Pyroptosis-related Genes Research Articles

Boosting wound healing in diabetic rats: The role of nicotinamide riboside and resveratrol in UPR modulation and pyroptosis inhibition

BackgroundDiabetes-related skin ulcers provide a substantial therapeutic issue, sometimes leading to amputation, needing immediate practical treatments for efficient wound care. While the exact mechanisms are unknown, pyroptosis and deregulation of the unfolded protein response (UPR) are known to exacerbate inflammation. Nicotinamide Riboside (NR) and Resveratrol (RV), which are known for their Nicotinamide adenine dinucleotide (NAD+) boosting and anti-inflammatory properties, are being studied as potential treatments. The purpose of this study was to shed light on the underlying molecular mechanisms and explore the medical application of NR and RV in diabetic wound healing. Methods54 male Sprague-Dawley rats divided into control, diabetic (DM), Gel Base, DM-NR, DM-RV, and DM-NR + RV. Rats were orally administered 50 mg/kg/day of RV and 300 mg/kg/day of NR for 5 weeks. Following diabetes induction, their wounds were topically treated with 5 % NR and RV gel for 15 days. The wound closure rate, body weight, and serum lipid profiles were examined. Gene expression study evaluated UPR and pyroptosis-related genes (BIP, PERK, ATF6, IRE1α, sXBP1, CHOP, NLRP3, caspase-1, NFκB, and IL1-β) in wound tissues, alongside histological assessment of cellular changes. ResultsNR and RV treatments greatly enhanced wound healing. Molecular investigation demonstrated UPR and pyroptosis marker modifications, suggesting UPR balance and anti-inflammatory effects. Histological investigation demonstrated decreased inflammation and increased re-epithelialization. The combination of NR and RV therapy had better results than either treatment alone. ConclusionThis study shows that NR and RV have therapeutic promise in treating diabetic wounds by addressing UPR dysregulation, and pyroptosis. The combination therapy is a viable strategy to improving the healing process, providing a multimodal intervention for diabetic skin ulcers. These findings pave the way for additional investigation and possible therapeutic applications, giving hope for better outcomes in diabetic wound care.

Inflammatory Consequences: Hepatitis C Virus-Induced Inflammasome Activation and Pyroptosis.

Hepatitis C virus (HCV), despite the availability of effective direct-acting antivirals (DAAs) that clear the virus from >95% of individuals treated, continues to cause significant health care burden due to disease progression that can lead to fibrosis, cirrhosis, and/or hepatocellular carcinoma. The fact that some people who are treated with DAAs still go on to develop worsening liver disease warrants further study into the immunopathogenesis of HCV. Many viral infections, including HCV, have been associated with activation of the inflammasome/pyroptosis pathway. This inflammatory cell death pathway ultimately results in cell lysis and release of inflammatory cytokines, IL-18 and IL-1β. This review will report on studies that investigated HCV and inflammasome activation/pyroptosis. This includes clinical in vivo data showing elevated pyroptosis-associated cytokines in the blood of individuals living with HCV, studies of genetic associations of pyroptosis-related genes and development of liver disease, and in vitro studies aimed at understanding the mechanism of pyroptosis induced by HCV. Finally, we discuss major gaps in understanding and outstanding questions that remain in the field of HCV-induced pyroptosis.

Development and validation of a pyroptosis-related prognostic signature associated with osteosarcoma metastasis and immune infiltration.

Pyroptosis is a programmed cell death, which has garnered increasing attention because it relates to the immune and therapy response. However, few studies focus on the application of pyroptosis-related genes (PRGs) in predicting osteosarcoma (OS) patients' prognoses. In this study, the gene expression and clinical information of OS patients were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Based on these PRGs and unsupervised clustering analysis, all OS samples can be classified into 2 clusters. The 8 key differential expressions for PRGs (LAG3, ITGAM, CCL2, TLR4, IL2RA, PTPRC, FCGR2B, and CD5) were established through the univariate Cox regression and utilized to calculate the risk score of all samples. According to the 8-gene signature, OS samples can be divided into high and low-risk groups and correlation analysis can be performed using immune cell infiltration and immune checkpoints. Finally, we developed a nomogram to improve the PRG-predictive model in clinical application. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low and high-risk groups. A nomogram was developed with clinical indicators and the risk scores were effective in predicting the prognosis of patients with OS. In this study, a prognostic model was constructed based on 8 PRGs were proved to be independent prognostic factors of OS and associated with tumor immune microenvironment. These 8 prognostic genes were involved in OS development and may serve as new targets for developing therapeutic drugs.

Enhancement of the Tumor Suppression Effect of High-dose Radiation by Low-dose Pre-radiation Through Inhibition of DNA Damage Repair and Increased Pyroptosis.

Radiation therapy has been a critical and effective treatment for cancer. However, not all cells are destroyed by radiation due to the presence of tumor cell radioresistance. In the current study, we investigated the effect of low-dose radiation (LDR) on the tumor suppressive effect of high-dose radiation (HDR) and its mechanism from the perspective of tumor cell death mode and DNA damage repair, aiming to provide a foundation for improving the efficacy of clinical tumor radiotherapy. We found that LDR pre-irradiation strengthened the HDR-inhibited A549 cell proliferation, HDR-induced apoptosis, and G2 phase cell cycle arrest under co-culture conditions. RNA-sequencing showed that differentially expressed genes after irradiation contained pyroptosis-related genes and DNA damage repair related genes. By detecting pyroptosis-related proteins, we found that LDR could enhance HDR-induced pyroptosis. Furthermore, under co-culture conditions, LDR pre-irradiation enhances the HDR-induced DNA damage and further suppresses the DNA damage-repairing process, which eventually leads to cell death. Lastly, we established a tumor-bearing mouse model and further demonstrated that LDR local pre-irradiation could enhance the cancer suppressive effect of HDR. To summarize, our study proved that LDR pre-irradiation enhances the tumor-killing function of HDR when cancer cells and immune cells were coexisting.

Identification of Novel Tumor Pyroptosis-Related Antigens and Pyroptosis Subtypes for Developing mRNA Vaccines in Pancreatic Adenocarcinoma

Background: As one of the important components of immunotherapies, mRNA vaccines have displayed promising clinical outcomes in solid tumors. Nonetheless, their efficacy remains unclear in pancreatic adenocarcinoma (PAAD). Given the interaction of pyroptosis with anticancer immunity, our study aims to identify pyroptosis-related antigens for mRNA vaccine development and discern eligible candidates for vaccination. Methods: Utilizing gene expression data from TCGA and ICGC, we integrated RNA-seq data and compared genetic alterations through cBioPortal. Differential gene expressions were integrated using GEPIA. Relationships between immune cell abundance and tumor antigens were analyzed and visualized via TIMER. WGCNA facilitated the clustering of pyroptosis-related genes, identification of hub genes, and pathway enrichment analyses. Pyroptosis landscape was depicted through graph learning-based dimensional reduction. Results: Four overexpressed and mutant pyroptosis-related genes associated with poor prognosis were identified as potential antigens for mRNA vaccines in PAAD, including ANO6, PAK2, CHMP2B, and RAB5A. These genes displayed positive associations with antigen-presenting cells. PAAD patients were stratified into three pyroptosis subtypes. Notably, the PS3 subtype, characterized by a lower mutation count and TMB, exhibited “cold” immunological traits and superior survival compared to other subtypes. The pyroptosis landscape exhibited considerable heterogeneity among individuals. Furthermore, the turquoise module emerged as an independent prognostic indicator and patients with high expressions of hub genes might not be suitable candidates for mRNA vaccination. Conclusions: In PAAD, ANO6, PAK2, CHMP2B, and RAB5A are prospective pyroptosis-related antigens for mRNA vaccine development, which holds potential benefits for patients classified as PS3 and those with diminished hub gene expressions, providing insights into personalized mRNA vaccine strategies.

Roles of pyroptosis and immune infiltration in aortic dissection.

Introduction: Aortic dissection (AD) is often fatal, and its pathogenesis involves immune infiltration and pyroptosis, though the molecular pathways connecting these processes remain unclear. This study aimed to investigate the role of immune infiltration and pyroptosis in AD pathogenesis using bioinformatics analysis. Methods: Two Gene Expression Omnibus datasets and a Gene Cards dataset of pyroptosis-related genes (PRGs) were utilized. Immunological infiltration was assessed using CIBERSORT, and AD diagnostic markers were identified through univariate logistic regression and least absolute shrinkage and selection operator regression. Interaction networks were constructed using STRING, and weighted gene correlation network analysis (WGCNA) was employed to identify important modules and essential genes. Single-sample gene set enrichment analysis determined immune infiltration, and Pearson correlation analysis assessed the association of key genes with infiltrating immune cells. Results: Thirty-one PRGs associated with inflammatory response, vascular epidermal growth factor receptor, and Rap1 signaling pathways were identified. WGCNA revealed seven important genes within a critical module. CIBERSORT detected immune cell infiltration, indicating significant changes in immune cell infiltration and pyroptosis genes in AD and their connections. Discussion: Our findings suggest that key PRGs may serve as indicators for AD or high-risk individuals. Understanding the role of pyroptosis and immune cell infiltration in AD pathogenesis may lead to the development of novel molecular-targeted therapies for AD. Conclusion: This study provides insights into the molecular mechanisms underlying AD pathogenesis, highlighting the importance of immune infiltration and pyroptosis. Identification of diagnostic markers and potential therapeutic targets may improve the management of AD and reduce associated morbidity and mortality.

Identification and Validation of the Pyroptosis-Related Hub Gene Signature and the Associated Regulation Axis in Diabetic Keratopathy.

Diabetic keratopathy (DK) poses a significant challenge in diabetes mellitus, yet its molecular pathways and effective treatments remain elusive. The aim of our research was to explore the pyroptosis-related genes in the corneal epithelium of the streptozocin-induced diabetic rats. After sixteen weeks of streptozocin intraperitoneal injection, corneal epithelium from three diabetic rats and three normal groups underwent whole-transcriptome sequencing. An integrated bioinformatics pipeline, including differentially expressed gene (DEG) identification, enrichment analysis, protein-protein interaction (PPI) network, coexpression, drug prediction, and immune deconvolution analyses, identified hub genes and key drivers in DK pathogenesis. These hub genes were subsequently validated in vivo through RT-qPCR. A total of 459 DEGs were screened out from the diabetic group and nondiabetic controls. Gene Set Enrichment Analysis highlighted significant enrichment of the NOD-like receptor, Toll-like receptor, and NF-kappa B signaling pathways. Intersection of DEGs and pyroptosis-related datasets showed 33 differentially expressed pyroptosis-related genes (DEPRGs) associated with pathways such as IL-17, NOD-like receptor, TNF, and Toll-like receptor signaling. A competing endogenous RNA network comprising 16 DEPRGs, 22 lncRNAs, 13 miRNAs, and 3 circRNAs was constructed. After PPI network, five hub genes (Nfkb1, Casp8, Traf6, Ptgs2, and Il18) were identified as upregulated in the diabetic group, and their expression was validated by RT-qPCR in streptozocin-induced rats. Immune infiltration characterization showed that diabetic corneas owned a higher proportion of resting mast cells, activated NK cells, and memory-resting CD4 T cells. Finally, several small compounds including all-trans-retinoic acid, Chaihu Shugan San, dexamethasone, and resveratrol were suggested as potential therapies targeting these hub genes for DK. The identified and validated hub genes, Nfkb1, Casp8, Traf6, Ptgs2, and Il18, may play crucial roles in DK pathogenesis and serve as therapeutic targets.

Comparison of left- and right-sided colorectal cancer to explore prognostic signatures related to pyroptosis

BackgroundColorectal cancer (CRC) is one of the most common malignancies, and pyroptosis exerts an immunoregulatory role in CRC. Although the location of the primary tumor is a prognostic factor for patients with CRC, the mechanisms of pyroptosis in left- and right-sided CRC remain unclear. MethodsExpression and clinical data were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Differences in clinical characteristics, immune cell infiltration, and somatic mutations between left- and right-sided CRC were then compared. After screening for differentially expressed genes, Pearson correlation analysis was performed to select pyroptosis-related genes, followed by a gene set enrichment analysis. Univariate and multivariate Cox regression analyses were used to construct and validate the prognostic model and nomogram for predicting prognosis. Collected left- and right-sided CRC samples were subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to validate the expression of key pyroptosis-related genes. ResultsLeft- and right-sided CRC exhibited significant differences in clinical features and immune cell infiltration. Five prognostic signatures were identified from among 134 pyroptosis-related differentially expressed genes to construct a risk score-based prognostic model, and adverse outcomes for high-risk patients were further verified using an external cohort. A nomogram was also generated based on three independent prognostic factors to predict survival probabilities, while calibration curves confirmed the consistency between the predicted and actual survival. Experiment data confirmed the significant differential expression of five genes between left- and right-sided CRC. ConclusionThe five identified pyroptosis-related gene signatures may be potential biomarkers for predicting prognosis in left- and right-sided CRC and may help improve the clinical outcomes of patients with CRC.

Prognostic model revealing pyroptosis-related signatures in oral squamous cell carcinoma based on bioinformatics analysis

One of the most common oral carcinomas is oral squamous cell carcinoma (OSCC), bringing a heavy burden to global health. Although progresses have been made in the intervention of OSCC, 5 years survival of patients suffering from OSCC is poor like before regarding to the high invasiveness of OSCC, which causes metastasis and recurrence of the tumor. The relationship between pyroptosis and OSCC remains to be further investigated as pyroptosis in carcinomas has gained much attention. Herein, the key pyroptosis-related genes were identified according to The Cancer Genome Atlas (TCGA) dataset. Additionally, a prognostic model was constructed based upon three key genes (CTLA4, CD5, and IL12RB2) through least absolute shrinkage and selection operator (LASSO) analyses, as well as univariate and multivariate COX regression in OSCC. It was discovered that the high expression of these three genes was associated with the low-risk group. We also identified LAIR2 as a hub gene, whose expression negatively correlated with the risk score and the different immune cell infiltration. Finally, we proved that these three genes were independent prognostic factors linked to overall survival (OS), and reliable consequences could be predicted by this model. Our study revealed the relationship between pyroptosis and OSCC, providing insights into new treatment targets for preventing and treating OSCC.

Dapagliflozin prevents kidney podocytes pyroptosis via miR-155-5p/HO-1/NLRP3 axis modulation

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1β in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

Preliminary investigation into the impact of BPA on osteoblast activity and bone development: In vitro and in vivo models

Bisphenol A (BPA), an ingredient in consumer products, has been suggested that it can interfere with bone development and maintenance, whereas the molecule mechanism remains unclear. The objective of this study is to investigate the effect of BPA on early bone differentiation and metabolism, and its potential molecule mechanism by employing hFOB1.19 cell as an in vitro model, as well as larval zebrafish as an in vivo model. The in vitro experiments indicated that BPA decreased cell viability, inhibited osteogenic activity (such as ALP, RUNX2), increased ROS production, upregulated transcriptional or protein levels of apoptosis-related molecules (such as Caspase 3, Caspase 9), while suppressed transcriptional or protein levels of pyroptosis-specific markers (TNF-α, TNF-β, IL-1β, ASC, Caspase 1, and GSDMD). Moreover, the evidences from in vivo model demonstrated that exposure to BPA distinctly disrupted pharyngeal cartilage, craniofacial bone development, and retarded bone mineralization. The transcriptional level of bone development-related genes (bmp2, dlx2a, runx2, and sp7), apoptosis-related genes (bcl2), and pyroptosis-related genes (cas1, nlrp3) were significantly altered after treating with BPA in zebrafish larvae. In summary, our study, combining in vitro and in vivo models, confirmed that BPA has detrimental effects on osteoblast activity and bone development. These effects may be due to the promotion of apoptosis, the initiation of oxidative stress, and the inhibition of pyroptosis.

The Critical Role of Pyroptosis in Peri-Implantitis.

Peri-implantitis (PI) is a prevalent complication of implant treatment. Pyroptosis, a distinctive inflammatory programmed cell death, is crucial to the pathophysiology of PI. Despite its importance, the pyroptosis-related genes (PRGs) influencing PI's progression remain largely unexplored. This study conducted histological staining and transcriptome analyze from three datasets. The intersection of differentially expressed genes (DEGs) and PRGs was identified as pyroptosis-related differentially expressed genes (PRDEGs). Functional enrichment analyses were conducted to shed light on potential underlying mechanisms. Weighted Gene Co-expression Network Analysis (WGCNA) and a pyroptotic macrophage model were utilized to identify and validate hub PRDEGs. Immune cell infiltration in PI and its relationship with hub PRDEGs were also examined. Furthermore, consensus clustering was performed to identify new PI subtypes. Protein-protein interaction (PPI) network, competing endogenous RNA (ceRNA) network, mRNA-mRNA binding protein regulatory (RBP) network, and mRNA-drugs regulatory network of hub PRDEGs were also analyzed. Eight hub PRDEGs were identified: PGF, DPEP1, IL36B, IFIH1, TCEA3, RIPK3, NET7, and TLR3, which are instrumental in the PI's progression. Two PI subtypes were distinguished, with Cluster 1 exhibiting higher immune cell activation. The exploration of regulatory networks provided novel mechanisms and therapeutic targets in PI. Our research highlights the critical role of pyroptosis and identifies eight hub PRDEGs in PI's progression, offering insights into novel immunotherapy targets and laying the foundation for advanced diagnostic and treatment strategies. This contributes to our understanding of PI and underscores the potential for personalized clinical management.

Bisphenol A and selenium deficiency exposure induces pyroptosis and myogenic differentiation disorder in chicken muscle stomach

Bisphenol A (BPA), which is commonly found in the environment due to its release from the use of plastics and food overpacks, has become a major stressor for environmental sustainability and livestock and poultry farming health. Selenium (Se) deficiency causes structural damage and inflammatory responses to the digestive system and muscle tissue, and there is a potential for concurrent space-time exposure to nutritional deficiency diseases and environmental toxicants in livestock and poultry. The mechanisms of damage to chicken muscular stomach from BPA or/and Se deficiency treatment are still not known. Here, we established a chicken model of BPA (20 mg/kg) or/and Se deficiency (0.039 mg/kg) exposure, and detected histopathological changes in the muscular stomach tissue, the levels of iNOS/NO pathway, IL-6/JAK/STAT3 pathway, pyroptosis, and myogenic differentiation by H&E staining, immunofluorescence staining, real-time quantitative PCR, and western blot methods. The data revealed that BPA or Se deficiency exposure caused gaps between muscle fibres with inflammatory cell infiltration; up-regulation of the iNOS/NO pathway and IL-6/JAK/STAT3 pathway; up-regulation of NLRP3/Caspase-1-dependent pyroptosis related genes; down-regulation of muscle-forming differentiation (MyoD, MyoG, and MyHC) genes. The combination of BPA and Se deficiency was associated with higher toxic impairment than alone exposure. In conclusion, we discovered that BPA and Se deficiency caused myogastric pyroptosis and myogenic differentiation disorder. These findings provide a theoretical basis for the co-occurrence of animal nutritional deficiency diseases and environmental toxicant exposures in livestock and poultry farming, and may provide important insights into limiting the production of harmful substances.

Combined analysis of bulk RNA and single-cell RNA sequencing to identify pyroptosis-related markers and the role of dendritic cells in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by dyspnea caused by airflow limitation. Further development may lead to decreased lung function and other lung diseases. Pyroptosis is a type of programmed cell death that involves multiple pathways. For example, the pathway induced by the NLR family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with COPD exacerbation. Therefore, in this study, various machine learning algorithms were applied to screen for diagnostically relevant pyroptosis-related genes from the GEO dataset, and the results were verified using external datasets. The results showed that deep neural networks and logistic regression algorithms had the highest AUC of 0.91 and 0.74 in the internal and external test sets, respectively. Here, we explored the immune landscape of COPD using diagnosis-related genes. We found that the infiltrating abundance of dendritic cells significantly differed between the COPD and control groups. Finally, the communication patterns of each cell type were explored based on scRNA-seq data. The critical role of significant pathways involved in communication between DCS and other cell populations in the occurrence and progression of COPD was identified.

Pyroptosis-Derived Long Noncoding RNA Profiles Reveal a Novel Signature for Evaluating the Prognosis of Patients With Lung Adenocarcinoma.

Long noncoding RNAs (lncRNAs) were recently implicated in modifying pyroptosis. Nonetheless, pyroptosis-related lncRNAs and their possible clinical relevance persist largely uninvestigated in lung adenocarcinoma (LUAD). A sum of 921 samples were collected from three independent data sets. We obtained pyroptosis-related genes from both the Molecular Signatures Database and relevant literature sources and used four machine learning techniques, comprising stepwise Cox, ridge regression, least absolute shrinkage and selection operator, and random forest. Multiple bioinformatics approaches were used to further investigate the underlying mechanisms. In total, 39 differentially expressed pyroptosis genes were identified by comparing normal and tumor samples. Correlation analysis revealed 933 pyroptosis-related lncRNAs. Furthermore, univariate Cox regression determined 11 lncRNAs that exhibited stable associations with prognosis in the three cohorts, which were used to construct the pyroptosis-derived lncRNA signature. After analyzing the optimal results from four machine learning algorithms, we ultimately selected random forest to develop the pyroptosis-derived lncRNA signature. This signature was proven to be an independent prognostic factor and exhibited robust performance in three cohorts. We provided novel insight and established a pyroptosis-derived lncRNA signature for patients with LUAD, exhibiting strong predictive capabilities in both the training and validation sets.

Identification and validation of a pyroptosis-related prognostic model for colorectal cancer based on bulk and single-cell RNA sequencing data.

Pyroptosis impacts the development of malignant tumors, yet its role in colorectal cancer (CRC) prognosis remains uncertain. To assess the prognostic significance of pyroptosis-related genes and their association with CRC immune infiltration. Gene expression data were obtained from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing dataset GSE178341 from the Gene Expression Omnibus (GEO). Pyroptosis-related gene expression in cell clusters was analyzed, and enrichment analysis was conducted. A pyroptosis-related risk model was developed using the LASSO regression algorithm, with prediction accuracy assessed through K-M and receiver operating characteristic analyses. A nomogram predicting survival was created, and the correlation between the risk model and immune infiltration was analyzed using CIBERSORTx calculations. Finally, the differential expression of the 8 prognostic genes between CRC and normal samples was verified by analyzing TCGA-COADREAD data from the UCSC database. An effective pyroptosis-related risk model was constructed using 8 genes-CHMP2B, SDHB, BST2, UBE2D2, GJA1, AIM2, PDCD6IP, and SEZ6L2 (P < 0.05). Seven of these genes exhibited differential expression between CRC and normal samples based on TCGA database analysis (P < 0.05). Patients with higher risk scores demonstrated increased death risk and reduced overall survival (P < 0.05). Significant differences in immune infiltration were observed between low- and high-risk groups, correlating with pyroptosis-related gene expression. We developed a pyroptosis-related prognostic model for CRC, affirming its correlation with immune infiltration. This model may prove useful for CRC prognostic evaluation.

Identification of Pyroptosis-Related Genes Regulating the Progression of Chronic Rhinosinusitis with Nasal Polyps

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is an immunologic disease, and pyroptosis, an inflammation-based cellular death, strictly modulates CRSwNP pathology, whereas the pyroptosis genes and mechanisms involved in CRSwNP remain unclear. Herein, we explored disease biomarkers and potential therapeutic targets for pyroptosis and immune regulation in CRSwNP using bioinformatics analysis and tissue-based verification. Methods: We retrieved the transcriptional profiles of the high-throughput dataset GSE136825 from the Gene Expression Omnibus database, as well as 170 pyroptosis-related gene expressions from GeneCards. Using R, we identified differentially expressed pyroptosis-related genes and examined the potential biological functions of the aforementioned genes using Gene Ontology, Kyoto Encyclopedia of the Genome pathway, immune infiltration, and protein-protein interaction (PPI) network analyses, thereby generating a list of hub genes. The hub genes were, in turn, verified using real-time quantitative polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), and Western blotting (WB). Ultimately, using the StarBase and miRTarBase databases, we estimated the targeting microRNAs and long chain non-coding RNAs. Results: We demonstrated that the identified pyroptosis-related genes primarily modulated bacterial defense activities, as well as inflammasome immune response and assembly. Moreover, they were intricately linked to neutrophil and macrophage infiltration. Furthermore, we validated the tissue contents of hub genes AIM2, NLPR6, and CASP5 and examined potential associations with clinical variables. We also developed a competitive endogenous RNA (ceRNA) modulatory axis to examine possible underlying molecular mechanisms. Conclusion: We found AIM2, CASP5, and NLRP6, three hub genes for pyroptosis in chronic rhinosinusitis with nasal polyps, by biological analysis, experimental validation, and clinical variable validation.

Fenpropathrin provoked kidney damage via controlling the NLRP3/Caspase-1/GSDMD–mediated pyroptosis: The palliative role of curcumin-loaded chitosan nanoparticles

This study assessed the ability of formulated curcumin-loaded chitosan nanoparticles (CU-CS-NPs) to reduce the kidney damage resulting from fenpropathrin (FPN) in rats compared to curcumin (CU) in rats. Sixty male Sprague Dawley rats were separated into six groups and orally administered 1 mL/kg b.wt corn oil, 50 mg CU/kg b.wt, 50 mg CU-CS-NPs /kg b.wt., 15 mg FPN /kg b.wt, CU+ FPN or CU-CS-NPs + FPN for 60 days. Then, serum renal damage products were assessed. Total antioxidant capacity, reactive oxygen species, interleukin 1β (IL-1β), malondialdehyde, NF-κB P65, cleaved-Caspase-1, and Caspase-8 were estimated in kidney homogenates. The cleaved Caspase-3 and TNF-α immunoexpression and pyroptosis-related genes were determined in renal tissues. The results showed that CU-CS-NPS significantly repressed the FPN-induced increment in kidney damage products (urea, uric acid, and creatinine). Moreover, the FPN-associated hypo-proteinemia, renal oxidative stress and apoptotic reactions, and impaired renal histology were considerably repaired by CU and CU-CS-NPs. Additionally, compared to FPN-exposed rats, CU, and CU-CS-NPs-treated rats had considerably lower immunoexpression of cleaved Caspase-3 and TNF-α in renal tissue. The pyroptosis-related genes NLRP3, GSDMD, IL-18, Caspase-3, Caspase-1, IL-1β, Caspase-8, TNF-α, and NF-κB dramatically upregulated by FPN exposure in the renal tissues. Yet, in CU and CU-CS-NPs-treated rats, the gene above expression deviations were corrected. Notably, CU-CS-NPs were superior to CU in preventing oxidative damage and inflammation and regulating pyroptosis in the renal tissues of the FPN-exposed group. The results of the present study conclusively showed the superior favorable effect of CU-CS-NPs in counteracting renal impairment linked to environmental pollutants.

Alterations in Adipocytokine Signaling Pathway and Pyroptosis in Neonatal Hypoxic-ischemic Encephalopathy.

The aims of this study are to discover dysregulated adipocytokine signaling pathway and pyroptosis-related genes to predict neonatal hypoxic-ischemic encephalopathy (HIE) occurrence. HIE is an important cause of infant death and long-term neurological sequelae. Current treatment options for HIE are relatively limited and the pathogenesis of HIE remains to be fully explored. This study investigated the alterations of adipocytokine signaling pathway and pyroptosis in neonatal HIE. To reveal the alterations of adipocytokine signaling pathway and pyroptosis relevant to HIE occurrence. Data on neonatal HIE were downloaded from the Gene Expression Omnibus (GEO) database. Pathway analyses of single-sample gene set enrichment analysis (ss- GSEA) and GSEA were performed on the adipocytokine signaling pathway and pyroptosis. Proportions of immune cells in a single sample were also calculated by ssGSEA and CIBERSORT algorithm. The relationship between the adipocytokine signaling pathway and pyroptosis was analyzed according to Pearson correlation analysis. The activities of KEGG pathways changed after the occurrence of HIE, and adipocytokine signaling pathway was activated with related overexpressed genes. For the three energy metabolisms, carbohydrate metabolism was enhanced; lipid metabolism showed increased fatty acids metabolism and decreased ability of fatty acids synthesis; metabolic levels of phosphate and phenylalanine in amino acid metabolism were elevated. Enhanced pyroptosis and relevant overexpressed genes were accompanied by increased immune cells. A positive connection between adipocytokine signaling pathway and pyroptosis was observed. These results indicated that the adipocytokine signaling pathway may promote HIE occurrence by upregulating the expression of pyroptosis-related genes, providing a novel mechanism for HIE.

Nrf2 functions as a pyroptosis-related mediator in traumatic brain injury and is correlated with cytokines and disease severity: a bioinformatics analysis and retrospective clinical study.

Traumatic brain injury (TBI) is a serious hazard to human health. Evidence has accumulated that pyroptosis plays an important role in brain trauma. The aim of this study is to screen potential key molecules between TBI and pyroptosis, and further explore their relationships with disease severity and cytokines. To acquire differentially expressed genes (DEGs) before and after brain injury, the GSE89866 dataset was downloaded from the Gene Expression Omnibus (GEO) database. Meanwhile, pyroptosis-related genes were obtained from the GeneCards database, and the intersected genes were identified as differentially expressed pyroptosis-related genes (DEPGs). Moreover, the hub genes were screened via four algorithms (namely Maximum Clique Centrality, Edge Percolated Component, BottleNeck and EcCentricity) in Cytoscape software. Blood levels of Nrf2 were measured by ELISA using a commercially available kit. Finally, we further investigated the correlation between Nrf2 levels and medical indicators in TBI such as clinical characteristics, inflammatory cytokines, and severity. Altogether, we found 1,795 DEGs in GSE89866 and 98 pyroptosis-related genes in the GeneCards database. Subsequently, four hub genes were obtained, and NFE2L2 was adopted for further clinical study. By using Kruskal-Wallis test and Spearman correlation test, we found that the serum Nrf2 levels in severe TBI patients were negatively correlated with GCS scores. On the contrary, there was a positive correlation between serum Nrf2 levels and pupil parameters, Helsinki CT scores, IL-1 β and IL-18. In summary, bioinformatic analyses showed NFE2L2 plays a significant role in the pathology of TBI. The clinical research indicated the increase in serum Nrf2 levels was closely related to the severity of trauma and cytokines. We speculate that serum Nrf2 may serve as a promising biochemical marker for the assessment of TBI in clinical practice.