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Article: Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling

TitleGlycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling
Authors
KeywordsHemorrhagic transformation (HT)
High mobility group box protein 1 (HMGB1)
Glycyrrhizin
Peroxynitrite (ONOO−)
Tissue plasminogen activator (t-PA)
Issue Date2020
PublisherSpringer New York LLC. The Journal's web site is located at http://www.springer.com/biomed/neuroscience/journal/12975
Citation
Translational Stroke Research, 2020, v. 11 n. 5, p. 967-982 How to Cite?
AbstractPeroxynitrite (ONOO−) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO− in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO− could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO−) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO− decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO− donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO− could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO− production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO− production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO−/HMGB1/TLR2 signaling cascades.
Persistent Identifierhttp://hdl.handle.net/10722/293269
ISSN
2023 Impact Factor: 3.8
2023 SCImago Journal Rankings: 1.595
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChen, H-
dc.contributor.authorGuan, B-
dc.contributor.authorWang, B-
dc.contributor.authorPu, H-
dc.contributor.authorBAI, X-
dc.contributor.authorChen, X-
dc.contributor.authorLiu, J-
dc.contributor.authorLi, C-
dc.contributor.authorQiu, J-
dc.contributor.authorYang, D-
dc.contributor.authorLiu, K-
dc.contributor.authorWang, Q-
dc.contributor.authorQi, S-
dc.contributor.authorShen, J-
dc.date.accessioned2020-11-23T08:14:17Z-
dc.date.available2020-11-23T08:14:17Z-
dc.date.issued2020-
dc.identifier.citationTranslational Stroke Research, 2020, v. 11 n. 5, p. 967-982-
dc.identifier.issn1868-4483-
dc.identifier.urihttp://hdl.handle.net/10722/293269-
dc.description.abstractPeroxynitrite (ONOO−) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO− in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO− could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO−) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO− decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO− donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO− could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO− production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO− production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO−/HMGB1/TLR2 signaling cascades.-
dc.languageeng-
dc.publisherSpringer New York LLC. The Journal's web site is located at http://www.springer.com/biomed/neuroscience/journal/12975-
dc.relation.ispartofTranslational Stroke Research-
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: https://doi.org/[insert DOI]-
dc.subjectHemorrhagic transformation (HT)-
dc.subjectHigh mobility group box protein 1 (HMGB1)-
dc.subjectGlycyrrhizin-
dc.subjectPeroxynitrite (ONOO−)-
dc.subjectTissue plasminogen activator (t-PA)-
dc.titleGlycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling-
dc.typeArticle-
dc.identifier.emailYang, D: yangdan@hku.hk-
dc.identifier.emailShen, J: shenjg@hku.hk-
dc.identifier.authorityYang, D=rp00825-
dc.identifier.authorityShen, J=rp00487-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s12975-019-00772-1-
dc.identifier.pmid31872339-
dc.identifier.scopuseid_2-s2.0-85076934487-
dc.identifier.hkuros319904-
dc.identifier.volume11-
dc.identifier.issue5-
dc.identifier.spage967-
dc.identifier.epage982-
dc.identifier.isiWOS:000504163200001-
dc.publisher.placeUnited States-

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