Neuropathic pain (NP) is a pathological state caused by damage or disease to the somatosensory nervous system. Programmed cell death (PCD) is an orderly process of cell death regulated by both intrinsic signals and external stimuli. In recent years, an increasing number of studies have shown that PCD plays a key regulatory role in the pathogenesis of NP. This article reviews the molecular mechanisms of various types of PCD and their specific roles in NP, in order to provide new research directions for the prevention, diagnosis, and treatment of NP.
ObjectiveTo summarize a comprehensive overview of the mechanism of ferroptosis and its associated microRNAs in the occurrence and development of hepatocellular carcinoma (HCC), and to offer novel insights and potential avenues for tumor marker screening and targeted treatment in clinical hepatocellular carcinoma patients. MethodThe literatures on the basic and clinical application research of ferroptosis and related microRNA in the occurrence, development and prognosis of HCC at home and abroad in recent years were reviewed and summarized, and the research progress of microRNA regulating ferroptosis in HCC was summarized. ResultsMicroRNA, a type of non-coding small RNA, had the ability to regulate gene expression at the post-transcriptional and translational levels. It held promising potential in the diagnosis and treatment of HCC. Ferroptosis, on the other hand, was a form of cell death triggered by iron-dependent lipid peroxidation. It played a crucial role in the development of HCC. A series of miRNAs related to ferroptosis might act as HCC growth regulators to regulate the growth of cancer cells, or reverse the drug resistance of cancer cells, thereby promoting or inhibiting the occurrence and progression of HCC. ConclusionsMicroRNA can regulate the occurrence and development of HCC through the ferroptosis pathway and may become tumor markers for the early diagnosis of HCC. Additionally, microRNA may also serve as a related therapeutic target and provide a new treatment option for HCC.
Objective To summarize the papers about the research status and prospects of ferroptosis in hepatocellular carcinoma (HCC) and its drug resistance in recent years in order to provide directions and ideas for the treatment of HCC. Method The relevant literatures at home and abroad in recent years about ferroptosis in HCC and its drug resistance were reviewed. Results The mechanism of ferroptosis in the development and drug resistance of HCC was complicated, involving multiple protein and molecular pathways. Ferroptosis played an important role in improving chemotherapy and sorafenib resistance, and it had a broad application prospect in HCC. Conclusions The molecular mechanism of ferroptosis in HCC and its drug resistance has not been fully elucidated. Further research on the mechanism of ferroptosis in HCC may provide new molecular therapeutic targets for HCC. Ferroptosis has a broad application prospect in the treatment of HCC.
Objective To identify genes of lipopolysaccharide (LPS) -induced acute lung injury (ALI) in mice base on bioinformatics and machine learning. Methods The acute lung injury dataset (GSE2411, GSE111241 and GSE18341) were download from the Gene Expression Database (GEO). Differential gene expression analysis was conducted. Gene ontology (GO) analysis, KEGG pathway analysis, GSEA enrichment analysis and protein-protein interaction analysis (PPI) network analysis were performed. LASSO-COX regression analysis and Support Vector Machine Expression Elimination (SVM-RFE) was utilized to identify key biomarkers. Receiver operator characteristic curve was used to evaluate the diagnostic ability. Validation was performed in GSE18341. Finally, CIBERSORT was used to analyze the composition of immune cells, and immunocorrelation analysis of biomarkers was performed. Results A total of 29 intersection DEGs were obtained after the intersection of GSE2411 and GSE111241 differentially expressed genes. Enrichment analysis showed that differential genes were mainly involved in interleukin-17, cytokine - cytokine receptor interaction, tumor necrosis factor and NOD-like receptor signaling pathways. Machine learning combined with PPI identified Gpx2 and Ifi44 were key biomarkers. Gpx2 is a marker of ferroptosis and Ifi44 is an type I interferon-induced protein, both of which are involved in immune regulation. Immunocorrelation analysis showed that Gpx2 and Ifi44 were highly correlated with Neutrophils, TH17 and M1 macrophage cells. Conclusion Gpx2 and Ifi44 have potential immunomodulatory abilities, and may be potential biomarkers for predicting and treating ALI in mince.
Objective To investigate the regulatory role of PLA2G4A targeting in ferroptosis and its sensitizing effect on the ferroptosis inducer Erastin. Methods PLA2G4A expression in lung adenocarcinoma (LUAD) was assessed by analyzing data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases, followed by immunohistochemical validation. PLA2G4A expression was knocked down in H1299 lung cancer cells using small interfering RNA. The correlation between PLA2G4A and ferroptosis marker genes was examined through gene correlation analysis and Western blotting. The regulatory relationship between PLA2G4A and ferrous ion (Fe2+) was analyzed using high-content fluorescence imaging. Cell proliferation after PLA2G4A inhibition and Erastin treatment was measured by CCK-8 assay. Flow cytometry and high-content fluorescence imaging were employed to evaluate the effects of PLA2G4A suppression combined with Erastin on intracellular Fe2+ and lipid peroxidation levels. Results Both mRNA (P<0.05) and protein (P<0.001) levels of PLA2G4A were significantly upregulated in LUAD tissues, and its high expression was associated with poor prognosis in LUAD patients (P<0.05). PLA2G4A expression was positively correlated with SLC7A11 expression (r=0.23, P<0.001). PLA2G4A knockdown suppressed SLC7A11 protein expression and increased cellular Fe2+ levels (P<0.01). Compared with the control group, PLA2G4A-silenced cells exhibited significantly reduced viability upon Erastin treatment (P<0.001). Furthermore, Erastin enhanced PLA2G4A targeting-induced Fe2+ accumulation and lipid peroxidation (P<0.001). Conclusion Targeting PLA2G4A induces ferroptosis in lung cancer cells by inhibiting SLC7A11 expression and enhances their sensitivity to Erastin.
ObjectiveTo summarize the mechanism and research progress of ferroptosis in acute liver injury. MethodThe domestic and foreign literatures related of ferroptosis and acute liver injury were searched and reviewed. ResultsFerroptosis was a newly identified form of iron-dependent cell death. The loss of lipid peroxidation repair activity of glutathione peroxidase 4, the presence of redox active iron and the oxidation of phospholipids containing polyunsaturated fatty acids were considered to be distinctive features of ferroptosis. At present, the research on the regulation of ferroptosis genes involved common liver diseases, including drug-induced liver injury, hepatocellular carcinoma, liver fibrosis, liver ischemia-reperfusion injury, liver failure, nonalcoholic fatty liver and so on. Based on the high correlation between ferroptosis and acute liver injury, chemical therapy targeting ferroptosis could provide individualized treatment for patients with acute liver injury in the future. ConclusionsThe ferroptosis plays a critical role in governing various cellular processes and downstream effects. Its aberrant expression contributes to the development and advancement of acute liver injury through diverse mechanisms. Thoroughly exploring the involvement of the ferroptosis in acute liver injury is of utmost significance, as it holds the potential to unveil novel therapeutic targets for effective management of acute liver injury.
Objective A series of bioinformatics methods were used to identify ferroptosis related biomarkers in lupus nephritis (LN). Methods We retrieved sequencing data of GSE112943 from the GEO (Gene Expression Omnibus) database and screened LN differentially expressed genes. We searched for ferroptosis-related gene (FRG) through FerrDb database, and screened LN-FRG. We conducted enrichment analysis on the LN-FRGs using David online bioinformatics database and screened the core LN-FRG using cytoHubba. We used external data sets to verify the core LN-FRGs, constructed competing endogenous RNA networks, and conducted molecular docking analysis. Results A total of 37 LN-FRGs were selected through screening. These genes are mainly enriched in inflammation, immune regulation and ferroptosis related signaling pathways. Through the cytoHubba and external dataset validation, the key core LN-FRG of ATF3 (activating transcription factor 3) was ultimately identified, and its expression was significantly increased in LN (P<0.05). Molecular docking analysis showed that ATF3 was closely bound to SLC7A11 and NRF2, and may participate in the occurrence and development of LN through the microRNA-27-ATF3 regulation axis. Conclusion The pivotal gene ATF3 may participate in the inflammation and immune injury of LN through ferroptosis.
ObjectiveTo construct a prognostic prediction model for hepatocellular carcinoma (HCC) based on disulfidptosis-associated genes (DAGs) and ferroptosis-associated genes (FAGs) using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases and explore the immune characteristics and antitumor drug sensitivity of HCC patients with high- and low-risk score. MethodsThe transcriptomic and clinical data of HCC were downloaded from the TCGA and ICGC databases. The expression levels of DAGs and FAGs were extracted. Subsequently, the differentially expressed and prognostically relevant DAGs and FAGs (DFAGs) were screened through differential expression and prognostic analysis. A prognostic prediction model for HCC was constructed by LASSO regression analysis. The prognostic value of risk factors was evaluated using univariate and multivariate Cox regression analyses, Kaplan-Meier survival analysis, receiver operating characteristic curves, principal component analysis, and t-distributed stochastic neighbor embedding. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to further elucidate the mechanisms of genes associated with HCC prognosis. The impact of risk factors on immune cells and immune cells functions was analyzed using single-sample gene set enrichment analysis. Based on the Genomics of Drug Sensitivity in Cancer database, the oncoPredict package was used to predict responses to antitumor drugs in for different risk groups. ResultsFour DFAGs (SLC7A11, SLC1A5, G6PD, and LRPPRC) with respective risk coefficients of 0.0350, 0.0442, 0.1597, and 0.0132 were selected to construct the prognostic prediction model. The risk score of prognostic prediction model was calculated as: Risk score =(0.0350×SLC7A11 expression level) + (0.0442×SLC1A5 expression level) + (0.159 7×G6PD expression level) + (0.013 2×LRPPRC expression level). The multivariate Cox regression analysis indicated that a high-risk score was an independent risk factor for HCC patient survival [HR (95%CI) = 5.414 (1.918, 15.279), P<0.001]. Both TCGA and ICGC datasets demonstrated that the high-risk patients had significantly worse survival than low-risk patients (P<0.001 and P=0.003, respectively). Enrichment analysis revealed that the risk-associated genes influenced HCC progression through multiple pathways, such as immune response, cell cycle, glycolysis, gluconeogenesis. Immune analysis showed that the high-risk patients exhibited increased infiltration of immunosuppressive cells, such as activated dendritic cells, macrophages, and regulatory T cells, while natural killer cell infiltration was significantly reduced. The drug sensitivity analysis suggested that the high-risk HCC patients might respond better to 5-fluorouracil, afatinib, cyclophosphamide, and lapatinib, whereas the low-risk patients might benefit more from oxaliplatin and sorafenib. ConclusionsHCC prognosis prediction model based on DFAGs in this study suggests a certain predictive value for the survival of HCC patients in the data from both TCGA and ICGC datasets. There are significant differences in pionts of immune cells infiltration and immune cells functions between high-risk and low-risk HCC patients. Additionally, significant differences exist in sensitivity to targeted drugs and chemotherapeutic drugs. This model can provide some references for immunotherapy, personalized treatment, and prognosis evaluation of HCC patients.
Objective To investigate the effects of sodium valproate (VPA) in inhibiting Erastin-induced ferroptosis in bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanisms. Methods BMSCs were isolated from bone marrow of 8-week-old Spragur Dawley rats and identified [cell surface antigens CD90, CD44, and CD45 were analyzed by flow cytometry, and osteogenic and adipogenic differentiation abilities were assessed by alizarin red S (ARS) and oil red O staining, respectively]. Cells of passage 3 were used for the Erastin-induced ferroptosis model, with different concentrations of VPA for intervention. The optimal drug concentration was determined using the cell counting kit 8 assay. The experiment was divided into 4 groups: group A, cells were cultured in osteogenic induction medium for 24 hours; group B, cells were cultured in osteogenic induction medium containing optimal concentration Erastin for 24 hours; group C, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA for 24 hours; group D, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA, and 8 μmol/L EX527 for 24 hours. The mitochondrial state of the cells was evaluated, including the levels of malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS). Osteogenic capacity was assessed by alkaline phosphatase (ALP) activity and ARS staining. Western blot analysis was performed to detect the expressions of osteogenic-related proteins [Runt-related transcription factor 2 (RUNX2) and osteopontin (OPN)], ferroptosis-related proteins [glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11)], and pathway-related proteins [adenosine monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1)]. Results The cultured cells were identified as BMSCs. VPA inhibited Erastin-induced ferroptosis and the decline of osteogenic ability in BMSCs, acting through the activation of the AMPK/SIRT1 pathway. VPA significantly reduced the levels of ROS and MDA in Erastin-treated BMSCs and significantly increased GSH levels. Additionally, the expression levels of ferroptosis-related proteins (GPX4, FTH1, and SLC7A11) significantly decreased. VPA also upregulated the expressions of osteogenic-related proteins (RUNX2 and OPN), enhanced mineralization and osteogenic differentiation, and increased the expressions of pathway-related proteins (AMPK and SIRT1). These effects could be reversed by the SIRT1 inhibitor EX527. ConclusionVPA inhibits ferroptosis in BMSCs through the AMPK/SIRT1 axis and promotes osteogenesis.
Objective To observe the expression of hepcidin-ferroportin (FPN) pathway in adenine-induced chronic kidney disease (CKD) rat model and to explore the mechanism of its involvement in renal fibrosis in CKD. Methods A total of 20 6-week-old male SD rats without specific pathogen were selected. The rats were divided into control group and CKD group, with 10 rats in each group, using a simple random method. Rats were sacrificed at the end of the second and sixth weeks after modeling. The levels of serum creatinine (Scr), blood urea nitrogen (BUN) and 24 h urine protein quantification were measured. The pathological changes of rats were observed. The iron content of rat kidney tissue was detected by colorimetric method, and the level of serum hepcidin-25 was detected by enzyme linked immunosorbent assay method in both groups. Immunohistochemistry and reverse transcription-polymerase chain reaction were used to detect the renal protein and mRNA expression of α-smooth muscle actin (α-SMA), collagen type Ⅰ (Col-Ⅰ), FPN1, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB) P65. Results Compared with the control group, the levels of Scr, BUN, and 24 h urine protein quantification were higher in the CKD group at the end of the second and sixth weeks of modeling (P<0.05). The results of renal tissue staining showed that the CKD group had obvious glomerular structural disorders, tubular dilation, and interstitial collagen fiber deposition. Compared with the control group, the serum hepcidin-25 level and the iron content of kidney tissues in the CKD group were significantly higher, and correlation analysis suggested that both were positively correlated with the renal function of rats (P<0.05). Compared with the control group, the protein and mRNA expression levels of α-SMA, Col-Ⅰ, HAMP, IL-6, TNF-α, NF-κB P65 were higher (P<0.05), while FPN1 expression was lower in CKD group at the end of the second and sixth weeks of modeling (P<0.05). Correlation analysis results showed that HAMP mRNA expression was positively correlated with α-SMA, Col-Ⅰ, IL-6, TNF-α, and NF-κB p65 (P<0.001), which was negatively correlated with FPN1 mRNA expression (P<0.001). FPN1 mRNA expression was significantly negatively correlated with α-SMA, Col-Ⅰ (P<0.001). Conclusions Ferroptosis may be present in the adenine-induced rat model of CKD, and it may be involved in the process of renal fibrosis through the interaction of HAMP-FPN signaling pathway with the inflammatory response. Serum hepcidin-25 is expected to be a serological marker for the early diagnosis of CKD.