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 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 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.
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.
ObjectiveTo understand the molecular mechanism of ferroptosis and its research progress and future prospects in pancreatic cancer. MethodThe relevant literature on the molecular mechanism of ferroptosis and its basic and clinical application in the occurrence and development of pancreatic cancer was retrievaled and reviewed. ResultsFerroptosis was a non-apoptotic form of cell death that depended on iron aggregation, and its molecular biological features included iron ion overload, reactive oxygen species accumulation, lipid peroxidation, and so on. Ferroptosis was closely related to cell metabolism, and the imbalance of ferroptosis caused by abnormal metabolism also existed during the tumorigenesis and progression of pancreatic cancer, which in turn triggered the abnormal proliferation of pancreatic cancer cells and leaded to their progression. By regulating the key molecular signaling pathways of ferroptosis, it was expected to find new drug targets and therapeutic pathways for pancreatic cancer treatment. The results of ferroptosis-related studies so far had shown the potential for future translational research in the field of pancreatic cancer treatment. ConclusionsThe mechanism of ferroptosis is of great value in pancreatic cancer research. At present, there are still many uncharted areas in the study of ferroptosis, and the molecular mechanisms involved are still poorly understood. In the future, as the study of ferroptosis continues, it is expected to provide new ideas for pancreatic cancer treatment and discover new targets for drug development.
ObjectiveTo investigate the effect of Huaier extract on the proliferation, invasion, and ferroptosis pathways of colorectal cancer (CRC) cells. MethodsThe CRC cell line SW620 was cultured in vitro, and the cells were treated with Huaier extract solution at different concentrations (0, 5, 10, 20, and 50 mg/mL). The cell counting kit 8 was used to detect the proliferation of CRC cells at different concentrations to scree the test dose of the Huaier extract. The Transwell and the scratch assays were used to detect the cell invasion and migration. The reactive oxygen species (ROS), glutathione (GSH), and malondialdehyde (MDA) kits were used to detect the cellular oxidative stress level. The Western blot was used to detect the ferroptosis-related proteins levels, including glutathione peroxidase 4 (GPX4), nuclear factor E2-related factor 2 (NRF2), and high mobility group box-1 (HMGB1). ResultsIn this study, it could statistically inhibit the proliferation of CRC cells after 48 h interfering with Huaier extract at 10, 20 mg/mL concentrations, so we chose 10, 20 mg/mL concentrations as the test dose, 0 mg/L as the control dose. Huaier extract effectively inhibited the migration and invasion abilities of SW620 cells in a dose-dependent manner (Transwell: F=480.0, P<0.001; scratch assay: F=24.3, P=0.001). The level of ROS in the SW620 cells increased with the increase of concentration in a dose-dependent manner (F=806.3, P<0.001). the level of GSH in the SW620 cells decreased with the increase of concentration in a dose-dependent manner (F=35.0, P=0.005), but the level of MDA was highest at 10 mg/mL (F=22.9, P=0.002) . Further the Huaier extract could effectively reduce the expressions of GPX4 (F=74.2, P<0.001), NRF2 (F=32.8, P=0.001), and HMGB1 (F=55.1, P<0.001) in a dose-dependent manner. ConclusionFrom the results of this study, Huaier extract at 10 and 20 mg/mL concentrations can inhibit the proliferation and invasion of CRC SW620 cells by inducing ferroptosis.
Immunoglobulin A nephropathy (IgAN) is an immune-mediated chronic inflammatory disease with a complex pathogenesis and diverse clinical manifestations. Currently, there is no specific treatment plan. Programmed cell death is an active and orderly way of cell death controlled by genes in the body, which maintains the homeostasis of the body and the development of organs and tissues by participating in various molecular signaling pathways. In recent years, programmed cell death has played an important regulatory role in the occurrence and development of IgAN, involving complex signaling pathways. Under pathological conditions, it may relieve kidney damage through various pathways such as reducing oxidative stress, inhibiting inflammation, and improving energy metabolism. This article provides a review of the research progress of IgAN in apoptosis, autophagy, pyroptosis, ferroptosis,and cuproptosis in order to provide new therapeutic targets for IgAN.
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.
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 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.