key: cord-0787541-ykllt62g
authors: Yan, Wei-Tao; Yang, Yan-Di; Hu, Xi-Min; Ning, Wen-Ya; Liao, Lyu-Shuang; Lu, Shuang; Zhao, Wen-Juan; Zhang, Qi; Xiong, Kun
title: Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies
date: 2022-01-07
journal: Neural Regen Res
DOI: 10.4103/1673-5374.331539
sha: e48b245d195d2b661bfa8c3ad0ebca7f70fdafa9
doc_id: 787541
cord_uid: ykllt62g

Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis, apoptosis and necroptosis act in consort in a multimeric protein complex, PANoptosome. This allows all the components of PANoptosis to be regulated simultaneously. PANoptosis provides a new way to study the regulation of cell death, in that different types of cell death may be regulated at the same time. To test whether PANoptosis exists in diseases other than infectious diseases, we chose cerebral ischemia/reperfusion injury as the research model, collected articles researching cerebral ischemia/reperfusion from three major databases, obtained the original research data from these articles by bibliometrics, data mining and other methods, then integrated and analyzed these data. We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion. In the cell model simulating ischemic brain injury, pyroptosis, apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons. Pyroptosis, apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury. This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.

Researchers studying forms of cell death found that the main processes of regulated cell death (RCD) included pyroptosis, apoptosis and regulated necrosis (including necroptosis) Hu et al., 2021; Yan et al., 2021) . The majority of the research topics on RCD focused on one of these three forms of cell death alone, but a few focused on the simultaneous interaction of these three forms of cell death. Some previous reports into cancer or bacterial/viral infection found that the key regulatory proteins of pyroptosis, apoptosis and necroptosis interacted with each other (Malireddi et al., 2010; Gurung et al., 2014 Gurung et al., , 2016 Malireddi et al., 2018 Malireddi et al., , 2020b Jiang et al., 2021; Meng et al., 2021) . However, it was not clear how the regulatory mechanisms of pyroptosis, apoptosis and necroptosis intersected. The later research indicated that an innate immune response can simultaneously regulate pyroptosis, apoptosis and necroptosis after the transforming growth factor beta-activated kinase 1 (TAK1) was suppressed or knocked out (Malireddi et al., 2019 . This view was confirmed in research on coronavirus disease 2019 (COVID-19) (Karki et al., 2021) . This suggests that, in the pathophysiological process of some diseases, pyroptosis, apoptosis and necroptosis can occur and be regulated at the same time. In a study by the team of Professor Kanneganti (Malireddi et al., 2019) , this phenomenon when pyroptosis (P), apoptosis (A) and necroptosis (N) are regulated at the same time was named PANoptosis, and they showed that there is a multimeric protein complex, named a PANoptosome (Christgen et al., 2020; Samir et al., 2020) , that can regulate the occurrence of PANoptosis.

A series of studies on PANoptosis reported by the Kanneganti team (Karki et al., 2020b Kesavardhana et al., 2020; Zheng et al., 2020; Briard et al., 2021) suggest that, in diseases caused by bacterial, fungal or viral infection, pathogens induce the autoimmune response and produce various inflammatory cytokines. These inflammatory cytokines activate the promoter proteins of pyroptosis, apoptosis and necroptosis through specific pathways, and drive them to assemble inflammasomes that are specific to different RCD forms (Cain et al., 2000; Chu et al., 2001; Acehan et al., 2002; Martinon et al., 2002; Agostini et al., 2004; Ogura et al., 2006; Kanneganti et al., 2007; Wallach et al., 2011; Lu et al., 2019b) , and further assemble a protein complex, PANoptosome , that can simultaneously drive pyroptosis, apoptosis and necroptosis to aggravate cell death caused by the pathogens. Apart from diseases caused by pathogens, most other diseases or pathological conditions are more or less related to an immune response, which suggests that PANoptosis associated with an immune response is highly probable. For example, one study found that interferon regulatory factor 1, as the upstream regulator of PANoptosis, can induce cell death in the process of tumorigenesis in colorectal cancer . In addition, in the exploration of the treatment of melanoma, a compound of metformin and doxorubicin initiated pyroptosis, apoptosis and necroptosis (PANoptosis) of melanoma cells, reducing the development of the melanoma .

Published studies related to PANoptosis mainly focus on diseases induced by bacterial or viral infections plus a few types of tumors Malireddi et al., 2020b; Song et al., 2021) . It is unknown whether PANoptosis and PANoptosomes exist in other types of diseases but it is worth further investigation. Many central nervous system (CNS) diseases involve the death of nerve cells, including PANoptosis (Yuan and Yankner, 2000; McKenzie et al., 2020; Yan et al., 2021) . All these diseases or pathological conditions are generally associated with inflammatory reactions (Pender and Rist, 2001; Hoffmann et al., 2009; Degterev et al., 2019; Voet et al., 2019; Yuan et al., 2019; Lünemann et al., 2021) . The expression of cell death and the pathophysiological mechanism related to inflammation in these CNS diseases are similar to the phenotype and mechanism in the existing studies of PANoptosis, which provides basic evidence for the possible existence of PANoptosis and PANoptosomes in CNS diseases.

In the Web of Science database, we investigated the experimental research articles about pyroptosis, apoptosis and necroptosis in the field of the nervous system and sorted the related articles according to the citation frequency, from high to low. Selecting the top 2% articles (referring to and expanding Essential Science Indicators standards) for keyword extraction and analysis, it was found that ischemia accounted for the highest proportion among the three death forms of PANoptosis in nervous system. Stroke is the second major cause of disability and death in adults, with ischemic stroke accounting for the majority of all stroke cases (Virani et al., 2020) , and the main injury of ischemic stroke is caused by ischemia/ reperfusion (I/R) (Meschia and Brott, 2018; Campbell et al., 2019; Yan et al., 2020a) . The pathophysiological state of I/R can cause serious brain damage, and the pathophysiological process frequently involves an inflammatory reaction and immune system activation (Chamorro et al., 2016; Lambertsen et al., 2019; Shi et al., 2019; Yan et al., 2020b) . Following the above argument we chose ischemia injury of the CNS as the analysis object.

We use bibliometrics, knowledge discovery and data-mining methods to capture evidence and analyze bibliometrics on the research of RCD related to ischemic injury of the CNS (Yan et al., 2020b) to assess the experimental research evidence on the involvement of PANoptosis in nervous system diseases. The demonstration of PANoptosis in ischemic injury of the CNS broadens the scope of PANoptosis research. This study takes a new approach to RCD research by exploring multiple RCD synchronously, pluralistically and comprehensively in ischemic injury of the CNS, and explores new ways to improve the intervention efficiency of RCD in nervous system diseases. 

We chose PubMed, Scopus and Web of Science as the target databases. The key words were divided into three groups: (1) RCD, including pyroptosis, apoptosis and necroptosis; (2) CNS and their MeSH appositive words, hyponyms or hypernyms; and (3) ischemia. The refining function of the database limited the retrieval field to neuroscience or neurosurgery or neurology. The article type was limited to research articles. The retrieval of literature was completed on June 20, 2021. The end time of the publishing time range of the literature collections retrieved, with three cell death forms as the core theme, was June 20, 2021 but their start times differed as follows: (1) PubMed database: pyroptosis was on November 1, 2018; apoptosis was on May 1, 1995; necroptosis was on January 12, 2007.

(2) Scopus database: The starting time of pyroptosis was on July 1, 2008; apoptosis on December 24, 1993. necroptosis started on July 1, 2005. (3) Web of Science database: The starting time of pyroptosis was on April 1, 2014; apoptosis on December 24, 1993; necroptosis on July 1, 2005. The retrieval strategy of each database was customized according to the usage standard of the database and the scale of the retrieved documents. Articles retrieved from each database were merged according to the three forms of cell death, and duplicate documents were screened and removed according to the inclusion criteria. The process of literature screening was shown in Figure 1 .

Studies were potentially included if they met the following criteria:

(1) The core content of the paper was to study ischemia or I/R injury or animal or cell models that can represent ischemia or I/R; (2) Rodents or primary cells or subculture cell lines were used as the experimental materials; (3) The target organ damaged in the experiment was either the brain or primary cells and subculture cells that can represent neurons; (4) The experimental results included two or more corresponding detection results that proved the existence of the three kinds of cell death: pyroptosis, apoptosis and necroptosis, one of which must be the key protein detection results of these three kinds of cell death forms; and (5) Damage treatment group and blank control group were included in the experimental design.

Studies were excluded if they met any of the criteria: (1) Druginduced animal model or cell model; (2) The target cells of the experimental study were non-neuronal cells (glial cells, endothelial cells, etc.); (3) The process and standard description of establishing the model were not given; and (4) The experimental evidence to prove the existence of any of the three cell death forms was insufficient.

Data such as cell types, animal species, modeling methods, evaluation of cell death and detection results of representative molecules of different cell death types were extracted from the included literature. The literature items exported from the database were imported into the literature management software, and two researchers with medical and biological knowledge independently read the literature one by one, conducted article selection and data mining, and obtained relevant data from the literature. The data obtained by the two researchers were compared, and the consistent results were summarized in a table. When any inconsistent results occurred, the discussion and decision for inclusion involved the participation of the third researcher. The cluster analysis of in vitro experiments was based on the cell type and had to be that used in the study of pyroptosis, apoptosis and necroptosis. Cluster analysis of in vivo experiments of animals was carried out according to the classification of common rodents, ensuring that the I/R operations performed on animals were of the same class. To summarize, the acquired core data was collated and analyzed using EndNote software (version X7.8, Clarivate Analytics, Boston, MA, USA) and Microsoft Excel software (version 2016, Microsoft Corporation, Redmond, WA, USA).

A total of 57 articles were included in this study (18 articles in pyroptosis, 22 articles in apoptosis, and 17 articles in necroptosis; Figure 1 ), of which 22 were conducted on rodents only (including rats and mice) and 31 were conducted on primary cultured cells or cell lines only and 4 studies included both in vitro cell and in vivo rodent experiments. One of the 31 articles that had experimented on two types of cell. From the included literature, we extracted 62 experiments that assessed pyroptosis or apoptosis or necroptosis. Of these studies, it was necessary to satisfy two conditions that would determine whether I/R injury in the experiment induced the occurrence of pyroptosis or apoptosis or necroptosis. One condition was that commonly used or academically recognized detection methods were used in the experiment, such as propidium iodide staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) assay, flow cytometry, cell counting kit-8 assay or lactate dehydrogenase assay to evaluate the degree of cell death induced by I/R injury. The other condition was that the key proteins of pyroptosis or apoptosis or necroptosis were detected ( Table 1) (Fink and Cookson, 2005; Bergsbaken et al., 2009; Kaczmarek et al., 2013; Nikoletopoulou et al., 2013; Czabotar et al., 2014; Kovacs and Miao, 2017; Hu et al., 2021) and that they should contain at least two or more key proteins. Both the conditions mentioned above had to give results that were statistically significant compared to the control group and be clearly stated in the paper. neuroblastoma cells) cells for the experiments. We show the results according to the cell types used in the experiments (Tables 2-5). In the included studies, most were based on rodent models, middle cerebral artery occlusion (MCAO) or modified MCAO to simulate ischemia or I/R injury but some used the method of electric shock cardiac arrest and resuscitation. These modeling methods simulate cerebral I/R injury in experimental animals and are recognized in the research field. The studies used Sprague-Dawley rats or C57 mice, and we tabulated the results according to animal type and modeling method used in the experiment (Tables 6 and 7). In the process of data mining, we found that experimental models, apart from MCAO and OGD models, did not meet the condition that pyroptosis, apoptosis and necroptosis were studied simultaneously. We extracted 62 experiments from the 57 included papers. According to the experimental results included in our analysis it appears that in the same cell model or animal disease model three kinds of RCD, i.e., pyroptosis, apoptosis, necroptosis, were likely to occur simultaneously, which would mean that PANoptosis occurs in these experiments.

In this study we selected MCAO and OGD as in vivo and in vitro experimental models, respectively, that can simulate I/R injury and its pathophysiology in the CNS. These two methods are the most widely used and generally recognized by researchers (Ryou and Mallet, 2018; Salvador et al., 2018) . Many have studied RCD induced by I/R injury of CNS using MCAO and OGD (Yanamoto et al., 2003; Tuttolomondo et al., 2009; McBride and Zhang, 2017; Ryou and Mallet, 2018; Wang et al., 2018; Li et al., 2019; Zhang et al., 2019a) , and these two methods have often been used to study the inflammatory reaction related to this kind of injury (Tuttolomondo et al., 2009; Rizzo and Leaver, 2010; Mo et al., 2020a; Stanzione et al., 2020; . Therefore, it is pertinent to discuss PANoptosis in MCAO and OGD models.

Kanneganti's proposal is that PANoptosis is a newly defined form of cell death in diseases related to the immune response and can be regulated by a multimeric protein complex, named PANoptosome (Malireddi et al., 2019) . This new form of cell death includes pyroptosis, apoptosis and necroptosis. He proposes that a PANoptosome can interfere with pyroptosis, apoptosis and necroptosis, each of which have been studied independently by other investigators. The existing research on PANoptosis suggests cysteinyl aspartate-specific protease (CASP) 1 and CASP-11 that drive pyroptosis, CASP-8 that drives apoptosis and RIP3 that drives necroptosis can all be assembled into a PANoptosome, together with other components. The process of PANoptosis can be regulated by Z-DNA-binding protein 1 and TAK1 (Christgen et al., 2020; . To support the theory that PANoptosis is a major factor in the I/R injury of the CNS first it is necessary to confirm that pyroptosis, apoptosis and necroptosis have been shown to occur simultaneously from reports in existing literature on I/R injury. Second, a PANoptosome has to have been identified in I/R injury, and have been confirmed that it can simultaneously initiate the three kinds of RCD. Third, there must be a regulatory system that controls PANoptosome activity.

The data we mined from the literature showed that in the study of cerebral I/R, under the same model condition, the three forms of cell death could occur simultaneously. According to our integrated data, after MCAO induced I/R injury in rat or mouse brain tissue and OGD induced ischemia-hypoxia injury in neurons or cell lines derived from nerve cells, pyroptosis, apoptosis and necroptosis coexisted. This phenomenon accords with the first condition of the PANoptosis definition, and suggests that it is very possible that PANoptosis exists in nervous system diseases from the phenomenon level or the phenotype level of cerebral ischemia injury. We can see from the related studies of the three kinds of RCD-pyroptosis, apoptosis and necroptosis-that the molecular mechanisms of these three kinds of cell death all have inflammation-related parts (Linkermann et al., 2013; Lu et al., 2019a; Guo et al., 2020; Wang et al., 2020c Wang et al., , 2021b Chen et al., 2021; Liu et al., 2021c) . There are also reports that glial cells can interfere with these three forms of cell death after being stimulated by injury Xu et al., 2019; Naito et al., 2020; Wang et al., 2020a; Li et al., 2021a; Liu et al., 2021b; Lu et al., 2021) and these overlap with the inflammation-related and immunerelated reports of existing studies of PANoptosis. This suggests the possibility of PANoptosis in CNS diseases at the pathological mechanism level. In the 36 cell-model-based experiments, oxygen and glucose deprivation (OGD) or OGD/recovery was used in most cell experiments to simulate ischemia or I/R injury. The researchers used primary hippocampal cells, primary cortical cells, PC12 cells (rat adrenal pheochromocytoma cells) and SH-SY5Y (human 

The latest research suggests that a PANoptosome includes three kinds of protein: (1) Z-DNA-binding protein 1, a nucleotide-binding domain and a leucine-rich repeat pyrin-domain containing protein 3 that play the role of sensor, (2) an apoptosis-associated speck-like protein, containing a caspase recruit domain, and a Fas-associated protein with death domain that are composite adapters and (3) a receptor-interacting protein kinase (RIP) 1, RIP3, CASP-1 and CASP-8 that have a catalytic effect (Christgen et al., 2020; Samir et al., 2020; Zheng and Kanneganti, 2020a, b) . These studies on the PANoptosome are related to infectious diseases and cancer, but there has been no study on PANoptosomes in the study of I/R injury of CNS. It can be seen from the data mined by us that nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 3, CASP-1 and apoptosis-associated speck-like protein containing a caspase recruit domain related to pyroptosis, CASP-8 and Fas-associated protein with death domain related to apoptosis, RIP1 and RIP3 related to necroptosis have all been detected as marker proteins in animal models of I/R and/or cell models of OGD/recovery (Tables 2-7) . All these proteins are considered to be components of a PANoptosome in infectious diseases. Although there is no study on the assembly of components of a PANoptosome in I/R injury of CNS, the existing data of the "raw materials" that make up a PANoptosome are highly expressed, indicating that there is a molecular basis for finding PANoptosomes in ischemia-induced brain injury.

There are studies that showed there are some molecules that can interfere with two of the components of PANoptosis simultaneously under the condition of I/R injury. For example, nucleotide oligomerization domain-like receptors with caspase activation and recruitment domain 4 inflammasome complex can regulate apoptosis and pyroptosis (Poh et al., 2019) . Also blocking thromboxane A synthase/thromboxane A2/thromboxane prostanoid signal can inhibit apoptosis and pyroptosis at the same time ( ASC: Apoptosis-associated speck-like protein containing a caspase recruit domain; Bax: B-cell lymphoma 2-associated X; Bcl-2: B cell lymphoma 2; CaMKII: Calcium/calmodulin-dependent kinase II; CASP: cysteinyl aspartate-specific protease; C-CASP: cleaved CASP; CCK-8: al., 2012; Kim and Li, 2013; Thapa et al., 2013; Guo et al., 2020; Wang et al., 2020b; Liao et al., 2021) , can interact with the Jun N-terminal kinase-mediated inflammatory signaling pathway that is closely related to neuronal apoptosis induced by ischemia (Wang et al., 2011; Liu et al., 2016 Liu et al., , 2018 and to cell pyroptosis Jiang et al., 2020a) . All this information suggests that pyroptosis, apoptosis and necroptosis (PANoptosis) induced by I/R injury could be subject to intervention and regulation simultaneously.

The existing studies on PANoptosis show that TAK1 and Z-DNA-binding protein 1 intervene in PANoptosome activity, and thus participate in the regulation of PANoptosis (Malireddi et al., 2019; Kesavardhana et al., 2020; Samir et al., 2020; Zheng and Kanneganti, 2020b) . We have not found any internal or external molecules that can interfere with all three of pyroptosis, apoptosis and necroptosis in cerebral ischemia injury, but some studies have shown that inhibiting TAK1 can reduce neuronal death induced by cerebral I/R (Neubert et al., 2011) . This indicates that TAK1 can be used as an important target in RCD induced by hypoxia-reperfusion injury (Neubert et al., 2011; Ridder and Schwaninger, 2013; Wu et al., 2020b) . TAK1 can affect the function of microglia and interact with inflammatory pathway, thus affecting neuronal apoptosis and pyroptosis (Gong et al., 2015; Zeyen et al., 2020) . It also plays an important role in the interaction between programmed necrosis and apoptosis of neurons mediated by RIP3 during cerebral I/R injury (Naito et al., 2020) . All these data suggest that there may be molecules, like TAK1, that can regulate PANoptosomes in a brain subject to I/R injury.

Although this paper verifies the possibility of PANoptosis in cerebral ischemia reperfusion injury by collecting data from cell experiments and animal experiments, we admit that this paper has some limitations. First, the limits of paper length and research scale meant we could not conduct data mining for all CNS diseases, therefore we selected only cerebral I/R injury as the research object. This limited the outcome to only showing whether PANoptosis exists in cerebral I/R injury. Whether PANoptosis occurs in other CNS diseases remains to be studied. Second, the data we mined were mainly cell experiments and animal experiments, without clinical samples. Whether PANoptosis occurs in actual clinical stroke needs further verification. Third, the disease models we analyzed were only MCAO and OGD, therefore other ischemia/reperfusion models would need to be studied. Fourth, we only selected three databases for retrieval, whereas there are other databases. Fifth, our retrieval fields are mainly from title, abstract and keywords, so some relevant papers may have been missed. These limitations need to be addressed in future studies.

Analysis of existing research highlights how important PANoptosis is and shows how its interaction network of processes is associated with RCD in infectious diseases. The concept of PANoptosis improves our understanding of RCD, suggesting that we should treat and understand RCD systematically, plurally and as a network. Although the current research focuses mainly on infectious diseases, this review proposes expanding investigations of PANoptosis to other diseases. In the pathophysiological mechanism of CNS diseases the inflammatory response and immune response play important roles that are similar to their effects in infectious diseases. Moreover, there are interactions between regulatory proteins that regulate the disease response and immune response of CNS diseases. However, systematic and comprehensive research on these interactions still needs further study. In future, the research on PANoptosis in CNS diseases should examine the interaction network of key regulatory proteins, identify a PANoptosome linked to CNS diseases, find the target of PANoptosis that can intervene in neurons and find new treatment strategies for diseases related to RCD. 

Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation

NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder

Hispidulin exhibits neuroprotective activities against cerebral ischemia reperfusion injury through suppressing NLRP3-mediated pyroptosis

Irisin peptide protects brain against ischemic injury through reducing apoptosis and enhancing BDNF in a rodent model of stroke

ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis)

Pyroptosis: host cell death and inflammation

Role of inflammasomes/pyroptosis and PANoptosis during fungal infection

Ozone alleviates ischemia/reperfusion injury by inhibiting mitochondrion-mediated apoptosis pathway in SH-SY5Y cells

Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes

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YiQiFuMai powder injection ameliorates cerebral ischemia by inhibiting endoplasmic reticulum stress-mediated neuronal apoptosis

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Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury

The MC(4) receptor agonist RO27-3225 inhibits NLRP1-dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

Treatment with enriched environment reduces neuronal apoptosis in the periinfarct cortex after cerebral ischemia/reperfusion injury

Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice

Bibliometric analysis of the inflammasome and pyroptosis in brain

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Thromboxane A2 synthase and thromboxane receptor deletion reduces ischaemia/reperfusion-evoked inflammation, apoptosis, autophagy and pyroptosis

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Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-mediated RIPK3/MLKL signaling

Hypothermia protects neurons against ischemia/reperfusion-induced pyroptosis via m6A-mediated activation of PTEN and the PI3K/Akt/ GSK-3β signaling pathway

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Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer

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Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

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Baicalin attenuates oxygen-glucose deprivation/reoxygenation-induced injury by modulating the BDNF-TrkB/PI3K/Akt and MAPK/Erk1/2 signaling axes in neuron-astrocyte cocultures

Pretreatment of indobufen and aspirin and their combinations with clopidogrel or ticagrelor alleviates inflammasome mediated pyroptosis via inhibiting NF-κB/NLRP3 pathway in ischemic stroke

Effect and mechanism of tilianin against necroptosis on cerebral ischemia-reperfusion

TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis

Caspase-1 inhibition prevents neuronal death by targeting the canonical inflammasome pathway of pyroptosis in a murine model of cerebral ischemia

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Progranulin protects against cerebral ischemia-reperfusion (I/R) injury by inhibiting necroptosis and oxidative stress

Long non-coding RNA MEG3 promotes cerebral ischemiareperfusion injury through increasing pyroptosis by targeting miR-485/AIM2 axis

Inhibition of caspase-1 ameliorates ischemia-associated blood-brain barrier dysfunction and integrity by suppressing pyroptosis activation

The role of HSP90α in methamphetamine/hyperthermia-induced necroptosis in rat striatal neurons

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Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes

EF1A1/HSC70 cooperatively suppress brain endothelial cell apoptosis via regulating JNK activity

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ZBP1 and TAK1: master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis)

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Ischaemic stroke

Autophagy and inflammation in ischemic stroke

Icariin protects neurons from endoplasmic reticulum stressinduced apoptosis after OGD/R injury via suppressing IRE1α-XBP1 signaling pathway

Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

RIP1K contributes to neuronal and astrocytic cell death in ischemic stroke via activating autophagic-lysosomal pathway

Crosstalk between apoptosis, necrosis and autophagy

The inflammasome: first line of the immune response to cell stress

Apoptosis of inflammatory cells in immune control of the nervous system: role of glia

Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke

SIRT1 protects against apoptosis by promoting autophagy in the oxygen glucose deprivation/reperfusion-induced injury

TAK1 inhibition for treatment of cerebral ischemia

Brain endothelial cell death: modes, signaling pathways, and relevance to neural development, homeostasis, and disease

Temporal pattern and crosstalk of necroptosis markers with autophagy and apoptosis associated proteins in ischemic hippocampus

An in vitro oxygen-glucose deprivation model for studying ischemiareperfusion injury of neuronal cells

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The PANoptosome: a deadly protein complex driving pyroptosis, apoptosis, and necroptosis (PANoptosis)

Neuroprotective effect of glycosides in Buyang Huanwu Decoction on pyroptosis following cerebral ischemia-reperfusion injury in rats

Global brain inflammation in stroke

Self-assembled polymeric nanocarriermediated co-delivery of metformin and doxorubicin for melanoma therapy

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Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase

Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/ reperfusion injury

Bradykinin B2 receptors play a neuroprotective role in Hypoxia/reoxygenation injury related to pyroptosis pathway

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

Inflammation as a therapeutic target in acute ischemic stroke treatment

Ischemic insults induce necroptotic cell death in hippocampal neurons through the up-regulation of endogenous RIP3

Inflammasomes in neuroinflammatory and neurodegenerative diseases

Necrosome'-induced inflammation: must cells die for it?

Ablation of GSDMD improves outcome of ischemic stroke through blocking canonical and non-canonical inflammasomes dependent pyroptosis in microglia

USP10 protects against cerebral ischemia injury by suppressing inflammation and apoptosis through the inhibition of TAK1 signaling

RSK3 mediates necroptosis by regulating phosphorylation of RIP3 in rat retinal ganglion cells

The protective activity of imperatorin in cultured neural cells exposed to hypoxia re-oxygenation injury via anti-apoptosis

K252a suppresses neuronal cells apoptosis through inhibiting the translocation of Bax to mitochondria induced by the MLK3/JNK signaling after transient global brain ischemia in rat hippocampal CA1 subregion

Pyroptosis: a pro-inflammatory type of cell death in cardiovascular disease

MiR-139 protects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced nerve injury through targeting c-Jun to inhibit NLRP3 inflammasome activation

Pomelo peel oil suppresses TNF-α-induced necroptosis and cerebral ischaemia-reperfusion injury in a rat model of cardiac arrest

Inhibition of extracellular signal-regulated kinase/calpain-2 pathway reduces neuroinflammation and necroptosis after cerebral ischemia-reperfusion injury in a rat model of cardiac arrest

Medioresinol as a novel PGC-1α activator prevents pyroptosis of endothelial cells in ischemic stroke through PPARα-GOT1 axis

Inhibition of HSP90α protects cultured neurons from oxygen-glucose deprivation induced necroptosis by decreasing RIP3 expression

Lycium barbarum polysaccharide pretreatment attenuates cerebral ischemic reperfusion injury by inhibiting apoptosis in mice

Clausenamide alleviated ER stress and apoptosis induced by OGD/R in primary neuron cultures

She ZG (2020b) CARD3 promotes cerebral ischemia-reperfusion injury via activation of TAK1

Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke

Associations between lesion locations and stroke recurrence in survivors of first-ever ischemic stroke: a prospective cohort study

Analysis of factors related to prognosis and death of fish bile poisoning in China: a retrospective study

Research trends, hot spots and prospects for necroptosis in the field of neuroscience

Evaluation of MCAO stroke models in normotensive rats: standardized neocortical infarction by the 3VO technique

Neuroprotective effect of β-caryophyllene on cerebral ischemia-reperfusion injury via regulation of necroptotic neuronal death and inflammation: in vivo and in vitro

Arctium lappa L. roots ameliorates cerebral ischemia through inhibiting neuronal apoptosis and suppressing AMPK/mTOR-mediated autophagy

Lycium barbarum polysaccharide protects against oxygen glucose deprivation/reoxygenation-induced apoptosis and autophagic cell death via the PI3K/Akt/mTOR signaling pathway in primary cultured hippocampal neurons

Apoptosis in the nervous system

Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases

Up-regulated tumor necrosis factor-associated factor 6 level is correlated with apoptosis in the rat cerebral ischemia and reperfusion

Triad3A displays a critical role in suppression of cerebral ischemic/ reperfusion (I/R) injury by regulating necroptosis

Exosomes secreted from bone marrow mesenchymal stem cells attenuate oxygen-glucose deprivation/reoxygenationinduced pyroptosis in PC12 cells by promoting AMPK-dependent autophagic flux

Microglial-specific depletion of TAK1 is neuroprotective in the acute phase after ischemic stroke

Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro

MicroRNA-25 negatively regulates cerebral ischemia/reperfusion injury-induced cell apoptosis through Fas/FasL pathway

Early exercise protects against cerebral ischemic injury through inhibiting neuron apoptosis in cortex in rats

Gualou Guizhi granule protects against OGD/ R-induced injury by inhibiting cell pyroptosis via the PI3K/Akt signaling pathway

Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation

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

Regulation of microglial activation in stroke

Newly identified function of caspase-6 in ZBP1-mediated innate immune responses, NLRP3 inflammasome activation, PANoptosis, and host defense

The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection

JLX001 ameliorates ischemia/reperfusion injury by reducing neuronal apoptosis via down-regulating JNK signaling pathway

Valproic acid attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-pyroptosis pathways

2020) FK866 alleviates cerebral pyroptosis and inflammation mediated by Drp1 in a rat cardiopulmonary resuscitation model

Pomelo peel oil alleviates cerebral NLRP3 inflammasome activation in a cardiopulmonary resuscitation rat model