Dataset Information

Study on pyroptosis-related genes Casp8, Gsdmd and Trem2 in mice with cerebral infarction.

ABSTRACT:

Objective

Cerebral infarction is the main cause of death in patients with cerebrovascular diseases. Our research aimed to screen and validate pyroptosis-related genes in cerebral infarction for the targeted therapy of cerebral infarction.

Methods and results

A total of 1,517 differentially expressed genes (DEGs) were obtained by DESeq2 software analysis. Gene set enrichment analysis results indicated that genes of middle cerebral artery occlusion (MCAO) mice aged 3 months and 18 months were enriched in pyroptosis, respectively. Differentially expressed pyroptosis-related genes (including Aim2, Casp8, Gsdmd, Naip2, Naip5, Naip6 and Trem2) were obtained through intersection of DEGs and genes from pyroptosis Gene Ontology Term (GO:0070269), and they were up-regulated in the brain tissues of MCAO mice in GSE137482. In addition, Casp8, Gsdmd, and Trem2 were verified to be significantly up-regulated in MCAO mice in GSE93376. The evaluation of neurologic function and triphenyltetrazolium chloride staining showed that the MCAO mouse models were successfully constructed. Meanwhile, the expressions of TNF-α, pyroptosis-related proteins, Casp8, Gsdmd and Trem2 in MCAO mice were significantly up-regulated. We selected Trem2 for subsequent functional analysis. OGD treatment of BV2 cell in vitro significantly upregulated the expressions of Trem2. Subsequent downregulation of Trem2 expression in OGD-BV2 cells further increased the level of pyroptosis. Therefore, Trem2 is a protective factor regulating pyroptosis, thus influencing the progression of cerebral infarction.

Conclusions

Casp8, Gsdmd and Trem2 can regulate pyroptosis, thus affecting cerebral infarction.

SUBMITTER: Liang S

PROVIDER: S-EPMC10860548 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Study on pyroptosis-related genes Casp8, Gsdmd and Trem2 in mice with cerebral infarction.

Liang Shunli S Xu Linsheng L Xin Xilin X Zhang Rongbo R Wu You Y

PeerJ 20240209

<h4>Objective</h4>Cerebral infarction is the main cause of death in patients with cerebrovascular diseases. Our research aimed to screen and validate pyroptosis-related genes in cerebral infarction for the targeted therapy of cerebral infarction.<h4>Methods and results</h4>A total of 1,517 differentially expressed genes (DEGs) were obtained by DESeq2 software analysis. Gene set enrichment analysis results indicated that genes of middle cerebral artery occlusion (MCAO) mice aged 3 months and 18 m ...[more]

PMID: 38348100

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Project description:BackgroundSkin cutaneous melanoma (SKCM) is the most aggressive skin cancer, accounting for more than 75% mortality rate of skin-related cancers. As a newly identified programmed cell death, pyroptosis has been found to be closely associated with tumor progression. Nevertheless, the prognostic significance of pyroptosis in SKCM remains elusive.MethodsA total of 469 SKCM samples and 812 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Firstly, differentially expressed pyroptosis-related genes (PRGs) between normal samples and SKCM samples were identified. Secondly, we established a prognostic model based on univariate Cox and LASSO Cox regression analyses, which was validated in the test cohort from GSE65904. Thirdly, a nomogram was used to predict the survival probability of SKCM patients. The R package "pRRophetic" was utilized to identify the drug sensitivity between the low- and high-risk groups. Tumor immune infiltration was evaluated using "immuneeconv" R package. Finally, the function of GSDMD and SB525334 was explored in A375 and A2058 cells.ResultsBased on univariate Cox and LASSO regression analyses, we established a prognostic model with identified eight PRGs (AIM2, CASP3, GSDMA, GSDMC, GSDMD, IL18, NLRP3, and NOD2), which was validated in the test cohort. SKCM patients were divided into low- and high-risk groups based on the median of risk score. Kaplan-Meier survival analysis showed that high-risk patients had shorter overall survival than low-risk patients. Additionally, time-dependent ROC curves validated the accuracy of the risk model in predicting the prognosis of SKCM. More importantly, 4 small molecular compounds (SB525334, SR8278, Gemcitabine, AT13387) were identified, which might be potential drugs for patients in different risk groups. Finally, overexpression of GSDMD and SB525334 treatment inhibit the proliferation, migration, and invasion of SKCM cells.ConclusionIn this study, we constructed a prognostic model based on PRGs and identified GSDMD as a potential therapeutic target, which provide new insights into SKCM treatment.

Project description:Ischemic stroke is a major condition that remains extremely problematic to treat. A cerebral reperfusion injury becomes apparent after an ischemic accident when reoxygenation of the afflicted area produces pathological side effects that are different than those induced by the initial oxygen and nutrient deprivation insult. Pyroptosis is a form of lytic programmed cell death that is distinct from apoptosis, which is initiated by inflammasomes and depends on the activation of Caspase-1. Then, Caspase-1 mobilizes the N-domain of gasdermin D (GSDMD), resulting in the release of cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). X-box binding protein l (XBP-1) is activated under endoplasmic reticulum (ER) stress to form an important transcription factor XBP-1 splicing (XBP-1s). The cerebral ischemia/reperfusion (CI/R) causes cytotoxicity, which correlates with the activation of splicing XBP-1 mRNA and NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasomes, along with increases in the expression and secretion of proinflammatory cytokines and upregulation of pyroptosis-related genes in HT22 cells and in the middle cerebral artery occlusion (MCAO) rat model. However, whether XBP-1 plays a role in regulating pyroptosis involved in CI/R is still unknown. Our present study showed that behavior deficits, cerebral ischemic lesions, and neuronal death resulted from CI/R. CI/R increased the mRNA level of XBP-1s, NLRP3, IL-1β, and IL-18 and the expressions of XBP-1s, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18. We further repeated this process in HT22 cells and C8-B4 cells and found that OGD/R decreased cell viability and increased LDH release, XBP-1s, NLRP3, Caspase-1, GSDMD-N, IL-1β, IL-18, and especially the ratio of pyroptosis, which were reversed by Z-YVAD-FMK and downregulated XBP-1. Our results suggest that downregulated XBP-1 inhibited pyroptosis through the classical NLRP3/Caspase-1/GSDMD pathway to protect the neurons.

Dataset Information

Study on pyroptosis-related genes Casp8, Gsdmd and Trem2 in mice with cerebral infarction.

Objective

Methods and results

Conclusions

Publications

Study on pyroptosis-related genes Casp8, Gsdmd and Trem2 in mice with cerebral infarction.

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