{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:57:38Z","timestamp":1787500658331,"version":"build-2736575974"},"reference-count":30,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T00:00:00Z","timestamp":1591660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T00:00:00Z","timestamp":1591660800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:p>\n                    Human lungs single-cell RNA sequencing data from healthy donors (elderly and young; GEO accession no. GSE122960) were analyzed to isolate and specifically study gene expression in alveolar type II cells. Colocalization of angiotensin-converting enzyme 2 (\n                    <jats:italic toggle=\"yes\">ACE2<\/jats:italic>\n                    ) and\n                    <jats:italic toggle=\"yes\">TMPRSS2<\/jats:italic>\n                    enables severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) to enter the cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable and, therefore, do not seem to be responsible for worse outcomes observed in coronavirus disease 2019 (COVID-19) affected elderly. In cells from the elderly, 263 genes were downregulated and 95 upregulated. Superoxide dismutase 3 (\n                    <jats:italic toggle=\"yes\">SOD3<\/jats:italic>\n                    ) was identified as the top-ranked gene that was most downregulated in the elderly. Other redox-active genes that were also downregulated in cells from the elderly included activating transcription factor 4 (\n                    <jats:italic toggle=\"yes\">ATF4<\/jats:italic>\n                    ) and metallothionein 2A (\n                    <jats:italic toggle=\"yes\">M2TA<\/jats:italic>\n                    ).\n                    <jats:italic toggle=\"yes\">ATF4<\/jats:italic>\n                    is an endoplasmic reticulum stress sensor that defends lungs\n                    <jats:italic toggle=\"yes\">via<\/jats:italic>\n                    induction of heme oxygenase 1. The study of downstream factors known to be induced by\n                    <jats:italic toggle=\"yes\">ATF4<\/jats:italic>\n                    , according to Ingenuity Pathway Analysis\u2122, identified 24 candidates. Twenty-one of these were significantly downregulated in the cells from the elderly. These downregulated candidates were subjected to enrichment using the Reactome Database identifying that in the elderly, the ability to respond to heme deficiency and the\n                    <jats:italic toggle=\"yes\">ATF4<\/jats:italic>\n                    -dependent ability to respond to endoplasmic reticulum stress is significantly compromised.\n                    <jats:italic toggle=\"yes\">SOD3<\/jats:italic>\n                    -based therapeutic strategies have provided beneficial results in treating lung disorders including fibrosis. The findings of this study propose the hypotheses that lung-specific delivery of\n                    <jats:italic toggle=\"yes\">SOD3<\/jats:italic>\n                    \/\n                    <jats:italic toggle=\"yes\">ATF4<\/jats:italic>\n                    -related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.\n                  <\/jats:p>","DOI":"10.1089\/ars.2020.8111","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T05:51:12Z","timestamp":1587621072000},"page":"59-65","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":91,"title":["Is Low Alveolar Type II Cell\n                    <i>SOD3<\/i>\n                    in the Lungs of Elderly Linked to the Observed Severity of COVID-19?"],"prefix":"10.1177","volume":"33","author":[{"given":"Ahmed S.","family":"Abouhashem","sequence":"first","affiliation":[{"name":"Indiana Center for Regenerative Medicine and Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanhaiya","family":"Singh","sequence":"additional","affiliation":[{"name":"Indiana Center for Regenerative Medicine and Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan M.E.","family":"Azzazy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, New Cairo, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandan K.","family":"Sen","sequence":"additional","affiliation":[{"name":"Indiana Center for Regenerative Medicine and Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,6,9]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0276-y"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1081-1206(10)62960-2"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200603-319OC"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.17.4.2826"},{"key":"e_1_3_4_6_2","first-page":"e40","article-title":"Metronidazole; a potential novel addition to the COVID-19 treatment regimen","volume":"8","author":"Gharebaghi R","year":"2020","unstructured":"Gharebaghi R, , Heidary F, , Moradi M, , and Parvizi M. Metronidazole; a potential novel addition to the COVID-19 treatment regimen. Arch Acad Emerg Med, 8: e40, 2020.","journal-title":"Arch Acad Emerg Med"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080119"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-63245-2_5"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"e_1_3_4_11_2","first-page":"D498","article-title":"The reactome pathway knowledgebase","volume":"48","author":"Jassal B","year":"2020","unstructured":"Jassal B, , Matthews L, , Viteri G, , Gong C, , Lorente P, , Fabregat A, , Sidiropoulos K, , Cook J, , Gillespie M, , Haw R, , Loney F, , May B, , Milacic M, , Rothfels K, , Sevilla C, , Shamovsky V, , Shorser S, , Varusai T, , Weiser J, , Wu G, , Stein L, , Hermjakob H, , and D'Eustachio P. The reactome pathway knowledgebase. 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