Programmed Necrosis and Disease:We interrupt your regular programming to bring you necroinflammation

Kim, Eui Ho; Wong, Sing‐Wai; Martinez, Jennifer

doi:10.1038/s41418-018-0179-3

Cited by 121 publications

(72 citation statements)

References 198 publications

(228 reference statements)

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“…It has been proven that ferroptotic cells trigger the innate immune system in mouse models of the brain and kidney disease [60]. The activated innate immune system can initiate local inflammation and subsequently lead to necroinflammation in remote organs via spreading damage-associated molecular patterns and cytokines to systemic circulation from primary ischemic organ [59, 61]. In the present study, I/R-induced ferroptosis likely activated the innate immune system and led to the infiltration of immune cells [62] in the intestine.…”

Section: Discussionmentioning

confidence: 99%

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion

et al. 2019

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Ferroptosis is a recently identified form of regulated cell death defined by the iron-dependent accumulation of lipid reactive oxygen species. Ferroptosis has been studied in various diseases such as cancer, Parkinson’s disease, and stroke. However, the exact function and mechanism of ferroptosis in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. Considering the unique conditions required for ferroptosis, we hypothesize that ischemia promotes ferroptosis immediately after intestinal reperfusion. In contrast to conventional strategies employed in I/R studies, we focused on the ischemic phase. Here we verified ferroptosis by assessing proferroptotic changes after ischemia along with protein and lipid peroxidation levels during reperfusion. The inhibition of ferroptosis by liproxstatin-1 ameliorated I/R-induced intestinal injury. Acyl-CoA synthetase long-chain family member 4 (ACSL4), which is a key enzyme that regulates lipid composition, has been shown to contribute to the execution of ferroptosis, but its role in I/R needs clarification. In the present study, we used rosiglitazone (ROSI) and siRNA to inhibit ischemia/hypoxia-induced ACSL4 in vivo and in vitro. The results demonstrated that ACSL4 inhibition before reperfusion protected against ferroptosis and cell death. Further investigation revealed that special protein 1 (Sp1) was a crucial transcription factor that increased ACSL4 transcription by binding to the ACSL4 promoter region. Collectively, this study demonstrates that ferroptosis is closely associated with intestinal I/R injury, and that ACSL4 has a critical role in this lethal process. Sp1 is an important factor in promoting ACSL4 expression. These results suggest a unique and effective mechanistic approach for intestinal I/R injury prevention and treatment.

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Section: Discussionmentioning

confidence: 99%

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion

et al. 2019

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“…After localization onto the lipid bilayer, MLKL promotes the formation of pores across the membrane, leading to the swelling and rupture of organelles or cytoplasm [ 35 , 36 ]. In addition, mPTP-mediated ATP depletion is a feature of necroptosis [ 37 ]. Although Ripk3 upregulation, PGAM5 activation, and mPTP opening have been observed in the context of cardiac microvascular I/R injury [ 25 , 26 ], the downstream events and molecular alterations in endothelial cells have not been identified.…”

Section: Introductionmentioning

confidence: 99%

SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways

Toan

et al. 2020

Redox Biology

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Endothelial cells lining the microvasculature are particularly vulnerable to the deleterious effects of cardiac ischemia/reperfusion (I/R) injury, a susceptibility that is partially mediated by dysregulated intracellular calcium signals. Sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) functions to recycle calcium from the cytosol back to the endoplasmic reticulum. The purpose of this study is to explore the roles and mechanisms of SERCA in protecting microcirculation against cardiac I/R injury. Our data showed that overexpression of SERCA significantly reduced I/R-induced luminal stenosis and vascular wall edema, possibly through normalization of the ratio between eNOS and ET-1. I/R-induced erythrocyte morphological changes in micro-vessels could be reversed by SERCA overexpression through transcriptional inhibition of the expression of adhesive factors. In addition, SERCA-sustained endothelial barrier integrity reduced the likelihood of inflammatory cells infiltrating the myocardium. Furthermore, we found that SERCA overexpression attenuated intracellular calcium overload, suppressed mitochondrial calcium uniporter (MCU) expression, and prevented the abnormal opening of mitochondrial permeability transition pores (mPTP) in I/R-treated cardiac microvascular endothelial cells (CMECs). Interestingly, the administration of calcium activator or MCU agonist induced endothelial necroptosis in vitro and thus abolished the microvascular protection afforded by SERCA in reperfused heart tissue in vivo . In conclusion, by using gene delivery strategies to specifically target SERCA in vitro and in vivo , we identify a potential novel pathway by which SERCA overexpression protects microcirculation against cardiac I/R injury in a manner dependent on the calcium/MCU/necroptosis pathway. These findings should be taken into consideration in the development of pharmacological strategies for therapeutic interventions against cardiac microvascular I/R injury.

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“…Enhancement of TrxR2 could attenuate LPS-mediated N2a cell death via inhibiting apoptosis. 61 Besides, TrxR2 overexpression also sustained mitochondrial function, alleviated oxidative stress and blocked mitochondrial apoptosis. As far as we know, this is the first study to explore the influence of TrxR2 in the LPS-mediated neural dysfunction and mitochondrial apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…In cerebral ischemia reperfusion injury, the Akt pathway is inactivated and promotes the neuronal autophagic injury in a manner dependent on the PI3K/mTOR signaling pathway. 61 In seizure-induced brain injury, dynorphin activation protects against neuronal death via activating the Akt/HO-1 pathway. Besides, blood brain barrier function is also sustained by KY226 via the Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

TrxR2 overexpression alleviates inflammation-mediated neuronal death via reducing the oxidative stress and activating the Akt–Parkin pathway

Gao¹,

Li²,

Li³

et al. 2019

Toxicology Research

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Neuronal death caused by inflammatory cytokine-mediated neuroinflammation is being extensively explored. Thioredoxin reductase (TrxR) 2 is a novel mediator of inflammation response. In the current study, we focus on the mechanisms of TrxR2 overexpression in inflammation-mediated neuronal death. LPS was used to induce neuroinflammation in N2a cells in vitro. Adenovirus-loaded TrxR2 was transfected into N2a cells to up-regulate TrxR2 expression. Then, cell viability was determined via MTT assay and TUNEL assay. Apoptosis was measured via western blotting and ELISA. Oxidative stress was detected via ELISA and flow cytometry. A pathway inhibitor was used to verify the role of the Akt–Parkin pathway in the LPS-mediated N2a cell death in the presence of TrxR2 overexpression. With the help of immunofluorescence assay and western blotting, we found that TrxR2 expression was significantly reduced in response to LPS treatment, and this effect was associated with N2a cell death via apoptosis. At the molecular level, TrxR2 overexpression elevated the activity of the Akt–Parkin pathway, as evidenced by the increased expression of p-Akt and Parkin. Interestingly, inhibition of the Akt–Parkin pathway abolished the regulatory effect of TrxR2 on LPS-treated N2a cells, as evidenced by the decreased cell viability and increased apoptotic ratio. Besides, TrxR2 overexpression also reduced oxidative stress, inflammation factor transcription and mitochondrial apoptosis. However, inhibition of Akt–Parkin axis abrogated the protective effects of TrxR2 on redox balance, mitochondrial performance and cell survival. LPS-mediated neuronal death was linked to a drop in TrxR2 overexpression and the inactivation of the Akt–Parkin pathway. Overexpression of TrxR2 sustained mitochondrial function, inhibited oxidative stress, repressed inflammation response, and blocked mitochondrial apoptosis, finally sending a pro-survival signal for the N2a cells in the setting of LPS-mediated inflammation environment.

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Programmed Necrosis and Disease:We interrupt your regular programming to bring you necroinflammation

Cited by 121 publications

References 198 publications

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion

SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways

TrxR2 overexpression alleviates inflammation-mediated neuronal death via reducing the oxidative stress and activating the Akt–Parkin pathway

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