{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:02:25Z","timestamp":1787022145427,"version":"build-2736575974"},"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"crossref","award":["2017\/26402-9"],"award-info":[{"award-number":["2017\/26402-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Anti-VEGF (vascular endothelial growth factor) drugs such as aflibercept (AFL) and bevacizumab (BVZ) inhibit pathological neo-angiogenesis and vascular permeability in retinal vascular diseases. As cytokines and growth factors are produced by M\u00fcller glial cells under stressful and pathological conditions, we evaluated the\n                    <jats:italic>in vitro<\/jats:italic>\n                    effect of AFL (Eylea\n                    <jats:sup>\u00ae<\/jats:sup>\n                    , 0.5 mg\/mL) and BVZ (Avastin\n                    <jats:sup>\u00ae<\/jats:sup>\n                    , 0.5 mg\/mL) on cell viability\/metabolism, and cytokine\/growth factor production by M\u00fcller cells (MIO-M1) under cobalt chloride (CoCl\n                    <jats:sub>2<\/jats:sub>\n                    )-induced hypoxia after 24h, 48h and 72h. Cell viability\/metabolism were analyzed by Trypan Blue and MTT assays and cytokine\/growth factors in supernatants by Luminex xMAP-based multiplex bead-based immunoassay. Cell viability increased with AFL at 48h and 72h and decreased with BVZ or hypoxia at 24h. BVZ-treated cells showed lower cell viability than AFL at all exposure times. Cell metabolism increased with AFL but decreased with BVZ (72h) and hypoxia (48h and72h). As expected, AFL and BVZ decreased VEGF levels. AFL increased PDGF-BB, IL-6 and TNF-\u03b1 (24h) and BVZ increased PDGF-BB (72h). Hypoxia reduced IL-1\u03b2, -6, -8, TNF-\u03b1 and PDGF-BB at 24h, and its suppressive effect was more prominent than AFL (EGF, PDGF-BB, IL-1\u03b2, IL-6, IL-8, and TNF-\u03b1) and BVZ (PDGF-BB and IL-6) effects. Hypoxia increased bFGF levels at 48h and 72h, even when combined with anti-VEGFs. However, the stimulatory effect of BVZ predominated over hypoxia for IL-8 and TNF-\u03b1 (24h), as well as for IL-1\u03b2 (72h). Thus, AFL and BVZ exhibit distinct exposure times effects on MIO-M1 cells viability, metabolism, and cytokines\/growth factors. Hypoxia and BVZ decreased MIO-M1 cell viability\/metabolism, whereas AFL likely induced gliosis. Hypoxia resulted in immunosuppression, and BVZ stimulated inflammation in hypoxic MIO-M1 cells. These findings highlight the complexity of the cellular response as well as the interplay between anti-VEGF treatments and the hypoxic microenvironment.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0300370","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T13:45:31Z","timestamp":1711547131000},"page":"e0300370","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effects of aflibercept and bevacizumab on cell viability, cell metabolism and inflammation in hypoxic human M\u00fcller cells"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4451-9712","authenticated-orcid":true,"given":"Monique","family":"Matsuda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-1853","authenticated-orcid":true,"given":"Rafael Andr\u00e9","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4252-3152","authenticated-orcid":true,"given":"Vinicius Moraes de Paiva","family":"Roda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f4nica Val\u00e9ria","family":"Marquezini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7281-2791","authenticated-orcid":true,"given":"M\u00e1rio Luiz Ribeiro","family":"Monteiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e2nia Emi","family":"Hamassaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"issue":"6","key":"pone.0300370.ref001","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","article-title":"VEGF in Signaling and Disease: Beyond Discovery and Development","volume":"176","author":"RS Apte","year":"2019","journal-title":"Cell"},{"key":"pone.0300370.ref002","doi-asserted-by":"crossref","first-page":"100954","DOI":"10.1016\/j.preteyeres.2021.100954","article-title":"VEGFR1 signaling in retinal angiogenesis and microinflammation","volume":"84","author":"A Uemura","year":"2021","journal-title":"Prog Retin Eye Res"},{"issue":"8","key":"pone.0300370.ref003","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1016\/j.ophtha.2011.02.022","article-title":"Sustained benefits from ranibizumab for macular edema following branch retinal vein 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