Ligustroflavone reduces necroptosis in rat brain after ischemic stroke through targeting RIPK1/RIPK3/MLKL pathway

Zhang, Yiyue; Liu, Weining; Li, Yue-Qi; Zhang, Xiaojie; Yang, Jie; Luo, Xiu-Ju; Peng, Jun

doi:10.1007/s00210-019-01656-9

Cited by 40 publications

(21 citation statements)

References 22 publications

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“…For example, Gsk′872 (RIP3 inhibitor) combined with RIP3 siRNA reduces the levels of RIP1, RIP3, and MLKL and MLKL phosphorylation, which protects the neurological system [ 171 ]. Chinese herbs or their active ingredients reduce the content of necroptosis-related proteins (RIP3, MLKL, and phosphorylated MLKL), which suppresses necroptosis and improves neurological function in rats following MCAO [ 190 ].…”

Section: Pharmacotherapies For Ischemic Stroke Targeting Ferroptosis and Necroptosismentioning

confidence: 99%

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.

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Section: Pharmacotherapies For Ischemic Stroke Targeting Ferroptosis and Necroptosismentioning

confidence: 99%

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Assembly of RIPK1 and RIPK3 through a series of RIPK1 and RIPK3 auto-and trans-phosphorylation events leads to the formation of necrosome complex followed by the recruitment of MLKL and creation of a supramolecular protein complex at the plasma membrane, which is responsible for executing the necroptosis [13]. The studies from other labs and ours have repeatedly demonstrated that brain cell necroptosis occurred in ischemic stroke animal models and targeting necroptosis signi cantly reduced the cerebral ischemic injury in vivo and hypoxic injury in the cultured nerve cells [14][15][16][17].Since necroptosis is mediated by RIPK1/RIPK3/MLKL signaling pathway, most of the current interventions thus focus on RIPK1, RIPK3 or MLKL. For example, necrostatin-1 can reduce infarct volume and improve neurological scores in the ischemic stroke animals via inhibition of RIPK1 while GSK'872 can prevent brain cell necroptosis in stroke rats via targeting RIPK3 [18,19].…”

Section: Discussionmentioning

confidence: 57%

“…For example, necrostatin-1 can reduce infarct volume and improve neurological scores in the ischemic stroke animals via inhibition of RIPK1 while GSK'872 can prevent brain cell necroptosis in stroke rats via targeting RIPK3 [18,19]. Recently, we have reported that both ponatinib, a tyrosine kinase receptor inhibitor for therapy of chronic myelogenous leukemia (CML), and ligustro avone, an ingredient from natural herb named common privet, can protect the rat brain from ischemic injury via targeting RIPK1 and/or RIPK3 [14,20]. Among these RIPK1/RIPK3 inhibitors or regulators, the clinical prospect for necrostatin-1, GSK'872 and ligustro avone remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Caspofungin suppresses brain cell necroptosis in the ischemic stroke rat via up-regulation of Pellino3

Zhang

Tian

Peng

et al. 2021

Preprint

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Purpose Pellino3, an ubiquitin E3 ligase, prevents the formation of the death-induced signaling complex in response to TNF-α via targeting receptor-interacting protein kinase 1 (RIPK1), and bioinformatics analysis predicts the interaction between Pellino3 and caspofungin, a common antifungal drug used in clinic. This study aims to explore the effect of caspofungin on brain injury in ischemic stroke and the underlying mechanisms. Methods The SD rat brains (or nerve cells) were subjected to 2h-ischemia (or 8h-hypoxia) plus 24h-reperfusion (or 24h-reoxygenation) to establish the I/R (or H/R) injury model. The cerebral injury was assessed by the methods of triphenyltetrazolium chloride (TTC) staining and Hematoxylin & eosin (H&E) staining. The correlations among caspofungin, Pellino3 and necroptosis in I/R-treated brain or H/R-treated nerve cells were evaluated by biochemistry, molecular and gene overexpression assays. Results The I/R-treated brain showed the injuries (increase in neurological deficit score and infarct volume), downregulation of Pellino3, decreased ubiquitination of RIPK1 and up-regulation of necroptosis-associated proteins [RIPK1, RIPK3, mixed lineage kinase domain-like protein (MLKL), p-RIPK1, p-RIPK3 and p-MLKL]. Caspofungin treatment improved neurological function, reduced infarct volume, up-regulated Pellino3, increased RIPK1 ubiquitination and down-regulated levels of RIPK1, p-RIPK1, p-RIPK3 and p-MLKL. In PC12 cells, H/R treatment caused cellular injury (LDH release and necroptosis), downregulation of Pellino3, decreased ubiquitination of RIPK1 and up-regulation of necroptosis-associated proteins, these phenomena were reversed by overexpression of Pellino3. Conclusion Pellino3 has an important role in counteracting necroptosis via ubiquitination of RIPK1 and caspofungin can suppress the brain cell necroptosis in ischemic stroke via upregulation of Pellino3.

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“…RIPK1 and RIPK3 were both critical regulators of necroptosis. As necroptosis occurred, RIPK3 level consistently increased, but RIPK1 level may increase (Xu et al, 2019;Zhang et al, 2019) or decrease (Motani et al, 2011;Tian et al, 2013) under different stimuli-inducing necroptosis. In our study, the RIPK1 expression decreased after the combination treatment of rapamycin and MK-2206.…”

Section: Discussionmentioning

confidence: 97%

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

et al. 2020

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Neuroblastoma (NB) is the most common pediatric malignant extracranial solid tumor. Despite multi-modality therapies, the emergence of drug resistance is an obstacle in the treatment of high-risk NB patients (with MYCN amplification). In our previous study, we found that rapamycin and MK-2206 synergistically induced cell death in MYCN-amplified cell lines but the mechanisms remained unclear. In our present study, either 3-MA or necroatatin-1 blocked the cell death induced by rapamycin and MK-2206, but z-VAD-fmk did not block this cell death. The expressions of autophagy markers (ATG5, ATG7, Beclin-1, LC3 B) and the necroptosis marker RIPK3 increased and another necroptosis marker RIPK1 decreased after the combination treatment of rapamycin and MK-2206, and were accompanied by the morphological characteristics of autophagy and necroptosis. In NB xenograft tumor tissues, the expressions of autophagy and necroptosis markers were consistent with observations in vitro. These data suggested that autophagy and necroptosis contributed to the cell death induced by rapamycin and MK-2206 in NB cells. To understand the role of MYCN in this process, MYCN expression was downregulated in MYCN-amplified cell lines (NGP, BE2) using siRNAs and was upregulated in MYCN non-amplified cell lines (AS, SY5Y) using plasmid. We found the cell death induced by rapamycin and MK-2206 was MYCN-dependent. We also found that the metabolic activity in NB cells was correlated with the expression level of MYCN. This study delineates the role of MYCN in the cell death induced by combination treatment of rapamycin and MK-2206 in MYCN-amplified NB cells.

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Ligustroflavone reduces necroptosis in rat brain after ischemic stroke through targeting RIPK1/RIPK3/MLKL pathway

Cited by 40 publications

References 22 publications

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Caspofungin suppresses brain cell necroptosis in the ischemic stroke rat via up-regulation of Pellino3

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

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