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Journal of Neuroinflammation Mar 2020Inflammatory response mediated by oxidative stress is considered as an important pathogenesis of spinal cord injury (SCI). Advanced oxidation protein products (AOPPs)...
BACKGROUND
Inflammatory response mediated by oxidative stress is considered as an important pathogenesis of spinal cord injury (SCI). Advanced oxidation protein products (AOPPs) are novel markers of oxidative stress and their role in inflammatory response after SCI remained unclear. This study aimed to investigate the role of AOPPs in SCI pathogenesis and explore the possible underlying mechanisms.
METHODS
A C5 hemi-contusion injury was induced in Sprague-Dawley rats to confirm the involvement of AOPPs after SCI. For in vivo study, apocynin, the NADPH oxidase inhibitor was used to study the neuroprotective effects after SCI. For in vitro study, the BV2 microglia cell lines were pretreated with or without the inhibitor or transfected with or without small interference RNA (siRNA) and then stimulated with AOPPs. A combination of molecular and histological methods was used to clarify the mechanism and explore the signaling pathway both in vivo and in vitro. One-way analysis of variance (ANOVA) was conducted with Bonferroni post hoc tests to examine the differences between groups.
RESULTS
The levels of AOPPs in plasma and cerebrospinal fluid as well as the contents in the spinal cord showed significant increase after SCI. Meanwhile, apocynin ameliorated tissue damage in the spinal cord after SCI, improving the functional recovery. Immunofluorescence staining and western blot analysis showed activation of microglia after SCI, which was in turn inhibited by apocynin. Pretreated BV2 cells with AOPPs triggered excessive generation of reactive oxygen species (ROS) by activating NADPH oxidase. Increased ROS induced p38 MAPK and JNK phosphorylation, subsequently triggering nuclear translocation of NF-κB p65 to express pro-inflammatory cytokines. Also, treatment of BV2 cells with AOPPs induced NLRP3 inflammasome activation and cleavage of Gasdermin-d (GSDMD), causing pyroptosis. This was confirmed by cleavage of caspase-1, production of downstream mature interleukin (IL)-1β and IL-18 as well as rupture of rapid cell membrane.
CONCLUSIONS
Collectively, these data indicated AOPPs as biomarkers of oxidative stress, modulating inflammatory response in SCI by multiple signaling pathways, which also included the induction of NADPH oxidase dependent ROS, and NLRP3-mediated pyroptosis, and activation of MAPKs and NF-κB.
Topics: Advanced Oxidation Protein Products; Animals; Cell Line; Inflammation; MAP Kinase Signaling System; Male; Mice; Microglia; NF-kappa B; Oxidative Stress; Pyroptosis; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries
PubMed: 32192500
DOI: 10.1186/s12974-020-01751-2 -
CNS Neuroscience & Therapeutics Mar 2022Multiple sclerosis (MS) still maintains increasing prevalence and poor prognosis, while glucagon-like peptide-1 receptor (GLP-1R) agonists show excellent neuroprotective...
AIMS
Multiple sclerosis (MS) still maintains increasing prevalence and poor prognosis, while glucagon-like peptide-1 receptor (GLP-1R) agonists show excellent neuroprotective capacities recently. Thus, we aim to evaluate whether the GLP-1R agonist liraglutide (Lira) could ameliorate central nervous system demyelination and inflammation.
METHODS
The therapeutic effect of Lira was tested on experimental autoimmune encephalitis (EAE) in vivo and a microglia cell line BV2 in vitro.
RESULTS
Lira administration could ameliorate the disease score of EAE mice, delay the disease onset, ameliorate pathological demyelination and inflammation score in lumbar spinal cord, reduce pathogenic T helper cell transcription in spleen, restore phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) level, autophagy level, and inhibit pyroptosis-related NLR family, pyrin domain-containing protein 3 (NLRP3) pathway in lumbar spinal cord. Additionally, cell viability test, lactate dehydrogenase release test, and dead/live cell staining test for BV2 cells showed Lira could not salvage BV2 from nigericin-induced pyroptosis significantly.
CONCLUSION
Lira has anti-inflammation and anti-demyelination effect on EAE mice, and the protective effect of Lira in the EAE model may be related to regulation of pAMPK pathway, autophagy, and NLRP3 pathway. However, Lira treatment cannot significantly inhibit pyroptosis of BV2 cells in vitro. Our study provides Lira as a potential candidate for Multiple Sclerosis treatment.
Topics: AMP-Activated Protein Kinases; Animals; Demyelinating Diseases; Inflammation; Liraglutide; Mice; Multiple Sclerosis; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 34985189
DOI: 10.1111/cns.13791 -
Cell May 2019Active cell death, in its many forms, is a fundamental biological process. Studies over the past several decades have explored the functions and consequences of cellular... (Review)
Review
Active cell death, in its many forms, is a fundamental biological process. Studies over the past several decades have explored the functions and consequences of cellular demise and elucidated several of the key cell death pathways. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.
Topics: Animals; Humans; Pyroptosis
PubMed: 31100266
DOI: 10.1016/j.cell.2019.04.024 -
Nature Communications Jan 2023The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic...
The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic parapoxvirus ovis (ORFV) and other OVs are thought to induce apoptosis, but apoptosis, being the immunogenically inert compared to other types of cell death, does not explain the highly inflamed microenvironment in OV-challenged tumors. Here we show that ORFV and its recombinant therapeutic derivatives are able to trigger tumor cell pyroptosis via Gasdermin E (GSDME). This effect is especially prominent in GSDME-low tumor cells, in which ORFV-challenge pre-stabilizes GSDME by decreasing its ubiquitination and subsequently initiates pyroptosis. Consistently, GSDME depletion reduces the proportion of intratumoral cytotoxic T lymphocytes, pyroptotic cell death and the success of tumor ORFV virotherapy. In vivo, the OV preferentially accumulates in the tumour upon systemic delivery and elicits pyroptotic tumor killing. Consequentially, ORFV sensitizes immunologically 'cold' tumors to checkpoint blockade. This study thus highlights the critical role of GSDME-mediated pyroptosis in oncolytic ORFV-based antitumor immunity and identifies combinatorial cancer therapy strategies.
Topics: Humans; Gasdermins; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Parapoxvirus; Pyroptosis; Tumor Microenvironment
PubMed: 36641456
DOI: 10.1038/s41467-023-35917-2 -
BMC Cancer Apr 2022The relationship between pyroptosis and cancer is complex. It is controversial that whether pyroptosis represses or promotes tumor development. This study aimed to...
BACKGROUND
The relationship between pyroptosis and cancer is complex. It is controversial that whether pyroptosis represses or promotes tumor development. This study aimed to explore prognostic molecular characteristics to predict the prognosis of breast cancer (BRCA) based on a comprehensive analysis of pyroptosis-related gene expression data.
METHODS
RNA-sequcing data of BRCA were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Ominibus (GEO) datasets. First, pyroptosis-related differentially expressed genes (DEGs) between normal and tumor tissues were identified from the TCGA database. Based on the DEGs, 1053 BRCA patients were divided into two clusters. Second, DEGs between the two clusters were used to construct a signature by a least absolute shrinkage and selection operator (LASSO) Cox regression model, and the GEO cohort was used to validate the signature. Various statistical methods were applied to assess this gene signature. Finally, Single-sample gene set enrichment analysis (ssGSEA) was employed to compare the enrichment scores of 16 types of immune cells and 13 immune-related pathways between the low- and high-risk groups. We calculated the tumor mutational burden (TMB) of TCGA cohort and evaluated the correlations between the TMB and riskscores of the TCGA cohort. We also compared the TMB between the low- and high-risk groups.
RESULTS
A total of 39 pyroptosis-related DEGs were identified from the TCGA-breast cancer dataset. A prognostic signature comprising 16 genes in the two clusters of DEGs was developed to divide patients into high-risk and low-risk groups, and its prognostic performance was excellent in two independent patient cohorts. The high-risk group generally had lower levels of immune cell infiltration and lower activity of immune pathway activity than did the low-risk group, and different risk groups revealed different proportions of immune subtypes. The TMB is higher in high-risk group compared with low-risk group. OS of low-TMB group is better than that of high-TMB group.
CONCLUSION
A 16-gene signature comprising pyroptosis-related genes was constructed to assess the prognosis of breast cancer patients and its prognostic performance was excellent in two independent patient cohorts. The signature was found closely associated with the tumor immune microenvironment and the potential correlation could provide some clues for further studies. The signature was also correlated with TMB and the mechanisms are still warranted.
Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Prognosis; Pyroptosis; Tumor Microenvironment
PubMed: 35443644
DOI: 10.1186/s12885-022-09526-z -
Cell Death & Disease Aug 2020Regulated necrosis has been reported to exert an important role in the pathogenesis of various diseases, including renal ischemia-reperfusion (I/R) injury. Damage to...
Regulated necrosis has been reported to exert an important role in the pathogenesis of various diseases, including renal ischemia-reperfusion (I/R) injury. Damage to renal tubular epithelial cells and subsequent cell death initiate the progression of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). We found that ferroptosis appeared in tubular epithelial cells (TECs) of various human kidney diseases and the upregulation of tubular proferroptotic gene ACSL4 was correlated with renal function in patients with acute kidney tubular injury. XJB-5-131, which showed high affinity for TECs, attenuated I/R-induced renal injury and inflammation in mice by specifically inhibiting ferroptosis rather than necroptosis and pyroptosis. Single-cell RNA sequencing (scRNA-seq) indicated that ferroptosis-related genes were mainly expressed in tubular epithelial cells after I/R injury, while few necroptosis- and pyroptosis-associated genes were identified to express in this cluster of cell. Taken together, ferroptosis plays an important role in renal tubular injury and the inhibition of ferroptosis by XJB-5-131 is a promising therapeutic strategy for protection against renal tubular cell injury in kidney diseases.
Topics: Adult; Animals; Coenzyme A Ligases; Cyclic N-Oxides; Drug Stability; Epithelial Cells; Female; Ferroptosis; Gene Expression Regulation; Humans; Inflammation; Kidney Tubules; Male; Mice, Inbred C57BL; Middle Aged; Pyroptosis; Reperfusion Injury
PubMed: 32796819
DOI: 10.1038/s41419-020-02871-6 -
Frontiers in Immunology 2022Sepsis remains a life-threatening disease with a high mortality rate that causes millions of deaths worldwide every year. Many studies have suggested that pyroptosis...
BACKGROUND
Sepsis remains a life-threatening disease with a high mortality rate that causes millions of deaths worldwide every year. Many studies have suggested that pyroptosis plays an important role in the development and progression of sepsis. However, the potential prognostic and diagnostic value of pyroptosis-related genes in sepsis remains unknown.
METHODS
The GSE65682 and GSE95233 datasets were obtained from Gene Expression Omnibus (GEO) database and pyroptosis-related genes were obtained from previous literature and Molecular Signature Database. Univariate cox analysis and least absolute shrinkage and selection operator (LASSO) cox regression analysis were used to select prognostic differentially expressed pyroptosis-related genes and constructed a prognostic risk score. Functional analysis and immune infiltration analysis were used to investigate the biological characteristics and immune cell enrichment in sepsis patients who were classified as low- or high-risk based on their risk score. Then the correlation between pyroptosis-related genes and immune cells was analyzed and the diagnostic value of the selected genes was assessed using the receiver operating characteristic curve.
RESULTS
A total of 16 pyroptosis-related differentially expressed genes were identified between sepsis patients and healthy individuals. A six-gene-based (, and ) prognostic risk score was developed. Based on the risk score, sepsis patients were divided into low- and high-risk groups, and patients in the low-risk group had a better prognosis. Functional enrichment analysis found that NOD-like receptor signaling pathway, hematopoietic cell lineage, and other immune-related pathways were enriched. Immune infiltration analysis showed that some innate and adaptive immune cells were significantly different between low- and high-risk groups, and correlation analysis revealed that all six genes were significantly correlated with neutrophils. Four out of six genes (, and also have potential diagnostic value in sepsis diagnosis.
CONCLUSION
We developed and validated a novel prognostic predictive risk score for sepsis based on six pyroptosis-related genes. Four out of the six genes also have potential diagnostic value in sepsis diagnosis.
Topics: Humans; Prognosis; Pyroptosis; Risk Factors; Sepsis
PubMed: 36618365
DOI: 10.3389/fimmu.2022.1110602 -
Cells Feb 2021Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron. The inducible form of the enzyme,... (Review)
Review
Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron. The inducible form of the enzyme, heme oxygenase-1 (HO-1), exerts a central role in cellular protection. The substrate, heme, is a potent pro-oxidant that can accelerate inflammatory injury and promote cell death. HO-1 has been implicated as a key mediator of inflammatory cell and tissue injury, as validated in preclinical models of acute lung injury and sepsis. A large body of work has also implicated HO-1 as a cytoprotective molecule against various forms of cell death, including necrosis, apoptosis and newly recognized regulated cell death (RCD) programs such as necroptosis, pyroptosis, and ferroptosis. While the antiapoptotic potential of HO-1 and its reaction product CO in apoptosis regulation has been extensively characterized, relatively fewer studies have explored the regulatory role of HO-1 in other forms of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). HO-1 may provide anti-inflammatory protection in necroptosis or pyroptosis. In contrast, in ferroptosis, HO-1 may play a pro-death role via enhancing iron release. HO-1 has also been implicated in co-regulation of autophagy, a cellular homeostatic program for catabolic recycling of proteins and organelles. While autophagy is primarily associated with cell survival, its occurrence can coincide with RCD programs. This review will summarize the roles of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease.
Topics: Apoptosis; Autophagy; Heme Oxygenase-1; Humans; Inflammation; Necroptosis; Pyroptosis; Regulated Cell Death
PubMed: 33671004
DOI: 10.3390/cells10030515 -
Nature Reviews. Gastroenterology &... Jun 2023Since the identification and characterization of gasdermin (GSDM) D as the main effector of inflammatory regulated cell death (or pyroptosis), literature on the GSDM... (Review)
Review
Since the identification and characterization of gasdermin (GSDM) D as the main effector of inflammatory regulated cell death (or pyroptosis), literature on the GSDM family of pore-forming proteins is rapidly expanding, revealing novel mechanisms regulating their expression and functions that go beyond pyroptosis. Indeed, a growing body of evidence corroborates the importance of GSDMs within the gastrointestinal system, underscoring their critical contributions to the pathophysiology of gastrointestinal cancers, enteric infections and gut mucosal inflammation, such as inflammatory bowel disease. However, with this increase in knowledge, several important and controversial issues have arisen regarding basic GSDM biology and its role(s) during health and disease states. These include critical questions centred around GSDM-dependent lytic versus non-lytic functions, the biological activities of cleaved versus full-length proteins, the differential roles of GSDM-expressing mucosal immune versus epithelial cells, and whether GSDMs promote pathogenic or protective effects during specific disease settings. This Review provides a comprehensive summary and interpretation of the current literature on GSDM biology, specifically focusing on the gastrointestinal tract, highlighting the main controversial issues and their clinical implications, and addressing future areas of research to unravel the specific role(s) of this intriguing, yet enigmatic, family of proteins.
Topics: Humans; Gasdermins; Neoplasm Proteins; Pyroptosis; Gastrointestinal Neoplasms
PubMed: 36781958
DOI: 10.1038/s41575-023-00743-w -
Signal Transduction and Targeted Therapy Mar 2023In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic...
In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency (DICAR) mice, whereas the DCM was alleviated in DICAR-overexpressed DICAR mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Cardiomyopathies; Myocytes, Cardiac; Pyroptosis; RNA, Circular; Transcription Factors
PubMed: 36882410
DOI: 10.1038/s41392-022-01306-2