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A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation

Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective,...

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Autores principales: Marchese, Pietro, Mahajan, Nipun, O’Connell, Enda, Fearnhead, Howard, Tuohy, Maria, Krawczyk, Janusz, Thomas, Olivier P., Barry, Frank, Murphy, Mary J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230868/
https://www.ncbi.nlm.nih.gov/pubmed/32260516
http://dx.doi.org/10.3390/md18040192
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author Marchese, Pietro
Mahajan, Nipun
O’Connell, Enda
Fearnhead, Howard
Tuohy, Maria
Krawczyk, Janusz
Thomas, Olivier P.
Barry, Frank
Murphy, Mary J.
author_facet Marchese, Pietro
Mahajan, Nipun
O’Connell, Enda
Fearnhead, Howard
Tuohy, Maria
Krawczyk, Janusz
Thomas, Olivier P.
Barry, Frank
Murphy, Mary J.
author_sort Marchese, Pietro
collection PubMed
description Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair ectopic calcification. Bioactive small molecule discovery is critical to address ectopic tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort.
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spelling pubmed-72308682020-05-22 A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation Marchese, Pietro Mahajan, Nipun O’Connell, Enda Fearnhead, Howard Tuohy, Maria Krawczyk, Janusz Thomas, Olivier P. Barry, Frank Murphy, Mary J. Mar Drugs Article Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair ectopic calcification. Bioactive small molecule discovery is critical to address ectopic tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort. MDPI 2020-04-05 /pmc/articles/PMC7230868/ /pubmed/32260516 http://dx.doi.org/10.3390/md18040192 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marchese, Pietro
Mahajan, Nipun
O’Connell, Enda
Fearnhead, Howard
Tuohy, Maria
Krawczyk, Janusz
Thomas, Olivier P.
Barry, Frank
Murphy, Mary J.
A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation
title A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation
title_full A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation
title_fullStr A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation
title_full_unstemmed A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation
title_short A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibitors of Mesenchymal Stem Cell Differentiation
title_sort novel high-throughput screening platform identifies itaconate derivatives from marine penicillium antarcticum as inhibitors of mesenchymal stem cell differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230868/
https://www.ncbi.nlm.nih.gov/pubmed/32260516
http://dx.doi.org/10.3390/md18040192
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