Multiple forms of cell death: A focus on the PI3K/AKT pathway.

Cell death is a natural biological process that occurs in living organisms. Since 1963, extensive research has shed light on the occurrence, progress, and final outcome of cell death. According to different cell phenotypes, it is classified into different types, including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and so on. However, regardless of the form of cell death, what we ultimately expect is the disappearance of abnormal cells, such as tumor cells, while normal cells survive. As a result, it is vital to investigate the details of cell death, including death triggers, potent regulators, and executioners. Although significant progress has been made in understanding molecular pathways of cell death, many aspects remain unclear because of the complex regulatory networks in cells. Among them, the phosphoinositide-3-kinase (PI3K)/protein kinase B(AKT) pathway is discovered to be a crucial regulator of the cell death process. AKT, as a proto-oncogene, has become a major focus of attention in the medical community due to its role in regulating a multiplicity of cellular functions counting metabolism, immunity, proliferation, survival, transcription, and protein synthesis. Here, we explored the connection between the PI3K/AKT pathway and cell death, aiming to enhance our comprehension of the mechanism underlying this process. Such knowledge may pave the way for the subsequent development of more effective disease treatments, such as finding suitable targets for drug intervention.

Srs11-92, a ferrostatin-1 analog, improves oxidative stress and neuroinflammation via Nrf2 signal following cerebral ischemia/reperfusion injury.

AIM: Ferroptosis is increasingly becoming to be considered as an important mechanism of pathological cell death during stroke, and specific exogenous ferroptosis inhibitors have the ability to reverse cerebral ischemia/reperfusion injury. However, research on Srs11-92 (AA9), a ferrostatin-1 (Fer-1) analog, in preclinical studies is limited. METHODS: In the middle cerebral artery occlusion-reperfusion (MCAO/R) mice model or oxygen-glucose deprivation/reperfusion (OGD/R) cell model, Fer-1, AA9, and/or ML385 were administered, and brain infarct size, neurological deficits, neuronal damage, oxidative stress, and neuroinflammation were determined after the damage, in vitro and in vivo. RESULTS: Fer-1 and AA9 improved brain infarct size, neuronal damage, and neurological deficits in mice model of MCAO/R, and inhibited the overloaded iron deposition, ROS accumulation, and neuroinflammation response: it also increased the expression of GPx4, Nrf2, and HO-1 and suppressed the expression of HMGB1 and NF-κB p65 in the epicenter of injured hippocampal formation. However, Nrf2 inhibitor ML385 reversed the neuroprotective effect of AA9, including the oxidative stress and neuroinflammation. In vitro studies showed that AA9 relieved OGD/R-induced neuronal oxidative stress and neuroinflammation via the Nrf2 pathway, which was impaired by ML385 in primary neurons. CONCLUSION: The findings imply that Fer-1 analog AA9 may be suitable for further translational studies for the protection of neuronal damage via Nrf2 signal pathway-mediated oxidative stress and neuroinflammation in stroke and others neurological diseases.

Bibliometric analysis of the global research trends and hotspots in chordoma from 2000 to 2020.

INTRODUCTION: Chordoma is formed from embryonic residues or ectopic chordae and locally aggressive or malignant tumors. We visually analyzed the research tendency and hotspot of chordoma. METHODS: The bibliometric analysis was conducted from the Web of Science Core Collection database over the past two decades. The term and strategies were as follows: "TS = (chordoma) OR TS = (chordoblastoma) OR TS = (chordocarcinoma) OR TS = (chordoepithelioma) OR TS = (chordosarcoma) OR TS = (notochordoma). AND Language: English. AND Reference Type: Article OR Review". A total of 2,118 references were retrieved and used to make a visual analysis by VOSviewer 1.6.15. RESULTS: The chordoma was on a steady rise and chordoma but remained the focus of scholars and organizations over the last two decades. The Chinese institutions and scholars lacked cooperation with their counterparts in other countries. The citations of documents and co-citation analysis of cited references suggested that M.L. McMaster, B.P. Walcott, P. Bergh, and S. Stacchiotti were leading researchers in this field of chordoma and their papers had been widely accepted and inspired recent researches. Keywords associated with recent chemotherapy, PD-1-related immunotherapy, and SMARCB1/integrase interactor 1 (INI1) in chordoma were a shortage of research and there may be more research ideas in the future by scholars. The research of chordoma will continue to be the hotspot. CONCLUSIONS: Thus, explaining the molecular mechanism and potential role of transcriptional inhibition and immunologic responses to SMARCB1/INI1-negative poorly differentiated chordoma will be available for preclinical experiments and clinical trials and lead to new therapeutic opportunities for chordoma patients.

A Review of the Ethical Use of Animals in Functional Experimental Research in China Based on the "Four R" Principles of Reduction, Replacement, Refinement, and Responsibility.

Use of live laboratory animals is essential in the process of functional experimentation teaching. There are ethical problems, such as poor experimental environment, non-standard operation, and neglect of animal rights in experimental teaching. As an important basic course in life science education, functional experimentation should establish the correct ethics of use of laboratory animals. The welfare of laboratory animals has become one of the frontier directions of medical ethics research. The "4R" principle of animal welfare is based on the principles of reduction, replacement, refinement, and responsibility, which may provide a way to solve ethical problems in the teaching and research activities of functional experimentation. In addition to receiving relevant knowledge and education, laboratory animal practitioners and students in functional experimentation teaching should consciously abide by relevant regulations and rules and actively follow the "4R" principles. Animal ethics education is reflected in all teaching and research activities. Based on the principle of "4R" and the premise of guaranteeing teaching objectives, virtual simulation experiment teaching is a great supplement to functional experimentation. In teaching, medical ethics education should be strengthened to cultivate the consciousness of respecting the life of experimental animals, and awareness of laboratory animal ethics should be improved among teachers and students of functional experimentation to further promote ideological and political education in colleges and universities. This brief summary analyzes the general situation of animal ethics in functional experimentation in China based on the principle of "4R" and provides certain references and support for course teaching and training.

[Effects of elevated CO2 concentration on photosynthetic acclimation of winter wheat under drought condition]. / 大气CO2æµ“åº¦å‡é«˜å¯¹å¹²æ—±æ¡ä»¶ä¸‹å†¬å°éº¦å¶ç‰‡å ‰åˆé€‚åº”çš„å½±å“.

Mechanisms underlying leaf photosynthetic acclimation in winter wheat under elevation of CO2 concentration ([CO2]) remain unclear. The aim of the study was to investigate the effects of source-sink variation on photosynthetic acclimation induced by drought under elevated [CO2]. A winter wheat (Triticum aestivum L. 'Zhengmai 9023') pot experiment was conducted in open top climate chambers with [CO2] of 400µmol·mol-1 or 600 µmol·mol-1 and soil water content at 80%±5% or 55%±5% of field capacity. The parameters of chlorophyll fluorescence, electron transport rate, photosynthetic curve, leaf nitrogen content, and grain yield were measured at the elongation and heading stages. Under drought condition, leaf PSⅡ photochemical efficiency was not affected by elevated [CO2], but the maximum electron transport rate and the ratio of electron partitioned to carboxylation reaction in Calvin cycle was increased at the elongation stage, and thus the Rubisco carboxylation rate and maximum photosynthetic rate were increased. Although the maximum electron transportation rate and partitioning ratio of electron to carboxylation reaction in Calvin cycle remained high at the heading stage, the PSⅡ photochemical efficiency, Rubisco carboxylation rate, and triose phosphate utilization rate were decreased by elevated [CO2], which consequently reduced the maximum photosynthetic rate for plant under drought stress. Under drought condition, elevated [CO2] increased wheat tiller biomass, kernel number, and kernel weight per ear, but decreased infertile kernel number, resulting in an overall increase in grain weight. In conclusion, the elevated [CO2]-induced increase in wheat grain yield per tiller under drought condition was mainly caused by enhanced photosynthetic performance at the elongation stage. The photosynthetic acclimation in source leaves during the heading stage under elevated [CO2] was mainly attributed to the reduction in PSⅡ photochemical efficiency and triose phosphate utilization rate, but not to the maximum electron transportation rate, ratio of electron partitioned to carboxylation in Calvin cycle or sink leaf strength.

Phosphoglycerate Mutase 5 Knockdown Alleviates Neuronal Injury After Traumatic Brain Injury Through Drp1-Mediated Mitochondrial Dysfunction.

Aims: Traumatic brain injury (TBI) is a major cause of disability and death, and a better understanding of the underlying mechanisms of mitochondrial dysfunction will provide important targets for preventing damage from neuronal insults. Phosphoglycerate mutase 5 (PGAM5) is localized to the mitochondrial outer-inner membrane contact sites, and the PGAM5-Drp1 pathway is involved in mitochondrial dysfunction and cell death. The purpose of this project was to evaluate the effects of PGAM5 on neuronal injury and mitochondrial dysfunction. Results: PGAM5 was overexpressed in mice subjected to TBI and in primary cortical neurons injured by mechanical equiaxial stretching. PGAM5 deficiency alleviated neuroinflammation, blocked Parkin, PINK1, and Drp1 translocation to mitochondria and abnormal phosphorylation of Drp1, mitochondrial ultrastructural changes, and nerve malfunction in TBI mouse model. PGAM5-shRNA (short hairpin RNA) reduced Drp1 translocation and activation, including dephosphorylation of p-Drp1 on Ser622 (human Drp1 Ser616) and phosphorylation of Drp1 on Ser643 (human Drp1 Ser637). The levels of inflammatory cytokines, the degree of mitochondrial impairment (mitochondrial membrane potential, ADP/ATP, AMP/ADP, antioxidant capacity), and neuronal injury in stretch-induced primary cortical neurons were reduced by blocking expression of PGAM5. The inhibition of PGAM5 is neuroprotective via attenuation of Drp1 activation, similar to that achieved by mitochondrial division inhibitor-1 (Mdivi1)-mediated Drp1 inhibition. Innovation and Conclusion: Our findings demonstrate the critical role of PGAM5 in progression of neuronal injury from TBI via Drp1 activation (dephosphorylation of p-Drp1 on Ser622 and phosphorylation of Drp1 on Ser643)-mediated mitochondrial dysfunction. The data may open a window for developing new drugs to prevent the neuropathology of TBI.

Rhein Protects Against Neurological Deficits After Traumatic Brain Injury in Mice via Inhibiting Neuronal Pyroptosis.

Neurological dysfunction provoked by traumatic brain injury (TBI) makes a huge impact on individual learning ability, memory level, social participation, and quality of life. Pyroptosis, the caspase-1-dependent cell death, which is associated with the release of numerous pro-inflammatory factors, plays a major role in the pathological process after TBI. Inhibition of pyroptosis has been shown to be an attractive strategy for the treatment of various neurological disorders. Here, we found that Rhein, an anthraquinone derived from the medicinal plant rhubarb, attenuated TBI-induced upregulation of pro-inflammatory cytokines, blood lactate dehydrogenase (LDH), and pyroptosis-related proteins, as well as reduced neurological dysfunction in a mouse TBI model. Consistently, Rhein inhibitd equiaxial stretch-induced neuron pyroptosis, LDH release, and upregulation of pro-inflammatory factors in vitro. Thus, our study suggested that Rhein protected against neurological deficits after TBI via inhibiting neuronal pyroptosis.

Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-κB Pathway.

Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-κB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-κB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-κB signaling.

EGCG protects vascular endothelial cells from oxidative stress-induced damage by targeting the autophagy-dependent PI3K-AKT-mTOR pathway.

BACKGROUND: Autophagy plays an important role in cellular homeostasis. Epigallocatechin gallate (EGCG), a polyphenol derived from green tea, has been shown to elicit vascular protective effects. Our study aimed to investigate the protective effect of EGCG in an endothelial injury model induced by hydrogen peroxide (H2O2) and reveal the possible mechanisms. METHODS: Human vascular endothelial cells (HUVECs) were pretreatment with different concentration of EGCG, then exposed to H2O2. Cell viability was measured with MTS assay. Apoptosis was evaluated with TUNEL staining and apoptosis-related protein was determined by western blot. Autophagy flux was assessed by transmission electron microscopy and LC3 plasmid transfection. Besides, the role mTOR in EGCG-mediated antioxidant responses was validated with siRNA transfection. RESULTS: The results showed that pretreatment with EGCG significantly improved the survival of HUVECs from H2O2-induced cell death. After exposed to H2O2, EGCG upregulated the levels of Atg5, Atg7, LC3 II/I, and the Atg5-Atg12 complex in HUVECs, while downregulated apoptosis-related protein. Besides, EGCG inhibited the PI3K-AKT-mTOR signaling pathway. Knockdown of mTOR partially promoted EGCG-induced autophagy. CONCLUSIONS: These results suggest that EGCG induces autophagy by targeting the mTOR pathway, indicating that EGCG has the potential to prevent and treat oxidative stress-related cardiovascular diseases.

Bibliometric Analysis of the Inflammasome and Pyroptosis in Brain.

Background: Considering the pivotal role of inflammasome/pyroptosis in biological function, we visually analyzed the research hotspots of inflammasome/pyroptosis related to the brain in this work through the method of bibliometrics from the Web of Science (WOS) Core database over the past two decades. Methods: Documents were retrieved from WOS Core Collection on October 16, 2020. The search terms and strategies used for the WOS database are as follow: # 1, "pyroptosis"; # 2, "pyroptotic"; # 3, "inflammasome"; # 4, "pyroptosome"; # 5 "brain"; # 6, "# 1" OR "# 2" OR "# 3" OR "# 4"; # 7, "# 5" AND "# 6". We selected articles and reviews published in English from 2000 to 2020. Visualization analysis and statistical analysis were performed by VOSviewer 1.6.15 and CiteSpace 5.7. R2. Results: 1,222 documents were selected for analysis. In the approximately 20 years since the pyroptosis was first presented, the publications regarding the inflammasome and pyroptosis in brain were presented since 2005. The number of annual publications increased gradually over a decade, which are involved in this work, and will continue to increase in 2020. The most prolific country was China with 523 documents but the United States was with 16,328 citations. The most influential author was Juan Pablo de Rivero Vaccari with 27 documents who worked at the University of Miami. The bibliometric analysis showed that inflammasome/pyroptosis involved a variety of brain cell types (microglia, astrocyte, neuron, etc.), physiological processes, ER stress, mitochondrial function, oxidative stress, and disease (traumatic brain injuries, stroke, Alzheimer's disease, and Parkinson's disease). Conclusion: The research of inflammasome/pyroptosis in brain will continue to be the hotspot. We recommend investigating the mechanism of mitochondrial molecules involved in the complex crosstalk of pyroptosis and regulated cell deaths (RCDs) in brain glial cells, which will facilitate the development of effective therapeutic strategies targeting inflammasome/pyroptosis and large-scale clinical trials. Thus, this study presents the trend and characteristic of inflammasome/pyroptosis in brain, which provided a helpful bibliometric analysis for researchers to further studies.

Pterostilbene attenuates amyloid-ß induced neurotoxicity with regulating PDE4A-CREB-BDNF pathway.

Amyloid-ß (Aß) is considered partially responsible for cognitive dysfunction in Alzheimer's disease (AD). Resveratrol is known as an anti-neurotoxicity potential natural product, however low blood-brain-barrier (BBB) permissibility and low oral-bioavailability (OB) are the main limitations on its clinical potential. In this study, we illustrated that Pterostilbene (PTS), a kind of resveratrol analog which showed higher scores on BBB and OB, could overcome Aß-induced neurotoxicity in vitro and in vivo. In silico simulation indicated PTS binding with PDE4A may contribute to its anti-apoptosis and anti-neurotoxicity effects. Behavioral tests further confirmed PTS' potential of overcoming memory deficits in APP/PS1 mice (AD model). Interestingly, PTS also rescued the reducing in dendritic spine density in APP/PS1 mice based on Golgi-Cox staining. Besides, as results of reversing Aß-induced decreases in cyclic-AMP level, PTS increased the pVASP, pCREB, BDNF, and PSD95 expression. Overall, PTS protects neurons against Aß-induced neurotoxicity and cognitive dysfunction through regulating the PDE4A-CREB-BDNF pathway. Therefore, targeting on PDE4A, PTS would be a qualified natural product for alleviating Aß-induced neurotoxicity in AD.

Corrigendum: NEK7 Regulates NLRP3 Inflammasome Activation and Neuroinflammation Post-traumatic Brain Injury.

[This corrects the article DOI: 10.3389/fnmol.2019.00202.].

EK7 Regulates NLRP3 Inflammasome Activation and Neuroinflammation Post-traumatic Brain Injury.

As one of the most common causes of mortality and disability, traumatic brain injury (TBI) is a huge psychological and economic burden to patients, families, and societies worldwide. Neuroinflammation reduction may be a favorable option to alleviate secondary brain injuries and ameliorate the outcome of TBI. The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome, has been shown to be involved in TBI. NIMA-related kinase 7 (NEK7) has been verified as an essential mediator of NLRP3 inflammasome activation that is recruited upstream of the formation of inflammasomes in response to NLRP3 activators. However, the underlying mechanism by which NEK7 operates post-TBI remains undefined. In this study, we performed both in vivo and in vitro experiments. Using an in vivo mouse TBI model, mice were administered an intracerebroventricular injection of NEK7-shRNA virus. For the in vitro analysis, primary cortical neurons with NEK7-shRNA were stimulated with lipopolysaccharide (LPS)/ATP or potassium (K+). We evaluated the effects of NEK7 knock-down on neurological deficits, NLRP3 inflammasomes, caspase-1 activation, and neuronal injury. During the 0-168 h post-TBI period in vivo, NEK7 and NLRP3 inflammasome activation increased in what appeared to be a time-dependent manner. As well as pyroptosis-related markers, caspase-1 activation (p20) and interleukin-1ß (IL-1ß) activation (p17) were up-regulated. NEK7 down-regulation attenuated neurological deficits, NLRP3 inflammasomes, caspase-1 activation, and neuronal injury. The same phenomena were observed during the in vitro experiments. Furthermore, NEK7 knock-down suppressed NLRP3 inflammasome activation and pyroptosis, which were triggered by K+ efflux, and the LPS + ATP-triggered NEK7-NLRP3 complex was reversed in primary cortical neurons placed in 50 mM K+ medium. Collectively, the data demonstrated that NEK7, as a modulator, regulates NLRP3 inflammasomes and downstream neuroinflammation in response to K+ efflux, through NEK7-NLRP3 assembly, pro-caspase-1 recruitment, caspase-1 activation, and pyroptosis in nerve injuries, post-TBI. NEK7 may be a potential therapeutic target for attenuating neuroinflammation and nerve injury post-TBI.

EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC.

BACKGROUND: Several EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib (Gef), have been used as effective clinical therapies for patients with non-small cell lung cancer (NSCLC). However, due to acquired resistance, the efficacy of Gef treatment is severely blocked. Our preliminary study found that epigallocatechin gallate (EGCG) in combination with Gef could work synergistically to increase the sensitivity to Gef in NSCLC, but the mechanisms responsible for this have not been completely defined. PURPOSE: In our present study, we devoted to investigate the synergistic effects of combined EGCG and Gef treatment and the importance of autophagy and ERK signaling pathway in overcoming acquired drug resistance to Gef in NSCLC. METHODS: We evaluated the synergistic effects of combined EGCG and Gef treatment through in vitro cell proliferation/viability assays and in vivo xenograft studies, respectively. Autophagic flux was assessed by GFP-microtubule-associated protein 1 light chain 3 (LC3) plasmid transfection and western blot detection of autophagy-related proteins. Besides, the role of ERK on acquired resistance was validated with a ERK inhibitor. RESULTS: We discovered that EGCG can synergize with Gef to inhibit the proliferation of Gef-resistant NSCLC cells and suppress tumor growth in a xenograft mouse model. The underlying mechanisms of synergism were investigated, and the results showed that co-treatment with Gef and EGCG could inhibit Gef-induced autophagy and ERK phosphorylation. Consistently, the expression of LC3-II/I and ATG5 were inhibited, whereas the expression of p62 was enhanced in EGCG and Gef combination treatment groups. Further, inhibition of autophagy in Gef-resistant A549 cells could augment cell death. CONCLUSION: In conclusion, EGCG overcomes Gef resistance by inhibiting autophagy and augmenting cell death through targeting ERK pathway in NSCLC. Gef and EGCG combination therapy may be an effective strategy to overcome acquired resistance in NSCLC.

Rapamycin improves the neuroprotection effect of inhibition of NLRP3 inflammasome activation after TBI.

Inflammation is the focus of many studies on traumatic brain injury (TBI) treatment and outcomes improvement. Some studies have demonstrated that the inhibition of NOD-like receptor protein-3 (NLRP3) inflammasome activation is a potential strategy for TBI therapy. Mitophagy is thought to play a crucial role in pathological conditions of TBI. We hypothesize simultaneous mitophagy activation and NLRP3 inflammsome inhibition, plays preferable role in delaying the progression and nerve damage post-TBI. In this study, TBI-mice and oxygen and glucose deprivation (OGD)-induced primary cortical neurons were treated with MCC950 (a NLRP3 selective inhibitor) or Rapamycin (Rap, a mTOR inhibitor, stimulated autophagy and mitophagy). We evaluated the effects of Rap and NLRP3 inhibition on the neurological deficits, neurological damage, and inflammatory response, to determine if Rap further induced the neuroprotection of suppression of NLRP3 inflammasome activation in vivo and in vitro TBI-model. TBI induced NLRP3 inflammasome activation and mitochondrial dysfunction, including increased caspase-1 p20 expression, exacerbated the secretion of LDH, IL-1ß and IL-18, and disorder of ATP, MMP, ROS and mitophagy (Pink1 and LC3 expression in mitochondria). NLRP3 inhibition and Rap attenuated the neurological damage and mitochondrial dysfunction, while combined treatment showed better neuroprotection compared with single treatment. Collectively, the data demonstrate that mitophagy and NLRP3 inflammasome have the interactivity, and Rap-induced mitophagy further enhances the neuroprotection of inhibition of NLRP3 inflammasome activation post-TBI. Our findings suggest that Rap-activated mitophagy combined with MCC950-induced NLRP3 inflammasome repression may be a potential strategy for TBI therapy.

Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo.

BACKGROUND: Traumatic brain injury (TBI) is a critical public health and socioeconomic problem throughout the world. Inflammation-induced secondary injury is one of the vital pathogenic parameters of TBI. Molecular signaling cascades of pyroptosis, a specific type of cellular necrosis, are key drivers of TBI-induced inflammation. METHODS: In this study, mice with genetically ablated caspase-1 (caspase-1-/-) were subjected to controlled cortical impact injury in vivo, and primary neuron deficient in caspase-1 through siRNA knockdown and pharmacologic inhibition was stimulated by mechanical scratch, equiaxial stretch, and LPS/ATP in vitro. We evaluated the effects of caspase-1 deficiency on neurological deficits, inflammatory factors, histopathology, cell apoptosis, and pyroptosis. RESULTS: During the acute post-injury period (0-48 h) in vivo, motor deficits, anti-inflammatory cytokines (TGF-ß and IL-10), pro-inflammatory cytokines (IFN-γ, IL-1ß, and IL-18), and blood lactate dehydrogenase (LDH), as well as pyroptosis-related proteins (caspase-1, caspase-1 fragments, caspase-11 and GSDMD), were increased. Caspase-1 was activated in the cortex of TBI mice. Inflammatory activation was more profound in injured wild-type mice than in caspase-1-/- mice. In vitro, mechanical scratch, equiaxial stretch, and LPS/ATP-induced neuron pyroptosis, apoptosis, LDH release, and increased expression of inflammatory factors. The effects of mechanical and inflammatory stress were reduced through inhibition of caspase-1 activity through siRNA knockdown and pharmacologic inhibition. CONCLUSION: Collectively, these data demonstrate that pyroptosis is involved in neuroinflammation and neuronal injury after TBI, and ablation of caspase-1 inhibits TBI-induced pyroptosis. Our findings suggest that caspase-1 may be a potential target for TBI therapy.