{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:57Z","timestamp":1792790337947,"version":"4.5.0"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"11","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Guangzhou Eighth People\u00e2??s Hospital, Guangzhou Medical University","id":[{"id":"https:\/\/ror.org\/00zat6v61","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background and purpose: Cerebral ischemia-reperfusion injury is commonly induced during the treatment of ischemic stroke and is reported to be related to the blood\u2013brain barrier destruction and brain vascular endothelial cell dysfunction. Anagliptin is a novel antidiabetic agent recently reported to protect neurons from oxidative stress. In the present study, we aim to investigate the protective property of anagliptin against oxygen\u2013glucose deprivation and reperfusion (OGD\/R)-induced injury on endothelial cells and clarify the potential underlying mechanism. Methods: OGD\/R modeling was established on bEnd.3 brain endothelial cells. Cell viability was detected using the MTT assay, and the mitochondrial reactive oxygen species (ROS) level was measured using the mitoses red staining assay. The endothelial monolayer permeability was determined using an FITC-dextran permeation assay. The expression levels of NOX-4 and ZO-1 were evaluated using qRT-PCR and Western blot assays. The expressions of MLC-2, p-MLC-2, and myosin light chain kinase (MLCK) were determined using Western blot. Results: First, the decreased cell viability, upregulated NOX-4, and elevated mitochondrial ROS level in the endothelial cells induced by OGD\/R were reversed by treatment with anagliptin. Second, the enlarged endothelial permeability and the decreased expression level of ZO-1 in the endothelial cells induced by OGD\/R were alleviated by anagliptin. Third, the downregulation of ZO-1 and enlarged brain endothelial monolayer permeability induced by OGD\/R were ameliorated by an MLCK inhibitor, ML-7. Lastly, the elevated expressions of MLCK and p-MLC-2 induced by OGD\/R were suppressed by anagliptin. Conclusion: Anagliptin protected against hypoxia\/reperfusion-induced brain vascular endothelial permeability by increasing the expression ZO-1, mediated by inhibition of the MLCK\/MLC-2 signaling pathway.<\/jats:p>","DOI":"10.1021\/acsomega.1c00242","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T07:11:28Z","timestamp":1615533088000},"page":"7771-7777","source":"Crossref","is-referenced-by-count":15,"title":["Anagliptin Protected against Hypoxia\/Reperfusion-Induced\nBrain Vascular Endothelial Permeability by Increasing ZO\u20111"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9318-8716","authenticated-orcid":true,"given":"Chuo","family":"Li","sequence":"first","affiliation":[{"name":"Guangzhou Eighth People\u2019s Hospital of Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510440"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University , , , ,","place":["Guangzhou, Guangdong, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University , , , ,","place":["Guangzhou, Guangdong, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhen","family":"Mai","sequence":"additional","affiliation":[{"name":"Guangzhou Eighth People\u2019s Hospital of Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510440"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"2026081415090802600_cit1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s12974-017-0897-3","article-title":"Sac-1004, a vascular leakage blocker, reduces cerebral\nischemia-reperfusion injury by suppressing blood-brain barrier disruption\nand inflammation","volume":"14","author":"Zhang","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"2026081415090802600_cit2","doi-asserted-by":"publisher","first-page":"108629","DOI":"10.1016\/j.abb.2020.108629","article-title":"The possible\nroles of necroptosis during cerebral ischemia and ischemia \/ reperfusion\ninjury","volume":"695","author":"Liao","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"2026081415090802600_cit3","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.3389\/fimmu.2019.02505","article-title":"Platelets as Modulators of Cerebral\nIschemia\/Reperfusion Injury","volume":"10","author":"Stegner","year":"2019","journal-title":"Front. Immunol."},{"key":"2026081415090802600_cit4","first-page":"V08170576","article-title":"The blood-brain barrier in ageing\npersons","volume":"180","author":"Haaning","year":"2018","journal-title":"Ugeskr. Laeg."},{"key":"2026081415090802600_cit5","doi-asserted-by":"publisher","first-page":"213","DOI":"10.4172\/2167-0501.1000213","article-title":"Ischemia-reperfusion Injury in the Brain: Mechanisms and Potential\nTherapeutic Strategies","volume":"5","author":"Lin","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"2026081415090802600_cit6","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s12031-019-01402-z","article-title":"Anfibatide Preserves Blood-Brain Barrier Integrity\nby Inhibiting TLR4\/RhoA\/ROCK Pathway After Cerebral Ischemia\/Reperfusion\nInjury in Rat","volume":"70","author":"Gong","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"2026081415090802600_cit7","doi-asserted-by":"publisher","first-page":"24","DOI":"10.3390\/cells7040024","article-title":"Towards Improvements for Penetrating\nthe Blood-Brain Barrier-Recent Progress from a Material and Pharmaceutical\nPerspective","volume":"7","author":"He","year":"2018","journal-title":"Cells"},{"key":"2026081415090802600_cit8","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.nbd.2018.03.013","article-title":"Stepwise impairment\nof neural stem cell proliferation and neurogenesis concomitant with\ndisruption of blood-brain barrier in recurrent ischemic stroke","volume":"115","author":"Lin","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"2026081415090802600_cit9","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1248\/bpb.b17-00848","article-title":"Noncovalent\nStrategy with Cell-Penetrating Peptides to Facilitate the Brain Delivery\nof Insulin through the Blood-Brain Barrier","volume":"41","author":"Kamei","year":"2018","journal-title":"Biol. Pharm. Bull."},{"key":"2026081415090802600_cit10","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1016\/j.ymthe.2018.02.032","article-title":"A Blood-Brain-Barrier-Penetrating\nAnti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic\nMucopolysaccharidosis II","volume":"26","author":"Sonoda","year":"2018","journal-title":"Mol. Ther."},{"key":"2026081415090802600_cit11","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1002\/jcp.24523","article-title":"Kruppel-like factor 4 regulates blood-tumor barrier permeability\nvia ZO-1, occludin and claudin-5","volume":"229","author":"Ma","year":"2014","journal-title":"J. Cell. Physiol."},{"key":"2026081415090802600_cit12","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.mod.2015.07.007","article-title":"Formation and maintenance of the BBB","volume":"138","author":"Blanchette","year":"2015","journal-title":"Mech. Dev."},{"key":"2026081415090802600_cit13","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1016\/j.freeradbiomed.2011.06.003","article-title":"The role\nof free radical generation in increasing cerebrovascular permeability","volume":"51","author":"Fraser","year":"2011","journal-title":"Free Radical Biol. Med."},{"key":"2026081415090802600_cit14","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1038\/jcbfm.2008.60","article-title":"Role of the p38 mitogen-activated protein kinase\/cytosolic\nphospholipase A2 signaling pathway in blood-brain barrier disruption\nafter focal cerebral ischemia and reperfusion","volume":"28","author":"Nito","year":"2008","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2026081415090802600_cit15","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1016\/j.freeradbiomed.2009.07.034","article-title":"Oxidative stress\nupregulates the NMDA receptor on cerebrovascular endothelium","volume":"47","author":"Betzen","year":"2009","journal-title":"Free Radical Biol. Med."},{"key":"2026081415090802600_cit16","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/1742-2094-7-42","article-title":"Cytosolic\nphospholipase A2 alpha amplifies early cyclooxygenase-2 expression,\noxidative stress and MAP kinase phosphorylation after cerebral ischemia\nin mice","volume":"7","author":"Kishimoto","year":"2010","journal-title":"J. Neuroinflammation"},{"key":"2026081415090802600_cit17","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.vph.2015.04.012","article-title":"Wogonin inhibits LPS-induced vascular\npermeability via suppressing MLCK\/MLC pathway","volume":"72","author":"Huang","year":"2015","journal-title":"Vasc. Pharmacol."},{"key":"2026081415090802600_cit18","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.3892\/ijmm.2017.2928","article-title":"AGR2 ameliorates tumor necrosis factor-alpha-induced epithelial barrier\ndysfunction via suppression of NF-kappaB p65-mediated MLCK\/p-MLC pathway\nactivation","volume":"39","author":"Ye","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"2026081415090802600_cit19","doi-asserted-by":"publisher","DOI":"10.4161\/21688370.2014.978720","article-title":"Blood cells and endothelial barrier function","volume":"3","author":"Rodrigues","year":"2015","journal-title":"Tissue Barriers"},{"key":"2026081415090802600_cit20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0228004","article-title":"Dipeptidyl\npeptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48\nlevels in patients with type 2 diabetes: A randomized controlled trial","volume":"15","author":"Onoue","year":"2020","journal-title":"PLoS One"},{"key":"2026081415090802600_cit21","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/s41598-020-57935-6","article-title":"Dipeptidyl peptidase-4 inhibition prevents nonalcoholic\nsteatohepatitis-associated liver fibrosis and tumor development in\nmice independently of its anti-diabetic effects","volume":"10","author":"Kawakubo","year":"2020","journal-title":"Sci. Rep."},{"key":"2026081415090802600_cit22","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1507\/endocrj.ej19-0389","article-title":"Anagliptin suppresses diet-induced\nobesity through enhancing leptin sensitivity and ameliorating hyperphagia\nin high-fat high-sucrose diet fed mice","volume":"67","author":"Kohno","year":"2020","journal-title":"Endocr.\nJ."},{"key":"2026081415090802600_cit23","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1080\/21691401.2019.1609979","article-title":"Anagliptin\nprotects neuronal cells against endogenous amyloid beta (Abeta)-induced\ncytotoxicity and apoptosis","volume":"47","author":"Chen","year":"2019","journal-title":"Artif. Cells, Nanomed.,\nBiotechnol."},{"key":"2026081415090802600_cit24","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1007\/s12020-014-0376-x","article-title":"The effect\nof anagliptin treatment on glucose metabolism and lipid metabolism,\nand oxidative stress in fasting and postprandial states using a test\nmeal in Japanese men with type 2 diabetes","volume":"48","author":"Kakuda","year":"2015","journal-title":"Endocrine"},{"key":"2026081415090802600_cit25","doi-asserted-by":"publisher","first-page":"2183026","DOI":"10.1155\/2016\/2183026","article-title":"ROS-Mediated NLRP3 Inflammasome Activation\nin Brain, Heart, Kidney, and Testis Ischemia\/Reperfusion Injury","volume":"2016","author":"Minutoli","year":"2016","journal-title":"Oxid. Med. Cell. Longevity"},{"key":"2026081415090802600_cit26","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.bbrc.2018.12.170","article-title":"DUSP14 rescues cerebral\nischemia\/reperfusion (IR) injury by reducing inflammation and apoptosis\nvia the activation of Nrf-2","volume":"509","author":"Jianrong","year":"2019","journal-title":"Biochem. Biophys.\nRes. Commun."},{"key":"2026081415090802600_cit27","doi-asserted-by":"publisher","first-page":"7156941","DOI":"10.1155\/2017\/7156941","article-title":"Research Progress on Signaling Pathway-Associated Oxidative Stress\nin Endothelial Cells","volume":"2017","author":"Liang","year":"2017","journal-title":"Oxid. Med. Cell. Longevity"},{"key":"2026081415090802600_cit28","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00011-011-0309-6","article-title":"Reactive oxygen species and NADPH\noxidase 4 induced by transforming growth factor beta1 are the therapeutic\ntargets of polyenylphosphatidylcholine in the suppression of human\nhepatic stellate cell activation","volume":"60","author":"Ikeda","year":"2011","journal-title":"Inflammation\nRes."},{"key":"2026081415090802600_cit29","doi-asserted-by":"publisher","first-page":"3989","DOI":"10.2147\/DDDT.S85426","article-title":"A bioinformatic and\nmechanistic study elicits the antifibrotic effect of ursolic acid\nthrough the attenuation of oxidative stress with the involvement of\nERK, PI3K\/Akt, and p38 MAPK signaling pathways in human hepatic stellate\ncells and rat liver","volume":"9","author":"He","year":"2015","journal-title":"Drug Des., Dev. Ther."},{"key":"2026081415090802600_cit30","doi-asserted-by":"publisher","first-page":"6704851","DOI":"10.1155\/2016\/6704851","article-title":"Early Intervention of Didang Decoction on MLCK Signaling Pathways\nin Vascular Endothelial Cells of Type 2 Diabetic Rats","volume":"2016","author":"Ye","year":"2016","journal-title":"Int. J. Endocrinol."},{"key":"2026081415090802600_cit31","doi-asserted-by":"publisher","first-page":"2639","DOI":"10.1091\/mbc.e04-02-0163","article-title":"Role for actin filament\nturnover and a myosin II motor in cytoskeleton-driven disassembly\nof the epithelial apical junctional complex","volume":"15","author":"Ivanov","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"2026081415090802600_cit32","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1242\/jcs.02915","article-title":"Myosin light chain phosphorylation\nregulates barrier function by remodeling tight junction structure","volume":"119","author":"Shen","year":"2006","journal-title":"J. Cell Sci."},{"key":"2026081415090802600_cit33","doi-asserted-by":"publisher","first-page":"C1678","DOI":"10.1152\/ajpcell.1996.271.5.c1678","article-title":"Expression\nof the catalytic domain of myosin light chain kinase increases paracellular\npermeability","volume":"271","author":"Hecht","year":"1996","journal-title":"Am. J. Physiol."},{"key":"2026081415090802600_cit34","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1002\/jcp.1134","article-title":"Actin filament assembly and actin-myosin contractility\nare necessary for anchorage- and EGF-dependent activation of phospholipase\nCgamma","volume":"189","author":"Suzuki","year":"2001","journal-title":"J. Cell. Physiol."},{"key":"2026081415090802600_cit35","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1002\/1097-0029(20001015)51:2&lt;156::aid-jemt7&gt;3.0.co;2-j","article-title":"Mechanism of extracellular calcium regulation of intestinal\nepithelial tight junction permeability: role of cytoskeletal involvement","volume":"51","author":"Ma","year":"2000","journal-title":"Microsc. Res. Tech."},{"key":"2026081415090802600_cit36","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.yexcr.2015.05.026","article-title":"Myofibrillogenesis\nregulator-1 attenuates hypoxia\/reoxygenation-induced injury by repairing\nmicrofilaments in neonatal rat cardiomyocytes","volume":"337","author":"Tao","year":"2015","journal-title":"Exp. Cell Res."},{"key":"2026081415090802600_cit37","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.cell.2019.10.006","article-title":"Mechanosensation\nof Tight Junctions Depends on ZO-1 Phase Separation and Flow","volume":"179","author":"Schwayer","year":"2019","journal-title":"Cell"},{"key":"2026081415090802600_cit38","doi-asserted-by":"publisher","first-page":"3210","DOI":"10.1002\/jcb.26477","article-title":"Neuroprotective effect of licochalcone\nA against oxygen-glucose deprivation\/reperfusion in rat primary cortical\nneurons by attenuating oxidative stress injury and inflammatory response\nvia the SIRT1\/Nrf2 pathway","volume":"119","author":"Liu","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"2026081415090802600_cit39","doi-asserted-by":"publisher","first-page":"10506","DOI":"10.1038\/s41598-019-46848-8","article-title":"Directed differentiation of human induced pluripotent stem cells\ninto mature stratified bladder urothelium","volume":"9","author":"Suzuki","year":"2019","journal-title":"Sci.\nRep."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.1c00242","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/6\/11\/7771\/3729174\/ao1c00242.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/6\/11\/7771\/3729174\/ao1c00242.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T19:23:22Z","timestamp":1786735402000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/6\/11\/7771\/384714\/Anagliptin-Protected-against-Hypoxia-Reperfusion"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,3,12]]},"published-print":{"date-parts":[[2021,3,23]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.1c00242","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]}}}