{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T23:05:31Z","timestamp":1772233531609,"version":"3.50.1"},"reference-count":33,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["1R21EY034634-01A1"],"award-info":[{"award-number":["1R21EY034634-01A1"]}]},{"name":"Research to Prevent Blindness (RPB) New Chair Challenge Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Aberrant wound healing in the retina can manifest as proliferative vitreoretinopathy (PVR), which involves the myofibroblast transdifferentiation of retinal pigment epithelial (RPE) cells. In this study, experiments were conducted to examine the structure\u2013activity relationships of endocannabinoid-like compounds, N-acyl dopamines, on the myofibroblast transdifferentiation of RPE cells. The collagen matrix contraction assay was used to assess myofibroblast function. Western blot analysis and immunocytochemistry techniques were used to evaluate myofibroblast markers. N-palmitoyl dopamine (PALDA), N-oleoyl dopamine (OLDA), and N-arachidonoyl dopamine (NADA), in a concentration-dependent manner, inhibited contraction of collagen matrices mediated by either primary porcine RPE cells treated with TGF-\u03b22, or human RPE cells treated with TGF-\u03b22 plus TNF\u03b1 (TNT). The rank order of potency was PLDA = OLDA &gt; NADA. In contrast, the substitution of dopamine with other polar head groups led to a complete loss of their ability to inhibit myofibroblast transdifferentiation. Western blot analysis demonstrated that PALDA, OLDA, and NADA down-regulated the myofibroblast markers fibronectin and \u03b1-SMA. Immunocytochemistry experiments showed that these N-acyl dopamines reduced the incorporation of \u03b1-SMA into F-actin stress fibers. Overall, these structure\u2013activity relationship studies demonstrate that the dopamine head group is crucial for N-acyl dopamine to inhibit myofibroblast transdifferentiation of RPE cell, whereas the fatty acid side chain determines the potency of it. This study points to the potential of N-acyl dopamines as a novel class of therapeutic agents for treating retinal fibrotic conditions, such as PVR.<\/jats:p>","DOI":"10.3390\/biom15111526","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"1526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structure\u2013Activity Relationships of N-Acyl Dopamines in Inhibiting Myofibroblast Transdifferentiation of Retinal Pigment Epithelial Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Dandan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"},{"name":"Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40292, USA"},{"name":"Eye Hospital of China Academy of Chinese Medical Sciences, Beijing 100040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishaka","family":"Motheramgari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riley","family":"Freudenberger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah H.","family":"Shrader","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy J.","family":"Sloan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-3370","authenticated-orcid":false,"given":"Zoe","family":"Lung","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0840-5574","authenticated-orcid":false,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeo","family":"Tamiya","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao-Hui","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ku, J.C., Raiten, J., and Li, Y. (2024). Understanding fibrosis: Mechanisms, clinical implications, current therapies, and prospects for future interventions. Biomed. Eng. Adv., 7.","DOI":"10.1016\/j.bea.2024.100118"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0074-7696(07)57004-X","article-title":"Fibroblast differentiation in wound healing and fibrosis","volume":"257","author":"Darby","year":"2007","journal-title":"Int. Rev. Cytol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/IIO.0000000000000258","article-title":"Proliferative Vitreoretinopathy: A Review","volume":"59","author":"Idrees","year":"2019","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/s00417-023-06264-1","article-title":"Proliferative vitreoretinopathy: An update on the current and emerging treatment options","volume":"262","author":"Artemiev","year":"2024","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/ICU.0000000000001119","article-title":"Recent advances in pharmacological treatments of proliferative vitreoretinopathy","volume":"36","author":"Kim","year":"2025","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.exer.2015.02.008","article-title":"Role of epithelial-mesenchymal transition in proliferative vitreoretinopathy","volume":"142","author":"Tamiya","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"263","DOI":"10.21037\/atm.2020.03.86","article-title":"RPE epithelial-mesenchymal transition plays a critical role in the pathogenesis of proliferative vitreoretinopathy","volume":"8","author":"Li","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33594\/000000371","article-title":"Cannabidiol Signaling in the Eye and Its Potential as an Ocular Therapeutic Agent","volume":"55","author":"Aebersold","year":"2021","journal-title":"Cell Physiol. Biochem."},{"key":"ref_9","first-page":"607","article-title":"Review of the Endocannabinoid System","volume":"6","author":"Lu","year":"2021","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Di Marzo, V. (2011). Endocannabinoid System. eLS, Elsevier.","DOI":"10.1002\/9780470015902.a0023403"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.bbrc.2019.12.004","article-title":"Discovery of endogenous inverse agonists for G protein-coupled receptor 6","volume":"522","author":"Shrader","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1111\/j.1476-5381.2010.00862.x","article-title":"N-acyl amino acids and N-acyl neurotransmitter conjugates: Neuromodulators and probes for new drug targets","volume":"160","author":"Connor","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","unstructured":"Akimov, M., and Bezuglov, V. (2012). N-Acylated Dopamines: A New Life for the Old Dopamine. Dopamine: Functions, Regulation and Health Effects, Nova Science Publishers."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.bbrc.2023.05.040","article-title":"Effect of N-oleoyl dopamine on myofibroblast trans-differentiation of retinal pigment epithelial cells","volume":"667","author":"Sloan","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.ajpath.2014.01.022","article-title":"Role of retinal pigment epithelial cell \u03b2-catenin signaling in experimental proliferative vitreoretinopathy","volume":"184","author":"Umazume","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.stemcr.2020.03.009","article-title":"Epigenomic and Transcriptomic Changes During Human RPE EMT in a Stem Cell Model of Epiretinal Membrane Pathogenesis and Prevention by Nicotinamide","volume":"14","author":"Boles","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1007\/s00417-020-05037-4","article-title":"Sustained dasatinib treatment prevents early fibrotic changes following ocular trauma","volume":"259","author":"Ueda","year":"2021","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4910","DOI":"10.1167\/iovs.12-9768","article-title":"Proliferative vitreoretinopathy in the Swine-a new model","volume":"53","author":"Umazume","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1167\/iovs.12-10418","article-title":"Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine","volume":"54","author":"Umazume","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/sj.eye.6700194","article-title":"Proliferative vitreoretinopathy-developments in adjunctive treatment and retinal pathology","volume":"16","author":"Charteris","year":"2002","journal-title":"Eye"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13633","DOI":"10.1074\/jbc.M211231200","article-title":"N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia","volume":"278","author":"Chu","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0960-894X(00)00689-2","article-title":"Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine","volume":"11","author":"Bezuglov","year":"2001","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/sj.bjp.0705924","article-title":"Actions of two naturally occurring saturated N-acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels","volume":"143","author":"Chu","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8400","DOI":"10.1073\/pnas.122196999","article-title":"An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors","volume":"99","author":"Huang","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/sj.bjp.0706093","article-title":"The expanding field of cannabimimetic and related lipid mediators","volume":"144","author":"Bradshaw","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1111\/bph.15010","article-title":"The peripheral CB(1) receptor antagonist JD5037 attenuates liver fibrosis via a CB(1) receptor\/beta-arrestin1\/Akt pathway","volume":"177","author":"Tan","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nm1421","article-title":"CB1 cannabinoid receptor antagonism: A new strategy for the treatment of liver fibrosis","volume":"12","author":"Julien","year":"2006","journal-title":"Nat. Med."},{"key":"ref_28","first-page":"1243","article-title":"Presence and regulation of cannabinoid receptors in human retinal pigment epithelial cells","volume":"15","author":"Wei","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_29","first-page":"357","article-title":"Cannabinoid receptor 1 blockade protects human retinal pigment epithelial cells from oxidative injury","volume":"19","author":"Wei","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"517","DOI":"10.3390\/cells3020517","article-title":"TRPV1: A Potential Drug Target for Treating Various Diseases","volume":"3","author":"Brito","year":"2014","journal-title":"Cells"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ben\u00edtez-Angeles, M., Morales-L\u00e1zaro, S.L., Ju\u00e1rez-Gonz\u00e1lez, E., and Rosenbaum, T. (2020). TRPV1: Structure, Endogenous Agonists, and Mechanisms. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103421"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Peng, G., Tang, X., Gui, Y., Yang, J., Ye, L., Wu, L., Ding, Y.h., and Wang, L. (2022). Transient receptor potential vanilloid subtype 1: A potential therapeutic target for fibrotic diseases. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.951980"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101114","DOI":"10.1016\/j.preteyeres.2022.101114","article-title":"Retinal TRP channels: Cell-type-specific regulators of retinal homeostasis and multimodal integration","volume":"92","author":"Cordeiro","year":"2023","journal-title":"Prog. Retin. Eye Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1526\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:56:27Z","timestamp":1761875787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":33,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111526"],"URL":"https:\/\/doi.org\/10.3390\/biom15111526","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]}}}