{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:11:01Z","timestamp":1772169061417,"version":"3.50.1"},"reference-count":147,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["107475\/Z\/15\/Z"],"award-info":[{"award-number":["107475\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>\n                    <ns3:bold>Background<\/ns3:bold>\n                    :\n                    <ns3:italic>Schistosoma mansoni<\/ns3:italic>\n                    , a parasitic worm species responsible for the neglected tropical disease schistosomiasis, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic and epigenetic processes. As inhibition of\n                    <ns3:italic>S. mansoni<\/ns3:italic>\n                    epigenetic machinery components impairs key transitions throughout the parasite\u2019s digenetic lifecycle, a greater understanding of how epi-drugs affect molecular processes in schistosomes could lead to the development of new anthelmintics.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods:<\/ns3:bold>\n                    \u00a0\n                    <ns3:italic>In<\/ns3:italic>\n                    <ns3:italic>vitro<\/ns3:italic>\n                    whole organism assays were used to assess the anti-schistosomal activity of 39\n                    <ns3:italic>Homo sapiens<\/ns3:italic>\n                    Lysine Specific Demethylase 1 (HsLSD1) inhibitors on different parasite life cycle stages. Moreover, tissue-specific stains and genomic analysis shed light on the effect of these small molecules on the parasite biology.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results:<\/ns3:bold>\n                    Amongst this collection of small molecules, compound\n                    <ns3:bold>33<\/ns3:bold>\n                    was the most potent in reducing\n                    <ns3:italic>ex vivo<\/ns3:italic>\n                    viabilities of schistosomula, juveniles, miracidia and adults. At its sub-lethal concentration to adults (3.13 \u00b5M), compound\n                    <ns3:bold>33<\/ns3:bold>\n                    also significantly impacted oviposition, ovarian as well as vitellarian architecture and gonadal\/neoblast stem cell proliferation. ATAC-seq analysis of adults demonstrated that compound\n                    <ns3:bold>33<\/ns3:bold>\n                    significantly affected chromatin structure (intragenic regions &gt; intergenic regions), especially in genes differentially expressed in cell populations (e.g., germinal stem cells, hes2\n                    <ns3:italic>\n                      <ns3:sup>+<\/ns3:sup>\n                    <\/ns3:italic>\n                    stem cell progeny, S1 cells and late female germinal cells) associated with these\n                    <ns3:italic>ex vivo<\/ns3:italic>\n                    phenotypes. KEGG analyses further highlighted that chromatin structure of genes associated with sugar metabolism as well as TGF-beta and Wnt signalling were also significantly perturbed by compound\n                    <ns3:bold>33<\/ns3:bold>\n                    treatment.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions:<\/ns3:bold>\n                    This work confirms the importance of histone methylation in\n                    <ns3:italic>S. mansoni<\/ns3:italic>\n                    lifecycle transitions, suggesting that evaluation of LSD1 - targeting epi-drugs may facilitate the search for next-generation anti-schistosomal drugs. The ability of compound\n                    <ns3:bold>33<\/ns3:bold>\n                    to modulate chromatin structure as well as inhibit parasite survival, oviposition and stem cell proliferation warrants further investigations of this compound and its epigenetic target SmLSD1.\n                  <\/ns3:p>","DOI":"10.12688\/wellcomeopenres.18826.1","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T09:45:20Z","timestamp":1680169520000},"page":"146","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T10:45:43Z","timestamp":1690454743000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":147,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.18826.1","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.20872.r62557","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20872.r55971","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20872.r55971","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20872.r62556","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20872.r62557","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.20872.r55971, Philip T LoVerde, Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 06 Apr 2023, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1#referee-response-55971","order":0,"name":"referee-response-55971","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Gilda Padalino<\/b>; \n<i>Posted: 16 Jun 2023<\/i>; \n<b>We thank the reviewer very much for the detailed and constructive comments on our manuscript entitled: \u201c<\/b>\n<b>Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes<\/b>\n<b>\u201d<\/b>\n<b>, submitted to <i>Wellcome Open Research<\/i>. <\/b> &nbsp; \n<u>Reviewer question:<\/u> &nbsp; \n<u>To be extremely useful the drug should demonstrate pan-schistosomal cidal activity. Have the authors looked for similar lysine specific demethylases in other human schistosome species and determined their effectiveness?<\/u>&nbsp;We have explored the epigenetic enzymes involved in the methylation pathway in the other two major human infecting \n<i>Schistosome<\/i> species (\n<i>S. haematobium<\/i> and \n<i>S. japonicum<\/i> \u2013 data unpublished). Briefly, the 14 \n<i>S. mansoni<\/i> Histone Demethylases (SmHDMs) homologous sequences (presented in a previous publication doi: https:\/\/doi.org\/10.1016\/j.ijpddr.2018.10.005) were used to identify the most closely related HDM homologues in \n<i>S. haematobium<\/i> and \n<i>S. japonicum<\/i>, respectively (Sh\/SjHDMs). We used a BLASTp search within WormBase-Parasite using as threshold an E value of 1e\n<sup>-5<\/sup> or lower. As shown in \n<b>Figure 1<\/b>, we have identified at least a putative Lysine Specific Demethylase (LSD1) in \n<i>S. haematobium <\/i>(MS3 02208). Based on the stringent criteria set for this study, no close LSD1 homologue was identified in \n<i>S. japonicum<\/i>. We agree with the reviewer that exploring the biological role of this LSD1 homologue would be a valuable next step in progressing this epigenetic target (and its putative inhibitors), but we have yet to perform these experiments. However, the presence of homologous epigenetic enzymes in both \n<i>S. haematobium<\/i> and \n<i>S. japonicum<\/i> suggests the potential for developing a pan-schistosome drug capable of treating the three main species responsible for human schistosomiasis.&nbsp; FIGURE &nbsp; \n<b>Figure 1<\/b>. Schematic phylogeny of the HMTs and HDMs within the Schistosoma genus. Phylogenetic tree of \n<i>S. mansoni<\/i> HDMs and the closest S. haematobium or S. japonicum homologue is inferred from Maximum Likelihood analysis using MEGA. Bootstrap support values on the nodes range from 30-50 (highlighted with a circle), between 50 and 70 (highlighted with a square) and between 70 and 100 (highlighted with a star). Bootstrap support values below 30 are omitted. The phylogenetic tree is constructed with MEGA5 and the layout is modified with iTOL: Interactive Tree of Life (freely available on https:\/\/itol.embl.de\/upload.cgi). Smp xxxxxx, Sjp xxxxxxx and MS3 xxxxx (with x representing any number) indicate respectively \n<i>S. mansoni<\/i>, \n<i>S. japonicum<\/i> and \n<i>S. haematobium<\/i> proteins. &nbsp;  We would like to thank the reviewer and the editor very much for the detailed and very constructive comments.  Kind regards, Gilda Padalino (on behalf of the authors)","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1#referee-comment-5356","order":1,"name":"referee-comment-5356","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.20872.r62557, Giovina Ruberti, Institute of Biochemistry and Cell Biology, Italian National Research Council (IBBC-CNR), Rome, 27 Jul 2023, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-146\/v1#referee-response-62557","order":2,"name":"referee-response-62557","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [107475] assigned to KFH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}