Propolis regulates the p38 MAPK pathway and acts in synergy with curcumin

Propolis regulates the p38 MAPK pathway and acts in synergy with curcumin | 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 Article Propolis regulates the p38 MAPK pathway and acts in synergy with curcumin Yoshio Kano, Nobuaki Okumura, Hirotoshi Motoda, Mitsunobu Mio, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8909935/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 15 You are reading this latest preprint version Abstract Several natural products are beneficial for improving conditions in which neurogenesis is compromised. We found that the combined use of propolis and curcumin in PC12m321 cells resulted in synergistic neurogenesis. Propolis activates p38 MAPK, and curcumin activates both p38 MAPK and ERK. The increase in p38 MAPK activity that was observed when the amount of propolis or curcumin was individually increased followed a sigmoidal function, whereas the increase in p38 MAPK activity observed when propolis and curcumin were combined followed a Michaelis–Menten function. The TRPA1 receptor activated by the binding of artepillin C, which is the main component of propolis, activates the MKK/p38 MAPK pathway. We found that curcumin-activated ERK crosstalk with the p38 MAPK pathway converts the artepillin C-activated p38 MAPK behavior from a sigmoidal function to a Michaelis–Menten function, which may explain the synergistic neurogenesis induced by the combination of propolis and curcumin. Biological sciences/Cell biology Biological sciences/Drug discovery Biological sciences/Molecular biology Biological sciences/Neuroscience Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations No competing interests reported. Supplementary Files Suppl.KANOFig.1.pdf Suppl.KANOFig.2.pdf Suppl.KANOFig..pdf Suppl.KANOFig..pdf Suppl.KANOFig..pdf Suppl.KANOFig..pdf Suppl.KANOFig..pdf Suppl.KANOFig..pdf Suppl.KANOFig..pdf Suppl.KANOFig.10.pdf Suppl.KANOFig.11.pdf Suppl.KANOFig.12.pdf Suppl.KANOFig.13.pdf Suppl.KANOFig.14.pdf Suppl.KANOFig.15.pdf Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 11 May, 2026 Reviews received at journal 05 May, 2026 Reviews received at journal 02 May, 2026 Reviews received at journal 22 Apr, 2026 Reviewers agreed at journal 20 Apr, 2026 Reviewers agreed at journal 16 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviews received at journal 15 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers invited by journal 14 Apr, 2026 Editor assigned by journal 13 Apr, 2026 Editor invited by journal 12 Apr, 2026 Submission checks completed at journal 25 Mar, 2026 First submitted to journal 25 Mar, 2026 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. 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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-8909935","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":625947498,"identity":"69924d16-9b20-4ce6-a109-01122c0110b5","order_by":0,"name":"Yoshio Kano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYHACNoYEBhs7xmb2gw+APB4+IrWkJTO38yQbgLSwEaWFgeEwY3s/g5kEjIsXGBxvf/bgQQUzM28zQ1rl1xw7GTYG5oePbuDTcuaMuUHCGTY+yWbGY7dltyUDHcZmbJyDT8uNHDaJxDYeZkOgLbcltzEDtfCwSePXkv4MqEWCcf9hBrNiyW31xGhJMANqMWBsbGYwY/y47TBhLZJnzphJJJxJSGZs5kmWZtx2nIeNmYBf+IAhJvmj4r8dY//xgx9/bqu252dvfvgYnxaFA0gcZh4wiUc5CMg3IHEYfxBQPQpGwSgYBSMTAAAookXf6YM0JAAAAABJRU5ErkJggg==","orcid":"","institution":"Shujitsu University","correspondingAuthor":true,"prefix":"","firstName":"Yoshio","middleName":"","lastName":"Kano","suffix":""},{"id":625947504,"identity":"f2c761a0-5200-491d-8cba-3a99eaaa3036","order_by":1,"name":"Nobuaki Okumura","email":"","orcid":"","institution":"Yamada Bee Company, Inc","correspondingAuthor":false,"prefix":"","firstName":"Nobuaki","middleName":"","lastName":"Okumura","suffix":""},{"id":625947508,"identity":"addf6daa-f17d-4d5e-9f54-768dce689a07","order_by":2,"name":"Hirotoshi Motoda","email":"","orcid":"","institution":"Kibi International University","correspondingAuthor":false,"prefix":"","firstName":"Hirotoshi","middleName":"","lastName":"Motoda","suffix":""},{"id":625947509,"identity":"27bb0205-4810-496d-820d-281c733af593","order_by":3,"name":"Mitsunobu Mio","email":"","orcid":"","institution":"Shujitsu University","correspondingAuthor":false,"prefix":"","firstName":"Mitsunobu","middleName":"","lastName":"Mio","suffix":""},{"id":625947511,"identity":"8b512cf9-6de7-43cc-b899-98c81bbaf74b","order_by":4,"name":"Takashi Ito","email":"","orcid":"","institution":"Yamada Bee Company, Inc","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Ito","suffix":""},{"id":625947513,"identity":"d2c18915-d2c4-41ed-9278-3c9523151900","order_by":5,"name":"Yoshihisa Kitamura","email":"","orcid":"","institution":"Shujitsu University","correspondingAuthor":false,"prefix":"","firstName":"Yoshihisa","middleName":"","lastName":"Kitamura","suffix":""},{"id":625947516,"identity":"1f31c00b-925d-42a8-96d1-12611071365d","order_by":6,"name":"Shigeki Inoue","email":"","orcid":"","institution":"Kibi International University","correspondingAuthor":false,"prefix":"","firstName":"Shigeki","middleName":"","lastName":"Inoue","suffix":""},{"id":625947521,"identity":"5957e4ac-5b2a-4b59-8383-89d0e8d76b69","order_by":7,"name":"Soichiro Ushio","email":"","orcid":"","institution":"Fukuoka University","correspondingAuthor":false,"prefix":"","firstName":"Soichiro","middleName":"","lastName":"Ushio","suffix":""},{"id":625947527,"identity":"7f96715c-0642-4ae5-9785-6e0f66177fc1","order_by":8,"name":"Satoru Esumi","email":"","orcid":"","institution":"Okayama University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoru","middleName":"","lastName":"Esumi","suffix":""},{"id":625947529,"identity":"a6ce8d06-4ec2-4777-8380-b7a9105f8040","order_by":9,"name":"Ayanori Yamaki","email":"","orcid":"","institution":"Yamada Bee Company, Inc","correspondingAuthor":false,"prefix":"","firstName":"Ayanori","middleName":"","lastName":"Yamaki","suffix":""},{"id":625947531,"identity":"f999c1ae-cbe7-41e8-830a-a938f631b311","order_by":10,"name":"Yutaka Gomita","email":"","orcid":"","institution":"Okayama University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yutaka","middleName":"","lastName":"Gomita","suffix":""}],"badges":[],"createdAt":"2026-02-18 13:40:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8909935/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8909935/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107489637,"identity":"305d6b63-5d49-4447-9dd0-a87e713baf58","added_by":"auto","created_at":"2026-04-22 02:48:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99435,"visible":true,"origin":"","legend":"\u003cp\u003eDose-dependent neurite outgrowth induced by the combination of propolis and curcumin in PC12m321 cells and the effects of propolis and curcumin toxicity on PC12m321 cell survival. In the survival experiments, PC12m321 cells were treated with propolis (A) at various concentrations ranging from 40 to 250 μg/ml or curcumin (B) at various concentrations ranging from 6.7 to 18.6 μg/ml in the absence (○) or presence (●) of 1 μM SB203580. For the neurite outgrowth experiments, PC12m321 cells were treated with the indicated concentrations of propolis and curcumin, in combination. The frequency of neurite outgrowth in treated cells is shown as the relative frequency against the frequency of neurite outgrowth in nontreated control cells, with neurites set to 1. Each value is the mean ±s.e.m. for 600 (C) or 1200 (D) cells sampled from three (C) or six (D) independent experiments. *P \u0026lt; 0.05 and **P \u0026lt; 0.01 indicate significant differences (C, D).\u003c/p\u003e","description":"","filename":"KANOFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-8909935/v1/e1d9b89f6255cdf513eba92a.png"},{"id":108180890,"identity":"be6d3ce0-61eb-49df-bc90-ada50d1bf487","added_by":"auto","created_at":"2026-04-30 08:54:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":487827,"visible":true,"origin":"","legend":"\u003cp\u003eDose-dependent neurite outgrowth induced by the combination of propolis and curcumin in PC12m321 cells. PC12m321 cells were treated with the indicated concentrations of propolis and curcumin, in combination. Phase-contrast photomicrographs of treated cells were taken six days after treatment (× 200).\u003c/p\u003e","description":"","filename":"KANOFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-8909935/v1/348f4d9425c74b368a78b0ee.png"},{"id":107414281,"identity":"0d2530af-d765-48a8-9a7a-c74840389867","added_by":"auto","created_at":"2026-04-21 09:37:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86216,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of ERK inhibitor U0126, TRPAR inhibitor HC-030031, and p38 MAPK inhibitor SB203580 on neurite outgrowth induced by propolis or curcumin alone and in combination in PC12m321 cells. To investigate the effects of various inhibitors on propolis and curcumin alone, PC12m321 cells were treated (+) or not treated (-) with propolis or curcumin in the presence (+) or absence (-) of U0126, HC-030031 (A), and SB203580 (B) at the indicated concentrations. The frequency of neurite outgrowth in treated cells is shown as the relative frequency against the frequency of neurite outgrowth in nontreated control cells, with neurites set to 1. Each value is the mean ±s.e.m. for 600 cells sampled from three independent experiments. *1 indicates P \u0026lt; 0.05 vs. 20 μg/ml propolis, and *2 and *3 indicate P \u0026lt; 0.05 vs. 2 μg/ml curcumin (A). *1 indicates P \u0026lt; 0.05 vs. 20 μg/ml propolis and **2 indicates P \u0026lt; 0.01 vs. 2 μg/ml curcumin (B). To investigate the effects of various inhibitors on the combination of propolis and curcumin, PC12m321 cells were treated with the combination of propolis and curcumin in the presence or absence (-) of U0126 (C) and SB203580 (D) at the indicated concentrations. The frequency of neurite outgrowth in treated cells is shown as the relative frequency against the frequency of neurite outgrowth in nontreated control cells, with neurites set to 1. Each value is the mean ±s.e.m. for 600 cells sampled from three independent experiments. **1 28 indicates P \u0026lt; 0.05 vs. 6.7 μg/ml propolis + 0.67 μg/ml curcumin, *2 indicates P \u0026lt; 0.05 vs. 13.4 μg/ml propolis + 1.34 μg/ml curcumin, and **3 indicates P \u0026lt; 0.05 vs. 20 μg/ml propolis + 2.0 μg/ml curcumin (C, D).\u003c/p\u003e","description":"","filename":"KANOFig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-8909935/v1/d3ca6a008fd80a1400630c7a.png"},{"id":107486310,"identity":"3cea38fe-c1c3-492f-8dfc-efa506635a6e","added_by":"auto","created_at":"2026-04-22 02:38:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":208627,"visible":true,"origin":"","legend":"\u003cp\u003eDose-dependent activation of p38 MAPK and ERK induced by propolis or curcumin and their combination in PC12m321 cells. PC12m321 cells were serum-starved and treated for 30 min with propolis or curcumin and their combination at the indicated concentrations. After treatment, cells were lysed, and protein extracts were analyzed by western blotting with an anti-phospho-p38 MAPK antibody (A, B, C) or an anti-phospho-ERK 1/2 antibody (B, C). The levels of activated p38 MAPK and ERK were quantified by densitometric scanning (B, C). Each value represents the mean with S.D. of three independent experiments. * indicates P \u0026lt; 0.05 vs. 4 μg/ml curcumin, and ** indicates P \u0026lt; 0.01 vs. 4 μg/ml curcumin (C). (D) Based on the data in A, B, and C, curve-fitting software was used to generate a graph showing the concentration-dependent changes in p38 MAPK activity for propolis and curcumin. The density of the bands, which indicates the degree of p38 MAPK phosphorylation by each component, was measured with the untreated value set at 1 to calculate how many times higher the concentration of each component was. The increase in p38 MAPK phosphorylation when the amount of propolis or curcumin was individually increased showed a sigmoidal curve, whereas the increase in p38 MAPK phosphorylation when propolis and curcumin were combined showed a Michaelis–Menten curve. *1 indicates P \u0026lt; 0.05 vs. 50 μg/ml propolis, *2 indicates P \u0026lt; 0.05 vs. 75 μg/ml propolis, and *3 indicates P \u0026lt; 0.05 vs. 100 μg/ml propolis.\u003c/p\u003e","description":"","filename":"KANOFig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-8909935/v1/7cfafa52076cc4a42809621d.png"},{"id":107414284,"identity":"898c3e7d-caea-4586-a1a2-45b981836071","added_by":"auto","created_at":"2026-04-21 09:37:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":242443,"visible":true,"origin":"","legend":"\u003cp\u003e(A) The binding of p38 MAPK to the MKK4 binding site through the addition of propolis is facilitated by the preferential binding of curcumin-activated ERK to MKK4. PCm321 cells were serum-starved and treated for 30 min with propolis or the combination of propolis and curcumin at the indicated concentrations. After treatment, lysates were subjected to immunoprecipitation with an anti-MKK4 antibody. The binding of p38 MAPK to MKK4 and of ERK to MKK4 was detected by western blot analysis with a p38 MAPK antibody and an ERK antibody. Data are shown as the mean ± s.e.m. ** indicates P \u0026lt; 0.01 vs. 100 μg/ml propolis. (B) Regulation of p38 MAPK activity by MKK4. When the artepillin C contained in propolis binds to the TRPA1 receptor, MKK4 activates p38 MAPK through phosphorylation. MKK4 has an allosteric site and a substrate-binding site, and when p38 MAPK binds to the substrate-binding site, it is phosphorylated, but when it binds to the allosteric site, it is not phosphorylated. When there is only a small amount of propolis, there is little activation of MKK4, and p38 MAPK preferentially binds to the allosteric site of MKK4, so p38 MAPK is not activated (a). When the amount of propolis increases, the amount of activated MKK4 also increases, and p38 MAPK binds to the substrate-binding site of MKK4, activating p38 MAPK (b). When there is only a small amount of propolis, ERK binds only to the allosteric site of MKK4, inhibiting the activity of the allosteric site, which allows p38 MAPK to bind to the substrate-binding site of MKK4, activating p38 MAPK (c: our speculation based on the data in A). This may explain why the combined use of propolis and curcumin converts p38 MAPK activity from a sigmoidal function to a Michaelis–Menten function.\u003c/p\u003e","description":"","filename":"KANOFig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-8909935/v1/773917fe62d232df2751ccb1.png"},{"id":108183469,"identity":"bd7653c3-a5c2-460d-97b2-46eeeabee8af","added_by":"auto","created_at":"2026-04-30 09:01:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":528890,"visible":true,"origin":"","legend":"","description":"","filename":"procur31.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8909935/v1_covered_cf45cab3-2f0a-4982-ad57-7c335a4c8f73.pdf"},{"id":107414278,"identity":"d60d0628-9ddc-49a1-a86f-753e6f7a99c6","added_by":"auto","created_at":"2026-04-21 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curcumin\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8909935/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8909935/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Several natural products are beneficial for improving conditions in which neurogenesis is compromised. We found that the combined use of propolis and curcumin in PC12m321 cells resulted in synergistic neurogenesis. Propolis activates p38 MAPK, and curcumin activates both p38 MAPK and ERK. The increase in p38 MAPK activity that was observed when the amount of propolis or curcumin was individually increased followed a sigmoidal function, whereas the increase in p38 MAPK activity observed when propolis and curcumin were combined followed a Michaelis–Menten function. The TRPA1 receptor activated by the binding of artepillin C, which is the main component of propolis, activates the MKK/p38 MAPK pathway. We found that curcumin-activated ERK crosstalk with the p38 MAPK pathway converts the artepillin C-activated p38 MAPK behavior from a sigmoidal function to a Michaelis–Menten function, which may explain the synergistic neurogenesis induced by the combination of propolis and curcumin.","manuscriptTitle":"Propolis regulates the p38 MAPK pathway and acts in synergy with curcumin","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 09:37:00","doi":"10.21203/rs.3.rs-8909935/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-12T03:29:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T12:40:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T10:32:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T07:21:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3112617531254432901864388517429311896","date":"2026-04-20T04:06:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227516588940712657952780254293148557157","date":"2026-04-16T04:05:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160877315208145980606339477616746029611","date":"2026-04-15T23:22:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-15T08:54:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139297900875316147045363365570228341671","date":"2026-04-15T08:12:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194102314793399372844197714748721775479","date":"2026-04-15T04:51:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-14T17:36:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-13T20:53:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-12T20:42:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-25T13:12:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-25T13:10:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"642b88d4-6b93-4fd4-bcec-30c9d934f38c","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-12T03:29:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T12:40:36+00:00","index":51,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T10:32:37+00:00","index":50,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":66716689,"name":"Biological sciences/Cell biology"},{"id":66716690,"name":"Biological sciences/Drug discovery"},{"id":66716691,"name":"Biological sciences/Molecular biology"},{"id":66716692,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-12T03:40:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 09:37:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8909935","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8909935","identity":"rs-8909935","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}