{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:02Z","timestamp":1787028542836,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Korean government (MEST)","doi-asserted-by":"publisher","award":["2021R1I1A1A0104231611"],"award-info":[{"award-number":["2021R1I1A1A0104231611"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MEST)","doi-asserted-by":"publisher","award":["2022R1A2B5B01001861"],"award-info":[{"award-number":["2022R1A2B5B01001861"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MEST)","doi-asserted-by":"publisher","award":["2022R1I1A1A01067661"],"award-info":[{"award-number":["2022R1I1A1A01067661"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MEST)","doi-asserted-by":"publisher","award":["2021R1A6A1A03044501"],"award-info":[{"award-number":["2021R1A6A1A03044501"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2021R1I1A1A0104231611"],"award-info":[{"award-number":["2021R1I1A1A0104231611"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2022R1A2B5B01001861"],"award-info":[{"award-number":["2022R1A2B5B01001861"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2022R1I1A1A01067661"],"award-info":[{"award-number":["2022R1I1A1A01067661"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2021R1A6A1A03044501"],"award-info":[{"award-number":["2021R1A6A1A03044501"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Loss of the inner blood\u2013retinal barrier (BRB) integrity is a main feature of ocular diseases such as diabetic macular edema. However, there is a lack of clarity on how inner BRB function is modulated within the diabetic retina. The current study examined whether eucalyptol inhibited inner BRB destruction and aberrant retinal angiogenesis in 33 mM glucose-exposed human retinal microvascular endothelial (RVE) cells and db\/db mice. This study further examined the molecular mechanisms underlying endothelial dysfunction including retinal endoplasmic reticulum (ER) stress and angiopoietin (Ang)\/Tie axis in conjunction with vascular endothelial growth factor (VEGF). Eucalyptol is a naturally occurring monoterpenoid and an achiral aromatic component of many plants including eucalyptus leaves. Nontoxic eucalyptol reduced the production of amyloid-\u03b2 (A\u03b2) protein in glucose-loaded RVE cells and in diabetic mice. This natural compound blocked apoptosis of A\u03b2-exposed RVE cells in diabetic mouse eyes by targeting ER stress via the inhibition of PERK-eIF2\u03b1-ATF4-CHOP signaling. Eucalyptol promoted activation of the Ang-1\/Tie-2 pathway and dual inhibition of Ang-2\/VEGF in A\u03b2-exposed RVE cells and in diabetic eyes. Supply of eucalyptol reversed the induction of junction proteins in glucose\/A\u03b2-exposed RVE cells within the retina and reduced permeability. In addition, oral administration of eucalyptol reduced vascular leaks in diabetic retinal vessels. Taken together, these findings clearly show that eucalyptol inhibits glucose-induced A\u03b2-mediated ER stress and manipulates Ang signaling in diabetic retinal vessels, which ultimately blocks abnormal angiogenesis and loss of inner BRB integrity. Therefore, eucalyptol provides new treatment strategies for diabetes-associated RVE defects through modulating diverse therapeutic targets including ER stress, Ang-1\/Tie-2 signaling, and Ang-2\/VEGF.<\/jats:p>","DOI":"10.3390\/ijms25147826","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T16:35:58Z","timestamp":1721234158000},"page":"7826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Eucalyptol Ameliorates Retinal Microvascular Defects through Modulating ER Stress and Angiopoietin\u2013Tie Signaling in Diabetic Eyes"],"prefix":"10.3390","volume":"25","author":[{"given":"Dong Yeon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Food and Nutrition, Andong National University, Andong 36729, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-185X","authenticated-orcid":false,"given":"Sin-Hye","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaee","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition, Andong National University, Andong 36729, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition, Andong National University, Andong 36729, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Kyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition, Andong National University, Andong 36729, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2039-7968","authenticated-orcid":false,"given":"Young-Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.preteyeres.2012.08.004","article-title":"Role of the retinal vascular endothelial cell in ocular disease","volume":"32","author":"Bharadwaj","year":"2013","journal-title":"Prog. 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