{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T10:36:44Z","timestamp":1779273404270,"version":"3.51.4"},"reference-count":81,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T00:00:00Z","timestamp":1540944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.81872867, No.81503150, No.21502071"],"award-info":[{"award-number":["No.81872867, No.81503150, No.21502071"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions and the Policy Directive Program of Jiangsu Province","award":["BY2015072-03"],"award-info":[{"award-number":["BY2015072-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3K\u03b3) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3K\u03b3 signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3K\u03b3\/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3K\u03b3\/AKT\/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3K\u03b3-mediated neuroinflammation.<\/jats:p>","DOI":"10.3390\/molecules23112828","type":"journal-article","created":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T11:55:41Z","timestamp":1540986941000},"page":"2828","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["8e Protects against Acute Cerebral Ischemia by Inhibition of PI3K\u03b3-Mediated Superoxide Generation in Microglia"],"prefix":"10.3390","volume":"23","author":[{"given":"Linna","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"},{"name":"Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"},{"name":"Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"},{"name":"Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E146","DOI":"10.1161\/CIR.0000000000000485","article-title":"Heart Disease and Stroke Statistics-2017 Update A Report from the American Heart Association","volume":"135","author":"Benjamin","year":"2017","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJMoa0804656","article-title":"Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke","volume":"359","author":"Hacke","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1161\/STROKEAHA.110.598763","article-title":"Reperfusion Therapies for Acute Ischemic Stroke Current Pharmacological and Mechanical Approaches","volume":"42","author":"Molina","year":"2011","journal-title":"Stroke"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S396","DOI":"10.1038\/sj.bjp.0707626","article-title":"Experimental models, neurovascular mechanisms and translational issues in stroke research","volume":"153","author":"Lo","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuron.2010.07.002","article-title":"The Science of Stroke: Mechanisms in Search of Treatments","volume":"67","author":"Moskowitz","year":"2010","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nm1735","article-title":"A new penumbra: Transitioning from injury into repair after stroke","volume":"14","author":"Lo","year":"2008","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrn2038","article-title":"Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms","volume":"8","author":"Block","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_8","first-page":"73","article-title":"Microglia and ischemic stroke: A double-edged sword","volume":"5","author":"Patel","year":"2013","journal-title":"Int. JPPP"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1126\/science.1110647","article-title":"Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo","volume":"308","author":"Nimmerjahn","year":"2005","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nm.2399","article-title":"The immunology of stroke: From mechanisms to translation","volume":"17","author":"Iadecola","year":"2011","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.tins.2005.12.005","article-title":"Microglial phenotype: Is the commitment reversible?","volume":"29","author":"Schwartz","year":"2006","journal-title":"Trends Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/glia.22654","article-title":"What is microglia neurotoxicity (Not)?","volume":"62","author":"Biber","year":"2014","journal-title":"Glia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.4049\/jimmunol.176.2.1046","article-title":"Microglia proliferation is regulated by hydrogen peroxide from NADPH oxidase","volume":"176","author":"Mander","year":"2006","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5827","DOI":"10.1523\/JNEUROSCI.1236-08.2008","article-title":"Zinc triggers microglial activation","volume":"28","author":"Kauppinen","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1089\/ars.2013.5607","article-title":"NADPH Oxidases in Vascular Pathology","volume":"20","author":"Konior","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","article-title":"An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex","volume":"34","author":"Zhang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.freeradbiomed.2014.07.046","article-title":"Nox family NADPH oxidases: Molecular mechanisms of activation","volume":"76","author":"Brandes","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.1073\/pnas.1031526100","article-title":"Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase","volume":"100","author":"Hoyal","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"H105","DOI":"10.1152\/ajpheart.00298.2011","article-title":"Membrane depolarization is the trigger for PI3K\/Akt activation and leads to the generation of ROS","volume":"302","author":"Chatterjee","year":"2012","journal-title":"Am. J. Physiol. Heart C"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1146\/annurev-immunol-032712-095946","article-title":"Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells","volume":"31","author":"Okkenhaug","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nm1284","article-title":"Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis","volume":"11","author":"Camps","year":"2005","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/nm1291","article-title":"PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus","volume":"11","author":"Barber","year":"2005","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1161\/CIRCRESAHA.109.207449","article-title":"Involvement of Phosphoinositide 3-Kinase gamma in Angiogenesis and Healing of Experimental Myocardial Infarction in Mice","volume":"106","author":"Siragusa","year":"2010","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/nrd2145","article-title":"PI3K gamma inhibition: Towards an \u2018aspirin of the 21st century\u2019?","volume":"5","author":"Ruckle","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bbi.2009.12.003","article-title":"Involvement of phosphoinositide 3-kinase gamma in the neuro-inflammatory response and cognitive impairments induced by beta-amyloid 1\u201340 peptide in mice","volume":"24","author":"Passos","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10390","DOI":"10.1523\/JNEUROSCI.0546-15.2015","article-title":"Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury","volume":"35","author":"Huang","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.bbrc.2010.07.116","article-title":"Phosphoinositide 3-kinase-gamma expression is upregulated in brain microglia and contributes to ischemia-induced microglial activation in acute experimental stroke","volume":"399","author":"Jin","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1161\/STROKEAHA.110.601369","article-title":"Phosphatidylinositol-3-Kinase Gamma Plays a Central Role in Blood-Brain Barrier Dysfunction in Acute Experimental Stroke","volume":"42","author":"Jin","year":"2011","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1007\/s12035-015-9472-z","article-title":"Phosphoinositide 3-Kinase gamma Restrains Neurotoxic Effects of Microglia After Focal Brain Ischemia","volume":"53","author":"Schmidt","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1038\/nn.2937","article-title":"PI3K gamma is required for NMDA receptor-dependent long-term depression and behavioral flexibility","volume":"14","author":"Kim","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1146\/annurev-pharmtox-010510-100505","article-title":"Hydrogen Sulfide and Cell Signaling","volume":"51","author":"Li","year":"2011","journal-title":"Annu. Rev. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ijcard.2010.07.012","article-title":"The protective role of hydrogen sulfide in myocardial ischemia-reperfusion-induced injury in diabetic rats","volume":"152","author":"Gao","year":"2011","journal-title":"Int. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H801","DOI":"10.1152\/ajpheart.00377.2008","article-title":"Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: Role of antioxidant and antiapoptotic signaling","volume":"295","author":"Jha","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1002\/bjs.8956","article-title":"Effects of hydrogen sulphide in an experimental model of renal ischaemia-reperfusion injury","volume":"99","author":"Hunter","year":"2012","journal-title":"Br. J. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"32124","DOI":"10.1074\/jbc.M112.374124","article-title":"A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death","volume":"287","author":"Marutani","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1039\/C4OB00830H","article-title":"Design, synthesis and biological evaluation of hydrogen sulfide releasing derivatives of 3-n-butylphthalide as potential antiplatelet and antithrombotic agents","volume":"12","author":"Wang","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1089\/ars.2013.5587","article-title":"CaMKKbeta-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation","volume":"21","author":"Zhou","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1111\/jnc.12695","article-title":"Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia","volume":"129","author":"Wang","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1002\/glia.22553","article-title":"NOSH-aspirin (NBS-1120), a novel nitric oxide and hydrogen sulfide releasing hybrid, attenuates neuroinflammation induced by microglial and astrocytic activation: A new candidate for treatment of neurodegenerative disorders","volume":"61","author":"Lee","year":"2013","journal-title":"Glia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.phrs.2014.04.009","article-title":"Hydrogen sulfide attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation","volume":"84","author":"Zhang","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12974-016-0488-8","article-title":"Sodium thiosulfate attenuates glial-mediated neuroinflammation in degenerative neurological diseases","volume":"13","author":"Lee","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.brainres.2012.10.046","article-title":"Exogenous hydrogen sulfide protects against global cerebral ischemia\/reperfusion injury via its anti-oxidative, anti-inflammatory and anti-apoptotic effects in rats","volume":"1491","author":"Yin","year":"2013","journal-title":"Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/j.1474-9726.2009.00543.x","article-title":"Neuroprotective effects of hydrogen sulfide on Parkinson\u2019s disease rat models","volume":"9","author":"Hu","year":"2010","journal-title":"Aging Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.1074\/jbc.M116.766758","article-title":"Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells","volume":"292","author":"Lee","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13024-017-0150-7","article-title":"NADPH oxidase in brain injury and neurodegenerative disorders","volume":"12","author":"Ma","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB signaling: Navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e580","DOI":"10.1038\/cddis.2013.111","article-title":"Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death","volume":"4","author":"Shen","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nrd2425","article-title":"Hydrogen sulphide and its therapeutic potential","volume":"6","author":"Szabo","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1089\/ars.2013.5604","article-title":"Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide","volume":"21","author":"Xie","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"H1310","DOI":"10.1152\/ajpheart.00339.2009","article-title":"Hydrogen sulfide protects cardiomyocytes from hypoxia\/reoxygenation-induced apoptosis by preventing GSK-3 beta-dependent opening of mPTP","volume":"298","author":"Yao","year":"2010","journal-title":"Am. J. Physiol. Heart C"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9161","DOI":"10.1073\/pnas.1202916109","article-title":"Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation","volume":"109","author":"Coletta","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11788","DOI":"10.1039\/C4CC00968A","article-title":"Hydrogen sulfide (H2S) releasing agents: Chemistry and biological applications","volume":"50","author":"Zhao","year":"2014","journal-title":"Chem. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1089\/ars.2009.2899","article-title":"The effect of hydrogen sulfide donors on lipopolysaccharide-induced formation of inflammatory mediators in macrophages","volume":"12","author":"Whiteman","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1161\/01.STR.0000204184.34946.41","article-title":"Hydrogen sulfide is a mediator of cerebral ischemic damage","volume":"37","author":"Qu","year":"2006","journal-title":"Stroke"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.bcp.2012.10.019","article-title":"Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras","volume":"85","author":"Kashfi","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"17318","DOI":"10.1074\/jbc.M110.115261","article-title":"Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation: Potential for treating Parkinson disease","volume":"285","author":"Lee","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.neuint.2011.01.023","article-title":"ACS84, a novel hydrogen sulfide-releasing compound, protects against amyloid beta-induced cell cytotoxicity","volume":"58","author":"Liu","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jns.2016.03.029","article-title":"Comparisons between Garcia, Modo, and Longa rodent stroke scales: Optimizing resource allocation in rat models of focal middle cerebral artery occlusion","volume":"364","author":"Bachour","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0006-8993(00)02100-4","article-title":"Neurological impairment in rats after transient middle cerebral artery occlusion: A comparative study under various treatment paradigms","volume":"863","author":"Zausinger","year":"2000","journal-title":"Brain Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"227","DOI":"10.2217\/fnl.10.1","article-title":"Microglia in ischemic brain injury","volume":"5","author":"Weinstein","year":"2010","journal-title":"Future Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1189\/jlb.1109766","article-title":"Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells","volume":"87","author":"Jin","year":"2010","journal-title":"J. Leukocyte Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1161\/STROKEAHA.108.534503","article-title":"Temporal and spatial dynamics of cerebral immune cell accumulation in stroke","volume":"40","author":"Gelderblom","year":"2009","journal-title":"Stroke"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.neuroscience.2009.04.025","article-title":"Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice","volume":"161","author":"Schilling","year":"2009","journal-title":"Neuroscience"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0014-4886(03)00082-7","article-title":"Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: A study in green fluorescent protein transgenic bone marrow chimeric mice","volume":"183","author":"Schilling","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.expneurol.2005.08.004","article-title":"Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: An investigation using green fluorescent protein transgenic bone marrow chimeric mice","volume":"196","author":"Schilling","year":"2005","journal-title":"Exp. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/sj.jcbfm.9600324","article-title":"Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: Histochemical and myeloperoxidase correlation with temporal changes in brain injury","volume":"27","author":"Weston","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5134","DOI":"10.1038\/s41598-017-05457-z","article-title":"Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR\/ERK\/MMP-2 and PTEN\/AKT signaling pathways","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.nbd.2015.04.020","article-title":"Oxidative and nitrative stress in neurodegeneration","volume":"84","author":"Cobb","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1038\/nrn1434","article-title":"Oxidative stress in neurodegeneration: Cause or consequence?","volume":"10","author":"Andersen","year":"2004","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1089\/ars.2012.4721","article-title":"Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2","volume":"18","author":"Kahles","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1089\/ars.2013.5778","article-title":"Pathophysiology and Treatments of Oxidative Injury in Ischemic Stroke: Focus on the Phagocytic NADPH Oxidase 2","volume":"23","author":"Carbone","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/00004647-200104000-00006","article-title":"Induction of gp91-phox, a component of the phagocyte NADPH oxidase, in microglial cells during central nervous system inflammation","volume":"21","author":"Green","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1021\/jm4001693","article-title":"Novel Hybrids of Optically Active Ring-Opened 3-n-Butylphthalide Derivative and Isosorbide as Potential Anti-Ischemic Stroke Agents","volume":"56","author":"Wang","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.bbi.2016.03.019","article-title":"Nafamostat mesilate improves function recovery after stroke by inhibiting neuroinflammation in rats","volume":"56","author":"Li","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1161\/01.STR.20.1.84","article-title":"Reversible middle cerebral artery occlusion without craniectomy in rats","volume":"20","author":"Longa","year":"1989","journal-title":"Stroke"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1523\/JNEUROSCI.3834-03.2004","article-title":"Efficacy of rehabilitative experience declines with time after focal ischemic brain injury","volume":"24","author":"Biernaskie","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1097\/00004647-199607000-00010","article-title":"Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion","volume":"16","author":"Hara","year":"1996","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1523\/JNEUROSCI.5643-07.2008","article-title":"Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra","volume":"28","author":"Kaushal","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1124\/jpet.107.120097","article-title":"Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral Hemorrhage","volume":"322","author":"Jung","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/1742-2094-11-107","article-title":"Adjudin protects against cerebral ischemia reperfusion injury by inhibition of neuroinflammation and blood-brain barrier disruption","volume":"11","author":"Liu","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fncel.2017.00154","article-title":"NOSH-NBP, a Novel Nitric Oxide and Hydrogen Sulfide- Releasing Hybrid, Attenuates Ischemic Stroke-Induced Neuroinflammatory Injury by Modulating Microglia Polarization","volume":"11","author":"Ji","year":"2017","journal-title":"Front. Cell. 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