{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T16:44:12Z","timestamp":1788194652998,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":81,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7232009"],"award-info":[{"award-number":["7232009"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7244289"],"award-info":[{"award-number":["7244289"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neonatal purulent meningitis (NPM) is a life\u2010threatening condition associated with high mortality rates and a substantial risk of severe long\u2010term neurological sequelae among survivors. Extraintestinal pathogenic\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      (ExPEC) is the predominant causative agent of NPM and exhibits multidrug resistance. Targeting host signaling pathways is a promising therapeutic approach. In this study, we aimed to evaluate the therapeutic potential of LY294002 (a PI3K\/Akt inhibitor) and lithium chloride (LiCl) (a GSK3\u03b2 inhibitor) in a neonatal mouse model of ExPEC meningitis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Neonatal mice were infected with clinical ExPEC isolates to induce meningitis. LY294002 or LiCl was administered as an intervention. Brain bacterial load was quantified via culture, while inflammation was assessed using RT\u2010qPCR to evaluate the expression of inflammatory cytokines; hematoxylin\u2013eosin (HE) staining was also performed. The expression and localization of tight junction (TJ) proteins were analyzed using immunohistochemistry, and western blotting was used to quantify TJ proteins and key signaling molecules, including Akt, phosphorylated Akt (p\u2010Akt Ser473), GSK3\u03b2, and phosphorylated GSK3\u03b2 (p\u2010GSK3\u03b2 Ser9).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ExPEC colonization in the brain tissue was confirmed via bacterial culture. Early intervention with LiCl significantly reduced bacterial load. HE staining revealed meningeal thickening in infected mice, which was alleviated by both LY294002 and LiCl treatments. Western blotting and immunohistochemistry consistently demonstrated a marked reduction in the expression of TJ proteins following ExPEC infection, and their levels were substantially restored by both the interventions. These protective effects were associated with the modulation of the Akt\/GSK3\u03b2 signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LY294002 and LiCl reduced neuroinflammation and preserved the blood\u2013brain barrier (BBB) integrity in the neonatal ExPEC meningitis model, likely via modulation of the Akt\/GSK3\u03b2 pathway. These results underscore the potential of this pathway as a therapeutic target and provide a basis for further preclinical investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/mi\/5086440","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:10:57Z","timestamp":1774278657000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["LY294002 and LiCl Mitigate Neonatal ExPEC Meningitis Through Akt\/GSK3\u03b2 Signaling Modulation"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7407-3227","authenticated-orcid":false,"given":"Peicen","family":"Zou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqi","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5080-9056","authenticated-orcid":false,"given":"Sihan","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8830-7255","authenticated-orcid":false,"given":"Yajuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/S1474-4422(18)30387-9","article-title":"Meningitis Collaborators, Global, Regional, and National Burden of Meningitis, 1990\u20132016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"17","author":"Zunt J. R.","year":"2016","journal-title":"The Lancet Neurology"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S317299"},{"key":"e_1_2_13_3_2","doi-asserted-by":"publisher","DOI":"10.21037\/tp-22-236"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/apa.14942"},{"key":"e_1_2_13_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.03255-12"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S207857"},{"key":"e_1_2_13_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0000000000002247"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2022.09.014"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.115132"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13111779"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.08.004"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-023-00489-2"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1103"},{"key":"e_1_2_13_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-020-00270-5"},{"key":"e_1_2_13_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-021-01466-3"},{"key":"e_1_2_13_16_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.56817"},{"key":"e_1_2_13_17_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.64.3.35"},{"key":"e_1_2_13_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007382200"},{"key":"e_1_2_13_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113607"},{"key":"e_1_2_13_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-022-07752-1"},{"key":"e_1_2_13_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae978"},{"key":"e_1_2_13_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/gpbjnl\/qzaf010"},{"key":"e_1_2_13_23_2","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.4574"},{"key":"e_1_2_13_24_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/916234"},{"key":"e_1_2_13_25_2","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.911860"},{"key":"e_1_2_13_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1293-3"},{"key":"e_1_2_13_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells10071677"},{"key":"e_1_2_13_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2015.10.025"},{"key":"e_1_2_13_29_2","doi-asserted-by":"crossref","first-page":"S220","DOI":"10.1086\/344284","article-title":"Strategy of Escherichia coli for Crossing the Blood-Brain Barrier","volume":"186","author":"Kim K. S.","year":"2002","journal-title":"The Journal of infectious diseases"},{"key":"e_1_2_13_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241310432"},{"key":"e_1_2_13_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24129915"},{"key":"e_1_2_13_32_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115965"},{"key":"e_1_2_13_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103908"},{"key":"e_1_2_13_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.09.034"},{"key":"e_1_2_13_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22126343"},{"key":"e_1_2_13_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/advances\/nmz061"},{"key":"e_1_2_13_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(03)00206-2"},{"key":"e_1_2_13_38_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210829"},{"key":"e_1_2_13_39_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.011008.145634"},{"key":"e_1_2_13_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01853-x"},{"key":"e_1_2_13_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.11.003"},{"key":"e_1_2_13_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1952"},{"key":"e_1_2_13_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/ecosalplus.esp-0015-2015"},{"key":"e_1_2_13_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.64.1.146-153.1996"},{"key":"e_1_2_13_45_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.86130"}],"container-title":["Mediators of Inflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/mi\/5086440","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/mi\/5086440","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/mi\/5086440","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:10:59Z","timestamp":1774278659000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/mi\/5086440"}},"subtitle":[],"editor":[{"given":"Goran","family":"Omer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/mi\/5086440"],"URL":"https:\/\/doi.org\/10.1155\/mi\/5086440","archive":["Portico"],"relation":{},"ISSN":["0962-9351","1466-1861"],"issn-type":[{"value":"0962-9351","type":"print"},{"value":"1466-1861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-06-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"5086440"}}