Mesona chinensis Extract Ameliorates Retinal Angiopathy in a Zebrafish Model of Diabetic Retinopathy by Targeting Thymidylate Synthase in Folate Metabolism

Mesona chinensis Extract Ameliorates Retinal Angiopathy in a Zebrafish Model of Diabetic Retinopathy by Targeting Thymidylate Synthase in Folate Metabolism | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mesona chinensis Extract Ameliorates Retinal Angiopathy in a Zebrafish Model of Diabetic Retinopathy by Targeting Thymidylate Synthase in Folate Metabolism Shih-Wei Jao, Hsin-Hsuan Yu, Gang-Hui Lee, Ting-Wen Ma, Yi-Sheng Chang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8091004/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Retinal neovascularization in diabetic retinopathy (DR) is a major cause of vision loss. Folate-mediated one-carbon metabolism (OCM) is crucial for nucleotide synthesis and cell proliferation. We hypothesized that dysregulated OCM, particularly involving thymidylate synthase (TYMS), contributes to DR pathogenesis. Using a zebrafish DR model and human retinal endothelial cells, we assessed high glucose’s effects on retinal vessel development and TYMS expression. We measured changes in gene and protein expression of OCM enzymes (TYMS, DHFR, SHMT) via RT-PCR and Western blotting. TYMS overexpression (via tyms mRNA microinjection) increased DR angiogenesis severity. We evaluated the anti-angiogenic efficacy and safety of M. chinensis extract and one of its key compounds, quercetin, using vessel imaging, optomotor response assays, and developmental toxicity comparisons against 5-fluorouracil and methotrexate. High glucose upregulated TYMS expression at both mRNA and protein levels, driving retinal hyper-angiogenesis and visual impairment in DR zebrafish. The pro-angiogenic effects of TYMS are tissue-specific. M. chinensis and quercetin dose-dependently inhibited both pathological angiogenesis and glucose-induced TYMS expression. The anti-angiogenic effect of M. chinensis was found to be TYMS-dependent, as evidenced by its ability to reverse hyper-angiogenesis caused by TYMS overexpression. Crucially, M. chinensis exhibited minimal toxicity compared to conventional anti-folate drugs. TYMS, a key enzyme in folate-mediated OCM, contributes to the pathological retinal angiogenesis in zebrafish DR model. The natural extract M. chinensis represents a potent, and cost-effective intervention that can prevent glucose-induced retinal pathology by modulating TYMS activity, providing a safe and promising alternative for the prevention and management of DR. Angiogenesis Diabetic retinopathy Folate metabolism Mesona chinensis Thymidylate synthase Zebrafish Full Text Additional Declarations No competing interests reported. Supplementary Files MCBSupplementarymaterialFiguresTable.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8091004","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":550039793,"identity":"d061b6d6-e11e-45e4-ad80-d163a0665ad0","order_by":0,"name":"Shih-Wei Jao","email":"","orcid":"","institution":"National Cheng Kung University","correspondingAuthor":false,"prefix":"","firstName":"Shih-Wei","middleName":"","lastName":"Jao","suffix":""},{"id":550039794,"identity":"b9be4def-2127-4bdb-b7f6-8eb50d1d8fa5","order_by":1,"name":"Hsin-Hsuan Yu","email":"","orcid":"","institution":"National Cheng Kung 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Metabolism","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Angiogenesis, Diabetic retinopathy, Folate metabolism, Mesona chinensis, Thymidylate synthase, Zebrafish","lastPublishedDoi":"10.21203/rs.3.rs-8091004/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8091004/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRetinal neovascularization in diabetic retinopathy (DR) is a major cause of vision loss. Folate-mediated one-carbon metabolism (OCM) is crucial for nucleotide synthesis and cell proliferation. We hypothesized that dysregulated OCM, particularly involving thymidylate synthase (TYMS), contributes to DR pathogenesis. Using a zebrafish DR model and human retinal endothelial cells, we assessed high glucose\u0026rsquo;s effects on retinal vessel development and TYMS expression. We measured changes in gene and protein expression of OCM enzymes (TYMS, DHFR, SHMT) via RT-PCR and Western blotting. TYMS overexpression (via \u003cem\u003etyms\u003c/em\u003e mRNA microinjection) increased DR angiogenesis severity. We evaluated the anti-angiogenic efficacy and safety of \u003cem\u003eM. chinensis\u003c/em\u003e extract and one of its key compounds, quercetin, using vessel imaging, optomotor response assays, and developmental toxicity comparisons against 5-fluorouracil and methotrexate. High glucose upregulated TYMS expression at both mRNA and protein levels, driving retinal hyper-angiogenesis and visual impairment in DR zebrafish. The pro-angiogenic effects of TYMS are tissue-specific. \u003cem\u003eM. chinensis\u003c/em\u003e and quercetin dose-dependently inhibited both pathological angiogenesis and glucose-induced TYMS expression. The anti-angiogenic effect of \u003cem\u003eM. chinensis\u003c/em\u003e was found to be TYMS-dependent, as evidenced by its ability to reverse hyper-angiogenesis caused by TYMS overexpression. Crucially, \u003cem\u003eM. chinensis\u003c/em\u003e exhibited minimal toxicity compared to conventional anti-folate drugs. TYMS, a key enzyme in folate-mediated OCM, contributes to the pathological retinal angiogenesis in zebrafish DR model. The natural extract \u003cem\u003eM. chinensis\u003c/em\u003e represents a potent, and cost-effective intervention that can prevent glucose-induced retinal pathology by modulating TYMS activity, providing a safe and promising alternative for the prevention and management of DR.\u003c/p\u003e","manuscriptTitle":"Mesona chinensis Extract Ameliorates Retinal Angiopathy in a Zebrafish Model of Diabetic Retinopathy by Targeting Thymidylate Synthase in Folate Metabolism","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 18:51:38","doi":"10.21203/rs.3.rs-8091004/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e2e528d3-65e5-405d-bf94-18fed50a6d8c","owner":[],"postedDate":"November 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-04T16:08:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-26 18:51:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8091004","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8091004","identity":"rs-8091004","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}