{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:27:11Z","timestamp":1780471631928,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["09\/SRC\/B1794"],"award-info":[{"award-number":["09\/SRC\/B1794"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["SFI\/15\/IA\/3100"],"award-info":[{"award-number":["SFI\/15\/IA\/3100"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002081","name":"Irish Research Council","doi-asserted-by":"publisher","award":["GOIPG\/2016\/1113"],"award-info":[{"award-number":["GOIPG\/2016\/1113"]}],"id":[{"id":"10.13039\/501100002081","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fulbright Commission Ireland","award":["PM2020"],"award-info":[{"award-number":["PM2020"]}]},{"name":"College of Medicine Nursing and 527 Health Sciences at NUI Galway","award":["PM2020"],"award-info":[{"award-number":["PM2020"]}]},{"name":"Irish Government\u2019s Pro- 530 gramme for Research in Third Level Institutions","award":["Cycles 4 and 5"],"award-info":[{"award-number":["Cycles 4 and 5"]}]},{"name":"Marine Institute and the European Regional Development Fund","award":["2014-2020"],"award-info":[{"award-number":["2014-2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Chronic diseases characterized by bone and cartilage loss are associated with a reduced ability of progenitor cells to regenerate new tissues in an inflammatory environment. A promising strategy to treat such diseases is based on tissue repair mediated by human mesenchymal stem cells (hMSCs), but therapeutic outcomes are hindered by the absence of small molecules to efficiently modulate cell behaviour. Here, we applied a high-throughput drug screening technology to bioprospect a large library of extracts from Irish deep-sea organisms to induce hMSC differentiation toward musculoskeletal lineages and reduce inflammation of activated macrophages. The library included extracts from deep-sea corals, sponges and filamentous fungi representing a novel source of compounds for the targeted bioactivity. A validated hit rate of 3.4% was recorded from the invertebrate library, with cold water sea pens (octocoral order Pennatulacea), such as Kophobelemnon sp. and Anthoptilum sp., showing the most promising results in influencing stem cell differentiation toward osteogenic and chondrogenic lineages. Extracts obtained from deep-sea fungi showed no effects on stem cell differentiation, but a 6.8% hit rate in reducing the inflammation of activated macrophages. Our results demonstrate the potential of deep-sea organisms to synthetize pro-differentiation and immunomodulatory compounds that may represent potential drug development candidates to treat chronic musculoskeletal diseases.<\/jats:p>","DOI":"10.3390\/md19070390","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T22:25:31Z","timestamp":1626215131000},"page":"390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Deep-Sea Coral Garden Invertebrates and Their Associated Fungi Are Genetic Resources for Chronic Disease Drug Discovery"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1492-4189","authenticated-orcid":false,"given":"Pietro","family":"Marchese","sequence":"first","affiliation":[{"name":"Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, H91W2TY Galway, Ireland"},{"name":"Department of Chemistry, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Young","sequence":"additional","affiliation":[{"name":"Martin Ryan Institute, School of Natural Sciences, National University of Ireland Galway, University Road, H91TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7441-0262","authenticated-orcid":false,"given":"Enda","family":"O\u2019Connell","sequence":"additional","affiliation":[{"name":"Genomics and Screening Core, National University of Ireland Galway, H91W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Afoullouss","sequence":"additional","affiliation":[{"name":"Martin Ryan Institute, School of Natural Sciences, National University of Ireland Galway, University Road, H91TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3033-5779","authenticated-orcid":false,"given":"Bill","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4806-0040","authenticated-orcid":false,"given":"A.","family":"Allcock","sequence":"additional","affiliation":[{"name":"Martin Ryan Institute, School of Natural Sciences, National University of Ireland Galway, University Road, H91TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Barry","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, H91W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, H91W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1006\/excr.2001.5278","article-title":"Chondrogenic Differentiation of Mesenchymal Stem Cells from Bone Marrow: Differentiation-Dependent Gene Expression of Matrix Components","volume":"268","author":"Barry","year":"2001","journal-title":"Exp. Cell Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2007.08.025","article-title":"Self-Renewing Osteoprogenitors in Bone Marrow Sinusoids Can Organize a Hematopoietic Microenvironment","volume":"131","author":"Sacchetti","year":"2007","journal-title":"Cell"},{"key":"ref_3","first-page":"19","article-title":"Bone marrow osteogenic stem cells","volume":"Volume 10","author":"Cohn","year":"1990","journal-title":"Calcium Regulation and Bone Metabolism. Basic and Clinical Aspects"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1089\/ten.teb.2013.0771","article-title":"Chondrogenic Differentiation of Mesenchymal Stem Cells: Challenges and Unfulfilled Expectations","volume":"20","author":"Somoza","year":"2014","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.biotechadv.2011.04.003","article-title":"Designs from the deep: Marine organisms for bone tissue engineering","volume":"29","author":"Clarke","year":"2011","journal-title":"Biotechnol. Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/(SICI)1097-4644(199702)64:2<295::AID-JCB12>3.0.CO;2-I","article-title":"Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro","volume":"64","author":"Jaiswal","year":"1997","journal-title":"J. Cell. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/jcb.20719","article-title":"Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6","volume":"98","author":"Friedman","year":"2006","journal-title":"J. Cell. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"998","DOI":"10.5301\/ijao.5000001","article-title":"Effects of osteogenic differentiation inducers on in vitro ex-panded adult mesenchymal stromal cells","volume":"34","author":"Fiorentini","year":"2011","journal-title":"Int. J. Artif. Organs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1006\/excr.1997.3858","article-title":"In Vitro Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells","volume":"238","author":"Johnstone","year":"1998","journal-title":"Exp. Cell Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ejpb.2016.12.021","article-title":"New scaffolds encapsulating TGF-beta3\/BMP-7 combinations driving strong chondrogenic differentiation","volume":"114","author":"Borrajo","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_11","first-page":"151","article-title":"Osteogenic Protein-1 (Bone Morphogenetic Protein-7) in the Treatment of Tibial Nonunions: A Prospective, Random-ized Clinical Trial Comparing rhOP-1 with Fresh Bone Autograft","volume":"83-A","author":"Friedlaender","year":"2001","journal-title":"J. Bone Jt. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.2106\/00004623-200212000-00001","article-title":"Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: A prospective, controlled, randomized study of four hundred and fifty patients","volume":"84","author":"Govender","year":"2002","journal-title":"J. Bone Jt. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4065","DOI":"10.1002\/art.23034","article-title":"Re-semblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: Limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation","volume":"56","author":"Vitters","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/rheumatology\/40.1.74","article-title":"High concentrations of dexamethasone suppress the prolifer-ation but not the differentiation or further maturation of human osteoblast precursors in vitro: Relevance to glucocorti-coid-induced osteoporosis","volume":"40","author":"Walsh","year":"2001","journal-title":"Rheumatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1097\/01.blo.0000144854.66565.8f","article-title":"The Role of Cytokines in Cartilage Matrix Degeneration in Osteoarthritis","volume":"427","author":"Goldring","year":"2004","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2174\/138945007779940179","article-title":"Cytokine Targeting in Osteoarthritis","volume":"8","author":"Blom","year":"2007","journal-title":"Curr. Drug Targets"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11201","DOI":"10.1073\/pnas.1932554100","article-title":"Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads","volume":"100","author":"Doherty","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/stem.2315","article-title":"Differentiation of Vascular Stem Cells Contributes to Ectopic Calcification of Atherosclerotic Plaque","volume":"34","author":"Leszczynska","year":"2016","journal-title":"Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1517\/14712598.1.5.817","article-title":"Anticytokine therapy for osteoarthritis","volume":"1","author":"Goldring","year":"2001","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_20","first-page":"1092","article-title":"Life in extreme environments","volume":"409","author":"Rothschild","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S1389-0344(03)00042-X","article-title":"Piezotolerance as a metabolic engineering tool for the biosynthesis of natural products","volume":"20","author":"Wright","year":"2003","journal-title":"Biomol. Eng."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1039\/b808743a","article-title":"Deep-sea natural products","volume":"25","author":"Skropeta","year":"2008","journal-title":"Nat. Prod. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1039\/C3NP70118B","article-title":"Recent advances in deep-sea natural products","volume":"31","author":"Skropeta","year":"2014","journal-title":"Nat. Prod. Rep."},{"key":"ref_24","first-page":"1717","article-title":"Cancer Chemopreventive and Anticancer Evaluation of Extracts and Fractions from Marine Macro-and Micro-organisms Collected from Twilight Zone Waters Around Guam","volume":"4","author":"Schupp","year":"2009","journal-title":"Nat. Prod. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1021\/jo961745j","article-title":"Isolation of Calyculins, Calyculinamides, and Swinholide H from the New Zealand Deep-Water Marine Sponge Lamellomorpha strongylata","volume":"62","author":"Dumdei","year":"1997","journal-title":"J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pilkington, L.I. (2019). A Chemometric Analysis of Deep-Sea Natural Products. Molecules, 24.","DOI":"10.3390\/molecules24213942"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1007\/s00044-015-1395-8","article-title":"Antiosteoporotic and antioxidant activi-ties of diterpenoids from the Vietnamese soft corals Sinularia maxima and Lobophytum crassum","volume":"24","author":"Thao","year":"2015","journal-title":"Med. Chem. Res."},{"key":"ref_28","unstructured":"Allemand, D., Tambutt\u00e9, \u00c9., Zoccola, D., and Tambutt\u00e9, S. (2011). Coral Reefs: An Ecosystem in Transition, Springer."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.2174\/138161209787846739","article-title":"Cartilage and Bone Extracellular Matrix","volume":"15","author":"Gentili","year":"2009","journal-title":"Curr. Pharm. Design"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1007\/s10126-008-9141-6","article-title":"Specific expression of BMP2\/4 ortholog in biomineralizing tissues of corals and action on mouse BMP receptor","volume":"11","author":"Zoccola","year":"2009","journal-title":"Mar. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.lfs.2008.12.017","article-title":"Mevinolin enhances osteogenic genes (ALP, type I collagen and osteocalcin), CD44, CD47 and CD51 expression during osteogenic differentiation","volume":"84","author":"Kim","year":"2009","journal-title":"Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Xu, J., Yi, M., Ding, L., and He, S. (2019). A Review of Anti-Inflammatory Compounds from Marine Fungi, 2000\u20132018. Mar. Drugs, 17.","DOI":"10.3390\/md17110636"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Marchese, P., Mahajan, N., O\u2019Connell, E., Fearnhead, H., Tuohy, M., Krawczyk, J., Thomas, O.P., Barry, F., and Murphy, M.J. (2020). A Novel High-Throughput Screening Platform Identifies Itaconate Derivatives from Marine Penicillium antarcticum as Inhibi-tors of Mesenchymal Stem Cell Differentiation. Mar. Drugs, 18.","DOI":"10.3390\/md18040192"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.5194\/bg-7-2851-2010","article-title":"Deep, diverse and definitely different: Unique attributes of the world\u2019s largest ecosystem","volume":"7","author":"Brandt","year":"2010","journal-title":"Biogeosciences"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.dsr2.2016.05.005","article-title":"Deep-sea genetic resources: New frontiers for science and stewardship in areas beyond national jurisdic-tion","volume":"137","year":"2017","journal-title":"Deep Sea Res. Part II Top. Stud. Oceanogr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.scitotenv.2018.04.049","article-title":"Eyes in the sea: Unlocking the mysteries of the ocean using industrial, remotely operated vehicles (ROVs)","volume":"634","author":"Macreadie","year":"2018","journal-title":"Sci. Total. Environ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1093\/icesjms\/fss195","article-title":"Coral-characterized benthic assemblages of the deep Northeast Atlantic: Defining \u201cCoral Gardens\u201d to support future habitat mapping efforts","volume":"70","author":"Bullimore","year":"2013","journal-title":"ICES J. Mar. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Marchese, P., Garzoli, L., Young, R., Allcock, L., Barry, F., Tuohy, M., and Murphy, M. (2021). Fungi populate deep-sea coral gardens as well as marine sediments in the Irish Atlantic Ocean. Environ. Microbiol.","DOI":"10.1111\/1462-2920.15560"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fbioe.2019.00009","article-title":"Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome","volume":"7","author":"Mancuso","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Demers, D.H., Knestrick, M.A., Fleeman, R., Tawfik, R., Azhari, A., Souza, A., Vesely, B., Netherton, M., Gupta, R., and Colon, B. (2018). Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery. Mar. Drugs, 16.","DOI":"10.3390\/md16100376"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecu-lar Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/1439-7633(20020703)3:7<619::AID-CBIC619>3.0.CO;2-9","article-title":"Big effects from small changes: Possible ways to explore nature\u2019s chemical diversity","volume":"3","author":"Bode","year":"2002","journal-title":"ChemBioChem"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/bit.22925","article-title":"High-throughput screening of a small molecule library for promoters and inhibitors of mesenchymal stem cell osteogenic differentiation","volume":"108","author":"Brey","year":"2011","journal-title":"Biotechnol. Bioeng."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Alves, H., Dechering, K., Van Blitterswijk, C., and De Boer, J. (2011). High-throughput assay for the identification of compounds regu-lating osteogenic differentiation of human mesenchymal stromal cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026678"},{"key":"ref_45","unstructured":"Roberts, J.M., Murray, F., Anagnostou, E., Hennige, S., Gori, A., Henry, L.-A., Fox, A., Kamenos, N., and Foster, G.L. (2016). The Cnidaria, Past, Present and Future, Springer."},{"key":"ref_46","first-page":"4","article-title":"Ecological Role of Submarine Canyons and Need for Canyon Conservation: A Review","volume":"4","author":"Aguzzi","year":"2017","journal-title":"Front. Mar. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pocean.2017.12.010","article-title":"Bottom trawling at Whit-tard Canyon: Evidence for seabed modification, trawl plumes and food source heterogeneity","volume":"169","author":"Daly","year":"2018","journal-title":"Prog. Oceanogr."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/7\/390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:29:56Z","timestamp":1760164196000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/7\/390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,13]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["md19070390"],"URL":"https:\/\/doi.org\/10.3390\/md19070390","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,13]]}}}