Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.
机构：[1]School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China[2]Institute of Research and Innovation (HKU-SIRI), The University of Hong Kong-Shenzhen, Shenzhen, China[3]School of Medical Technology, Xuzhou Medical University, Xuzhou 221002, China[4]Department of Chemistry, Morningside Laboratory for Chemical Biology, The University of Hong Kong, Hong Kong, SAR, China[5]Department of Core Facility, The People’s Hospital of Bao-an, Shenzhen, China深圳市宝安区人民医院深圳市康宁医院深圳医学信息中心[6]Department of Neurology, Huizhou First Hospital, Huizhou, Guangdong, China[7]Department of Pharmaceutical Sciences, College of Pharmacy, The University of New Mexico, Albuquerque, NM 87131, USA[8]Institution of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
Peroxynitrite (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.
基金：
This work is supported by Hong Kong General Research Fund (GRF No. 17102915, GRF No. 17118717), Research Grant Council, Hong Kong SAR and Health and Medical Research Fund, Hong Kong SAR (NO. 13142901), AoE/P-705/16 Areas of Excellence Scheme, RGC, Hong Kong SAR; SIRI/04/04/2015/06 Shenzhen Basic Research Plan Project. National Natural Science Foundation of China (No. 81671164).
第一作者机构：[1]School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China[2]Institute of Research and Innovation (HKU-SIRI), The University of Hong Kong-Shenzhen, Shenzhen, China
通讯作者：
通讯机构：[1]School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China[2]Institute of Research and Innovation (HKU-SIRI), The University of Hong Kong-Shenzhen, Shenzhen, China[8]Institution of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
推荐引用方式(GB/T 7714)：
Hansen Chen,Binghe Guan,Bin Wang,et al.Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.[J].TRANSLATIONAL STROKE RESEARCH.2020,11(5):967-982.doi:10.1007/s12975-019-00772-1.
APA：
Hansen Chen,Binghe Guan,Bin Wang,Haiwei Pu,Xiaoyu Bai...&Jiangang Shen.(2020).Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling..TRANSLATIONAL STROKE RESEARCH,11,(5)
MLA：
Hansen Chen,et al."Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.".TRANSLATIONAL STROKE RESEARCH 11..5(2020):967-982
医学