Inhibition of hypoxia inducible factor 1 by YC-1 attenuates tissue plasminogen activator induced hemorrhagic transformation by suppressing HMGB1/TLR4/NF-κB mediated neutrophil infiltration in thromboembolic stroke rats

Kong, Ling-Lei; Ma, Yinglong; Wang, Zhiyuan; Liu, Nannan; Ma, Guodong; Liu, Chengdi; Ruili, Shi; Du, Guanhua

doi:10.1016/j.intimp.2021.107507

Cited by 20 publications

(13 citation statements)

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“…Experimental and clinical studies have demonstrated the role of DAMPs (e.g., HMGB1 and Prxs) in TLR4-activated neuroinflammation after brain ischemia and hemorrhage [ 11 , 16 , 56 , 57 ]. HMGB1 levels significantly increased in tPA-treated ischemic stroke patients and tMCAO rats [ 21 , 22 ]. To our knowledge, only two recently published papers reported preventive effects of two compounds (glycyrrhizin and YC-1) against tPA-induced HT via the suppression of HMGB1/TLR2 or HMGB1/TLR4 signaling in ischemic stroke rats [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…HMGB1 levels significantly increased in tPA-treated ischemic stroke patients and tMCAO rats [ 21 , 22 ]. To our knowledge, only two recently published papers reported preventive effects of two compounds (glycyrrhizin and YC-1) against tPA-induced HT via the suppression of HMGB1/TLR2 or HMGB1/TLR4 signaling in ischemic stroke rats [ 21 , 22 ]. In the present study, we detected Prx1/TLR4 pathway activation in tPA-infused tMCAO mice.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MSR1 promoted macrophage M2-like polarization and induced the osteogenic differentiation of bone marrow stem cells (BMSCs) in a co-culture system [ 20 ]. Notably, recent research found that plasma levels of HMGB1 significantly increased in tPA-treated ischemic stroke patients, and HMGB1-triggered neuroinflammation aggravated tPA-mediated HT in a rat model of ischemic stroke [ 21 , 22 ]. Nevertheless, the therapeutic potential of MSR1 for thrombolysis-induced HT after acute ischemic stroke has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

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Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Liu

Hong

et al. 2021

J Neuroinflammation

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Background Hemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells. Methods The tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1−/−) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1−/− mice. Results Seventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1−/− mice, respectively. Conclusion The phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Liu

Hong

et al. 2021

J Neuroinflammation

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“…66 Moreover, YC-1 suppressed the release of neutrophil, inammatory factor and the activation of the HMGB1/TLR4/NF-NF-kB signaling pathway to protect BBB integrity. 67 Therefore, YC-1 has a protective effect on the cerebral vascular system. 66,67 Fig.…”

Section: Hypoxia-inducible Factor (Hif)mentioning

confidence: 99%

“…67 Therefore, YC-1 has a protective effect on the cerebral vascular system. 66,67 Fig. 12 Effects of YC-1 derivatives (46a-e, 45f-g) on platelet aggregation induced by thrombin, arachidonic acid (AA), collagen, and platelet-activating factor (PAF).…”

Section: Hypoxia-inducible Factor (Hif)mentioning

confidence: 99%

Synthetic strategy and structure–activity relationship (SAR) studies of 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1, Lificiguat): a review

Hung

2022

RSC Adv.

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HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation

Li,

Wang,

et al. 2024

Transl. Stroke Res.

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Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration of rtPA is essential for restoring perfusion in acute ischemic stroke, though it concurrently elevates the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player in neuroinflammation after brain ischemia and ischemia–reperfusion. Released passively by necrotic cells and actively secreted, including direct secretion of HMGB1 into the extracellular space and packaging of HMGB1 into intracellular vesicles by immune cells, glial cells, platelets, and endothelial cells, HMGB1 represents a prototypical damage-associated molecular pattern (DAMP). It is intricately involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Moreover, HMGB1 significantly contributes to neurovascular remodeling and functional recovery in later stages. Significantly, HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the integrity of the blood–brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells. This includes mediating excitotoxicity due to excitatory amino acids, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. In this review, we summarize the structure and redox properties, secretion and pathways, regulation of immune cell activity, the role of pathophysiological mechanisms in stroke, and hemorrhage transformation for HMGB1, which will pave the way for developing new neuroprotective drugs, reduction of post-stroke neuroinflammation, and expansion of thrombolysis time window.

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Inhibition of hypoxia inducible factor 1 by YC-1 attenuates tissue plasminogen activator induced hemorrhagic transformation by suppressing HMGB1/TLR4/NF-κB mediated neutrophil infiltration in thromboembolic stroke rats

Cited by 20 publications

References 51 publications

Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Synthetic strategy and structure–activity relationship (SAR) studies of 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1, Lificiguat): a review

HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation

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