les lésions des fibres périfasciculaires au cours de la dermatomyosite : une approche combinant l’analyse transcriptomique et topographique
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Debrut, L., primary, Laverny, G., additional, Lannes, B., additional, Chanson, J.B., additional, Mertz, P., additional, Sibilia, J., additional, Metzger, D., additional, Geny, B., additional, and Meyer, A., additional
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- 2020
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13. Androgen signaling negatively controls group 2 innate lymphoid cells
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Laffont, S, Blanquart, E, Savignac, M, Cenac, C, Laverny, G, Metzger, D, Girard, J-P, Belz, GT, Pelletier, L, Seillet, C, Guery, J-C, Laffont, S, Blanquart, E, Savignac, M, Cenac, C, Laverny, G, Metzger, D, Girard, J-P, Belz, GT, Pelletier, L, Seillet, C, and Guery, J-C
- Abstract
Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33-mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33-driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.
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- 2017
14. PROTEASOME INHIBITION AS A NEW TREATMENT FOR DERMATOMYOSITIS: RESULTS OF A DRUG REPURPOSING ANALYSIS BASED ON THE TRANSCRIPTOMIC SIGNATURE OF PATIENTS' PERIFASCICULAR FIBERS VALIDATED IN PRE-CLINICAL MODELS.
- Author
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Debrut, L., Giannini, M., Keime, C., Rovito, D., Mertz, P., Lannes, B., Charles, A. L., Metzger, D., Geny, B., Laverny, G., and Meyer, A.
- Published
- 2023
- Full Text
- View/download PDF
15. MUSCLE FIBRE PLAYS A CRUCIAL ROLE IN THE THERAPEUTIC RESPONSE OF MYOSITIS TO GLUCOCORTICOIDS THROUGH THE PARACRINE EFFECT OF EPINEPHRINE ON THE IMMUNE SYSTEM.
- Author
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Giannini, M., Rovito, D., Debrut, L., Lutzing, R., Charles, A. L., Geny, B., Metzger, D., Laverny, G., and Meyer, A.
- Published
- 2023
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16. AB0671 Vitamine D Serum Level Correlates with Quadriceps Muscle Strength in Inflammatory Myositis
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Meyer, A., primary, Laverny, G., additional, Javier, R.-M., additional, Gottenberg, J.-E., additional, Geny, B., additional, and Sibilia, J., additional
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- 2015
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17. OP0135 Interferon-Beta Induced Reactive Oxygen Species Participate in Muscle Inflammation and Mitochondrial Oxydative Phosphorilation Defects Contributing to Dermatomyositis Muscle Impairement
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Meyer, A., primary, Laverny, G., additional, Prevel, N., additional, Echaniz-Laguna, A., additional, Lannes, B., additional, Singh, F., additional, Charles, A.-L., additional, Benveniste, O., additional, Metzger, D., additional, Geny, B., additional, and Sibilia, J., additional
- Published
- 2015
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18. Conditional expression of Ki-RasG12Vin the mammary epithelium of transgenic mice induces estrogen receptor alpha (ERα)-positive adenocarcinoma
- Author
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Andò, S, Malivindi, R, Catalano, S, Rizza, P, Barone, I, Panza, S, Rovito, D, Emprou, C, Bornert, J-M, Laverny, G, and Metzger, D
- Abstract
Appropriate ‘in vivo’ models are crucial for studying breast cancer biology and evaluating the efficacy of therapeutic agents. Thus we engineered a novel transgenic mouse line expressing the human Ki-Ras bearing an activating mutation (Ki-Ras(G12V)) selectively in the mammary epithelium after lactation. These mice develop invasive ductal adenocarcinomas with 100% incidence within 3–9 months after Ki-Ras(G12V)induction. Immunophenotyping revealed that the mammary tumors express luminal markers, are positive for estrogen and progesterone receptors, negative for HER2 and have a low proliferation index. Moreover, cell lines derived from such tumors are estrogen-responsive and, when transplanted into nude mice, form tumors that respond to the antiestrogen ICI 182780. In conclusion, the mammary tumors of these transgenic mice and the derived cell lines exhibit key features of the major form of human breast cancer, that is, luminal A subtype and thus have a high potential for breast cancer research and treatment.
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- 2017
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19. Immunomodulatory properties of multi-walled carbon nanotubes in peripheral blood mononuclear cells
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Pons, F., primary, Laverny, G., additional, Purohit, A., additional, De Blay, F., additional, and Casset, A., additional
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- 2011
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20. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease
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Gadaleta, R. M., primary, van Erpecum, K. J., additional, Oldenburg, B., additional, Willemsen, E. C. L., additional, Renooij, W., additional, Murzilli, S., additional, Klomp, L. W. J., additional, Siersema, P. D., additional, Schipper, M. E. I., additional, Danese, S., additional, Penna, G., additional, Laverny, G., additional, Adorini, L., additional, Moschetta, A., additional, and Mil, S. W. C. v., additional
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- 2011
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21. HUMAN BENIGN PROSTATIC HYPERPLASIA CELLS AS INDUCERS AND TARGETS OF CHRONIC AUTOIMMUNE INFLAMMATION
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Penna, G., primary, Amuchastegui, S., additional, Laverny, G., additional, Fibbi, B., additional, Gacci, M., additional, Crescioli, C., additional, Colli, E., additional, Maggi, M., additional, and Adorini, L., additional
- Published
- 2008
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22. 93 HUMAN BENIGN PROSTATIC HYPERPLASIA CELLS AS INDUCERS AND TARGETS OF CHRONIC AUTOIMMUNE INFLAMMATION
- Author
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Penna, G., Amuchastegui, S., Laverny, G., Fibbi, B., Gacci, M., Crescioli, C., Colli, E., Maggi, M., and Adorini, L.
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- 2008
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23. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease
- Author
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Giuseppe Penna, Raffaella Maria Gadaleta, Bas Oldenburg, Marguerite E.I. Schipper, Saskia W.C. van Mil, Stefania Murzilli, Gilles Laverny, Antonio Moschetta, Luciano Adorini, Silvio Danese, Peter D. Siersema, Leo W. J. Klomp, Karel J. van Erpecum, Willem Renooij, Ellen C.L. Willemsen, Gadaleta, Rm, van Erpecum, Kj, Oldenburg, B, Willemsen, Ecl, Renooij, W, Murzilli, S, Klomp, Lwj, Siersema, Pd, Schipper, Mei, Danese, S, Penna, G, Laverny, G, Adorini, L, Moschetta, A, and van Mil, Swc
- Subjects
medicine.medical_specialty ,Colon ,Drug Evaluation, Preclinical ,Receptors, Cytoplasmic and Nuclear ,Inflammation ,Bile acid ,Biology ,Chenodeoxycholic Acid ,Inflammatory bowel disease ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Ileum ,Internal medicine ,medicine ,Animals ,Humans ,Colitis ,030304 developmental biology ,0303 health sciences ,Goblet cell ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,Dextran Sulfate ,Gastroenterology ,PostScript ,Inflammatory Bowel Diseases ,medicine.disease ,inflammatory bowel disorders ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Intestinal Absorption ,Trinitrobenzenesulfonic Acid ,Cancer research ,Cytokines ,030211 gastroenterology & hepatology ,Farnesoid X receptor ,Cytokine secretion ,Caco-2 Cells ,Inflammation Mediators ,medicine.symptom - Abstract
Background & aims Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. Methods Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. Results INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor a secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. Conclusions FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD. RI van Mil, Saskia/C-3751-2009
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- 2011
24. Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease
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Giuseppe Penna, Silvio Danese, Luciano Adorini, Carmen Correale, Gilles Laverny, Manuela Nebuloni, Stefania Vetrano, Laverny, G, Penna, G, Vetrano, S, Correale, C, Nebuloni, M, Danese, S, and Adorini, L
- Subjects
Adult ,Male ,Agonist ,medicine.medical_specialty ,Calcitriol ,Colon ,medicine.drug_class ,Immunology ,Anti-Inflammatory Agents ,Calcitriol receptor ,Inflammatory bowel disease ,Mice ,Young Adult ,Crohn Disease ,Ileum ,Internal medicine ,medicine ,Vitamin D and neurology ,Animals ,Humans ,Immunology and Allergy ,Colitis ,Cells, Cultured ,Aged ,Aged, 80 and over ,Crohn's disease ,Mucous Membrane ,business.industry ,Middle Aged ,Inflammatory Bowel Diseases ,medicine.disease ,Ulcerative colitis ,Mice, Inbred C57BL ,Treatment Outcome ,Endocrinology ,Leukocytes, Mononuclear ,Receptors, Calcitriol ,Colitis, Ulcerative ,Female ,business ,medicine.drug - Abstract
Deficiency in 1 alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has been suggested as an important environmental factor for immuno-mediated disorders including inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, both characterized by chronic intestinal inflammation. Administration of vitamin D receptor (VDR) agonists can ameliorate spontaneous and induced animal models of colitis, but hypercalcemia is a dose-limiting adverse event. Previous work in our laboratory has identified 1 alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (BXL-62) as a potent anti-inflammatory VDR agonist with a low calcemic activity. In the present study, we confirm the marked anti-inflammatory properties of BXL-62 and show its capacity to induce VDR primary response genes, like CYP24A1 and CAMP, at lower concentrations than 1,25D(3), in PBMCs from IBD patients. Its higher anti-inflammatory potency compared to 1,25D(3) was demonstrated by the significantly more potent inhibition in PBMCs and in lymphocyte-enriched lamina propria mononuclear cells of the pro-inflammatory cytokines TNF-alpha, IL-12/23p40, IL-6 and IFN-gamma, both at mRNA and protein level. The therapeutic efficacy of intra-rectal administration of BXL-62 in experimental IBD is shown by its beneficial effects, significantly higher than 1,25D(3), to induce recovery of clinical symptoms of colitis at normocalcemic doses in mice undergoing dextran sodium sulfate-induced colitis. These results confirm the therapeutic efficacy of VDR agonists in experimental colitis, and suggest BXL-62 as a promising compound for IBD treatment. (C) 2010 Elsevier B.V. All rights reserved.
- Published
- 2010
25. Sarcopenia assessed by DXA and hand-grip dynamometer: a potential marker of damage, disability and myokines imbalance in inflammatory myopathies.
- Author
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Giannini M, Charles AL, Evrard C, Blaess J, Bouchard-Marmen M, Debrut L, Perniola S, Laverny G, Javier RM, Charloux A, Geny B, and Meyer A
- Subjects
- Humans, Female, Male, Middle Aged, Adult, Prospective Studies, Aged, Fibronectins blood, Case-Control Studies, Muscle, Skeletal diagnostic imaging, Muscle, Skeletal physiopathology, Biomarkers blood, Disability Evaluation, Myokines, Sarcopenia physiopathology, Sarcopenia blood, Sarcopenia diagnostic imaging, Sarcopenia etiology, Hand Strength physiology, Absorptiometry, Photon, Muscle Strength Dynamometer, Myositis physiopathology, Myositis blood
- Abstract
Objectives: To assess the ability of dual-energy X-ray absorptiometry (DXA) and hand-grip dynamometer to measure damage in inflammatory myopathies (IM)., Methods: Forty adult IM patients with a disease duration ≥12 months, low or no disease activity for ≥6 months, were prospectively enrolled. Thirty healthy age and sex-matched volunteers were enrolled as controls. Whole-body DXA and hand-grip dynamometer were used to measure muscle mass, grip strength and diagnose sarcopenia (EWGSOP2 criteria). Relationships between the results of strength in 12 muscles, functional tests, patient-reported disability, IMACS damage score, and history of the disease were assessed. The serum levels of potential molecular actors in the damage were measured., Results: DXA and grip strength measurements took ≤20 min. Both muscle mass and grip strength were decreased in IM patients vs volunteers (-10% and -30%, respectively) with a dispersion that varied widely (interquartile range -24.3% to +7.8% and -51.3% to -18.9%, respectively). Muscle mass and grip strength were non-redundantly correlated (r up to 0.6, P = 0.0001) with strength in 14 muscles (manual muscle test and hand-held dynamometer), functions (of limbs, respiratory and deglutition muscles), patient-reported disability, damage (extension and severity in muscular and extra-muscular domains) and blood levels of several myokines. Seven IM patients (17.5%) were sarcopenic. They had the worst damage, impaired functions, disability and history of severe myopathy. Decreased irisin and osteonectin levels were associated with sarcopenia (area under the curve 0.71 and 0.80, respectively)., Conclusion: DXA and hand-grip dynamometer are useful tools to assess damage in IM. Irisin and osteonectin may play a role in IM damage pathogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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26. A vitamin D-based strategy overcomes chemoresistance in prostate cancer.
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Len-Tayon K, Beraud C, Fauveau C, Belorusova AY, Chebaro Y, Mouriño A, Massfelder T, Chauchereau A, Metzger D, Rochel N, and Laverny G
- Subjects
- Male, Humans, Animals, Mice, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm drug effects, Vitamin D pharmacology, Vitamin D analogs & derivatives, Docetaxel pharmacology, Docetaxel therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Receptors, Calcitriol metabolism, Receptors, Calcitriol agonists
- Abstract
Background and Purpose: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC., Experimental Approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC., Key Results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells., Conclusion and Implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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- 2024
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27. 4-Hydroxy-1α,25-Dihydroxyvitamin D 3 : Synthesis and Structure-Function Study.
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Peluso-Iltis C, Pierrat N, Rovito D, Osz J, Sawada D, Kittaka A, Laverny G, and Rochel N
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- Animals, Mice, Structure-Activity Relationship, Rats, Calcitriol analogs & derivatives, Calcitriol chemistry, Calcitriol metabolism, Calcitriol chemical synthesis, Male, Vitamin D analogs & derivatives, Vitamin D metabolism, Vitamin D chemistry, Hypercalcemia metabolism, Kidney metabolism, Receptors, Calcitriol metabolism, Receptors, Calcitriol chemistry, Receptors, Calcitriol genetics
- Abstract
The active vitamin D metabolites, 25-hydroxyvitamin D
3 (25D3 ) and 1,25-dihydroxyvitamin D3 (1,25D3 ), are produced by successive hydroxylation steps and play key roles in several cellular processes. However, alternative metabolic pathways exist, and among them, the 4-hydroxylation of 25D3 is a major one. This study aims to investigate the structure-activity relationships of 4-hydroxy derivatives of 1,25D3 . Structural analysis indicates that 1,4α,25(OH)3 D3 and 1,4β,25(OH)3 D3 maintain the anchoring hydrogen bonds of 1,25D3 and form additional interactions, stabilizing the active conformation of VDR. In addition, 1,4α,25D3 and 1,4β,25D3 are as potent as 1,25D3 in regulating the expression of VDR target genes in rat intestinal epithelial cells and in the mouse kidney. Moreover, these two 4-hydroxy derivatives promote hypercalcemia in mice at a dose similar to that of the parent compound.- Published
- 2024
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28. LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice.
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Cai Q, Sahu R, Ueberschlag-Pitiot V, Souali-Crespo S, Charvet C, Silem I, Cottard F, Ye T, Taleb F, Metzger E, Schuele R, Billas IML, Laverny G, Metzger D, and Duteil D
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, Gene Expression Regulation drug effects, Histone Demethylases metabolism, Histone Demethylases antagonists & inhibitors, Histone Demethylases genetics, Glucocorticoids pharmacology, Dexamethasone pharmacology, Receptors, Glucocorticoid metabolism, Muscular Atrophy chemically induced, Muscular Atrophy metabolism, Muscular Atrophy pathology, Muscular Atrophy drug therapy, Muscle, Skeletal metabolism, Muscle, Skeletal drug effects, Muscle, Skeletal pathology
- Abstract
Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects., (© 2024. The Author(s).)
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- 2024
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29. Targeting Mitochondrial Dynamics during Lower-Limb Ischemia Reperfusion in Young and Old Mice: Effect of Mitochondrial Fission Inhibitor-1 (mDivi-1).
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Paradis S, Charles AL, Giannini M, Meyer A, Lejay A, Talha S, Laverny G, Charloux A, and Geny B
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- Humans, Animals, Mice, Aged, Mitochondrial Dynamics, Calcium, Ischemia drug therapy, Muscle, Skeletal, Lactic Acid, Superoxide Dismutase, Peripheral Arterial Disease, Mitochondrial Diseases, Quinazolinones
- Abstract
Peripheral arterial disease (PAD) strikes more than 200 million people worldwide and has a severe prognosis by potentially leading to limb amputation and/or death, particularly in older patients. Skeletal muscle mitochondrial dysfunctions and oxidative stress play major roles in this disease in relation with ischemia-reperfusion (IR) cycles. Mitochondrial dynamics through impairment of fission-fusion balance may contribute to skeletal muscle pathophysiology, but no data were reported in the setting of lower-limb IR despite the need for new therapeutic options. We, therefore, investigated the potential protective effect of mitochondrial division inhibitor-1 (mDivi-1; 50 mg/kg) in young (23 weeks) and old (83 weeks) mice submitted to two-hour ischemia followed by two-hour reperfusion on systemic lactate, muscle mitochondrial respiration and calcium retention capacity, and on transcripts specific for oxidative stress and mitochondrial dynamics. At the systemic levels, an IR-related increase in circulating lactate was still major despite mDivi-1 use (+305.9% p < 0.0001, and +269.4% p < 0.0001 in young and old mice, respectively). Further, IR-induced skeletal muscle mitochondrial dysfunctions (more severely impaired mitochondrial respiration in old mice (OXPHOS CI state, -68.2% p < 0.0001 and -84.9% p < 0.0001 in 23- and 83-week mice) and reduced calcium retention capacity (-46.1% p < 0.001 and -48.2% p = 0.09, respectively) were not corrected by mDivi-1 preconditioning, whatever the age. Further, mDivi-1 treatment did not oppose superoxide anion production (+71.4% p < 0.0001 and +37.5% p < 0.05, respectively). At the transcript level, markers of antioxidant enzymes (SOD 1, SOD 2, catalase, and GPx) and fission markers (Drp1, Fis) remained unchanged or tended to be decreased in the ischemic leg. Fusion markers such as mitofusin 1 or 2 decreased significantly after IR in both groups. In conclusion, aging enhanced the deleterious effects or IR on muscle mitochondrial respiration, and in this setting of lower-limb IR, mDivi-1 failed to protect the skeletal muscle both in young and old mice.
- Published
- 2024
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30. Mouse Models of Mineral Bone Disorders Associated with Chronic Kidney Disease.
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Zaloszyc A, Bernardor J, Bacchetta J, Laverny G, and Schmitt CP
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- Mice, Animals, Humans, Quality of Life, Minerals, Chronic Kidney Disease-Mineral and Bone Disorder, Renal Insufficiency, Chronic complications, Bone Diseases
- Abstract
Patients with chronic kidney disease (CKD) inevitably develop mineral and bone disorders (CKD-MBD), which negatively impact their survival and quality of life. For a better understanding of underlying pathophysiology and identification of novel therapeutic approaches, mouse models are essential. CKD can be induced by surgical reduction of a functional kidney mass, by nephrotoxic compounds and by genetic engineering specifically interfering with kidney development. These models develop a large range of bone diseases, recapitulating different types of human CKD-MBD and associated sequelae, including vascular calcifications. Bones are usually studied by quantitative histomorphometry, immunohistochemistry and micro-CT, but alternative strategies have emerged, such as longitudinal in vivo osteoblast activity quantification by tracer scintigraphy. The results gained from the CKD-MBD mouse models are consistent with clinical observations and have provided significant knowledge on specific pathomechanisms, bone properties and potential novel therapeutic strategies. This review discusses available mouse models to study bone disease in CKD.
- Published
- 2023
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31. Vitamin D Analogs Bearing C-20 Modifications Stabilize the Agonistic Conformation of Non-Responsive Vitamin D Receptor Variants.
- Author
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Belorusova AY, Rovito D, Chebaro Y, Doms S, Verlinden L, Verstuyf A, Metzger D, Rochel N, and Laverny G
- Subjects
- Humans, Ligands, Protein Binding, Vitamin D, Receptors, Calcitriol agonists, Rickets
- Abstract
The Vitamin D receptor (VDR) plays a key role in calcium homeostasis, as well as in cell proliferation and differentiation. Among the large number of VDR ligands that have been developed, we have previously shown that BXL-62 and Gemini-72, two C-20-modified vitamin D analogs are highly potent VDR agonists. In this study, we show that both VDR ligands restore the transcriptional activities of VDR variants unresponsive to the natural ligand and identified in patients with rickets. The elucidated mechanisms of action underlying the activities of these C-20-modified analogs emphasize the mutual adaptation of the ligand and the VDR ligand-binding pocket.
- Published
- 2022
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32. Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression.
- Author
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Abu El Maaty MA, Terzic J, Keime C, Rovito D, Lutzing R, Yanushko D, Parisotto M, Grelet E, Namer IJ, Lindner V, Laverny G, and Metzger D
- Subjects
- Animals, Cell Plasticity, Disease Progression, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Male, Mice, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Prostatic Intraepithelial Neoplasia genetics, Prostatic Intraepithelial Neoplasia metabolism, Prostatic Intraepithelial Neoplasia pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten
(i)pe-/- mice that recapitulate prostate carcinogenesis in humans. We found that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, thus enhancing malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity, leading to the emergence of cells that overexpress Transglutaminase 2 (TGM2) and have impaired androgen signaling. Elevated TGM2 levels in patients with PCa are associated with shortened progression-free survival after prostatectomy. Last, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.- Published
- 2022
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33. Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D 3 Analogs with Locked Mobility at C-17.
- Author
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Fraga R, Len K, Lutzing R, Laverny G, Loureiro J, Maestro MA, Rochel N, Rodriguez-Borges E, and Mouriño A
- Subjects
- Ligands, Molecular Conformation, Calcitriol, Vitamin D analogs & derivatives
- Abstract
Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D
3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd0 -mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)- Published
- 2021
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34. Single-cell analyses unravel cell type-specific responses to a vitamin D analog in prostatic precancerous lesions.
- Author
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Abu El Maaty MA, Grelet E, Keime C, Rerra AI, Gantzer J, Emprou C, Terzic J, Lutzing R, Bornert JM, Laverny G, and Metzger D
- Subjects
- Animals, Humans, Male, Mice, Single-Cell Analysis, Tumor Microenvironment, Vitamin D pharmacology, Vitamin D therapeutic use, Precancerous Conditions drug therapy, Prostatic Intraepithelial Neoplasia drug therapy, Prostatic Intraepithelial Neoplasia metabolism, Prostatic Intraepithelial Neoplasia pathology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology
- Abstract
Epidemiological data have linked vitamin D deficiency to the onset and severity of various cancers, including prostate cancer, and although in vitro studies have demonstrated anticancer activities for vitamin D, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically engineered Pten
(i)pe-/- mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analog with reported anticancer activities. We show that this analog induces apoptosis in senescent PINs, normalizes extracellular matrix remodeling by stromal fibroblasts, and reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal cells expressing Krt8, Krt4, and Tacstd2 (termed luminal-C cells) is lost by such a treatment, antiapoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of PINs and the microenvironment to Gemini-72, and shed light on mechanisms that limit treatment's efficacy., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)- Published
- 2021
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35. Myod1 and GR coordinate myofiber-specific transcriptional enhancers.
- Author
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Rovito D, Rerra AI, Ueberschlag-Pitiot V, Joshi S, Karasu N, Dacleu-Siewe V, Rayana KB, Ghaibour K, Parisotto M, Ferry A, Jelinsky SA, Laverny G, Klaholz BP, Sexton T, Billas IML, Duteil D, and Metzger D
- Subjects
- Animals, Cell Line, Chromatin genetics, Chromatin Immunoprecipitation Sequencing, Gene Expression Regulation genetics, Histones genetics, Histones metabolism, Male, Metabolic Networks and Pathways genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Strength genetics, Muscle, Skeletal physiology, MyoD Protein genetics, Myoblasts metabolism, Nuclear Respiratory Factor 1 genetics, Receptors, Glucocorticoid genetics, Recombinant Proteins, Chromatin metabolism, Enhancer Elements, Genetic, Muscle, Skeletal metabolism, MyoD Protein metabolism, Nuclear Respiratory Factor 1 metabolism, Receptors, Glucocorticoid metabolism
- Abstract
Skeletal muscle is a dynamic tissue the size of which can be remodeled through the concerted actions of various cues. Here, we investigated the skeletal muscle transcriptional program and identified key tissue-specific regulatory genetic elements. Our results show that Myod1 is bound to numerous skeletal muscle enhancers in collaboration with the glucocorticoid receptor (GR) to control gene expression. Remarkably, transcriptional activation controlled by these factors occurs through direct contacts with the promoter region of target genes, via the CpG-bound transcription factor Nrf1, and the formation of Ctcf-anchored chromatin loops, in a myofiber-specific manner. Moreover, we demonstrate that GR negatively controls muscle mass and strength in mice by down-regulating anabolic pathways. Taken together, our data establish Myod1, GR and Nrf1 as key players of muscle-specific enhancer-promoter communication that orchestrate myofiber size regulation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
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36. Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.
- Author
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Rovito D, Belorusova AY, Chalhoub S, Rerra AI, Guiot E, Molin A, Linglart A, Rochel N, Laverny G, and Metzger D
- Subjects
- Animals, Calcitriol analogs & derivatives, Calcitriol pharmacology, Cell Line, Cell Line, Tumor, Cytosol metabolism, Gene Expression drug effects, HeLa Cells, Humans, Hypercalcemia genetics, Hypercalcemia prevention & control, Male, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Binding, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Rats, Receptors, Calcitriol genetics, Vitamin D analogs & derivatives, Calcium metabolism, Hypercalcemia metabolism, Receptors, Calcitriol metabolism, Vitamin D pharmacology
- Abstract
The bioactive vitamin D
3 , 1α,25(OH)2 D3 , plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D3 leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)2 D3 synthesis, but are poorly efficient. In this study, we identify WBP4 as a new VDR interactant, and demonstrate that it controls VDR subcellular localization. Moreover, we show that the vitamin D analogue ZK168281 enhances the interaction between VDR and WBP4 in the cytosol, and normalizes the expression of VDR target genes and serum calcium levels in 1α,25(OH)2 D3 -intoxicated mice. As ZK168281 also blunts 1α,25(OH)2 D3 -induced VDR signaling in fibroblasts of a patient with impaired vitamin D degradation, this VDR antagonist represents a promising therapeutic option for 1α,25(OH)2 D3 -induced hypercalcemia.- Published
- 2020
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37. Aging Exacerbates Ischemia-Reperfusion-Induced Mitochondrial Respiration Impairment in Skeletal Muscle.
- Author
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Paradis S, Charles AL, Georg I, Goupilleau F, Meyer A, Kindo M, Laverny G, Metzger D, and Geny B
- Abstract
Cycles of ischemia-reperfusion (IR) that occur during peripheral arterial disease (PAD) are associated with significant morbi-mortality, and aging is an irreversible risk factor of PAD. However, the effects of advanced age on IR-induced skeletal muscle mitochondrial dysfunction are not well known. Young and aged mice were therefore submitted to hindlimb IR (2 h ischemia followed by 2 h reperfusion). Skeletal muscle mitochondrial respiration, calcium retention capacity (CRC) and reactive oxygen species (ROS) production were determined using high resolution respirometry, spectrofluorometry and electronic paramagnetic resonance. IR-induced impairment in mitochondrial respiration was enhanced in old animals (V
ADP ; from 33.0 ± 2.4 to 18.4 ± 3.8 and 32.8 ± 1.3 to 5.9 ± 2.7 pmol/s/mg wet weight; -44.2 ± 11.4% vs. -82.0 ± 8.1%, in young and aged mice, respectively). Baseline CRC was lower in old animals and IR similarly decreased the CRC in both groups (from 11.8 ± 0.9 to 4.6 ± 0.9 and 5.5 ± 0.9 to 2.1 ± 0.3 µmol/mg dry weight; -60.9 ± 7.3 and -60.9 ± 4.6%, in young and aged mice, respectively). Further, IR-induced ROS production tended to be higher in aged mice. In conclusion, aging exacerbated the deleterious effects of IR on skeletal muscle mitochondrial respiration, potentially in relation to an increased oxidative stress.- Published
- 2019
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38. PGC-1β modulates statin-associated myotoxicity in mice.
- Author
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Singh F, Zoll J, Duthaler U, Charles AL, Panajatovic MV, Laverny G, McWilliams TG, Metzger D, Geny B, Krähenbühl S, and Bouitbir J
- Subjects
- Animals, Apoptosis drug effects, Apoptosis physiology, Atorvastatin metabolism, Female, Hydrogen Peroxide metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mitochondria, Muscle drug effects, Mitochondria, Muscle metabolism, Mitochondria, Muscle pathology, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Myosin Heavy Chains metabolism, Myotoxicity pathology, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Atorvastatin toxicity, Hydroxymethylglutaryl-CoA Reductase Inhibitors toxicity, Muscle, Skeletal drug effects, Myotoxicity etiology, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
- Abstract
Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1β expression in human and rat skeletal muscle, suggesting that PGC-1β may play a role in statin-induced myopathy. PGC-1β is a transcriptional co-regulator controlling the expression of important genes in mitochondrial biogenesis, antioxidative capacity and energy metabolism. The principle aim of the current study was to investigate the interaction between atorvastatin and PGC-1β in more detail. We therefore treated wild-type mice and mice with selective skeletal muscle knockout of PGC-1β (PGC-1β
(i)skm-/- mice) with oral atorvastatin (5 mg/kg/day) for 2 weeks. At the end of treatment, we determined body parameters, muscle function, structure, and composition as well as the function of muscle mitochondria, mitochondrial biogenesis and activation of apoptotic pathways. In wild-type mice, atorvastatin selectively impaired mitochondrial function in glycolytic muscle and caused a conversion of oxidative type IIA to glycolytic type IIB myofibers. Conversely, in oxidative muscle of wild-type mice, atorvastatin enhanced mitochondrial function via activation of mitochondrial biogenesis pathways and decreased apoptosis. In PGC-1β(i)skm-/- mice, atorvastatin induced a switch towards glycolytic fibers, caused mitochondrial dysfunction, increased mitochondrial ROS production, impaired mitochondrial proliferation and induced apoptosis in both glycolytic and oxidative skeletal muscle. Our work reveals that atorvastatin mainly affects glycolytic muscle in wild-type mice and demonstrates the importance of PGC-1β for oxidative muscle integrity during long-term exposure to a myotoxic agent.- Published
- 2019
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39. Diabetes Worsens Skeletal Muscle Mitochondrial Function, Oxidative Stress, and Apoptosis After Lower-Limb Ischemia-Reperfusion: Implication of the RISK and SAFE Pathways?
- Author
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Pottecher J, Adamopoulos C, Lejay A, Bouitbir J, Charles AL, Meyer A, Singer M, Wolff V, Diemunsch P, Laverny G, Metzger D, and Geny B
- Abstract
Objectives: Diabetic patients respond poorly to revascularization for peripheral arterial disease (PAD) but the underlying mechanisms are not well understood. We aimed to determine whether diabetes worsens ischemia-reperfusion (IR)-induced muscle dysfunction and the involvement of endogenous protective kinases in this process. Materials and Methods: Streptozotocin-induced diabetic and non-diabetic rats were randomized to control or to IR injury (3 h of aortic cross-clamping and 2 h of reperfusion). Mitochondrial respiration, reactive oxygen species (ROS) production, protein levels of superoxide dismutase (SOD2) and endogenous protective kinases (RISK and SAFE pathways) were investigated in rat gastrocnemius, together with upstream (GSK-3β) and downstream (cleaved caspase-3) effectors of apoptosis. Results: Although already impaired when compared to non-diabetic controls at baseline, the decline in mitochondrial respiration after IR was more severe in diabetic rats. In diabetic animals, IR-triggered oxidative stress (increased ROS production and reduced SOD2 levels) and effectors of apoptosis (reduced GSK-3β inactivation and higher cleaved caspase-3 levels) were increased to a higher level than in the non-diabetics. IR had no effect on the RISK pathway in non-diabetics and diabetic rats, but increased STAT 3 only in the latter. Conclusion: Type 1 diabetes worsens IR-induced skeletal muscle injury, endogenous protective pathways not being efficiently stimulated.
- Published
- 2018
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40. Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation.
- Author
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Meyer A, Laverny G, Bernardi L, Charles AL, Alsaleh G, Pottecher J, Sibilia J, and Geny B
- Subjects
- Animals, Bacteria, Dendritic Cells immunology, Humans, Immunity, Innate, Inflammation metabolism, Lymphocytes immunology, Mitochondria metabolism, Inflammation immunology, Mitochondria immunology
- Abstract
Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.
- Published
- 2018
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41. IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis.
- Author
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Meyer A, Laverny G, Allenbach Y, Grelet E, Ueberschlag V, Echaniz-Laguna A, Lannes B, Alsaleh G, Charles AL, Singh F, Zoll J, Lonsdorfer E, Maurier F, Boyer O, Gottenberg JE, Nicot AS, Laporte J, Benveniste O, Metzger D, Sibilia J, and Geny B
- Subjects
- Acetylcysteine pharmacology, Adult, Aged, Animals, Cell Line, Cytokines blood, Dermatomyositis drug therapy, Dermatomyositis pathology, Female, Free Radical Scavengers pharmacology, Freund's Adjuvant, Humans, Inflammation drug therapy, Inflammation pathology, Male, Mice, Inbred BALB C, Middle Aged, Mitochondria drug effects, Mitochondria pathology, Muscle Weakness drug therapy, Muscle Weakness metabolism, Muscle Weakness pathology, Muscle, Skeletal drug effects, Muscle, Skeletal pathology, Nervous System Autoimmune Disease, Experimental drug therapy, Nervous System Autoimmune Disease, Experimental metabolism, Nervous System Autoimmune Disease, Experimental pathology, Transcriptome, Dermatomyositis metabolism, Inflammation metabolism, Interferon-beta metabolism, Mitochondria metabolism, Muscle, Skeletal metabolism, Reactive Oxygen Species metabolism
- Abstract
Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.
- Published
- 2017
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42. Moderate Exercise Allows for shorter Recovery Time in Critical Limb Ischemia.
- Author
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Lejay A, Laverny G, Paradis S, Schlagowski AI, Charles AL, Singh F, Zoll J, Thaveau F, Lonsdorfer E, Dufour S, Favret F, Wolff V, Metzger D, Chakfe N, and Geny B
- Abstract
Whether and how moderate exercise might allow for accelerated limb recovery in chronic critical limb ischemia (CLI) remains to be determined. Chronic CLI was surgically induced in mice, and the effect of moderate exercise (training five times per week over a 3-week period) was investigated. Tissue damages and functional scores were assessed on the 4th, 6th, 10th, 20th, and 30th day after surgery. Mice were sacrificed 48 h after the last exercise session in order to assess muscle structure, mitochondrial respiration, calcium retention capacity, oxidative stress and transcript levels of genes encoding proteins controlling mitochondrial functions (PGC1α, PGC1β, NRF1) and anti-oxidant defenses markers (SOD1, SOD2, catalase). CLI resulted in tissue damages and impaired functional scores. Mitochondrial respiration and calcium retention capacity were decreased in the ischemic limb of the non-exercised group (V
max = 7.11 ± 1.14 vs. 9.86 ± 0.86 mmol 02/min/g dw, p < 0.001; CRC = 7.01 ± 0.97 vs. 11.96 ± 0.92 microM/mg dw, p < 0.001, respectively). Moderate exercise reduced tissue damages, improved functional scores, and restored mitochondrial respiration and calcium retention capacity in the ischemic limb (Vmax = 9.75 ± 1.00 vs. 9.82 ± 0.68 mmol 02/min/g dw; CRC = 11.36 ± 1.33 vs. 12.01 ± 1.24 microM/mg dw, respectively). Exercise also enhanced the transcript levels of PGC1α, PGC1β, NRF1, as well as SOD1, SOD2, and catalase. Moderate exercise restores mitochondrial respiration and calcium retention capacity, and it has beneficial functional effects in chronic CLI, likely by stimulating reactive oxygen species-induced biogenesis and anti-oxidant defenses. These data support further development of exercise therapy even in advanced peripheral arterial disease.- Published
- 2017
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43. Androgen signaling negatively controls group 2 innate lymphoid cells.
- Author
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Laffont S, Blanquart E, Savignac M, Cénac C, Laverny G, Metzger D, Girard JP, Belz GT, Pelletier L, Seillet C, and Guéry JC
- Subjects
- Androgens pharmacology, Animals, Asthma complications, Asthma immunology, Asthma pathology, Castration, Cell Proliferation drug effects, Disease Susceptibility, Female, Hypersensitivity complications, Hypersensitivity immunology, Hypersensitivity pathology, Interleukin-33 metabolism, Lung immunology, Lung pathology, Lymphocyte Count, Male, Mice, Inbred C57BL, Pneumonia complications, Pneumonia immunology, Pneumonia pathology, Pyroglyphidae immunology, Receptors, Androgen metabolism, Sexism, Androgens metabolism, Immunity, Innate immunology, Lymphocytes immunology, Signal Transduction
- Abstract
Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33-mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33-driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33., (© 2017 Laffont et al.)
- Published
- 2017
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44. The transcriptional coregulator PGC-1β controls mitochondrial function and anti-oxidant defence in skeletal muscles.
- Author
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Gali Ramamoorthy T, Laverny G, Schlagowski AI, Zoll J, Messaddeq N, Bornert JM, Panza S, Ferry A, Geny B, and Metzger D
- Subjects
- Animals, Electron Spin Resonance Spectroscopy, Electroporation, Exercise Test, Free Radicals metabolism, Gene Expression Profiling, Gene Knockout Techniques, Glucose Tolerance Test, Hand Strength physiology, Hydrogen Peroxide metabolism, Insulin Resistance genetics, Lipid Peroxidation, Mice, Muscle Contraction genetics, Muscle Fibers, Skeletal metabolism, Muscle Fibers, Skeletal pathology, Muscle Fibers, Skeletal physiology, Muscle Strength genetics, Muscle, Skeletal pathology, Muscle, Skeletal physiology, Oxidative Stress genetics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Transcription Factors metabolism, Gene Expression Regulation, Mitochondria, Muscle metabolism, Muscle, Skeletal metabolism, Myoblasts metabolism, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Transcription Factors genetics
- Abstract
The transcriptional coregulators PGC-1α and PGC-1β modulate the expression of numerous partially overlapping genes involved in mitochondrial biogenesis and energetic metabolism. The physiological role of PGC-1β is poorly understood in skeletal muscle, a tissue of high mitochondrial content to produce ATP levels required for sustained contractions. Here we determine the physiological role of PGC-1β in skeletal muscle using mice, in which PGC-1β is selectively ablated in skeletal myofibres at adulthood (PGC-1β((i)skm-/-) mice). We show that myofibre myosin heavy chain composition and mitochondrial number, muscle strength and glucose homeostasis are unaffected in PGC-1β((i)skm-/-) mice. However, decreased expression of genes controlling mitochondrial protein import, translational machinery and energy metabolism in PGC-1β((i)skm-/-) muscles leads to mitochondrial structural and functional abnormalities, impaired muscle oxidative capacity and reduced exercise performance. Moreover, enhanced free-radical leak and reduced expression of the mitochondrial anti-oxidant enzyme Sod2 increase muscle oxidative stress. PGC-1β is therefore instrumental for skeletal muscles to cope with high energetic demands.
- Published
- 2015
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45. VDR and gemini ligands.
- Author
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Laverny G and Metzger D
- Subjects
- Animals, Genotype, Humans, Ligands, Mice, Mutant Strains, Mutation, Phenotype, Receptors, Calcitriol genetics, Rickets genetics, Calcitriol metabolism, Receptors, Calcitriol metabolism, Rickets metabolism
- Published
- 2015
- Full Text
- View/download PDF
46. A vitamin D receptor selectively activated by gemini analogs reveals ligand dependent and independent effects.
- Author
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Huet T, Laverny G, Ciesielski F, Molnár F, Ramamoorthy TG, Belorusova AY, Antony P, Potier N, Metzger D, Moras D, and Rochel N
- Subjects
- Animals, Chromatin Immunoprecipitation, Crystallography, X-Ray, Fluorescence Polarization, Genotype, HEK293 Cells, Humans, MCF-7 Cells, Mice, Mice, Knockout, Mutation genetics, Protein Binding genetics, Receptors, Calcitriol genetics, Spectrometry, Mass, Electrospray Ionization, Vitamin D metabolism, Receptors, Calcitriol chemistry, Receptors, Calcitriol metabolism
- Abstract
The bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled the molecular mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDR(gem)) that is unresponsive to 1,25(OH)2D3, but the activity of which is efficiently induced by the gemini ligands. Moreover, we show that many VDR target genes are repressed by unliganded VDR(gem) and that mineral ion and bone homeostasis are more impaired in VDR(gem) mice than in VDR null mice, demonstrating that mutations abolishing VDR ligand binding result in more severe skeletal defects than VDR null mutations. As gemini ligands induce VDR(gem) transcriptional activity in mice and normalize their serum calcium levels, VDR(gem) is a powerful tool to further unravel both liganded and unliganded VDR signaling., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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47. Immunomodulatory properties of multi-walled carbon nanotubes in peripheral blood mononuclear cells from healthy subjects and allergic patients.
- Author
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Laverny G, Casset A, Purohit A, Schaeffer E, Spiegelhalter C, de Blay F, and Pons F
- Subjects
- Adult, Antigens, Dermatophagoides immunology, Cell Survival immunology, Cells, Cultured, Cytokines immunology, Female, Flow Cytometry, Humans, Hypersensitivity blood, Immunity, Innate drug effects, Immunity, Innate immunology, Leukocytes, Mononuclear immunology, Lipopolysaccharides immunology, Male, Microscopy, Electron, Transmission, Toll-Like Receptors agonists, Toll-Like Receptors immunology, Young Adult, Hypersensitivity immunology, Immunologic Factors toxicity, Leukocytes, Mononuclear drug effects, Nanotubes, Carbon toxicity
- Abstract
In the present study, we investigated the immunomodulatory activity of multi-walled carbon nanotubes (MWCNTs) in peripheral blood mononuclear cells (PBMCs) from healthy donors and mite-allergic subjects. Freshly prepared PBMCs, stimulated or not with Toll-like receptor (TLR)1-9 agonists, a T cell mitogen (phytohemagglutinin A) or mite allergen extract were cultured in the presence or absence of MWCNTs. Secretion of TNF-α, IL-2, IL-5, IL-6, IL-12/23p40 or IFN-γ was quantified in the culture supernatants by ELISA. Basal secretion of all the cytokines was not altered by MWCNTs in PBMCs from both healthy donors and allergic subjects. In PBMCs from healthy donors, TNF-α, IL-6 and IL-12/23p40 secretion in response to the TLR4 agonist, lipopolysaccharide was however increased in a dose-dependent manner by MWCNTs. Significant increases in the release of these cytokines were also observed in PBMCs stimulated with a TLR2 or TLR3 agonist. MWCNTs also increased the release of IL-2 and IFN-γ by PBMCs stimulated with a T cell mitogen. In contrast, MWCNTs inhibited allergen-induced IL-5 secretion by PBMCs from mite-allergic subjects. As well, MWCNTs altered the capacity of PBMC-derived monocytes to differentiate into functional dendritic cells. All together, our data suggest that according to its immune cell target, MWCNTs may either promote or suppress immune responses in humans. Further investigations are necessary to fully understand the complexity behind interactions of engineered nanoparticles with the immune system., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
48. Phospholipid-detergent conjugates as novel tools for siRNA delivery.
- Author
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Pierrat P, Laverny G, Creusat G, Wehrung P, Strub JM, VanDorsselaer A, Pons F, Zuber G, and Lebeau L
- Subjects
- Cell Line, Tumor, Drug Delivery Systems, Glycerylphosphorylcholine chemistry, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Phosphatidylcholines, RNA, Small Interfering metabolism, Transfection, Detergents chemistry, Detergents pharmacology, Glycerylphosphorylcholine analogs & derivatives, Nanoparticles chemistry, Nucleic Acids chemistry, Phospholipids pharmacology, Phosphorylcholine chemistry, Phosphorylcholine pharmacology, RNA, Small Interfering chemistry, RNA, Small Interfering pharmacology
- Abstract
One of the potential benefits of drug delivery systems in medicine is the creation of nanoparticle-based vectors that deliver a therapeutic cargo in sufficient quantity to a target site to enable a selective effect, width of the therapeutic window depending on the toxicity of the vector and the cargo. In this work, we intended to improve the siRNA delivery efficiency of a new kind of nucleic acid carrier, which is the result of the conjugation of the membrane phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) to the membrane-active species Triton X-100 (TX100). We hypothesized that by improving the biodegradability the cytotoxicity of the conjugate might by reduced, whereas its original transfection potential would be tentatively preserved. DOPC was conjugated to Triton X-100 through spacers displaying various resistance to chemical hydrolysis and enzyme degradation. The results obtained through in vitro siRNA delivery experiments showed that the initial phosphoester bond can be replaced with a phospho(alkyl)enecarbonate group with no loss in the transfection activity, whereas the associated cytotoxicity was significantly decreased, as assessed by metabolic activity and membrane integrity measurements. The toxicity of the conjugates incorporating a phospho(alkyl)enesuccinnate moiety proved even lower but was clearly balanced with a reduction of the siRNA delivery efficiency. Hydrolytic stability and intracellular degradation of the conjugates were investigated by NMR spectroscopy and mass spectrometry. A general trend was that the more readily degraded conjugates were those with the lower toxicity. Otherwise, the phospho(alkyl)enecarbonate conjugates revealed some hemolytic activity, whereas the parent phosphoester did not. The reason why these conjugates behave differently with respect to hemolysis might be a consequence of unusual fusogenic properties and probably reflects the difference in the stability of the conjugates in the intracellular environment., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF
49. A cationic phospholipid-detergent conjugate as a new efficient carrier for siRNA delivery.
- Author
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Pierrat P, Creusat G, Laverny G, Pons F, Zuber G, and Lebeau L
- Subjects
- Gene Transfer Techniques, Humans, Molecular Structure, Octoxynol chemistry, Phosphatidylcholines chemistry, Phospholipids chemistry, RNA, Small Interfering, Transfection methods
- Published
- 2012
- Full Text
- View/download PDF
50. Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease.
- Author
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Laverny G, Penna G, Vetrano S, Correale C, Nebuloni M, Danese S, and Adorini L
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacology, Calcitriol chemistry, Calcitriol pharmacology, Cells, Cultured, Colitis, Ulcerative drug therapy, Colon drug effects, Colon pathology, Crohn Disease drug therapy, Female, Humans, Ileum drug effects, Ileum pathology, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Mucous Membrane drug effects, Mucous Membrane pathology, Treatment Outcome, Young Adult, Anti-Inflammatory Agents therapeutic use, Calcitriol analogs & derivatives, Calcitriol therapeutic use, Inflammatory Bowel Diseases drug therapy, Receptors, Calcitriol agonists
- Abstract
Deficiency in 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has been suggested as an important environmental factor for immuno-mediated disorders including inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, both characterized by chronic intestinal inflammation. Administration of vitamin D receptor (VDR) agonists can ameliorate spontaneous and induced animal models of colitis, but hypercalcemia is a dose-limiting adverse event. Previous work in our laboratory has identified 1alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (BXL-62) as a potent anti-inflammatory VDR agonist with a low calcemic activity. In the present study, we confirm the marked anti-inflammatory properties of BXL-62 and show its capacity to induce VDR primary response genes, like CYP24A1 and CAMP, at lower concentrations than 1,25D(3), in PBMCs from IBD patients. Its higher anti-inflammatory potency compared to 1,25D(3) was demonstrated by the significantly more potent inhibition in PBMCs and in lymphocyte-enriched lamina propria mononuclear cells of the pro-inflammatory cytokines TNF-alpha, IL-12/23p40, IL-6 and IFN-gamma, both at mRNA and protein level. The therapeutic efficacy of intra-rectal administration of BXL-62 in experimental IBD is shown by its beneficial effects, significantly higher than 1,25D(3), to induce recovery of clinical symptoms of colitis at normocalcemic doses in mice undergoing dextran sodium sulfate-induced colitis. These results confirm the therapeutic efficacy of VDR agonists in experimental colitis, and suggest BXL-62 as a promising compound for IBD treatment., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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