{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:22:52Z","timestamp":1791001372934,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020","award":["765704"],"award-info":[{"award-number":["765704"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Neurodegenerative diseases are incurable and debilitating conditions, characterized by progressive loss and degeneration of vulnerable neuronal populations. Currently, there are no effective therapies available for the treatment of most neurodegenerative disorders. A panel of extracts exhibiting interesting chemical profiles among a high number of bacterial strains isolated from East Mediterranean marine sediments and macroorganisms were evaluated for their activity on TrkB-expressing cells. Among them, the actinobacterial strain Streptomyces sp. BI0788, exhibiting neuroprotective activity in vitro, was selected and cultivated in large-scale. The chemical analysis of its organic extract resulted in the isolation of four new butanolides (1, 4\u20136), along with two previously reported butanolides (2 and 3) and eight previously reported butenolides (7\u201314). Compounds 2\u20134 and 7\u201314 were evaluated for their neuroprotective effects on TrkB-expressing NIH-3T3 cells. Among them, metabolites 3, 4, 7, 10, 11, 13 and 14 exhibited significant protective activity on the aforementioned cells through the activation of TrkB, the high-affinity receptor for the Brain-Derived Neurotrophic Factor (BDNF), which is well known to play a crucial role in neuronal cell survival and maintenance.<\/jats:p>","DOI":"10.3390\/md21090465","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T08:42:20Z","timestamp":1692952940000},"page":"465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Butanolides and Butenolides from a Marine-Derived Streptomyces sp. Exert Neuroprotective Activity through Activation of the TrkB Neurotrophin Receptor"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3314-9990","authenticated-orcid":false,"given":"Paolo","family":"Giaccio","sequence":"first","affiliation":[{"name":"Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Despoina","family":"Charou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Crete, 71003 Heraklion, Greece"},{"name":"Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology-Hellas (IMBB-FORTH), 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafni-Ioanna","family":"Diakaki","sequence":"additional","affiliation":[{"name":"Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chita","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Crete, 71003 Heraklion, Greece"},{"name":"Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology-Hellas (IMBB-FORTH), 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achille","family":"Gravanis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Crete, 71003 Heraklion, Greece"},{"name":"Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology-Hellas (IMBB-FORTH), 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3415-7332","authenticated-orcid":false,"given":"Ioannis","family":"Charalampopoulos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Crete, 71003 Heraklion, Greece"},{"name":"Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology-Hellas (IMBB-FORTH), 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9856-4725","authenticated-orcid":false,"given":"Vassilios","family":"Roussis","sequence":"additional","affiliation":[{"name":"Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-4951","authenticated-orcid":false,"given":"Efstathia","family":"Ioannou","sequence":"additional","affiliation":[{"name":"Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bowerman, M. (2020). Recent advances and future perspectives in the development of therapeutic approaches for neurodegenerative diseases. Brain Sci., 10.","DOI":"10.3390\/brainsci10090633"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Barbe, C., Jolly, D., Morrone, I., Wolak-Thierry, A., Dram\u00e9, M., Novella, J.-L., and Mahmoudi, R. (2018). Factors associated with quality of life in patients with Alzheimer\u2019s disease. BMC Geriatr., 18.","DOI":"10.1186\/s12877-018-0855-7"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"693","DOI":"10.2165\/00002512-200623090-00001","article-title":"A review of the health-related quality of life and economic impact of Parkinson\u2019s disease","volume":"23","author":"Dowding","year":"2006","journal-title":"Drugs Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e551","DOI":"10.1016\/S2468-2667(20)30190-0","article-title":"The burden of neurological diseases in Europe: An analysis for the Global Burden of Disease Study 2017","volume":"5","author":"Deuschl","year":"2020","journal-title":"Lancet Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nrd3366","article-title":"Potential therapeutic uses of BDNF in neurological and psychiatric disorders","volume":"10","author":"Nagahara","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nrn3379","article-title":"Neurotrophin regulation of neural circuit development and function","volume":"14","author":"Park","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10482-004-6540-1","article-title":"Marine actinomycete diversity and natural product discovery","volume":"87","author":"Jensen","year":"2005","journal-title":"Antonie Leeuwenhoek"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1039\/C0NP90032J","article-title":"A sea of biosynthesis: Marine natural products meet the molecular age","volume":"28","author":"Lane","year":"2011","journal-title":"Nat. Prod. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jbiotec.2011.06.002","article-title":"Marine actinomycetes as an emerging resource for the drug development pipelines","volume":"158","author":"Zotchev","year":"2012","journal-title":"J. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Elmallah, M.I.Y., Cogo, S., Costantinescu, A.A., Elifio-Esposito, S., Abdelfattah, M.S., and Micheau, O. (2020). Marine actinomycetes-derived secondary metabolites overcome TRAIL-resistance via the intrinsic pathway through downregulation of survivin and XIAP. Cells, 9.","DOI":"10.3390\/cells9081760"},{"key":"ref_11","first-page":"267","article-title":"Pharmaceutically active secondary metabolites of marine actinobacteria","volume":"169","author":"Manivasagana","year":"2014","journal-title":"Microbiol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.etap.2014.05.014","article-title":"Marine actinobacteria: An important source of bioactive natural products","volume":"38","author":"Manivasagan","year":"2014","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Subramani, R., and Sipkema, D. (2019). Marine rare actinomycetes: A promising source of structurally diverse and unique novel natural products. Mar. Drugs, 17.","DOI":"10.3390\/md17050249"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1021\/jo00063a008","article-title":"Highly diastereoselective aldol reactions of cobalt-complexed and uncomplexed propynals with an O-silyl ketene O,S-acetal: Highly stereoselective total syntheses of (\u00b1)-blastmycinone and its three diastereoisomers from 3-(trimethylsilyl)propynal","volume":"58","author":"Mukai","year":"1993","journal-title":"J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7201","DOI":"10.1021\/jo00103a008","article-title":"New synthesis of all four isomers of 3-hydroxy-4-methyl-\u03b3-butyrolactone by stereoselective intramolecular lactonization. Application to asymmetric synthesis of biologically active compounds","volume":"59","author":"Takahata","year":"1994","journal-title":"J. Org. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1021\/np000599g","article-title":"New lactone-containing metabolites from a marine-derived bacterium of the genus Streptomyces","volume":"64","author":"Cho","year":"2001","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"724","DOI":"10.7164\/antibiotics.24.724","article-title":"Total synthesis of antimycin A3","volume":"24","author":"Kinoshita","year":"1971","journal-title":"J. Antibiot."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"373","DOI":"10.7164\/antibiotics.25.373","article-title":"absolute configurations of antimycin lactones and antimycin A","volume":"25","author":"Kinoshita","year":"1972","journal-title":"J. Antibiot."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"799","DOI":"10.3390\/md12020799","article-title":"Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria","volume":"12","author":"Strand","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_20","first-page":"254","article-title":"Studies on the chemical structure of blastmycin","volume":"11","author":"Yonehara","year":"1958","journal-title":"J. Antibiot."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1080\/14786419.2019.1686368","article-title":"Octyl substituted butenolides from marine-derived Streptomyces koyangensis","volume":"35","author":"Huang","year":"2021","journal-title":"Nat. Prod. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10600-015-1319-3","article-title":"A new furanone isolated from a marine-derived actinomycete M159","volume":"51","author":"Guo","year":"2015","journal-title":"Chem. Nat. Comp."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3389\/fphar.2016.00512","article-title":"BNN27, a 17-spiroepoxy steroid derivative, interacts with and activates p75 neurotrophin receptor, rescuing cerebellar granule neurons from apoptosis","volume":"7","author":"Pediaditakis","year":"2016","journal-title":"Front. Pharmacol."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/21\/9\/465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:38:46Z","timestamp":1760128726000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/21\/9\/465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":23,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["md21090465"],"URL":"https:\/\/doi.org\/10.3390\/md21090465","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,25]]}}}