{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:01:11Z","timestamp":1787724071363,"version":"build-2784847793"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY022618"],"award-info":[{"award-number":["EY022618"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY008126"],"award-info":[{"award-number":["EY008126"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>We previously demonstrated that the bile acid taurocholic acid (TCA) inhibits features of age-related macular degeneration (AMD) in vitro. The purpose of this study was to determine if the glycine-conjugated bile acids glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) can protect retinal pigment epithelial (RPE) cells against oxidative damage and inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in choroidal endothelial cells (CECs). Paraquat was used to induce oxidative stress and disrupt tight junctions in HRPEpiC primary human RPE cells. Tight junctions were assessed via transepithelial electrical resistance and ZO-1 immunofluorescence. GCA and GUDCA protected RPE tight junctions against oxidative damage at concentrations of 100\u2013500 \u00b5M, and GDCA protected tight junctions at 10\u2013500 \u00b5M. Angiogenesis was induced with VEGF in RF\/6A macaque CECs and evaluated with cell proliferation, cell migration, and tube formation assays. GCA inhibited VEGF-induced CEC migration at 50\u2013500 \u00b5M and tube formation at 10\u2013500 \u00b5M. GUDCA inhibited VEGF-induced CEC migration at 100\u2013500 \u00b5M and tube formation at 50\u2013500 \u00b5M. GDCA had no effect on VEGF-induced angiogenesis. None of the three bile acids significantly inhibited VEGF-induced CEC proliferation. These results suggest glycine-conjugated bile acids may be protective against both atrophic and neovascular AMD.<\/jats:p>","DOI":"10.3390\/biom11050626","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T12:08:30Z","timestamp":1619179710000},"page":"626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Glycine-Conjugated Bile Acids Protect RPE Tight Junctions against Oxidative Stress and Inhibit Choroidal Endothelial Cell Angiogenesis In Vitro"],"prefix":"10.3390","volume":"11","author":[{"given":"Cassandra","family":"Warden","sequence":"first","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Milam A.","family":"Brantley","sequence":"additional","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1194\/jlr.R900007-JLR200","article-title":"Bile Acids as Regulatory Molecules","volume":"50","author":"Hylemon","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_2","first-page":"1706","article-title":"Tool from Ancient Pharmacopoeia Prevents Vision Loss","volume":"12","author":"Boatright","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1167\/iovs.11-8544","article-title":"TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice","volume":"53","author":"Drack","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4998","DOI":"10.1167\/iovs.11-7496","article-title":"Tauroursodeoxycholic Acid Prevents Retinal Degeneration in Transgenic P23H Rats","volume":"52","author":"Lax","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/978-3-319-17121-0_57","article-title":"Tauroursodeoxycholic Acid Protects Retinal Function and Structure in Rd1 Mice","volume":"854","author":"Lawson","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1167\/iovs.07-1012","article-title":"Tauroursodeoxycholic Acid Preservation of Photoreceptor Structure and Function in the Rd10 Mouse through Postnatal Day 30","volume":"49","author":"Phillips","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/s41598-020-58039-x","article-title":"Ursodeoxycholic Acid Attenuates the Retinal Vascular Abnormalities in Anti-PDGFR-\u03b2 Antibody-Induced Pericyte Depletion Mouse Models","volume":"10","author":"Shiraya","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2337\/db18-0158","article-title":"Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in Db\/Db Mice","volume":"67","author":"Beli","year":"2018","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4189","DOI":"10.1096\/fj.201902496RR","article-title":"TGR5 Receptor Activation Attenuates Diabetic Retinopathy through Suppression of RhoA\/ROCK Signaling","volume":"34","author":"Zhu","year":"2020","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Alhasani, R.H., Almarhoun, M., Zhou, X., Reilly, J., Patterson, S., Zeng, Z., and Shu, X. (2020). Tauroursodeoxycholic Acid Protects Retinal Pigment Epithelial Cells from Oxidative Injury and Endoplasmic Reticulum Stress In Vitro. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090367"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jep.2016.03.026","article-title":"Protection of Tauroursodeoxycholic Acid on High Glucose-Induced Human Retinal Microvascular Endothelial Cells Dysfunction and Streptozotocin-Induced Diabetic Retinopathy Rats","volume":"185","author":"Wang","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1089\/jop.2010.0012","article-title":"Ursodeoxycholic Acid and Tauroursodeoxycholic Acid Suppress Choroidal Neovascularization in a Laser-Treated Rat Model","volume":"26","author":"Woo","year":"2010","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Osborn, M.P., Park, Y., Parks, M.B., Burgess, L.G., Uppal, K., Lee, K., Jones, D.P., and Brantley, M.A. (2013). Metabolome-Wide Association Study of Neovascular Age-Related Macular Degeneration. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072737"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4978","DOI":"10.1167\/iovs.18-25137","article-title":"The Carnitine Shuttle Pathway Is Altered in Patients With Neovascular Age-Related Macular Degeneration","volume":"59","author":"Mitchell","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107974","DOI":"10.1016\/j.exer.2020.107974","article-title":"Taurocholic Acid Inhibits Features of Age-Related Macular Degeneration in Vitro","volume":"193","author":"Warden","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/978-1-61779-191-8_12","article-title":"Measuring Permeability in Human Retinal Epithelial Cells (ARPE-19): Implications for the Study of Diabetic Retinopathy","volume":"763","author":"Villarroel","year":"2011","journal-title":"Methods Mol. Biol. Clifton NJ"},{"key":"ref_17","unstructured":"Justus, C.R., Leffler, N., Ruiz-Echevarria, M., and Yang, L.V. (2014). In Vitro Cell Migration and Invasion Assays. J. Vis. Exp. JoVE."},{"key":"ref_18","first-page":"610","article-title":"Review: The Bile Acids Urso- and Tauroursodeoxycholic Acid as Neuroprotective Therapies in Retinal Disease","volume":"25","author":"Daruich","year":"2019","journal-title":"Mol. Vis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3748\/wjg.15.1677","article-title":"Bile-Acid-Induced Cell Injury and Protection","volume":"15","author":"Perez","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"804","DOI":"10.3748\/wjg.15.804","article-title":"Bile Acids: Chemistry, Physiology, and Pathophysiology","volume":"15","author":"Monte","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/toxsci\/kfp223","article-title":"Differential Contribution of the Mitochondrial Respiratory Chain Complexes to Reactive Oxygen Species Production by Redox Cycling Agents Implicated in Parkinsonism","volume":"112","author":"Drechsel","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E393","DOI":"10.1002\/lary.27510","article-title":"ROS Is Involved in Disruption of Tight Junctions of Human Nasal Epithelial Cells Induced by HRV16","volume":"128","author":"Kim","year":"2018","journal-title":"Laryngoscope"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4555","DOI":"10.1167\/iovs.12-11572","article-title":"Disruption of Cell-Cell Junctions and Induction of Pathological Cytokines in the Retinal Pigment Epithelium of Light-Exposed Mice","volume":"54","author":"Narimatsu","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.etp.2015.09.010","article-title":"Paraquat Induce Pulmonary Epithelial\u2013Mesenchymal Transition through Transforming Growth Factor-\u03921-Dependent Mechanism","volume":"68","author":"Xie","year":"2016","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1111\/jcmm.12769","article-title":"HIF-1\u03b1 Regulates EMT via the Snail and \u0392-catenin Pathways in Paraquat Poisoning-induced Early Pulmonary Fibrosis","volume":"20","author":"Zhu","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e13294","DOI":"10.14814\/phy2.13294","article-title":"The Yin and Yang of Bile Acid Action on Tight Junctions in a Model Colonic Epithelium","volume":"5","author":"Sarathy","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1442-2050.2009.00993.x","article-title":"Protective Effects of Glycoursodeoxycholic Acid in Barrett\u2019s Esophagus Cells","volume":"23","author":"Goldman","year":"2010","journal-title":"Dis. Esophagus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1039\/C7MD00475C","article-title":"Deciphering the Role of Hydrophobic and Hydrophilic Bile Acids in Angiogenesis Using in Vitro and in Vivo Model Systems","volume":"8","author":"Kundu","year":"2017","journal-title":"MedChemComm"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/cphy.c120023","article-title":"Bile Acid Metabolism and Signaling","volume":"3","author":"Chiang","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Suga, T., Yamaguchi, H., Sato, T., Maekawa, M., Goto, J., and Mano, N. (2017). Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169719"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1158\/1535-7163.MCT-08-0539","article-title":"Profiling SLCO and SLC22 Genes in the NCI-60 Cancer Cell Lines to Identify Drug Uptake Transporters","volume":"7","author":"Okabe","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Daruich, A., Jaworski, T., Henry, H., Zola, M., Youale, J., Parenti, L., Naud, M.-C., Delaunay, K., Bertrand, M., and Berdugo, M. (2021). Oral Ursodeoxycholic Acid Crosses the Blood Retinal Barrier in Patients with Retinal Detachment and Protects Against Retinal Degeneration in an Ex Vivo Model. Neurother. J. Am. Soc. Exp. Neurother.","DOI":"10.1007\/s13311-021-01009-6"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/5\/626\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:41Z","timestamp":1760161901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/5\/626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,23]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["biom11050626"],"URL":"https:\/\/doi.org\/10.3390\/biom11050626","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,23]]}}}