{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:03:25Z","timestamp":1789473805236,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:00:00Z","timestamp":1668643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Study of Blindness and Visual Disorders, Sackler Faculty of Medicine, Tel Aviv University","award":["R01HL142975"],"award-info":[{"award-number":["R01HL142975"]}]},{"name":"National Institutes of Health","award":["R01HL142975"],"award-info":[{"award-number":["R01HL142975"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with pleiotropic cytoprotective properties albeit without the bleeding risks. The anti-inflammatory activities of 3K3A-APC were demonstrated in multiple preclinical injury models, including various neurological disorders. We determined the ability of 3K3A-APC to inhibit ocular inflammation in a murine model of lipopolysaccharide (LPS)-induced uveitis. Leukocyte recruitment, microglia activation, NLRP3 inflammasome and IL-1\u03b2 levels were assessed using flow cytometry, retinal cryosection histology, retinal flatmount immunohistochemistry and vascular imaging, with and without 3K3A-APC treatment. LPS triggered robust inflammatory cell recruitment in the posterior chamber. The 3K3A-APC treatment significantly decreased leukocyte numbers and inhibited leukocyte extravasation from blood vessels into the retinal parenchyma to a level similar to controls. Resident microglia, which underwent an inflammatory transition following LPS injection, remained quiescent in eyes treated with 3K3A-APC. An inflammation-associated increase in retinal thickness, observed in LPS-injected eyes, was diminished by 3K3A-APC treatment, suggesting its clinical relevancy. Finally, 3K3A-APC treatment inhibited inflammasome activation, determined by lower levels of NLRP3 and its downstream effector IL-1\u03b2. Our results highlight the anti-inflammatory properties of 3K3A-APC in ocular inflammation and suggest its potential use as a novel treatment for retinal diseases associated with inflammation.<\/jats:p>","DOI":"10.3390\/ijms232214196","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T03:12:20Z","timestamp":1668654740000},"page":"14196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["3K3A-Activated Protein C Prevents Microglia Activation, Inhibits NLRP3 Inflammasome and Limits Ocular Inflammation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9661-5680","authenticated-orcid":false,"given":"Dahlia","family":"Palevski","sequence":"first","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9993-1005","authenticated-orcid":false,"given":"Gil","family":"Ben-David","sequence":"additional","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5923-769X","authenticated-orcid":false,"given":"Yehonatan","family":"Weinberger","sequence":"additional","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabeei","family":"Haj Daood","sequence":"additional","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0804-1865","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6652-2667","authenticated-orcid":false,"given":"Ivan","family":"Budnik","sequence":"additional","affiliation":[{"name":"Sheba Medical Center, The Amalia Biron Thrombosis Research Institute, Tel-Hashomer 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3971-0336","authenticated-orcid":false,"given":"Sarina","family":"Levy-Mendelovich","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Sheba Medical Center, The Amalia Biron Thrombosis Research Institute, Tel-Hashomer 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3494-9823","authenticated-orcid":false,"given":"Gili","family":"Kenet","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Sheba Medical Center, The Amalia Biron Thrombosis Research Institute, Tel-Hashomer 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Nisgav","sequence":"additional","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dov","family":"Weinberger","sequence":"additional","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1279-2557","authenticated-orcid":false,"given":"Tami","family":"Livnat","sequence":"additional","affiliation":[{"name":"Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Petah-Tikva 49100, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Sheba Medical Center, The Amalia Biron Thrombosis Research Institute, Tel-Hashomer 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1182\/blood-2018-02-769026","article-title":"Activated protein C, protease activated receptor 1, and neuroprotection","volume":"132","author":"Griffin","year":"2018","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1182\/blood-2015-02-355974","article-title":"Activated protein C: Biased for translation","volume":"125","author":"Griffin","year":"2015","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/MOH.0000000000000473","article-title":"Cell biology of activated protein C","volume":"26","author":"Shahzad","year":"2019","journal-title":"Curr. Opin. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1055\/s-2007-1000658","article-title":"Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency","volume":"21","author":"Dreyfus","year":"1995","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ghassemi, F., Abdi, F., and Esfahani, M. (2020). Ophthalmic manifestations of congenital protein C deficiency: A case report and mini review. BMC Ophthalmol., 20.","DOI":"10.1186\/s12886-020-01424-x"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.oret.2018.07.012","article-title":"Activated Protein C for Ischemic Central Retinal Vein Occlusion: One-Year Results","volume":"3","author":"Hara","year":"2019","journal-title":"Ophthalmol. Retin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.1007\/s00417-021-05072-9","article-title":"Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: An extension trial","volume":"259","author":"Hara","year":"2021","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1056\/NEJMoa1202290","article-title":"Drotrecogin alfa (activated) in adults with septic shock","volume":"366","author":"Ranieri","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1182\/blood-2004-01-0110","article-title":"Activated protein C variants with normal cytoprotective but reduced anticoagulant activity","volume":"104","author":"Mosnier","year":"2004","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3389\/fnins.2020.00333","article-title":"Activated Protein C Attenuates Experimental Autoimmune Encephalomyelitis Progression by Enhancing Vascular Integrity and Suppressing Microglial Activation","volume":"14","author":"Kant","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1016\/S0049-3848(16)30368-1","article-title":"Activated protein C promotes neuroprotection: Mechanisms and translation to the clinic","volume":"141","author":"Griffin","year":"2016","journal-title":"Thromb. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/ana.25383","article-title":"Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke","volume":"85","author":"Lyden","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Livnat, T., Weinberger, Y., Fernandez, J.A., Bashir, A., Ben-David, G., Palevski, D., Levy-Mendelovich, S., Kenet, G., Budnik, I., and Nisgav, Y. (2021). Activated Protein C (APC) and 3K3A-APC-Induced Regression of Choroidal Neovascularization (CNV) Is Accompanied by Vascular Endothelial Growth Factor (VEGF) Reduction. Biomolecules, 11.","DOI":"10.3390\/biom11030358"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107695","DOI":"10.1016\/j.exer.2019.107695","article-title":"Activated protein C induces suppression and regression of choroidal neovascularization- A murine model","volume":"186","author":"Livnat","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1002\/JLB.3MIR0817-338R","article-title":"Regulation of immune cell signaling by activated protein C","volume":"103","author":"Healy","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1182\/blood-2017-05-782102","article-title":"Cytoprotective activated protein C averts Nlrp3 inflammasome-induced ischemia-reperfusion injury via mTORC1 inhibition","volume":"130","author":"Nazir","year":"2017","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/eye.2017.241","article-title":"Inflammasomes, the eye and anti-inflammasome therapy","volume":"32","author":"Yerramothu","year":"2018","journal-title":"Eye"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.3389\/fimmu.2019.01618","article-title":"IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases","volume":"10","author":"Wooff","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8442","DOI":"10.1167\/iovs.11-8152","article-title":"Neurodegenerative and inflammatory pathway components linked to TNF-alpha\/TNFR1 signaling in the glaucomatous human retina","volume":"52","author":"Yang","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108911","DOI":"10.1016\/j.exer.2021.108911","article-title":"The NLRP3 inflammasome in age-related eye disease: Evidence-based connexin hemichannel therapeutics","volume":"215","author":"Mugisho","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-1-62703-481-4_18","article-title":"Endotoxin-induced uveitis in rodents","volume":"1031","author":"Yadav","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.2174\/1381612821666150316122928","article-title":"Mouse models of autoimmune uveitis","volume":"21","author":"Klaska","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/286611a0","article-title":"Endotoxin-induced uveitis in rats as a model for human disease","volume":"286","author":"Rosenbaum","year":"1980","journal-title":"Nature"},{"key":"ref_24","first-page":"473","article-title":"Multimodal analysis of ocular inflammation using the endotoxin-induced uveitis mouse model","volume":"9","author":"Chu","year":"2016","journal-title":"Dis. Model. Mech."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1186\/s12974-018-1373-4","article-title":"Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation","volume":"15","author":"Kokona","year":"2018","journal-title":"J. Neuroinflam."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"326","DOI":"10.3389\/fphar.2018.00326","article-title":"Theissenolactone C Exhibited Ocular Protection of Endotoxin-Induced Uveitis by Attenuating Ocular Inflammatory Responses and Glial Activation","volume":"9","author":"Lin","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.exer.2016.08.007","article-title":"Flow cytometric analysis of inflammatory and resident myeloid populations in mouse ocular inflammatory models","volume":"151","author":"Liyanage","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e50","DOI":"10.1111\/aos.14221","article-title":"Characteristics of retinal layer thickness in acute anterior uveitis: An optical coherence tomography study","volume":"98","author":"Lee","year":"2020","journal-title":"Acta Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12974-014-0186-3","article-title":"Microglia activation in a model of retinal degeneration and TUDCA neuroprotective effects","volume":"11","author":"Noailles","year":"2014","journal-title":"J. Neuroinflam."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"593582","DOI":"10.3389\/fneur.2021.593582","article-title":"Stroke Treatment With PAR-1 Agents to Decrease Hemorrhagic Transformation","volume":"12","author":"Lyden","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e20211372","DOI":"10.1084\/jem.20211372","article-title":"Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C","volume":"219","author":"Huuskonen","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"O\u2019Leary, F., and Campbell, M. (2021). The blood-retina barrier in health and disease. FEBS J.","DOI":"10.1111\/febs.16330"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1182\/blood-2006-09-003004","article-title":"The cytoprotective protein C pathway","volume":"109","author":"Mosnier","year":"2007","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1161\/01.CIR.103.13.1799","article-title":"Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke","volume":"103","author":"Shibata","year":"2001","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1167\/iovs.10-5284","article-title":"Microglial activation in the visual pathway in experimental glaucoma: Spatiotemporal characterization and correlation with axonal injury","volume":"51","author":"Ebneter","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pneurobio.2018.05.006","article-title":"Retinal microglia\u2014A key player in healthy and diseased retina","volume":"173","author":"Rathnasamy","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/imm.13479","article-title":"Retinal microglia: Functions and diseases","volume":"166","author":"Fan","year":"2022","journal-title":"Immunology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1084\/jem.20181035","article-title":"3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice","volume":"216","author":"Lazic","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"671417","DOI":"10.1155\/2015\/671417","article-title":"Macrophages and Uveitis in Experimental Animal Models","volume":"2015","author":"Merida","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.preteyeres.2013.07.003","article-title":"Aging is not a disease: Distinguishing age-related macular degeneration from aging","volume":"37","author":"Ardeljan","year":"2013","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1017\/S0952523800173122","article-title":"Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats","volume":"17","author":"Zeng","year":"2000","journal-title":"Vis. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/jth.15133","article-title":"Activated protein C and PAR1-derived and PAR3-derived peptides are anti-inflammatory by suppressing macrophage NLRP3 inflammasomes","volume":"19","author":"Healy","year":"2021","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Coyle, S., Khan, M.N., Chemaly, M., Callaghan, B., Doyle, C., Willoughby, C.E., Atkinson, S.D., Gregory-Ksander, M., and McGilligan, V. (2021). Targeting the NLRP3 Inflammasome in Glaucoma. Biomolecules, 11.","DOI":"10.3390\/biom11081239"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108618","DOI":"10.1016\/j.exer.2021.108618","article-title":"The role of the inflammasomes in the pathogenesis of uveitis","volume":"208","author":"Xu","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e0010322","DOI":"10.1128\/iai.00103-22","article-title":"Essential Role of NLRP3 Inflammasome in Mediating IL-1beta Production and the Pathobiology of Staphylococcus aureus Endophthalmitis","volume":"90","author":"Kumar","year":"2022","journal-title":"Infect. Immun."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Marchesi, N., Fahmideh, F., Boschi, F., Pascale, A., and Barbieri, A. (2021). Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas. Cells, 10.","DOI":"10.3390\/cells10092394"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1167\/iovs.18-23800","article-title":"Endothelial Protein C-Targeting Liposomes Show Enhanced Uptake and Improved Therapeutic Efficacy in Human Retinal Endothelial Cells","volume":"59","author":"Arta","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Goldberg, Z., Sher, I., Qassim, L., Chapman, J., Rotenstreich, Y., and Shavit-Stein, E. (2022). Intrinsic Expression of Coagulation Factors and Protease Activated Receptor 1 (PAR1) in Photoreceptors and Inner Retinal Layers. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020984"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.brainres.2005.04.040","article-title":"Two types of protease-activated receptors (PAR-1 and PAR-2) mediate calcium signaling in rat retinal ganglion cells RGC-5","volume":"1047","author":"Luo","year":"2005","journal-title":"Brain Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3769","DOI":"10.1167\/iovs.16-19574","article-title":"PKC-zeta Regulates Thrombin-Induced Proliferation of Human Muller Glial Cells","volume":"57","author":"Lopez","year":"2016","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S1079-9796(03)00034-2","article-title":"Recombinant murine-activated protein C is neuroprotective in a murine ischemic stroke model","volume":"30","author":"Fernandez","year":"2003","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/j.1471-4159.2009.05921.x","article-title":"Species-dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity","volume":"109","author":"Guo","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/ceo.13453","article-title":"Effects of intravitreal bevacizumab in Gram-positive and Gram-negative models of ocular inflammation","volume":"47","author":"Lafreniere","year":"2019","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00011-011-0404-8","article-title":"The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis","volume":"61","author":"Rosenzweig","year":"2012","journal-title":"Inflamm. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:19:52Z","timestamp":1760145592000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,17]]},"references-count":54,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214196"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214196","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,17]]}}}