{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:44:20Z","timestamp":1785818660809,"version":"3.56.0"},"reference-count":61,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Advanced age and diabetes mellitus (DM) are major risk factors for severe COVID\u201019, associated with acute respiratory distress syndrome (ARDS), cytokine storm, and increased mortality. SARS\u2010CoV\u20102 spike protein (SP) binding to angiotensin\u2010converting enzyme 2 (ACE2) potentially disrupts the renin\u2013angiotensin system (RAS), promoting angiotensin II (Ang II) accumulation and vascular dysfunction. In individuals with preexisting endothelial dysfunction (ED), such as older adults with type 2 DM (T2DM), COVID\u201019 may exacerbate inflammation, vascular permeability, and tissue damage. This study aimed to elucidate the mechanisms by which SP exacerbates diabetes\u2010associated ED using an in\u00a0vitro aortic endothelial\u2013bronchial epithelial co\u2010culture model. Serum from healthy adults and T2DM patients was used to stimulate human aortic endothelial cells (HAoECs), with or without SP. ED was assessed via reactive oxygen species (ROS), intercellular adhesion molecule\u20101 (ICAM\u20101) and vascular cell adhesion molecule\u20101 (VCAM\u20101), and endothelial permeability. ACE2 expression and Ang II levels were measured in ACE2\u2010transfected human bronchial epithelial cells (BEAS\u20102B\n                    <jats:sup>ACE2\u2010eGFP<\/jats:sup>\n                    ). Combined effects on lung injury and cytokines (CXCL8, IL\u20101\u03b2, and IL\u20106) were evaluated using a co\u2010culture system. T2DM serum significantly increased ROS (609.33\u2009\u00b1\u2009108.23%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0016), ICAM\u20101 and VCAM\u20101 expression (68.55\u2009\u00b1\u20095.47 copies\/\u03bcL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0011 and 84.77\u2009\u00b1\u20093.81 copies\/\u03bcL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001, respectively), and permeability (3.86\u2009\u00d7\u200910\n                    <jats:sup>7<\/jats:sup>\n                    \u2009\u00b1\u20094.8\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    FU;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0119) in HAoECs. In BEAS\u20102B\n                    <jats:sup>ACE2\u2010eGFP<\/jats:sup>\n                    , T2DM serum significantly increased ACE2 expression (5.45\u2009\u00b1\u20091.99 copies\/\u03bcL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0089), whereas co\u2010exposure to T2DM\u2009+\u2009SP markedly reduced ACE2 (0.97\u2009\u00b1\u20090.29 copies\/\u03bcL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0086) and elevated Ang II (111.60\u2009\u00b1\u200915.81\u2009pg.\/mL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.1343). Co\u2010treatment with T2DM\u2009+\u2009SP further exacerbated ED, driving heightened inflammation, lung epithelial injury, and cytokine release. Diabetes\u2010associated ED synergizes with SP to aggravate vascular inflammation and lung injury, identifying adhesion molecules and pro\u2010inflammatory cytokines as potential biomarkers, and RAS dysregulation and endothelial activation as therapeutic targets for severe COVID\u201019 in T2DM.\n                  <\/jats:p>","DOI":"10.1002\/jat.70380","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T03:54:56Z","timestamp":1785815696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SARS\u2010CoV\u20102 Spike Protein Exacerbates Endothelial Dysfunction and Promotes Lung Injury in Aging Type 2 Diabetes Mellitus Cell Culture Model"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5016-4762","authenticated-orcid":false,"given":"Nur Fatin Zalikha","family":"Zailan","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui Yee","family":"Chee","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-8832","authenticated-orcid":false,"given":"Eusni Rahayu Mohd","family":"Tohit","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2839-6273","authenticated-orcid":false,"given":"Maha","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6054-2368","authenticated-orcid":false,"given":"Syafinaz Amin","family":"Nordin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irmi Zarina","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5926-0737","authenticated-orcid":false,"given":"Masriana","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine and Health Sciences Universiti Putra Malaysia  Serdang Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2021.11.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933\u2010023\u201001965\u20107"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/life13071598"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13010029"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1167773"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11182912"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb45080420"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.808797"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010\u2010021\u201004200\u20107"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cegh.2022.101107"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010020\u20101051\u20109"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.36877\/pmmb.0000341"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2022.06.030"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25770"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcd.2021.04.004"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v11.i4.359"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2020.05.009"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753\u2010024\u201002208\u2010x"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(20)30183\u20105"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12121640"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010020\u201000454\u20107"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9060639"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.52403\/ijshr.20220738"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010022\u201001735\u2010y"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.68563"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot095497"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.649525"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2018.07.014"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2022.01.015"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/postgradmedj\u20102020\u2010139542"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10081306"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1089\/rej.2010.1054"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00794\u201021"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12985\u2010022\u201001814\u20101"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103344"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054\u2010020\u201003120\u20100"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201000907\u20101"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2020.108132"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252111411"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2021.06.027"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1810327"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms12040775"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.629933"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101695"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.09.009"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9091220"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1350"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43440\u2010021\u201000303\u20106"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/2045\u2010824X\u20104\u201018"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.833355"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20200922"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/hemato6010004"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.47836\/mjmhs.21.s12.2"},{"key":"e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P.Van Eeckhoutte et\u00a0al.2020. \u201cExpression of ACE2 the SARS\u2010CoV\u20102 Receptor in Lung Tissue of Patients with Type 2 Diabetes.\u201d69:2691\u20132699.https:\/\/doi.org\/10.2337\/db20\u20100669.","DOI":"10.2337\/db20-0669"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.3791\/3357"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.3390\/life13020539"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.772865"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401\u2010022\u201000998\u20100"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1359255"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/3918723"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.70380","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jat.70380","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.70380","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T03:54:59Z","timestamp":1785815699000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.70380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":61,"alternative-id":["10.1002\/jat.70380"],"URL":"https:\/\/doi.org\/10.1002\/jat.70380","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]},"assertion":[{"value":"2026-05-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"jat.70380"}}