11 results on '"Baghdoyan S"'
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2. Quantitative analysis of highly parallel transfection in cell microarrays
- Author
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Baghdoyan, S., primary
- Published
- 2004
- Full Text
- View/download PDF
3. Pluripotent Stem Cells in Disease Modeling and Drug Discovery for Myotonic Dystrophy Type 1.
- Author
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Bérenger-Currias N, Martinat C, and Baghdoyan S
- Subjects
- Humans, Drug Discovery, Myotonic Dystrophy genetics, Myotonic Dystrophy metabolism, Myotonic Dystrophy pathology, Pluripotent Stem Cells metabolism
- Abstract
Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by the expansion of a CTG repeat tract within the 3' untranslated region (3' UTR) of the dystrophia myotonica protein kinase gene ( DMPK ). Although DM1 is considered to be the most frequent myopathy of genetic origin in adults, DM1 patients exhibit a vast diversity of symptoms, affecting many different organs. Up until now, different in vitro models from patients' derived cells have largely contributed to the current understanding of DM1. Most of those studies have focused on muscle physiopathology. However, regarding the multisystemic aspect of DM1, there is still a crucial need for relevant cellular models to cover the whole complexity of the disease and open up options for new therapeutic approaches. This review discusses how human pluripotent stem cell-based models significantly contributed to DM1 mechanism decoding, and how they provided new therapeutic strategies that led to actual phase III clinical trials.
- Published
- 2023
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- View/download PDF
4. Expression of miRNAs from the Imprinted DLK1/DIO3 Locus Signals the Osteogenic Potential of Human Pluripotent Stem Cells.
- Author
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Barrault L, Gide J, Qing T, Lesueur L, Tost J, Denis JA, Cailleret M, Aubry L, Peschanski M, Martinat C, and Baghdoyan S
- Subjects
- Biomarkers, Calcium-Binding Proteins metabolism, Cell Line, Gene Expression Regulation, Developmental, Genomic Imprinting, Humans, Immunophenotyping, Iodide Peroxidase metabolism, Membrane Proteins metabolism, Quantitative Trait Loci, RNA Interference, Calcium-Binding Proteins genetics, Cell Differentiation genetics, Iodide Peroxidase genetics, Membrane Proteins genetics, MicroRNAs genetics, Osteogenesis genetics, Pluripotent Stem Cells cytology, Pluripotent Stem Cells metabolism
- Abstract
Substantial variations in differentiation properties have been reported among human pluripotent cell lines (hPSC), which could affect their utility and clinical safety. We characterized the variable osteogenic capacity observed between different human pluripotent stem cell lines. By focusing on the miRNA expression profile, we demonstrated that the osteogenic differentiation propensity of human pluripotent stem cell lines could be associated with the methylation status and the expression of miRNAs from the imprinted DLK1/DIO3 locus. More specifically, quantitative analysis of the expression of six different miRNAs of that locus prospectively identified human embryonic stem cells and human-induced pluripotent stem cells with differential osteogenic differentiation capacities. At the molecular and functional levels, we showed that these miRNAs modulated the expression of the activin receptor type 2B and the downstream signal transduction, which impacted osteogenesis. In conclusion, miRNAs of the imprinted DLK1/DIO3 locus appear to have both a predictive value and a functional impact in determining the osteogenic fate of human pluripotent stem cells.
- Published
- 2019
- Full Text
- View/download PDF
5. Pluripotent Stem Cell-Based Drug Screening Reveals Cardiac Glycosides as Modulators of Myotonic Dystrophy Type 1.
- Author
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Maury Y, Poydenot P, Brinon B, Lesueur L, Gide J, Roquevière S, Côme J, Polvèche H, Auboeuf D, Alexandre Denis J, Pietu G, Furling D, Lechuga M, Baghdoyan S, Peschanski M, and Martinat C
- Abstract
There is currently no treatment for myotonic dystrophy type 1 (DM1), the most frequent myopathy of genetic origin. This progressive neuromuscular disease is caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors, resulting in alternative splicing misregulation. By combining human mutated pluripotent stem cells and phenotypic drug screening, we revealed that cardiac glycosides act as modulators for both upstream nuclear aggregations of DMPK mRNAs and several downstream alternative mRNA splicing defects. However, these occurred at different drug concentration ranges. Similar biological effects were recorded in a DM1 mouse model. At the mechanistic level, we demonstrated that this effect was calcium dependent and was synergic with inhibition of the ERK pathway. These results further underscore the value of stem-cell-based assays for drug discovery in monogenic diseases., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
6. [Pharmacological research and pluripotent stem cells: from the innovative experimental paradigm to the successful clinical trial].
- Author
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Baghdoyan S, Bassez G, Audureau E, and Peschanski M
- Subjects
- Animals, Drug Development methods, Drug Development trends, Drug Discovery methods, Drug Discovery trends, Humans, Models, Biological, Pluripotent Stem Cells drug effects, Validation Studies as Topic, Clinical Trials as Topic, Drug Evaluation, Preclinical methods, Inventions trends, Pluripotent Stem Cells cytology, Pluripotent Stem Cells physiology
- Published
- 2019
- Full Text
- View/download PDF
7. Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial.
- Author
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Bassez G, Audureau E, Hogrel JY, Arrouasse R, Baghdoyan S, Bhugaloo H, Gourlay-Chu ML, Le Corvoisier P, and Peschanski M
- Subjects
- Adult, Double-Blind Method, Female, Gait Disorders, Neurologic etiology, Humans, Hypoglycemic Agents therapeutic use, Male, Middle Aged, Muscle Strength drug effects, Myotonic Dystrophy complications, Quality of Life, Gait drug effects, Gait Disorders, Neurologic drug therapy, Metformin therapeutic use, Myotonic Dystrophy drug therapy
- Abstract
Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose-escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 ± 32.7 m, while the placebo group (n = 14) gained 3.7 ± 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.
- Published
- 2018
- Full Text
- View/download PDF
8. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin.
- Author
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Laustriat D, Gide J, Barrault L, Chautard E, Benoit C, Auboeuf D, Boland A, Battail C, Artiguenave F, Deleuze JF, Bénit P, Rustin P, Franc S, Charpentier G, Furling D, Bassez G, Nissan X, Martinat C, Peschanski M, and Baghdoyan S
- Abstract
Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.
- Published
- 2015
- Full Text
- View/download PDF
9. [Cell microarrays and functional genomics].
- Author
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Roupioz Y, Castel D, Pitaval A, Baghdoyan S, and Gidrol X
- Subjects
- Cells, Cultured, Humans, Transfection methods, Genomics methods, Oligonucleotide Array Sequence Analysis methods
- Abstract
With the complete sequencing of the human genome, research priorities have shifted from the identification of genes to the elucidation of their function. Methods currently used by scientists to characterize gene function, such as knock-out mice, are based upon loss of protein function and analysis of the resulting phenotypes to infer a potential role for the protein under scrutiny. Until now, these methods have been successful but time consuming and only a few genes at a time could be analyzed. Cell microarrays allow to simultaneously transfect thousands of different nucleic acid molecules, RNA or DNA, into adherent cells. It is then possible to analyze a large pallet of resulting phenotypes in clusters of transfected cells. We are currently manufacturing cell microarrays with collections of full-length cDNA cloned in expression vectors (gain of function analyses) or siRNA (loss of function studies) to unravel function of genes involved in differentiation and proliferation of human cells. Although there are still some technological difficulties to overcome, the potential for cell microarrays to speed up functional exploration of genomes is very promising.
- Published
- 2005
- Full Text
- View/download PDF
10. Id2 reverses cell cycle arrest induced by {gamma}-irradiation in human HaCaT keratinocytes.
- Author
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Baghdoyan S, Lamartine J, Castel D, Pitaval A, Roupioz Y, Franco N, Duarte M, Martin MT, and Gidrol X
- Subjects
- Cell Cycle physiology, Cell Proliferation radiation effects, Humans, Inhibitor of Differentiation Protein 2, Keratinocytes cytology, Keratinocytes metabolism, Cell Cycle radiation effects, DNA-Binding Proteins metabolism, Gamma Rays, Keratinocytes radiation effects, Repressor Proteins metabolism, Transcription Factors metabolism
- Abstract
Id2 plays a key role in epithelial cells, regulating differentiation, the cell cycle, and proliferation. Because human skin constantly renews itself and is the first target of irradiation, it is of primary interest to evaluate whether such a gene may be regulated in keratinocytes exposed to ionizing radiation. We show here that Id2 is induced in response to gamma-irradiation and have investigated the consequence of this regulation on cell fate. Using RNA interference, we observed that Id2 extinction significantly reduces cell growth in human keratinocytes through the control of the G(1)-S transition of the cell cycle. We have investigated whether the impact of Id2 on the cell cycle may have a physiological role on the cell's ability to cope with radiative stress. Indeed, when Id2 is down-regulated through interfering RNA, cells are more sensitive to irradiation. Conversely, when Id2 is overexpressed, this somehow protects the cell. We propose that Id2 favors reentering the cell cycle after radiation-induced cell cycle arrest to permit the recovery of keratinocytes exposed to ionizing radiation.
- Published
- 2005
- Full Text
- View/download PDF
11. Capture of cytokine-responsive genes (NACA and RBM3) using a gene trap approach.
- Author
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Baghdoyan S, Dubreuil P, Eberlé F, and Gomez S
- Subjects
- Adult, Antigens, CD34 blood, Base Sequence, Cell Division drug effects, Cell Line, Dactinomycin pharmacology, Genetic Vectors, Hematopoietic Stem Cells pathology, Humans, Lymphoma, Non-Hodgkin blood, Lymphoma, Non-Hodgkin pathology, Molecular Sequence Data, Recombinant Proteins, Retroviridae, Transcription, Genetic drug effects, Transfection, Virus Integration, Cytokines pharmacology, Gene Expression Regulation drug effects, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cells physiology, RNA-Binding Proteins genetics
- Abstract
We have developed a gene trap approach to select specific cytokine receptor/ligand responsive genes in the cell line TF-1. This cell line exhibits a dependency on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) and responds to interleukin-5 (IL-5). In an attempt to detect genes modulated by one of these factors, cells were infected with the Rosabetageo retrovirus in the presence of GM-CSF, IL-3, or IL-5 and clones were selected for retroviral integration on the basis of G418 resistance. Housekeeping and cytokine-regulated trapped genes were then differentiated on the basis of G418 resistance versus sensitivity in the presence of the different cytokines. To determine the reliability of this screen, DNA sequences upstream of the proviral integration site were identified by 5' rapid amplification of DNA ends polymerase chain reaction (RACE PCR) from selected GM-CSF-treated and -infected clones. Comparison of the sequences with those in the Genbank database revealed that 2 sequences correspond to known genes: NACA and RBM3. NACA was recently defined as a coactivator of c-jun-mediated transcription factors in osteoblasts, and RBM3 as a protein from the heterogeneous nuclear ribonucleoprotein family. Data from transcriptional analysis of these 2 genes in TF-1 cells showed a specific up-regulation by GM-CSF. Both transcripts were also found to be up-regulated in purified CD34(+) cells, suggesting their involvement in proliferative processes during hematopoiesis. Interestingly, down-regulation was observed during monocytic differentiation of TF-1 cells, suggesting their extinction could contribute to monocytic lineage development. This study demonstrates that this gene trap approach is a useful method for identifying novel, specific cytokine-responsive genes that are involved in the regulation of hematopoiesis. (Blood. 2000;95:3750-3757)
- Published
- 2000
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